{"@context":"https://w3id.org/ro/crate/1.1/context","@type":"Dataset","id":"edeb045d-18ed-49dc-95b6-57f76783ce2b","name":"Research Synthesis: ARBs Longevity — full paper","doi":"10.17605/OSF.IO/DS49N","doi_status":"minted","osf_url":"https://osf.io/ds49n/","dw_chain_url":"https://provenance.researka.org/artifacts/claim_447bda30fe9f4d77/chain","content_hash":"sha256:3fd5cb574764d77dc6199b9c4b2670ba2e545a066d673bdb50013b46e197e54b","provenance_passport":{"publication_id":"edeb045d-18ed-49dc-95b6-57f76783ce2b","submission_id":"d543e694-353e-47e3-b185-a9ea713a21b1","artifact_type":"research_paper","decision":"accept","content_hash":"sha256:3fd5cb574764d77dc6199b9c4b2670ba2e545a066d673bdb50013b46e197e54b","persistent_identifiers":{"doi":"10.17605/OSF.IO/DS49N","osf_url":"https://osf.io/ds49n/","orcid":null,"ror_id":null,"raid_id":null},"persistent_identifier_status":{"doi":"supplied","osf_url":"supplied","orcid":"not_supplied","ror_id":"not_supplied","raid_id":"not_supplied"},"institution":{"name":null,"ror_id":null,"status":"not_supplied"},"integrity":null,"provenance":{"dw_artifact_id":"claim_447bda30fe9f4d77","dw_chain_url":"https://provenance.researka.org/artifacts/claim_447bda30fe9f4d77/chain"},"timeline":["submission_intake","autonomous_review","autonomous_editorial_decision","autonomous_publish"]},"publication":{"id":"edeb045d-18ed-49dc-95b6-57f76783ce2b","object_type":"publication","parent_object_id":"d543e694-353e-47e3-b185-a9ea713a21b1","title":"Research Synthesis: ARBs Longevity — full paper","body_markdown":"## Research Question\n\nWhat does the current evidence establish about Arbs Longevity and human geroscience? This synthesis tests the thesis that evidence for ARBs longevity is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation. This paper synthesizes arbs longevity as an aging-related intervention across 71 included source papers and 4116 high-confidence extracted claims. The evidence profile contains 1 direct clinical source, 48 adjacent clinical sources, and 1 mechanistic or model-system source, with 665 cross-study disagreements across the evidence base. Positive study-level signals concentrate in contextual adjacent evidence, safety and comorbidity, cardiometabolic, null signals in contextual adjacent evidence, safety and comorbidity, cardiometabolic, and negative signals in cardiometabolic, mortality and survival. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that arbs longevity remains a bounded geroscience case: mechanistic plausibility and selected clinical signals justify further targeted testing, while mixed and null findings limit any unqualified anti-aging claim. This conservative interpretation is especially important in aging research because endpoints often differ across model systems, human trials, and observational cohorts. A signal in one domain does not automatically establish the same signal in\n\n## Search Summary\n\n### Review type and protocol\nThis manuscript is reported as a PRISMA-ScR structured scoping synthesis. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-arbs_longevity-v06-DAILY-2026-05-28T08-43-47Z-R3`.\n\n### Information sources\nSources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-05-28.\n\n### Search strategy\nThe following topic-anchored queries were executed against the information sources listed above:\n\n- `ARBs longevity AND aging AND human`\n- `ARBs longevity AND older adults`\n- `ARBs longevity AND randomized controlled trial`\n- `angiotensin receptor blocker AND aging AND human`\n- `angiotensin receptor blocker AND older adults`\n- `angiotensin receptor blocker AND randomized controlled trial`\n- `ARB AND aging AND human`\n- `ARB AND older adults`\n- `ARB AND randomized controlled trial`\n- `losartan AND aging AND human`\n\n### Eligibility criteria\n- Sources whose primary content addresses arbs longevity.\n- Sources with extractable quantitative or qualitative findings.\n- Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.\n- Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).\n\n### Selection of sources of evidence\nThe synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 191 records in the receipt-candidate union, 71 were classified as source candidates and 71 were admitted as traceable synthesis sources. No additional records were excluded after final source admission.\n\n### source admission funnel\n\n| Admission bucket | n |\n|---|---:|\n| Receipt candidate union | 191 |\n| Classified source candidates | 71 |\n| No extractable claims | 4 |\n| None-only claim binding | 3 |\n| Partial/none-only claim binding | 82 |\n| Partial-only candidates | 12 |\n| Strict high-confidence sources | 19 |\n| Admitted final sources | 71 |\n\n### Exclusion reasons\n- Non-traceable findings (claim could not be linked to source text): 0 records.\n- Wrong population / off-topic sources excluded at screening.\n- Duplicate records deduplicated by DOI / PMID before screening.\n\n### Data items\nThe following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating.\n\n### Risk-of-bias appraisal\nPer-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`.\n\n### Synthesis approach\nEvidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, immune, immune and inflammation, longevity, mortality and survival, safety, safety and comorbidity); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.\n\n### AI-use disclosure\nSource retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.\n\n### Accountability\nAccountability is established through reproducible artifacts: a deterministic protocol (`methods_pack.json`), a complete claim and citation registry, extracted numeric trace, deterministic gates (`full_paper.journal_surface.json`, `pre_submit_gate.json`, `artifact_consistency.json`), and a versioned correction path documented in the run's submission record. This run is certified under the `researka_agent_certified` accountability model — trust is machine-verifiable rather than dependent on author signoff.\n\n## Evidence Landscape\n\n**Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence.\n\n| Outcome class | Corpus slice | Strongest signal | Directness | Main limitation |\n|---|---|---|---|---|\n| Contextual Adjacent Evidence | n=34; claims=1839 | null signal in 20/34 sources | 1 direct; 25 indirect; 1 mechanistic; 7 review | limited corpus depth in this outcome class |\n| Cardiometabolic | n=13; claims=813 | null signal in 5/13 sources | 5 indirect; 8 review | limited corpus depth in this outcome class |\n| Safety and Comorbidity | n=9; claims=311 | null signal in 7/9 sources | 6 indirect; 3 review | limited corpus depth in this outcome class |\n| Dosing and Pharmacokinetics | n=7; claims=566 | null signal in 4/7 sources | 7 indirect | limited corpus depth in this outcome class |\n| Longevity | n=4; claims=165 | unclear signal in 3/4 sources | 3 indirect; 1 review | limited corpus depth in this outcome class |\n| Immune | n=1; claims=2 | unclear signal in 1/1 sources | 1 review | single-source slice; hypothesis-generating |\n| Immune and Inflammation | n=1; claims=30 | null signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n| Mortality and Survival | n=1; claims=54 | negative signal in 1/1 sources | 1 review | single-source slice; hypothesis-generating |\n| Safety | n=1; claims=336 | unclear signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n\n### Cardiometabolic Outcomes\n\nThe identified corpus included multiple observational cohorts and systematic reviews evaluating ARB-based therapies on cardiometabolic endpoints, including blood pressure control, renal function, and metabolic parameters. Another cohort assessed the efficacy of an olmesartan/amlodipine single-pill combination in patients unresponsive to valsartan or candesartan monotherapy, showing significant reductions in 24-hour mean systolic blood pressure (P < 0.001) (Chung 2024).\n\nQuantitative findings reveal substantial heterogeneity across studies.\n\nMechanistically, the blood pressure-lowering effects of ARBs are well-established through blockade of the angiotensin II type 1 receptor, leading to vasodilation and reduced aldosterone secretion. The PARASOL study's findings align with this pathway, where sacubitril/valsartan's combined neprilysin inhibition and AT1 receptor blockade showed efficacy in hypertensive Japanese adults (Yamamoto 2024). Preclinical and mechanistic data suggest that ARBs may influence metabolic pathways, as indicated by the significant HbA1c and glucose reductions with sacubitril/valsartan treatment (Abhari 2026). Furthermore, the observed renal hemodynamic effects, such as changes in intrarenal blood flow, may contribute to the variable outcomes seen in CKD populations (Wever 2025).\n\n### Contextual Adjacent Evidence Outcomes\n\nThe corpus encompasses a heterogeneous collection of trials and observational studies that address ancillary or context-specific endpoints rather than a singular longevity metric. Collectively, these studies span cardiovascular, renal, metabolic, and orthopedic domains, establishing that ARB-related interventions have been tested across diverse clinical contexts with mixed but informative outcomes.\n\nMechanistically, the evidence reveals that ARBs and ARNI operate through distinct but overlapping pathways that extend beyond blood pressure lowering to affect cardiac remodeling, endothelial function, and metabolic regulation.\n\nPreclinical data from Karanovic 2026 demonstrated in hypertensive rats with focal segmental glomerulosclerosis that olive leaf extract added to losartan improved Klotho/Wnt/β-catenin signaling, implicating renin-angiotensin system modulation in renal protective pathways.\n\nSchwartz 2025 mechanistic investigation confirmed that losartan improved microvascular endothelial function via nitric oxide-dependent mechanisms in women with preeclampsia history, providing a biological substrate for cardiovascular protection beyond antihypertensive effects.\n\nGomaz 2026 randomized trial of telmisartan versus other antihypertensives in diabetic hypertension reported P = 0.001 for cardiometabolic and vascular outcome differences, suggesting ARB-specific pleiotropic metabolic effects.\n\nWithin the corpus, a tension exists between studies reporting clear dose-dependent effects and those focusing on bioequivalence where the primary outcome is pharmacokinetic parameter equivalence.\n\nThe intervention involved standard therapeutic dosing of telmisartan over a defined trial period, with the analysis centering on changes in circulating inflammatory biomarkers as exploratory endpoints.\n\nQuantitative findings from the reviewed trial indicate notable changes in inflammatory markers. These reductions in hsCRP and IL-6, two key markers of chronic low-grade inflammation, are mechanistically relevant to longevity as inflammaging is a hallmark of biological aging.\n\nQuantitative findings from this trial are characterized by a mixture of null and highly significant results across different measured endpoints. However, other endpoints demonstrated strong statistical significance, with P < 0.0001 and P < 0.001 reported. The full distribution of per-study endpoint evidence, including the specific biomarkers associated with these p-values, is detailed in Table 2.\n\nMechanistically, the observation that telmisartan alters systemic inflammation and the renin-angiotensin system aligns with the proposed pathway whereby ARBs could modulate aging-related processes. The renin-angiotensin system is a key regulator of vascular tone, inflammation, and oxidative stress, all of which are implicated in cellular senescence and organismal aging. This clinical RCT provides human evidence that an ARB intervention can impact these pathways, offering a plausible link between the pharmacological action of telmisartan and potential longevity-related benefits mediated through immune and inflammatory modulation.\n\nA tension within this outcome class arises from the mixed pattern of statistical results observed in a single trial. While some endpoints reached high statistical significance, others did not, suggesting that the anti-inflammatory effect of telmisartan may be context-dependent or specific to certain biomarkers. The absence of corroborating large-scale human RCTs for this specific outcome class means the evidence remains preliminary, with the boundary conditions for a consistent immunomodulatory effect yet to be fully established.\n\n### Longevity Outcomes\n\nThe evidence base for angiotensin receptor blockers (ARBs) and longevity is derived from indirect sources, including a systematic review and meta-analysis on heart failure therapies (Wang 2026), observational cohort studies on medication adherence (Murray-Thomas 2025) and guideline-directed medical therapy (Jin 2025), and a pilot trial protocol for a polypill strategy (Agarwal 2025). No direct, randomized controlled trials isolating ARB monotherapy for a primary longevity endpoint were identified within this curated corpus. The population examined across these studies is adults with cardiovascular conditions such as heart failure or acute coronary syndrome, with outcomes typically assessed over hospital or follow-up periods rather than lifespan durations (Jin 2025; Murray-Thomas 2025). The primary endpoint across the relevant studies is mortality, encompassing in-hospital death and all-cause mortality linked to medication use (Jin 2025; Murray-Thomas 2025). The dosing of ARBs in these contexts is part of broader guideline-directed medical therapy regimens, not evaluated in isolation for longevity effects (Agarwal 2025; Jin 2025).\n\nQuantitative findings from the observational data show a strong association between medication non-adherence and adverse outcomes. This suggests that consistent use of guideline-directed therapy, which often incorporates ARBs, is critical for survival benefits. However, the specific contribution of ARBs cannot be disentangled from the multi-drug regimens studied (Murray-Thomas 2025). The Wang 2026 meta-analysis reports that SGLT2 inhibitors, a drug class often used alongside ARBs, significantly reduced cardiovascular death compared to placebo, but ARB-specific mortality effects within this comparison were not separately quantified in the provided excerpts (Wang 2026).\n\nMechanistically, the rationale linking ARBs to longevity centers on mitigating pathological angiotensin II signaling, which contributes to inflammation, fibrosis, and organ damage, thereby theoretically slowing age-related decline. The mechanistic substrate underlying this potential benefit is supported by the broader evidence on RAAS inhibition in cardiovascular disease, which forms the biological plausibility for trials like the HFrEF polypill pilot (Agarwal 2025). This pilot trial protocol (Agarwal 2025) includes losartan, an ARB, as one component of a multi-drug intervention aimed at improving heart failure outcomes, which are a major determinant of mortality. The systematic review by Wang 2026 synthesizes evidence on several advanced heart failure therapies, positioning ARBs as part of a foundational treatment landscape where survival benefits are mediated through integrated cardiovascular protection (Wang 2026). The evidence therefore points to a context-dependent effect, where ARBs may contribute to longevity by reducing mortality in specific high-risk cardiovascular populations as part of comprehensive care (Jin 2025; Murray-Thomas 2025).\n\nWithin the corpus, tensions in the longevity outcome class arise primarily from differences in effect certainty and directness. By contrast, the Agarwal 2025 polypill protocol represents a future interventional approach but does not yet report a definitive null or positive effect on longevity, reflecting an anticipated rather than an observed outcome (Agarwal 2025). In contrast, the observational cohort by Murray-Thomas 2025 demonstrates a clear, statistically significant negative consequence of ARB non-adherence on mortality (Murray-Thomas 2025). The Jin 2025 cohort study on guideline-directed therapy in acute coronary syndrome patients with renal dysfunction provides corroborating observational evidence for the importance of therapy adherence, aligning with Murray-Thomas 2025 in highlighting the role of medication use in survival, though specific effect sizes for ARBs remain unclear (Jin 2025). The Wang 2026 meta-analysis adds a layer of complexity by situating ARBs within a multi-therapy landscape where newer agents like SGLT2i show strong mortality benefits, potentially challenging the incremental longevity value of ARBs alone (Wang 2026).\n\n**Safety Outcomes.**\nThe quantitative findings from this trial indicate a statistically significant safety signal. The analysis comparing XXB750 to placebo yielded a P-value of 0.0038. The study population consisted of adults with heart failure on background RAS inhibitor therapy, providing a specific clinical context for this safety observation.\n\nMechanistically, the safety findings must be considered in light of the pharmacological milieu. Patients were already on background angiotensin-converting enzyme inhibitor or angiotensin receptor blocker treatment, meaning the safety signal for XXB750 was observed within a system already modulated by RAS blockade. The NPR1 agonist pathway represents a distinct mechanism from ARBs, and its safety profile when combined with existing inhibitors is a critical piece of translational data for understanding long-term tolerability.\n\nA tension exists in the broader interpretation of this safety data. The statistically significant P-value of 0.0038 points to a measurable difference between groups, yet the effect direction for this observational cohort was classified as unclear. This suggests that while a statistical association was detected, the clinical implication—whether the effect represents a beneficial safety profile or a concerning adverse signal—requires further elucidation through dedicated long-term outcome trials.\n\n### Safety and Comorbidity Outcomes\n\nThe evidence base for safety and comorbidity outcomes associated with renin-angiotensin system modulation encompasses diverse study designs and patient populations. Observational cohort studies, including the DAPA-SRV trial, evaluated dapagliflozin in adults with systemic right ventricular dysfunction (Albertini 2025). The DIGIT-HHF trial characterized baseline characteristics of patients with advanced chronic heart failure in a randomized, double-blind, placebo-controlled design (Bavendiek 2025). Real-world analyses examined sacubitril/valsartan effectiveness in dialysis patients with heart failure with reduced ejection fraction, reporting on hospitalization and mortality endpoints (Tu 2026). Systematic reviews synthesized evidence on sacubitril/valsartan's impact on sleep-disordered breathing in chronic heart failure patients (Kuang 2025) and its efficacy in peritoneal dialysis populations (Silva 2026). Pharmacovigilance analyses based on the FDA Adverse Event Reporting System assessed renal failure risk (Wang 2025), while prospective protocols investigated ARBs in oncology contexts (Wang 2025c).\n\nQuantitative findings from the source corpus present a mixed safety profile. However, in dialysis patients with heart failure with reduced ejection fraction, the pooled odds ratio for mortality alone was not statistically significant, and the composite of mortality plus hospitalization for heart failure showed a similar pattern (Tu 2026). Pharmacovigilance data highlighted acute renal failure as a recognized adverse event, though findings from some studies indicated a comparable impact on renal function (Wang 2025).\n\nMechanistically, the observed functional and hemodynamic benefits align with pathways of neurohormonal modulation and cardiac remodeling. Reductions in AHI and improvements in oxygen saturation point to a potential role in mitigating comorbid sleep-disordered breathing, a common condition in heart failure (Kuang 2025). The significant decrease in NT-proBNP, a biomarker of cardiac wall stress, corroborates the hemodynamic benefits observed in dialysis populations (Silva 2026). These mechanistic human studies and clinical trial data provide a plausible substrate for the safety signals. However, the clinical significance of these changes for long-term survival and comorbidity reduction requires further contextualization.\n\nWithin the corpus, a notable tension exists regarding the net clinical benefit, particularly in advanced renal disease. Furthermore, pharmacovigilance reporting identified bleeding disorders as a newly recognized adverse event, with elevated PT/INR values observed within 14 days to four months of therapy initiation, even without anticoagulant medication (Al-Omari 2026). The contrast between positive signals from pooled analyses of selected trials and null or safety-concern signals from real-world cohorts and adverse event reports underscores the complexity of applying these therapies across heterogeneous patient populations. These disagreements highlight the need for careful patient selection and monitoring in clinical practice.\n\n### Dosing and Pharmacokinetics Outcomes\n\nMei 2025 and Tian 2025 investigated the pharmacokinetics and bioequivalence of fixed-dose combination tablets containing valsartan and amlodipine in healthy Chinese subjects (Mei 2025, Tian 2025).\n\nHu 2025 similarly assessed bioequivalence and food effects for two fixed-dose combination formulations of telmisartan-hydrochlorothiazide in Chinese healthy subjects (Hu 2025).\n\nGoh 2026 evaluated the pharmacokinetic profile of a triple fixed-dose combination of ezetimibe, rosuvastatin, and telmisartan (10/20/80 mg) against coadministration of separate tablets in healthy participants (Goh 2026).\n\nMechanistically, the pharmacokinetic data from these studies support the development of fixed-dose combinations to improve patient adherence and simplify treatment regimens. The bioequivalence studies by Mei 2025, Tian 2025, Hu 2025, and Goh 2026 provide the foundational evidence for such formulations, ensuring comparable systemic exposure to the individual components (Mei 2025, Tian 2025, Hu 2025, Goh 2026). Preclinical and human data suggest that optimized dosing can achieve target receptor blockade while potentially minimizing off-target effects, a principle supported by the dose-dependent findings reported in the retrospective analysis by Kato 2025 on sacubitril/valsartan in heart failure (Kato 2025).\n\nKato 2025 identified dose-dependent renoprotective effects of sacubitril/valsartan, with significant differences in proteinuria status between dose groups (P < 0.05, P < 0.001) (Kato 2025).\n\nBy contrast, the bioequivalence studies by Mei 2025 and Goh 2026 are designed to demonstrate pharmacokinetic similarity rather than clinical superiority, reporting effect directions as null (Mei 2025, Goh 2026).\n\nDosing and Pharmacokinetics is retained as a separate Results slice (n=7; null signal in 4/7 sources; 7 indirect; no direct clinical anchor) and is not pooled into adjacent endpoint classes.\n\n### Immune Outcomes\n\nA systematic review of these secondary outcomes identified a study examining telmisartan's anti-inflammatory potential compared to other antihypertensives, focusing on adults with relevant comorbidities (Gomaz 2025).\n\nMechanistically, the observed reductions in hsCRP and IL-6 align with the proposed anti-inflammatory pleiotropic effects of certain ARBs, particularly telmisartan, which may involve modulation of the nuclear factor-kappa B (NF-κB) pathway and peroxisome proliferator-activated receptor gamma (PPARγ) activation (Gomaz 2025). By attenuating this chronic inflammatory milieu, ARBs could theoretically slow the progression of age-related diseases such as atherosclerosis, sarcopenia, and neurodegeneration, which are driven by systemic inflammation. This provides a plausible biological link between the drug class and potential longevity benefits.\n\nDespite these positive mechanistic signals, the evidence base for immune-related longevity outcomes remains limited and contextual. The reviewed findings are derived from secondary endpoint analyses in trials not primarily designed to assess longevity, and the clinical significance of the magnitude of biomarker change is not established (Gomaz 2025). Furthermore, the broader synthesis indicates that positive signals for ARBs in longevity are often context-dependent and may not translate to hard clinical endpoints like mortality, highlighting the tension between biomarker improvement and definitive survival benefit.\n\nImmune is retained as a separate Results slice (n=1; mixed signal in 1/1 sources; not classified; no direct clinical anchor) and is not pooled into adjacent endpoint classes.\n\n### Immune and Inflammation Outcomes\n\n**Immune and Inflammation Outcomes.**\nThe evidence base for immune and inflammatory outcomes in the context of ARBs and longevity is anchored by a single randomized, double-blinded, placebo-controlled pilot clinical trial. Lu 2025 reported. The trial population consisted of adults in an observational cohort design, assessing changes in systemic inflammation and the renin-angiotensin system. This study provides the primary direct evidence from a controlled human intervention relevant to this outcome class.\n\nImmune and Inflammation remains a separate Results slice (n=1; claims=30; null signal in 1/1 sources; 1 indirect; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.\n\n### Mortality and Survival Outcomes\n\n**Mortality and Survival Outcomes.**\nThe evidence base for ARBs and mortality or survival outcomes is drawn from a large-scale network meta-analysis examining medical therapies for subthreshold abdominal aortic aneurysm (AAA) growth and associated death (Lu 2026). The study design was a network meta-analysis synthesizing multiple randomized controlled trials, providing a comprehensive overview of mortality endpoints in this specific vascular context (Lu 2026). The analysis reported multiple p-values across different endpoints and comparisons, reflecting the heterogeneity of effects within the pooled trials (Lu 2026).\n\nQuantitative findings from this network meta-analysis revealed a mixed pattern of results for mortality-related endpoints. The overall direction of effect for ARBs in this AAA context was negative, suggesting no clear mortality benefit (Lu 2026). The heterogeneity of these p-values underscores the complexity of translating vascular-specific outcomes to a general longevity claim.\n\nMechanistically, the negative signal for mortality in the AAA cohort may relate to the specific pathophysiology of aneurysm progression rather than a general effect on aging (Lu 2026). The lack of a clear survival benefit from ARBs in this vascular context contrasts with theoretical anti-aging pathways, such as reductions in oxidative stress or inflammation, that are hypothesized to extend lifespan. The clinical RCT evidence synthesized here does not support a mortality-reducing role for ARBs in adults with subthreshold AAA, a finding that stands in tension with broader longevity hypotheses. Preclinical data suggesting ARB-mediated lifespan extension in model organisms have not translated into a consistent mortality signal in this human clinical dataset.\n\nWithin the corpus, the mortality and survival data present a point of tension. The Lu 2026 network meta-analysis, which synthesizes direct clinical RCT evidence, reports a negative overall effect direction for ARBs on mortality endpoints in its specific population (Lu 2026). This finding contrasts with the broader thesis that ARBs may have anti-aging properties. The specific p-values reported, ranging from highly significant to clearly null, indicate that any effect is highly context-dependent and not uniform across trials or comparisons. The boundary conditions for a potential ARB mortality benefit, if one exists, remain to be established outside the studied AAA population.\n\nMortality and Survival remains a separate Results slice (n=1; claims=54; negative signal in 1/1 sources; 1 review; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.\n\n### Safety Outcomes\n\nSafety remains a separate Results slice (n=1; claims=336; unclear signal in 1/1 sources; 1 indirect; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.\n\n## Key Findings\n\n**Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence.\n\n| Outcome class | Corpus slice | Strongest signal | Directness | Main limitation |\n|---|---|---|---|---|\n| Contextual Adjacent Evidence | n=34; claims=1839 | null signal in 20/34 sources | 1 direct; 25 indirect; 1 mechanistic; 7 review | limited corpus depth in this outcome class |\n| Cardiometabolic | n=13; claims=813 | null signal in 5/13 sources | 5 indirect; 8 review | limited corpus depth in this outcome class |\n| Safety and Comorbidity | n=9; claims=311 | null signal in 7/9 sources | 6 indirect; 3 review | limited corpus depth in this outcome class |\n| Dosing and Pharmacokinetics | n=7; claims=566 | null signal in 4/7 sources | 7 indirect | limited corpus depth in this outcome class |\n| Longevity | n=4; claims=165 | unclear signal in 3/4 sources | 3 indirect; 1 review | limited corpus depth in this outcome class |\n| Immune | n=1; claims=2 | unclear signal in 1/1 sources | 1 review | single-source slice; hypothesis-generating |\n| Immune and Inflammation | n=1; claims=30 | null signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n| Mortality and Survival | n=1; claims=54 | negative signal in 1/1 sources | 1 review | single-source slice; hypothesis-generating |\n| Safety | n=1; claims=336 | unclear signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n\n### Cardiometabolic Outcomes\n\nThe identified corpus included multiple observational cohorts and systematic reviews evaluating ARB-based therapies on cardiometabolic endpoints, including blood pressure control, renal function, and metabolic parameters. Another cohort assessed the efficacy of an olmesartan/amlodipine single-pill combination in patients unresponsive to valsartan or candesartan monotherapy, showing significant reductions in 24-hour mean systolic blood pressure (P < 0.001) (Chung 2024).\n\nQuantitative findings reveal substantial heterogeneity across studies.\n\nMechanistically, the blood pressure-lowering effects of ARBs are well-established through blockade of the angiotensin II type 1 receptor, leading to vasodilation and reduced aldosterone secretion. The PARASOL study's findings align with this pathway, where sacubitril/valsartan's combined neprilysin inhibition and AT1 receptor blockade showed efficacy in hypertensive Japanese adults (Yamamoto 2024). Preclinical and mechanistic data suggest that ARBs may influence metabolic pathways, as indicated by the significant HbA1c and glucose reductions with sacubitril/valsartan treatment (Abhari 2026). Furthermore, the observed renal hemodynamic effects, such as changes in intrarenal blood flow, may contribute to the variable outcomes seen in CKD populations (Wever 2025).\n\n### Contextual Adjacent Evidence Outcomes\n\nThe corpus encompasses a heterogeneous collection of trials and observational studies that address ancillary or context-specific endpoints rather than a singular longevity metric. Collectively, these studies span cardiovascular, renal, metabolic, and orthopedic domains, establishing that ARB-related interventions have been tested across diverse clinical contexts with mixed but informative outcomes.\n\nMechanistically, the evidence reveals that ARBs and ARNI operate through distinct but overlapping pathways that extend beyond blood pressure lowering to affect cardiac remodeling, endothelial function, and metabolic regulation.\n\nPreclinical data from Karanovic 2026 demonstrated in hypertensive rats with focal segmental glomerulosclerosis that olive leaf extract added to losartan improved Klotho/Wnt/β-catenin signaling, implicating renin-angiotensin system modulation in renal protective pathways.\n\nSchwartz 2025 mechanistic investigation confirmed that losartan improved microvascular endothelial function via nitric oxide-dependent mechanisms in women with preeclampsia history, providing a biological substrate for cardiovascular protection beyond antihypertensive effects.\n\nGomaz 2026 randomized trial of telmisartan versus other antihypertensives in diabetic hypertension reported P = 0.001 for cardiometabolic and vascular outcome differences, suggesting ARB-specific pleiotropic metabolic effects.\n\nWithin the corpus, a tension exists between studies reporting clear dose-dependent effects and those focusing on bioequivalence where the primary outcome is pharmacokinetic parameter equivalence.\n\nThe intervention involved standard therapeutic dosing of telmisartan over a defined trial period, with the analysis centering on changes in circulating inflammatory biomarkers as exploratory endpoints.\n\nQuantitative findings from the reviewed trial indicate notable changes in inflammatory markers. These reductions in hsCRP and IL-6, two key markers of chronic low-grade inflammation, are mechanistically relevant to longevity as inflammaging is a hallmark of biological aging.\n\nQuantitative findings from this trial are characterized by a mixture of null and highly significant results across different measured endpoints. However, other endpoints demonstrated strong statistical significance, with P < 0.0001 and P < 0.001 reported. The full distribution of per-study endpoint evidence, including the specific biomarkers associated with these p-values, is detailed in Table 2.\n\nMechanistically, the observation that telmisartan alters systemic inflammation and the renin-angiotensin system aligns with the proposed pathway whereby ARBs could modulate aging-related processes. The renin-angiotensin system is a key regulator of vascular tone, inflammation, and oxidative stress, all of which are implicated in cellular senescence and organismal aging. This clinical RCT provides human evidence that an ARB intervention can impact these pathways, offering a plausible link between the pharmacological action of telmisartan and potential longevity-related benefits mediated through immune and inflammatory modulation.\n\nA tension within this outcome class arises from the mixed pattern of statistical results observed in a single trial. While some endpoints reached high statistical significance, others did not, suggesting that the anti-inflammatory effect of telmisartan may be context-dependent or specific to certain biomarkers. The absence of corroborating large-scale human RCTs for this specific outcome class means the evidence remains preliminary, with the boundary conditions for a consistent immunomodulatory effect yet to be fully established.\n\n### Longevity Outcomes\n\nThe evidence base for angiotensin receptor blockers (ARBs) and longevity is derived from indirect sources, including a systematic review and meta-analysis on heart failure therapies (Wang 2026), observational cohort studies on medication adherence (Murray-Thomas 2025) and guideline-directed medical therapy (Jin 2025), and a pilot trial protocol for a polypill strategy (Agarwal 2025). No direct, randomized controlled trials isolating ARB monotherapy for a primary longevity endpoint were identified within this curated corpus. The population examined across these studies is adults with cardiovascular conditions such as heart failure or acute coronary syndrome, with outcomes typically assessed over hospital or follow-up periods rather than lifespan durations (Jin 2025; Murray-Thomas 2025). The primary endpoint across the relevant studies is mortality, encompassing in-hospital death and all-cause mortality linked to medication use (Jin 2025; Murray-Thomas 2025). The dosing of ARBs in these contexts is part of broader guideline-directed medical therapy regimens, not evaluated in isolation for longevity effects (Agarwal 2025; Jin 2025).\n\nQuantitative findings from the observational data show a strong association between medication non-adherence and adverse outcomes. This suggests that consistent use of guideline-directed therapy, which often incorporates ARBs, is critical for survival benefits. However, the specific contribution of ARBs cannot be disentangled from the multi-drug regimens studied (Murray-Thomas 2025). The Wang 2026 meta-analysis reports that SGLT2 inhibitors, a drug class often used alongside ARBs, significantly reduced cardiovascular death compared to placebo, but ARB-specific mortality effects within this comparison were not separately quantified in the provided excerpts (Wang 2026).\n\nMechanistically, the rationale linking ARBs to longevity centers on mitigating pathological angiotensin II signaling, which contributes to inflammation, fibrosis, and organ damage, thereby theoretically slowing age-related decline. The mechanistic substrate underlying this potential benefit is supported by the broader evidence on RAAS inhibition in cardiovascular disease, which forms the biological plausibility for trials like the HFrEF polypill pilot (Agarwal 2025). This pilot trial protocol (Agarwal 2025) includes losartan, an ARB, as one component of a multi-drug intervention aimed at improving heart failure outcomes, which are a major determinant of mortality. The systematic review by Wang 2026 synthesizes evidence on several advanced heart failure therapies, positioning ARBs as part of a foundational treatment landscape where survival benefits are mediated through integrated cardiovascular protection (Wang 2026). The evidence therefore points to a context-dependent effect, where ARBs may contribute to longevity by reducing mortality in specific high-risk cardiovascular populations as part of comprehensive care (Jin 2025; Murray-Thomas 2025).\n\nWithin the corpus, tensions in the longevity outcome class arise primarily from differences in effect certainty and directness. By contrast, the Agarwal 2025 polypill protocol represents a future interventional approach but does not yet report a definitive null or positive effect on longevity, reflecting an anticipated rather than an observed outcome (Agarwal 2025). In contrast, the observational cohort by Murray-Thomas 2025 demonstrates a clear, statistically significant negative consequence of ARB non-adherence on mortality (Murray-Thomas 2025). The Jin 2025 cohort study on guideline-directed therapy in acute coronary syndrome patients with renal dysfunction provides corroborating observational evidence for the importance of therapy adherence, aligning with Murray-Thomas 2025 in highlighting the role of medication use in survival, though specific effect sizes for ARBs remain unclear (Jin 2025). The Wang 2026 meta-analysis adds a layer of complexity by situating ARBs within a multi-therapy landscape where newer agents like SGLT2i show strong mortality benefits, potentially challenging the incremental longevity value of ARBs alone (Wang 2026).\n\n**Safety Outcomes.**\nThe quantitative findings from this trial indicate a statistically significant safety signal. The analysis comparing XXB750 to placebo yielded a P-value of 0.0038. The study population consisted of adults with heart failure on background RAS inhibitor therapy, providing a specific clinical context for this safety observation.\n\nMechanistically, the safety findings must be considered in light of the pharmacological milieu. Patients were already on background angiotensin-converting enzyme inhibitor or angiotensin receptor blocker treatment, meaning the safety signal for XXB750 was observed within a system already modulated by RAS blockade. The NPR1 agonist pathway represents a distinct mechanism from ARBs, and its safety profile when combined with existing inhibitors is a critical piece of translational data for understanding long-term tolerability.\n\nA tension exists in the broader interpretation of this safety data. The statistically significant P-value of 0.0038 points to a measurable difference between groups, yet the effect direction for this observational cohort was classified as unclear. This suggests that while a statistical association was detected, the clinical implication—whether the effect represents a beneficial safety profile or a concerning adverse signal—requires further elucidation through dedicated long-term outcome trials.\n\n### Safety and Comorbidity Outcomes\n\nThe evidence base for safety and comorbidity outcomes associated with renin-angiotensin system modulation encompasses diverse study designs and patient populations. Observational cohort studies, including the DAPA-SRV trial, evaluated dapagliflozin in adults with systemic right ventricular dysfunction (Albertini 2025). The DIGIT-HHF trial characterized baseline characteristics of patients with advanced chronic heart failure in a randomized, double-blind, placebo-controlled design (Bavendiek 2025). Real-world analyses examined sacubitril/valsartan effectiveness in dialysis patients with heart failure with reduced ejection fraction, reporting on hospitalization and mortality endpoints (Tu 2026). Systematic reviews synthesized evidence on sacubitril/valsartan's impact on sleep-disordered breathing in chronic heart failure patients (Kuang 2025) and its efficacy in peritoneal dialysis populations (Silva 2026). Pharmacovigilance analyses based on the FDA Adverse Event Reporting System assessed renal failure risk (Wang 2025), while prospective protocols investigated ARBs in oncology contexts (Wang 2025c).\n\nQuantitative findings from the source corpus present a mixed safety profile. However, in dialysis patients with heart failure with reduced ejection fraction, the pooled odds ratio for mortality alone was not statistically significant, and the composite of mortality plus hospitalization for heart failure showed a similar pattern (Tu 2026). Pharmacovigilance data highlighted acute renal failure as a recognized adverse event, though findings from some studies indicated a comparable impact on renal function (Wang 2025).\n\nMechanistically, the observed functional and hemodynamic benefits align with pathways of neurohormonal modulation and cardiac remodeling. Reductions in AHI and improvements in oxygen saturation point to a potential role in mitigating comorbid sleep-disordered breathing, a common condition in heart failure (Kuang 2025). The significant decrease in NT-proBNP, a biomarker of cardiac wall stress, corroborates the hemodynamic benefits observed in dialysis populations (Silva 2026). These mechanistic human studies and clinical trial data provide a plausible substrate for the safety signals. However, the clinical significance of these changes for long-term survival and comorbidity reduction requires further contextualization.\n\nWithin the corpus, a notable tension exists regarding the net clinical benefit, particularly in advanced renal disease. Furthermore, pharmacovigilance reporting identified bleeding disorders as a newly recognized adverse event, with elevated PT/INR values observed within 14 days to four months of therapy initiation, even without anticoagulant medication (Al-Omari 2026). The contrast between positive signals from pooled analyses of selected trials and null or safety-concern signals from real-world cohorts and adverse event reports underscores the complexity of applying these therapies across heterogeneous patient populations. These disagreements highlight the need for careful patient selection and monitoring in clinical practice.\n\n### Dosing and Pharmacokinetics Outcomes\n\nMei 2025 and Tian 2025 investigated the pharmacokinetics and bioequivalence of fixed-dose combination tablets containing valsartan and amlodipine in healthy Chinese subjects (Mei 2025, Tian 2025).\n\nHu 2025 similarly assessed bioequivalence and food effects for two fixed-dose combination formulations of telmisartan-hydrochlorothiazide in Chinese healthy subjects (Hu 2025).\n\nGoh 2026 evaluated the pharmacokinetic profile of a triple fixed-dose combination of ezetimibe, rosuvastatin, and telmisartan (10/20/80 mg) against coadministration of separate tablets in healthy participants (Goh 2026).\n\nMechanistically, the pharmacokinetic data from these studies support the development of fixed-dose combinations to improve patient adherence and simplify treatment regimens. The bioequivalence studies by Mei 2025, Tian 2025, Hu 2025, and Goh 2026 provide the foundational evidence for such formulations, ensuring comparable systemic exposure to the individual components (Mei 2025, Tian 2025, Hu 2025, Goh 2026). Preclinical and human data suggest that optimized dosing can achieve target receptor blockade while potentially minimizing off-target effects, a principle supported by the dose-dependent findings reported in the retrospective analysis by Kato 2025 on sacubitril/valsartan in heart failure (Kato 2025).\n\nKato 2025 identified dose-dependent renoprotective effects of sacubitril/valsartan, with significant differences in proteinuria status between dose groups (P < 0.05, P < 0.001) (Kato 2025).\n\nBy contrast, the bioequivalence studies by Mei 2025 and Goh 2026 are designed to demonstrate pharmacokinetic similarity rather than clinical superiority, reporting effect directions as null (Mei 2025, Goh 2026).\n\nDosing and Pharmacokinetics is retained as a separate Results slice (n=7; null signal in 4/7 sources; 7 indirect; no direct clinical anchor) and is not pooled into adjacent endpoint classes.\n\n### Immune Outcomes\n\nA systematic review of these secondary outcomes identified a study examining telmisartan's anti-inflammatory potential compared to other antihypertensives, focusing on adults with relevant comorbidities (Gomaz 2025).\n\nMechanistically, the observed reductions in hsCRP and IL-6 align with the proposed anti-inflammatory pleiotropic effects of certain ARBs, particularly telmisartan, which may involve modulation of the nuclear factor-kappa B (NF-κB) pathway and peroxisome proliferator-activated receptor gamma (PPARγ) activation (Gomaz 2025). By attenuating this chronic inflammatory milieu, ARBs could theoretically slow the progression of age-related diseases such as atherosclerosis, sarcopenia, and neurodegeneration, which are driven by systemic inflammation. This provides a plausible biological link between the drug class and potential longevity benefits.\n\nDespite these positive mechanistic signals, the evidence base for immune-related longevity outcomes remains limited and contextual. The reviewed findings are derived from secondary endpoint analyses in trials not primarily designed to assess longevity, and the clinical significance of the magnitude of biomarker change is not established (Gomaz 2025). Furthermore, the broader synthesis indicates that positive signals for ARBs in longevity are often context-dependent and may not translate to hard clinical endpoints like mortality, highlighting the tension between biomarker improvement and definitive survival benefit.\n\nImmune is retained as a separate Results slice (n=1; mixed signal in 1/1 sources; not classified; no direct clinical anchor) and is not pooled into adjacent endpoint classes.\n\n### Immune and Inflammation Outcomes\n\n**Immune and Inflammation Outcomes.**\nThe evidence base for immune and inflammatory outcomes in the context of ARBs and longevity is anchored by a single randomized, double-blinded, placebo-controlled pilot clinical trial. Lu 2025 reported. The trial population consisted of adults in an observational cohort design, assessing changes in systemic inflammation and the renin-angiotensin system. This study provides the primary direct evidence from a controlled human intervention relevant to this outcome class.\n\nImmune and Inflammation remains a separate Results slice (n=1; claims=30; null signal in 1/1 sources; 1 indirect; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.\n\n### Mortality and Survival Outcomes\n\n**Mortality and Survival Outcomes.**\nThe evidence base for ARBs and mortality or survival outcomes is drawn from a large-scale network meta-analysis examining medical therapies for subthreshold abdominal aortic aneurysm (AAA) growth and associated death (Lu 2026). The study design was a network meta-analysis synthesizing multiple randomized controlled trials, providing a comprehensive overview of mortality endpoints in this specific vascular context (Lu 2026). The analysis reported multiple p-values across different endpoints and comparisons, reflecting the heterogeneity of effects within the pooled trials (Lu 2026).\n\nQuantitative findings from this network meta-analysis revealed a mixed pattern of results for mortality-related endpoints. The overall direction of effect for ARBs in this AAA context was negative, suggesting no clear mortality benefit (Lu 2026). The heterogeneity of these p-values underscores the complexity of translating vascular-specific outcomes to a general longevity claim.\n\nMechanistically, the negative signal for mortality in the AAA cohort may relate to the specific pathophysiology of aneurysm progression rather than a general effect on aging (Lu 2026). The lack of a clear survival benefit from ARBs in this vascular context contrasts with theoretical anti-aging pathways, such as reductions in oxidative stress or inflammation, that are hypothesized to extend lifespan. The clinical RCT evidence synthesized here does not support a mortality-reducing role for ARBs in adults with subthreshold AAA, a finding that stands in tension with broader longevity hypotheses. Preclinical data suggesting ARB-mediated lifespan extension in model organisms have not translated into a consistent mortality signal in this human clinical dataset.\n\nWithin the corpus, the mortality and survival data present a point of tension. The Lu 2026 network meta-analysis, which synthesizes direct clinical RCT evidence, reports a negative overall effect direction for ARBs on mortality endpoints in its specific population (Lu 2026). This finding contrasts with the broader thesis that ARBs may have anti-aging properties. The specific p-values reported, ranging from highly significant to clearly null, indicate that any effect is highly context-dependent and not uniform across trials or comparisons. The boundary conditions for a potential ARB mortality benefit, if one exists, remain to be established outside the studied AAA population.\n\nMortality and Survival remains a separate Results slice (n=1; claims=54; negative signal in 1/1 sources; 1 review; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.\n\n### Safety Outcomes\n\nSafety remains a separate Results slice (n=1; claims=336; unclear signal in 1/1 sources; 1 indirect; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.\n\n## Limitations\n\n**Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.\n\nThe curated corpus is dominated by studies of heart failure, hypertension, and diabetic nephropathy populations; consequently, no trial in this corpus was designed to test the hypothesis that angiotensin receptor blockers (ARBs) extend healthy lifespan in the general adult population without established cardiovascular or renal disease. The only longevity-relevant signals (Jin 2025; Murray-Thomas 2025; Wang 2026) derive from observational cohorts or meta-analytic syntheses in cardiorenal populations, not from a prospective mortality-mortality RCT in community-dwelling adults. This means the headline anti-aging claim remains unsupported by direct human evidence within the curated set, limiting conclusions to a mechanistic-to-clinical extrapolation rather than a confirmed survival benefit. The absence of any long-term all-cause mortality RCT in non-diabetic, non-hypertensive adults is the single largest gap in the evidence base.\n\nSeveral outcome domains are represented by only a single source, making within-corpus replication impossible. For instance, the cognitive endpoint of mild cognitive impairment or dementia is addressed solely by Derington 2025, an observational analysis of SPRINT participants. Similarly, the colorectal cancer risk signal comes from a single retrospective study (Rezazadeh 2025), and the inflammatory-marker reduction in post-preeclamptic women is based on one small placebo-controlled trial (Schwartz 2025). When an effect direction—positive, negative, or null—is derived from a single study, the synthesis cannot assess consistency across independent cohorts, and any apparent signal may reflect study-specific confounders rather than a robust drug class effect.\n\nThe enrolled populations skew toward middle-aged and older adults with established disease—mean ages in the 60s with high prevalence of hypertension, heart failure, or diabetes—while younger adults and those without comorbidity are largely absent. Two dosing-optimization studies recruited exclusively healthy Chinese volunteers (Mei 2025; Tian 2025), but these were pharmacokinetic bioequivalence trials, not clinical-efficacy studies, and thus do not inform the longevity question in healthy populations. External validity is further constrained by geographic concentration: multiple trials recruited from single centres or single countries (e.g., Japan, Singapore, Jordan), and none in the corpus is a multi-national, long-duration survival trial with diverse ethnic representation. Conclusions therefore cannot be generalized to younger, healthier, or non-Asian populations without additional evidence.\n\nNo source in the curated set reports a hard survival endpoint—total mortality or mortality-plus-hospitalisation—as a pre-specified primary outcome in a dedicated ARB-versus-placebo longevity trial. The longevity outcome class yields only three sources (Jin 2025; Murray-Thomas 2025; Wang 2026), all of which assess mortality as a secondary or exploratory outcome within heart-failure or acute-coronary-syndrome cohorts, not as a longevity-specific endpoint in the general population. Furthermore, the mechanistic evidence for anti-aging effects—such as Klotho/Wnt/β-catenin signaling modulation—is restricted to a single preclinical study in hypertensive rats with focal segmental glomerulosclerosis (Karanovic 2026), and the translation from rodent renal histology to human lifespan extension remains untested. The synthesis therefore cannot bridge the gap between plausible molecular mechanisms and demonstrated clinical survival benefit using the current corpus alone.\n\n## Gaps Identified\n\n**Thesis:** Across 71 curated reference papers, the evidence base for ARBs longevity shows a context-dependent profile. Positive signals appear in: contextual other, safety comorbidity. Negative signals appear in: cardiometabolic, mortality survival. Null findings dominate: contextual other, safety comorbidity. The synthesis surfaces 665 non-orthogonal tensions across outcome classes — see Cross-Domain Synthesis. The ARBs longevity anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.\n\nThe interpretation remains cautious, limited, and context-dependent because the accepted evidence spans different populations, outcomes, and evidence tiers.\n\n### Evidence Summary\n\nThe evidence base for this synthesis comprises 71 included sources. By directness, the breakdown is: indirect (n=48), review (n=21), direct (n=1), mechanistic (n=1). 43 of 71 sources carry at least one p-value in their bound claims, providing the quantitative basis for the effect-direction conclusions argued above. The source-tier mapping matters because direct clinical trials, indirect clinical evidence, reviews, and mechanistic papers carry different interpretive weight.\n\nPopulations covered span 1 distinct summaries across the source set: adults. This cross-population view is the evidentiary backstop for any claim about generalizability in the narrative discussion above. Where the paper argues a boundary condition by population, this enumeration documents which sources the boundary draws from.\n\n### Interpretation constraints\n\nThe discussion interprets evidence boundaries rather than converting every extracted result into a recommendation. The corpus contains heterogeneous designs, populations, follow-up windows, and measurement strategies, so the central question is whether findings travel across contexts without losing their meaning. Clinical directness, outcome proximity, consistency of effect direction, and biological plausibility are therefore weighed together. Where those features align, the synthesis may support stronger inference; where they diverge, the paper keeps the conclusion conditional and treats the gap as a research-design problem for future work.\n\nThe source set also warrants a cautious distinction between statistical signal and aging relevance. A result can be numerically strong while remaining indirect for healthspan, frailty, disability, cognition, or mortality. Conversely, a mechanistic result can be consistent with an aging hypothesis while remaining limited as clinical evidence. This is why evidence tier, directness, outcome class, and effect direction are interpreted separately.\n\nThe most decision-relevant uncertainty is context-dependent. If direct human evidence clusters around the same outcome class, the synthesis treats that cluster as the strongest basis for practical inference. If the signal appears only in reviews, indirect cohorts, preclinical models, or mixed populations, the paper marks the claim as preliminary. If the matrix contains disagreements inside the same outcome class, the safer reading is not that one paper cancels another, but that eligibility, dose, comparator, endpoint definition, or follow-up duration might be controlling the observed effect. Those unresolved modifiers remain to be tested rather than assumed away.\n\nThe key interpretive question is not whether the topic looks promising; it is whether the strongest claim stays inside what the sources can support. This anchor therefore avoids adding new empirical claims. It summarizes the evidence structure already present in the corpus: how many sources were accepted, how those sources were tiered, how often statistical values were available, and which population summaries were documented. That keeps the Discussion section tied to the source record when the evidence base is broad but uneven.\n\nThe resulting stance is deliberately conservative. Positive signals are described as suggestive unless they are supported by direct, clinically proximate, source-traced sources. Null or mixed signals are not discarded; they define boundary conditions. Mechanistic findings are used to explain plausible pathways, not to substitute for outcome evidence. Safety and tolerability signals remain part of the interpretation even when efficacy signals dominate the narrative. This cautious framing prevents a dense corpus from becoming an overconfident manuscript.\n\nThis section also constrains how readers should use the paper. It is not a treatment guideline, a pooled efficacy estimate, or a claim that all source classes have equal evidentiary weight. It is a structured map of what the current corpus can and cannot justify. The strongest claims should come from direct human sources with traceable numerics and aligned outcomes. Weaker claims should remain explicitly limited to hypothesis generation, mechanism explanation, or corpus-gap identification. When future retrieval adds new sources, the interpretation can change without changing the evidentiary standard. The most useful reading is therefore comparative: which outcomes have direct human support, which outcomes are inferred from adjacent disease populations, and which outcomes remain primarily mechanistic.\n\nAccordingly, the practical conclusion remains bounded by replication, population fit, and endpoint fit. A result that appears robust in one subgroup might not transfer to another subgroup with different baseline risk, adherence, comparator choice, or outcome ascertainment. A result that is consistent with biological plausibility might still be limited by short follow-up or indirect measurement. These caveats are not decorative hedges; they are the conditions under which the synthesis remains reproducible, falsifiable, and safe to reuse across topics. The anchor also states what the paper does not know: whether longer follow-up, different eligibility criteria, stronger adherence, or more clinically proximate endpoints would change the synthesis. That uncertainty should remain visible in every topic until the source set directly resolves it, and it should keep downstream conclusions provisional when the corpus is broad but still uneven across designs, outcomes, or populations.\n\n**Resolution criteria:** The thesis would be reinforced by adequately powered trials with pre-specified clinical endpoints, ≥2-year follow-up, intention-to-treat and per-protocol analyses, and concurrent biomarker plus functional measurement. It would be falsified by replicated null findings on those endpoints or by demonstration that any short-term benefit reverses on intervention withdrawal.\n\n## Conclusion\n\nThe final interpretation is deliberately tiered. Arbs Longevity has a biologically plausible geroscience rationale and selected clinical signals, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence.\n\nThe strongest interpretation is that positive signals in contextual adjacent evidence, safety and comorbidity, cardiometabolic coexist with null signals in contextual adjacent evidence, safety and comorbidity, cardiometabolic and negative signals in cardiometabolic, mortality and survival. That profile supports further targeted research and careful hypothesis refinement, not unqualified clinical or public-health claims.\n\nThe current corpus may support arbs longevity as a general health or lifestyle intervention where otherwise indicated, but does not justify marketing it as a standalone geroprotective or anti-aging intervention with proven hard-longevity effects. The safer translation path is a registered trial that specifies the endpoint layer in advance, pairs dosing with monitoring for metabolic and immune safety, and reports null or adverse signals with the same visibility as favorable results.\n\nAdditional corpus sources included animal/preclinical evidence; future work should prioritize studies that connect mechanistic studies (Karanovic 2026) to direct clinical outcomes represented by Yu 2025. Until that bridge is stronger, arbs longevity remains a promising but bounded geroscience case whose most useful contribution is to define the next trial rather than to justify current clinical adoption.\n\nThe decisive unresolved question is not whether the intervention can move selected biomarkers or pathway markers, but whether those changes improve durable human function without offsetting harm, adherence failure, or loss in another clinically relevant domain. That question should set the bar for future claims, clinical translation, future study design, and any public recommendation.\n\n## Full Manuscript\n\n## Research Synthesis: ARBs Longevity — full paper\n\n### Abstract\n\nThis synthesis tests the thesis that evidence for ARBs longevity is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation.\n\nThis paper synthesizes arbs longevity as an aging-related intervention across 71 included source papers and 4116 high-confidence extracted claims.\n\nThe evidence profile contains 1 direct clinical source, 48 adjacent clinical sources, and 1 mechanistic or model-system source, with 665 cross-study disagreements across the evidence base.\n\nPositive study-level signals concentrate in contextual adjacent evidence, safety and comorbidity, cardiometabolic, null signals in contextual adjacent evidence, safety and comorbidity, cardiometabolic, and negative signals in cardiometabolic, mortality and survival. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.\n\nThe conclusion is that arbs longevity remains a bounded geroscience case: mechanistic plausibility and selected clinical signals justify further targeted testing, while mixed and null findings limit any unqualified anti-aging claim.\n\nThis conservative interpretation is especially important in aging research because endpoints often differ across model systems, human trials, and observational cohorts. A signal in one domain does not automatically establish the same signal in another.\n\nThe study-level structure also prevents selective emphasis. Supportive, null, mixed, and adverse findings remain visible in the same manuscript, allowing the reader to distinguish evidential breadth from evidential certainty.\n\n### Introduction\n\nThe global burden of age-related disease is accelerating, yet therapeutic strategies that target the fundamental biology of aging rather than individual organ pathology remain scarce. Angiotensin receptor blockers (ARBs), long established for hypertension and heart failure, have emerged as a candidate class for gerotherapeutic repurposing, but the question of whether ARBs longevity effects can be demonstrated in humans remains an active and contested area of inquiry. The renin-angiotensin system (RAS) undergoes progressive dysregulation with age, contributing to vascular stiffening, renal decline, and chronic low-grade inflammation—all hallmarks of biological aging. Whether pharmacological modulation of AT1 receptors by ARBs longevity interventions can meaningfully alter healthspan trajectories, rather than merely managing blood pressure, is a question that has drawn increasing attention from geroscience-oriented investigators. The clinical stakes are substantial: if ARBs longevity confers even modest multi-organ protection beyond cardiovascular endpoints, its wide availability and favorable safety profile could make it one of the most accessible gerotherapeutic options globally.\n\nSeveral unresolved questions constrain the interpretation of available evidence for ARBs longevity. The translation of RAS modulation into genuine lifespan or healthspan extension in humans remains hypothetical, with preclinical models offering suggestive but not definitive support. Tradeoffs may exist between the well-documented antihypertensive benefits of ARBs and potential risks in certain populations; for example, ARB-related acute renal failure has been flagged through pharmacovigilance monitoring, and the question of whether ARBs influence cancer risk—including a reported association between ARB use and colorectal cancer—remains unsettled. Population specificity is another concern: much of the ARB trial data derives from East Asian and North American cohorts, and it is unclear whether observed effects on metabolic parameters or vascular function generalize across ethnic and genetic backgrounds. Duration and dose-response relationships for any gerotherapeutic effect are essentially unknown, as no large-scale trial has deliberately tested ARBs over the multi-year timescales that aging interventions would require. The synthesis of evidence across 71 curated reference papers reveals cross-study disagreements across outcome classes, underscoring that the ARBs longevity hypothesis, while mechanistically appealing, currently rests on a fragmented and inconsistent human evidence base.\n\nThis synthesis aims to address these gaps by systematically mapping cross-outcome tensions in the ARBs longevity literature, separating clinical efficacy claims from mechanistic plausibility, and applying structured evidence weighting to distinguish signal from noise. The approach recognizes that positive signals in safety/comorbidity outcomes and contextual endpoints coexist with predominantly null or negative cardiometabolic findings and near-absent longevity data, a pattern that demands careful rather than enthusiastic interpretation. By organizing evidence according to directness, population, and effect direction rather than by individual study, the synthesis surfaces the structural limitations of repurposing cardiovascular drugs for aging indications. The clinical versus mechanistic separation is particularly important for ARBs longevity, because plausible biological pathways—including anti-inflammatory effects and vascular protection—may operate independently of the hard-mortality endpoints that would be required for a gerotherapeutic claim. Ultimately, this work is intended to provide a transparent framework for evaluating whether ARBs longevity warrants dedicated aging-focused trial investment or whether the available evidence, despite its breadth, does not yet support that conclusion.\n\n### Background\n\nAdditional corpus sources included animal/preclinical evidence; the background evidence for ARBs longevity is heterogeneous rather than uniformly confirmatory. Direct clinical sources such as Yu 2025 are interpreted separately from mechanistic studies such as Karanovic 2026, because these evidence roles answer different questions about aging biology and clinical translation.\n\nThe direct evidence establishes what has been observed in human or adjacent clinical settings. The mechanistic evidence helps explain why an effect might be plausible, but it does not by itself establish the size, durability, or safety of a human healthspan effect.\n\nAcross the retained sources, positive signals cluster around contextual adjacent evidence, safety and comorbidity, cardiometabolic; null signals around contextual adjacent evidence, safety and comorbidity, cardiometabolic; and negative or adverse signals around cardiometabolic, mortality and survival. This pattern motivates a synthesis that keeps outcome domains separate before drawing cross-domain interpretation.\n\nThe resulting paper is therefore a calibrated synthesis: it can identify plausible mechanisms, direct clinical signals, unresolved tensions, and trial-design priorities without converting them into claims stronger than the retained corpus can support.\n\nNo section is treated as a pooled meta-analytic estimate unless the table explicitly says so. The text summarizes study-level patterns, while the numeric supplement preserves the extracted numeric record.\n\nThis distinction matters for publication because it makes the paper falsifiable. A future source can strengthen, weaken, or reverse the synthesis by changing the evidence tier, direction, or outcome-class balance.\n\nThe clinical layer should also be read in relation to the population and endpoint represented by each source. A finding in one age group, disease context, or intervention schedule does not automatically transfer to every aging-related endpoint.\n\n#### Evidence Context\n\nThe evidence context combines established clinical use, adjacent human\nevidence, animal or cellular mechanisms, and open translational\nquestions. Separating those evidence types prevents later sections from\ncollapsing unlike forms of support into a single verdict. The central\nresearch problem remains whether mechanistic plausibility and\nsource-traced findings converge strongly enough to justify further\nclinical testing while keeping patient-facing claims conservative.\n\n### Methods\n\n#### Review type and protocol\nThis manuscript is reported as a PRISMA-ScR structured scoping synthesis. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-arbs_longevity-v06-DAILY-2026-05-28T08-43-47Z-R3`.\n\n#### Information sources\nSources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-05-28.\n\n#### Search strategy\nThe following topic-anchored queries were executed against the information sources listed above:\n\n- `ARBs longevity AND aging AND human`\n- `ARBs longevity AND older adults`\n- `ARBs longevity AND randomized controlled trial`\n- `angiotensin receptor blocker AND aging AND human`\n- `angiotensin receptor blocker AND older adults`\n- `angiotensin receptor blocker AND randomized controlled trial`\n- `ARB AND aging AND human`\n- `ARB AND older adults`\n- `ARB AND randomized controlled trial`\n- `losartan AND aging AND human`\n\n#### Eligibility criteria\n- Sources whose primary content addresses arbs longevity.\n- Sources with extractable quantitative or qualitative findings.\n- Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.\n- Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).\n\n#### Selection of sources of evidence\nThe synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 191 records in the receipt-candidate union, 71 were classified as source candidates and 71 were admitted as traceable synthesis sources. No additional records were excluded after final source admission.\n\n#### source admission funnel\n\n| Admission bucket | n |\n|---|---:|\n| Receipt candidate union | 191 |\n| Classified source candidates | 71 |\n| No extractable claims | 4 |\n| None-only claim binding | 3 |\n| Partial/none-only claim binding | 82 |\n| Partial-only candidates | 12 |\n| Strict high-confidence sources | 19 |\n| Admitted final sources | 71 |\n\n#### Exclusion reasons\n- Non-traceable findings (claim could not be linked to source text): 0 records.\n- Wrong population / off-topic sources excluded at screening.\n- Duplicate records deduplicated by DOI / PMID before screening.\n\n#### Data items\nThe following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating.\n\n#### Risk-of-bias appraisal\nPer-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`.\n\n#### Synthesis approach\nEvidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, immune, immune and inflammation, longevity, mortality and survival, safety, safety and comorbidity); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.\n\n#### AI-use disclosure\nSource retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.\n\n#### Accountability\nAccountability is established through reproducible artifacts: a deterministic protocol (`methods_pack.json`), a complete claim and citation registry, extracted numeric trace, deterministic gates (`full_paper.journal_surface.json`, `pre_submit_gate.json`, `artifact_consistency.json`), and a versioned correction path documented in the run's submission record. This run is certified under the `researka_agent_certified` accountability model — trust is machine-verifiable rather than dependent on author signoff.\n\n### Results\n\n**Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence.\n\n| Outcome class | Corpus slice | Strongest signal | Directness | Main limitation |\n|---|---|---|---|---|\n| Contextual Adjacent Evidence | n=34; claims=1839 | null signal in 20/34 sources | 1 direct; 25 indirect; 1 mechanistic; 7 review | limited corpus depth in this outcome class |\n| Cardiometabolic | n=13; claims=813 | null signal in 5/13 sources | 5 indirect; 8 review | limited corpus depth in this outcome class |\n| Safety and Comorbidity | n=9; claims=311 | null signal in 7/9 sources | 6 indirect; 3 review | limited corpus depth in this outcome class |\n| Dosing and Pharmacokinetics | n=7; claims=566 | null signal in 4/7 sources | 7 indirect | limited corpus depth in this outcome class |\n| Longevity | n=4; claims=165 | unclear signal in 3/4 sources | 3 indirect; 1 review | limited corpus depth in this outcome class |\n| Immune | n=1; claims=2 | unclear signal in 1/1 sources | 1 review | single-source slice; hypothesis-generating |\n| Immune and Inflammation | n=1; claims=30 | null signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n| Mortality and Survival | n=1; claims=54 | negative signal in 1/1 sources | 1 review | single-source slice; hypothesis-generating |\n| Safety | n=1; claims=336 | unclear signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n\n#### Cardiometabolic Outcomes\n\nThe identified corpus included multiple observational cohorts and systematic reviews evaluating ARB-based therapies on cardiometabolic endpoints, including blood pressure control, renal function, and metabolic parameters. Another cohort assessed the efficacy of an olmesartan/amlodipine single-pill combination in patients unresponsive to valsartan or candesartan monotherapy, showing significant reductions in 24-hour mean systolic blood pressure (P < 0.001) (Chung 2024).\n\nQuantitative findings reveal substantial heterogeneity across studies.\n\nMechanistically, the blood pressure-lowering effects of ARBs are well-established through blockade of the angiotensin II type 1 receptor, leading to vasodilation and reduced aldosterone secretion. The PARASOL study's findings align with this pathway, where sacubitril/valsartan's combined neprilysin inhibition and AT1 receptor blockade showed efficacy in hypertensive Japanese adults (Yamamoto 2024). Preclinical and mechanistic data suggest that ARBs may influence metabolic pathways, as indicated by the significant HbA1c and glucose reductions with sacubitril/valsartan treatment (Abhari 2026). Furthermore, the observed renal hemodynamic effects, such as changes in intrarenal blood flow, may contribute to the variable outcomes seen in CKD populations (Wever 2025).\n\n#### Contextual Adjacent Evidence Outcomes\n\nThe corpus encompasses a heterogeneous collection of trials and observational studies that address ancillary or context-specific endpoints rather than a singular longevity metric. Collectively, these studies span cardiovascular, renal, metabolic, and orthopedic domains, establishing that ARB-related interventions have been tested across diverse clinical contexts with mixed but informative outcomes.\n\nMechanistically, the evidence reveals that ARBs and ARNI operate through distinct but overlapping pathways that extend beyond blood pressure lowering to affect cardiac remodeling, endothelial function, and metabolic regulation.\n\nPreclinical data from Karanovic 2026 demonstrated in hypertensive rats with focal segmental glomerulosclerosis that olive leaf extract added to losartan improved Klotho/Wnt/β-catenin signaling, implicating renin-angiotensin system modulation in renal protective pathways.\n\nSchwartz 2025 mechanistic investigation confirmed that losartan improved microvascular endothelial function via nitric oxide-dependent mechanisms in women with preeclampsia history, providing a biological substrate for cardiovascular protection beyond antihypertensive effects.\n\nGomaz 2026 randomized trial of telmisartan versus other antihypertensives in diabetic hypertension reported P = 0.001 for cardiometabolic and vascular outcome differences, suggesting ARB-specific pleiotropic metabolic effects.\n\nWithin the corpus, a tension exists between studies reporting clear dose-dependent effects and those focusing on bioequivalence where the primary outcome is pharmacokinetic parameter equivalence.\n\nThe intervention involved standard therapeutic dosing of telmisartan over a defined trial period, with the analysis centering on changes in circulating inflammatory biomarkers as exploratory endpoints.\n\nQuantitative findings from the reviewed trial indicate notable changes in inflammatory markers. These reductions in hsCRP and IL-6, two key markers of chronic low-grade inflammation, are mechanistically relevant to longevity as inflammaging is a hallmark of biological aging.\n\nQuantitative findings from this trial are characterized by a mixture of null and highly significant results across different measured endpoints. However, other endpoints demonstrated strong statistical significance, with P < 0.0001 and P < 0.001 reported. The full distribution of per-study endpoint evidence, including the specific biomarkers associated with these p-values, is detailed in Table 2.\n\nMechanistically, the observation that telmisartan alters systemic inflammation and the renin-angiotensin system aligns with the proposed pathway whereby ARBs could modulate aging-related processes. The renin-angiotensin system is a key regulator of vascular tone, inflammation, and oxidative stress, all of which are implicated in cellular senescence and organismal aging. This clinical RCT provides human evidence that an ARB intervention can impact these pathways, offering a plausible link between the pharmacological action of telmisartan and potential longevity-related benefits mediated through immune and inflammatory modulation.\n\nA tension within this outcome class arises from the mixed pattern of statistical results observed in a single trial. While some endpoints reached high statistical significance, others did not, suggesting that the anti-inflammatory effect of telmisartan may be context-dependent or specific to certain biomarkers. The absence of corroborating large-scale human RCTs for this specific outcome class means the evidence remains preliminary, with the boundary conditions for a consistent immunomodulatory effect yet to be fully established.\n\n#### Longevity Outcomes\n\nThe evidence base for angiotensin receptor blockers (ARBs) and longevity is derived from indirect sources, including a systematic review and meta-analysis on heart failure therapies (Wang 2026), observational cohort studies on medication adherence (Murray-Thomas 2025) and guideline-directed medical therapy (Jin 2025), and a pilot trial protocol for a polypill strategy (Agarwal 2025). No direct, randomized controlled trials isolating ARB monotherapy for a primary longevity endpoint were identified within this curated corpus. The population examined across these studies is adults with cardiovascular conditions such as heart failure or acute coronary syndrome, with outcomes typically assessed over hospital or follow-up periods rather than lifespan durations (Jin 2025; Murray-Thomas 2025). The primary endpoint across the relevant studies is mortality, encompassing in-hospital death and all-cause mortality linked to medication use (Jin 2025; Murray-Thomas 2025). The dosing of ARBs in these contexts is part of broader guideline-directed medical therapy regimens, not evaluated in isolation for longevity effects (Agarwal 2025; Jin 2025).\n\nQuantitative findings from the observational data show a strong association between medication non-adherence and adverse outcomes. This suggests that consistent use of guideline-directed therapy, which often incorporates ARBs, is critical for survival benefits. However, the specific contribution of ARBs cannot be disentangled from the multi-drug regimens studied (Murray-Thomas 2025). The Wang 2026 meta-analysis reports that SGLT2 inhibitors, a drug class often used alongside ARBs, significantly reduced cardiovascular death compared to placebo, but ARB-specific mortality effects within this comparison were not separately quantified in the provided excerpts (Wang 2026).\n\nMechanistically, the rationale linking ARBs to longevity centers on mitigating pathological angiotensin II signaling, which contributes to inflammation, fibrosis, and organ damage, thereby theoretically slowing age-related decline. The mechanistic substrate underlying this potential benefit is supported by the broader evidence on RAAS inhibition in cardiovascular disease, which forms the biological plausibility for trials like the HFrEF polypill pilot (Agarwal 2025). This pilot trial protocol (Agarwal 2025) includes losartan, an ARB, as one component of a multi-drug intervention aimed at improving heart failure outcomes, which are a major determinant of mortality. The systematic review by Wang 2026 synthesizes evidence on several advanced heart failure therapies, positioning ARBs as part of a foundational treatment landscape where survival benefits are mediated through integrated cardiovascular protection (Wang 2026). The evidence therefore points to a context-dependent effect, where ARBs may contribute to longevity by reducing mortality in specific high-risk cardiovascular populations as part of comprehensive care (Jin 2025; Murray-Thomas 2025).\n\nWithin the corpus, tensions in the longevity outcome class arise primarily from differences in effect certainty and directness. By contrast, the Agarwal 2025 polypill protocol represents a future interventional approach but does not yet report a definitive null or positive effect on longevity, reflecting an anticipated rather than an observed outcome (Agarwal 2025). In contrast, the observational cohort by Murray-Thomas 2025 demonstrates a clear, statistically significant negative consequence of ARB non-adherence on mortality (Murray-Thomas 2025). The Jin 2025 cohort study on guideline-directed therapy in acute coronary syndrome patients with renal dysfunction provides corroborating observational evidence for the importance of therapy adherence, aligning with Murray-Thomas 2025 in highlighting the role of medication use in survival, though specific effect sizes for ARBs remain unclear (Jin 2025). The Wang 2026 meta-analysis adds a layer of complexity by situating ARBs within a multi-therapy landscape where newer agents like SGLT2i show strong mortality benefits, potentially challenging the incremental longevity value of ARBs alone (Wang 2026).\n\n**Safety Outcomes.**\nThe quantitative findings from this trial indicate a statistically significant safety signal. The analysis comparing XXB750 to placebo yielded a P-value of 0.0038. The study population consisted of adults with heart failure on background RAS inhibitor therapy, providing a specific clinical context for this safety observation.\n\nMechanistically, the safety findings must be considered in light of the pharmacological milieu. Patients were already on background angiotensin-converting enzyme inhibitor or angiotensin receptor blocker treatment, meaning the safety signal for XXB750 was observed within a system already modulated by RAS blockade. The NPR1 agonist pathway represents a distinct mechanism from ARBs, and its safety profile when combined with existing inhibitors is a critical piece of translational data for understanding long-term tolerability.\n\nA tension exists in the broader interpretation of this safety data. The statistically significant P-value of 0.0038 points to a measurable difference between groups, yet the effect direction for this observational cohort was classified as unclear. This suggests that while a statistical association was detected, the clinical implication—whether the effect represents a beneficial safety profile or a concerning adverse signal—requires further elucidation through dedicated long-term outcome trials.\n\n#### Safety and Comorbidity Outcomes\n\nThe evidence base for safety and comorbidity outcomes associated with renin-angiotensin system modulation encompasses diverse study designs and patient populations. Observational cohort studies, including the DAPA-SRV trial, evaluated dapagliflozin in adults with systemic right ventricular dysfunction (Albertini 2025). The DIGIT-HHF trial characterized baseline characteristics of patients with advanced chronic heart failure in a randomized, double-blind, placebo-controlled design (Bavendiek 2025). Real-world analyses examined sacubitril/valsartan effectiveness in dialysis patients with heart failure with reduced ejection fraction, reporting on hospitalization and mortality endpoints (Tu 2026). Systematic reviews synthesized evidence on sacubitril/valsartan's impact on sleep-disordered breathing in chronic heart failure patients (Kuang 2025) and its efficacy in peritoneal dialysis populations (Silva 2026). Pharmacovigilance analyses based on the FDA Adverse Event Reporting System assessed renal failure risk (Wang 2025), while prospective protocols investigated ARBs in oncology contexts (Wang 2025c).\n\nQuantitative findings from the source corpus present a mixed safety profile. However, in dialysis patients with heart failure with reduced ejection fraction, the pooled odds ratio for mortality alone was not statistically significant, and the composite of mortality plus hospitalization for heart failure showed a similar pattern (Tu 2026). Pharmacovigilance data highlighted acute renal failure as a recognized adverse event, though findings from some studies indicated a comparable impact on renal function (Wang 2025).\n\nMechanistically, the observed functional and hemodynamic benefits align with pathways of neurohormonal modulation and cardiac remodeling. Reductions in AHI and improvements in oxygen saturation point to a potential role in mitigating comorbid sleep-disordered breathing, a common condition in heart failure (Kuang 2025). The significant decrease in NT-proBNP, a biomarker of cardiac wall stress, corroborates the hemodynamic benefits observed in dialysis populations (Silva 2026). These mechanistic human studies and clinical trial data provide a plausible substrate for the safety signals. However, the clinical significance of these changes for long-term survival and comorbidity reduction requires further contextualization.\n\nWithin the corpus, a notable tension exists regarding the net clinical benefit, particularly in advanced renal disease. Furthermore, pharmacovigilance reporting identified bleeding disorders as a newly recognized adverse event, with elevated PT/INR values observed within 14 days to four months of therapy initiation, even without anticoagulant medication (Al-Omari 2026). The contrast between positive signals from pooled analyses of selected trials and null or safety-concern signals from real-world cohorts and adverse event reports underscores the complexity of applying these therapies across heterogeneous patient populations. These disagreements highlight the need for careful patient selection and monitoring in clinical practice.\n\n#### Dosing and Pharmacokinetics Outcomes\n\nMei 2025 and Tian 2025 investigated the pharmacokinetics and bioequivalence of fixed-dose combination tablets containing valsartan and amlodipine in healthy Chinese subjects (Mei 2025, Tian 2025).\n\nHu 2025 similarly assessed bioequivalence and food effects for two fixed-dose combination formulations of telmisartan-hydrochlorothiazide in Chinese healthy subjects (Hu 2025).\n\nGoh 2026 evaluated the pharmacokinetic profile of a triple fixed-dose combination of ezetimibe, rosuvastatin, and telmisartan (10/20/80 mg) against coadministration of separate tablets in healthy participants (Goh 2026).\n\nMechanistically, the pharmacokinetic data from these studies support the development of fixed-dose combinations to improve patient adherence and simplify treatment regimens. The bioequivalence studies by Mei 2025, Tian 2025, Hu 2025, and Goh 2026 provide the foundational evidence for such formulations, ensuring comparable systemic exposure to the individual components (Mei 2025, Tian 2025, Hu 2025, Goh 2026). Preclinical and human data suggest that optimized dosing can achieve target receptor blockade while potentially minimizing off-target effects, a principle supported by the dose-dependent findings reported in the retrospective analysis by Kato 2025 on sacubitril/valsartan in heart failure (Kato 2025).\n\nKato 2025 identified dose-dependent renoprotective effects of sacubitril/valsartan, with significant differences in proteinuria status between dose groups (P < 0.05, P < 0.001) (Kato 2025).\n\nBy contrast, the bioequivalence studies by Mei 2025 and Goh 2026 are designed to demonstrate pharmacokinetic similarity rather than clinical superiority, reporting effect directions as null (Mei 2025, Goh 2026).\n\nDosing and Pharmacokinetics is retained as a separate Results slice (n=7; null signal in 4/7 sources; 7 indirect; no direct clinical anchor) and is not pooled into adjacent endpoint classes.\n\n#### Immune Outcomes\n\nA systematic review of these secondary outcomes identified a study examining telmisartan's anti-inflammatory potential compared to other antihypertensives, focusing on adults with relevant comorbidities (Gomaz 2025).\n\nMechanistically, the observed reductions in hsCRP and IL-6 align with the proposed anti-inflammatory pleiotropic effects of certain ARBs, particularly telmisartan, which may involve modulation of the nuclear factor-kappa B (NF-κB) pathway and peroxisome proliferator-activated receptor gamma (PPARγ) activation (Gomaz 2025). By attenuating this chronic inflammatory milieu, ARBs could theoretically slow the progression of age-related diseases such as atherosclerosis, sarcopenia, and neurodegeneration, which are driven by systemic inflammation. This provides a plausible biological link between the drug class and potential longevity benefits.\n\nDespite these positive mechanistic signals, the evidence base for immune-related longevity outcomes remains limited and contextual. The reviewed findings are derived from secondary endpoint analyses in trials not primarily designed to assess longevity, and the clinical significance of the magnitude of biomarker change is not established (Gomaz 2025). Furthermore, the broader synthesis indicates that positive signals for ARBs in longevity are often context-dependent and may not translate to hard clinical endpoints like mortality, highlighting the tension between biomarker improvement and definitive survival benefit.\n\nImmune is retained as a separate Results slice (n=1; mixed signal in 1/1 sources; not classified; no direct clinical anchor) and is not pooled into adjacent endpoint classes.\n\n#### Immune and Inflammation Outcomes\n\n**Immune and Inflammation Outcomes.**\nThe evidence base for immune and inflammatory outcomes in the context of ARBs and longevity is anchored by a single randomized, double-blinded, placebo-controlled pilot clinical trial. Lu 2025 reported. The trial population consisted of adults in an observational cohort design, assessing changes in systemic inflammation and the renin-angiotensin system. This study provides the primary direct evidence from a controlled human intervention relevant to this outcome class.\n\nImmune and Inflammation remains a separate Results slice (n=1; claims=30; null signal in 1/1 sources; 1 indirect; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.\n\n#### Mortality and Survival Outcomes\n\n**Mortality and Survival Outcomes.**\nThe evidence base for ARBs and mortality or survival outcomes is drawn from a large-scale network meta-analysis examining medical therapies for subthreshold abdominal aortic aneurysm (AAA) growth and associated death (Lu 2026). The study design was a network meta-analysis synthesizing multiple randomized controlled trials, providing a comprehensive overview of mortality endpoints in this specific vascular context (Lu 2026). The analysis reported multiple p-values across different endpoints and comparisons, reflecting the heterogeneity of effects within the pooled trials (Lu 2026).\n\nQuantitative findings from this network meta-analysis revealed a mixed pattern of results for mortality-related endpoints. The overall direction of effect for ARBs in this AAA context was negative, suggesting no clear mortality benefit (Lu 2026). The heterogeneity of these p-values underscores the complexity of translating vascular-specific outcomes to a general longevity claim.\n\nMechanistically, the negative signal for mortality in the AAA cohort may relate to the specific pathophysiology of aneurysm progression rather than a general effect on aging (Lu 2026). The lack of a clear survival benefit from ARBs in this vascular context contrasts with theoretical anti-aging pathways, such as reductions in oxidative stress or inflammation, that are hypothesized to extend lifespan. The clinical RCT evidence synthesized here does not support a mortality-reducing role for ARBs in adults with subthreshold AAA, a finding that stands in tension with broader longevity hypotheses. Preclinical data suggesting ARB-mediated lifespan extension in model organisms have not translated into a consistent mortality signal in this human clinical dataset.\n\nWithin the corpus, the mortality and survival data present a point of tension. The Lu 2026 network meta-analysis, which synthesizes direct clinical RCT evidence, reports a negative overall effect direction for ARBs on mortality endpoints in its specific population (Lu 2026). This finding contrasts with the broader thesis that ARBs may have anti-aging properties. The specific p-values reported, ranging from highly significant to clearly null, indicate that any effect is highly context-dependent and not uniform across trials or comparisons. The boundary conditions for a potential ARB mortality benefit, if one exists, remain to be established outside the studied AAA population.\n\nMortality and Survival remains a separate Results slice (n=1; claims=54; negative signal in 1/1 sources; 1 review; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.\n\n#### Safety Outcomes\n\nSafety remains a separate Results slice (n=1; claims=336; unclear signal in 1/1 sources; 1 indirect; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes.\n\n### Cross-Domain Synthesis\n\nThe most severe tension in the corpus is the direct contradiction between blood-pressure efficacy studies and the claimed anti-aging benefit of ARBs, revealing a fundamental disconnect between the primary pharmacological action of these agents and any longevity rationale. On one hand, Chung 2024 demonstrates clear efficacy in a non-responder population, where an olmesartan/amlodipine combination achieved highly significant reductions in 24-hour mean systolic blood pressure (P < 0.001) compared to failing monotherapy with valsartan or candesartan. The mechanism-level reason for this tension likely involves the choice of active comparator and the specific endpoint measured; amlodipine is a potent vasodilator, and non-inferiority studies against it demand a high bar for diastolic pressure control, whereas the significance found by Chung 2024 was for systolic pressure in a broader, less differentiated population. The boundary condition is that monotherapy ARBs are consistently better than placebo for blood pressure, but in direct head-to-head comparisons against other first-line agents or in fixed-dose combination studies, their unique benefit is difficult to isolate, and effects on mortality or longevity endpoints are not reliably demonstrated by this evidence alone. The critical evidence gap is the absence of an RCT demonstrating that ARB-induced blood pressure control translates to superior longevity outcomes compared to an alternative agent that achieves identical blood pressure reduction; this remains the central, unresolved question for the longevity hypothesis.\n\nAnother major tension exists between the clear surrogate-marker benefits seen in heart failure and cardiometabolic cohorts versus the highly uncertain effect on hard survival endpoints. Taha 2025 provides a strong signal for the surrogate, reporting that in acute decompensated heart failure, ARNI use significantly reduced a composite of rehospitalization and all-cause mortality (RR: 0.71, 95% CI: 0.57-0.88; P < 0.01), alongside separate reductions in HF rehospitalization. The mechanistic disagreement arises because the benefit of ARBs and ARNIs appears to be most robust in populations with an activated renin-angiotensin system and preserved organ function, whereas in the dialysis cohort, advanced renal disease may drastically alter drug metabolism and limit the protective signaling through the AT1 receptor. The boundary condition is that the survival benefit is most strongly supported in non-renal-impaired HFrEF populations, but the effect attenuates or disappears in end-stage renal disease, suggesting that the longevity benefit is context-dependent on renal function. To resolve this, we would need RCTs powered for mortality in CKD stage 4-5 and dialysis populations, where the current evidence offers only uncertain estimates.\n\nA fundamental cross-domain tension exists between the modest mechanistic evidence for ARBs and the hard-mortality survival data that could justify a longevity claim, a gap that preclinical and inflammatory studies fail to bridge. Karanovic 2026 provides a mechanistic signal: in a hypertensive rat model with focal segmental glomerulosclerosis, olive leaf extract added to losartan improved Klotho/Wnt/β-catenin signaling, suggesting a pathway through which ARBs might modulate aging-related biology in a preclinical context. However, neither study measures a lifespan or healthspan endpoint; the Lu 2025 trial demonstrated a biological effect on the RAS axis, but this is a surrogate for anti-inflammatory action, not a direct measure of longevity. The tension is that this mechanistic plausibility coexists with highly uncertain hard-outcome data. Jin 2025 examines guideline-directed medical therapy (including ARBs) in acute coronary syndrome patients with advanced renal dysfunction and reports an unclear effect on in-hospital mortality, while Murray-2025 shows that non-adherence to ARBs is associated with worse outcomes (P < 0.001 for both mortality and hospitalization), but this is an observational association that cannot distinguish the drug's effect from the overall health behavior of the adherent cohort. The boundary condition is that the mechanistic data supports a biological rationale for a longevity effect in specific organ systems (kidney, vasculature), but the translation to human lifespan extension requires evidence that is currently missing from the corpus. The critical evidence gap is a large, long-duration RCT with mortality or healthspan as a primary endpoint in a general, non-heart-failure population, which remains a massive hole in the evidence base.\n\nAnother tension concerns the conflicting signals on renal protection versus safety, where some evidence suggests a benefit for kidney function while other evidence raises concerns about safety in renally-impaired populations. Kato 2025 demonstrates dose-dependent renoprotective effects of sacubitril/valsartan in heart failure, showing that the drug's impact on proteinuria and renal parameters differs significantly based on dose (P < 0.05), which is a positive signal for the longevity rationale since preserved renal function is a key component of healthspan. In contrast, Wang 2025 raises a safety flag through a pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS), identifying acute renal failure as an associated adverse event with sacubitril/valsartan. This creates a mechanistic disagreement: the drug's beneficial modulation of the renin-angiotensin system may be nephroprotective at the structural level in stable heart failure, but its hemodynamic effects can precipitate acute injury in vulnerable kidneys, particularly those with baseline renal dysfunction. The boundary condition for this tension is the severity of pre-existing renal impairment; in patients with CKD stage 3 or stable proteinuria, the long-term renoprotective signal may dominate, but in those with advanced CKD (e.g., on dialysis), the acute hemodynamic risks may outweigh any structural benefit. The evidence required to resolve this is a dedicated renal-outcome RCT stratifying by baseline eGFR, which is currently absent, leaving the renal benefit-versus-risk calculus unresolved for the longevity application.\n### Endpoint-Sensitivity Framework\n\nWe operationalize an Endpoint-Sensitivity framework for this corpus: the evidence should be interpreted along a gradient from proximal pathway effects, through intermediate functional or biomarker endpoints, to distal clinical outcomes.\n\nThe included evidence base contains direct, indirect, mechanistic evidence, so the manuscript should not collapse mechanistic plausibility and clinical efficacy into one verdict.\n\nThe framework is useful here because the matrix contains null-vs-positive tensions that can otherwise be mistaken for simple inconsistency.\n\nA falsifying test would be a direct clinical trial in the same dosing context that shows concordant movement across pathway markers, functional endpoints, and distal clinical outcomes; discordance across those layers would preserve the framework.\n\nThis is a paper-level organizing claim, not an added source: it can guide interpretation only where the underlying evidence record already supplies support.\n\n### Discussion\n\n**Thesis:** Across 71 curated reference papers, the evidence base for ARBs longevity shows a context-dependent profile. Positive signals appear in: contextual other, safety comorbidity. Negative signals appear in: cardiometabolic, mortality survival. Null findings dominate: contextual other, safety comorbidity. The synthesis surfaces 665 non-orthogonal tensions across outcome classes — see Cross-Domain Synthesis. The ARBs longevity anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.\n\nThe interpretation remains cautious, limited, and context-dependent because the accepted evidence spans different populations, outcomes, and evidence tiers.\n\n#### Evidence Summary\n\nThe evidence base for this synthesis comprises 71 included sources. By directness, the breakdown is: indirect (n=48), review (n=21), direct (n=1), mechanistic (n=1). 43 of 71 sources carry at least one p-value in their bound claims, providing the quantitative basis for the effect-direction conclusions argued above. The source-tier mapping matters because direct clinical trials, indirect clinical evidence, reviews, and mechanistic papers carry different interpretive weight.\n\nPopulations covered span 1 distinct summaries across the source set: adults. This cross-population view is the evidentiary backstop for any claim about generalizability in the narrative discussion above. Where the paper argues a boundary condition by population, this enumeration documents which sources the boundary draws from.\n\n#### Interpretation constraints\n\nThe discussion interprets evidence boundaries rather than converting every extracted result into a recommendation. The corpus contains heterogeneous designs, populations, follow-up windows, and measurement strategies, so the central question is whether findings travel across contexts without losing their meaning. Clinical directness, outcome proximity, consistency of effect direction, and biological plausibility are therefore weighed together. Where those features align, the synthesis may support stronger inference; where they diverge, the paper keeps the conclusion conditional and treats the gap as a research-design problem for future work.\n\nThe source set also warrants a cautious distinction between statistical signal and aging relevance. A result can be numerically strong while remaining indirect for healthspan, frailty, disability, cognition, or mortality. Conversely, a mechanistic result can be consistent with an aging hypothesis while remaining limited as clinical evidence. This is why evidence tier, directness, outcome class, and effect direction are interpreted separately.\n\nThe most decision-relevant uncertainty is context-dependent. If direct human evidence clusters around the same outcome class, the synthesis treats that cluster as the strongest basis for practical inference. If the signal appears only in reviews, indirect cohorts, preclinical models, or mixed populations, the paper marks the claim as preliminary. If the matrix contains disagreements inside the same outcome class, the safer reading is not that one paper cancels another, but that eligibility, dose, comparator, endpoint definition, or follow-up duration might be controlling the observed effect. Those unresolved modifiers remain to be tested rather than assumed away.\n\nThe key interpretive question is not whether the topic looks promising; it is whether the strongest claim stays inside what the sources can support. This anchor therefore avoids adding new empirical claims. It summarizes the evidence structure already present in the corpus: how many sources were accepted, how those sources were tiered, how often statistical values were available, and which population summaries were documented. That keeps the Discussion section tied to the source record when the evidence base is broad but uneven.\n\nThe resulting stance is deliberately conservative. Positive signals are described as suggestive unless they are supported by direct, clinically proximate, source-traced sources. Null or mixed signals are not discarded; they define boundary conditions. Mechanistic findings are used to explain plausible pathways, not to substitute for outcome evidence. Safety and tolerability signals remain part of the interpretation even when efficacy signals dominate the narrative. This cautious framing prevents a dense corpus from becoming an overconfident manuscript.\n\nThis section also constrains how readers should use the paper. It is not a treatment guideline, a pooled efficacy estimate, or a claim that all source classes have equal evidentiary weight. It is a structured map of what the current corpus can and cannot justify. The strongest claims should come from direct human sources with traceable numerics and aligned outcomes. Weaker claims should remain explicitly limited to hypothesis generation, mechanism explanation, or corpus-gap identification. When future retrieval adds new sources, the interpretation can change without changing the evidentiary standard. The most useful reading is therefore comparative: which outcomes have direct human support, which outcomes are inferred from adjacent disease populations, and which outcomes remain primarily mechanistic.\n\nAccordingly, the practical conclusion remains bounded by replication, population fit, and endpoint fit. A result that appears robust in one subgroup might not transfer to another subgroup with different baseline risk, adherence, comparator choice, or outcome ascertainment. A result that is consistent with biological plausibility might still be limited by short follow-up or indirect measurement. These caveats are not decorative hedges; they are the conditions under which the synthesis remains reproducible, falsifiable, and safe to reuse across topics. The anchor also states what the paper does not know: whether longer follow-up, different eligibility criteria, stronger adherence, or more clinically proximate endpoints would change the synthesis. That uncertainty should remain visible in every topic until the source set directly resolves it, and it should keep downstream conclusions provisional when the corpus is broad but still uneven across designs, outcomes, or populations.\n\n**Resolution criteria:** The thesis would be reinforced by adequately powered trials with pre-specified clinical endpoints, ≥2-year follow-up, intention-to-treat and per-protocol analyses, and concurrent biomarker plus functional measurement. It would be falsified by replicated null findings on those endpoints or by demonstration that any short-term benefit reverses on intervention withdrawal.\n### Limitations\n\n**Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.\n\nThe curated corpus is dominated by studies of heart failure, hypertension, and diabetic nephropathy populations; consequently, no trial in this corpus was designed to test the hypothesis that angiotensin receptor blockers (ARBs) extend healthy lifespan in the general adult population without established cardiovascular or renal disease. The only longevity-relevant signals (Jin 2025; Murray-Thomas 2025; Wang 2026) derive from observational cohorts or meta-analytic syntheses in cardiorenal populations, not from a prospective mortality-mortality RCT in community-dwelling adults. This means the headline anti-aging claim remains unsupported by direct human evidence within the curated set, limiting conclusions to a mechanistic-to-clinical extrapolation rather than a confirmed survival benefit. The absence of any long-term all-cause mortality RCT in non-diabetic, non-hypertensive adults is the single largest gap in the evidence base.\n\nSeveral outcome domains are represented by only a single source, making within-corpus replication impossible. For instance, the cognitive endpoint of mild cognitive impairment or dementia is addressed solely by Derington 2025, an observational analysis of SPRINT participants. Similarly, the colorectal cancer risk signal comes from a single retrospective study (Rezazadeh 2025), and the inflammatory-marker reduction in post-preeclamptic women is based on one small placebo-controlled trial (Schwartz 2025). When an effect direction—positive, negative, or null—is derived from a single study, the synthesis cannot assess consistency across independent cohorts, and any apparent signal may reflect study-specific confounders rather than a robust drug class effect.\n\nThe enrolled populations skew toward middle-aged and older adults with established disease—mean ages in the 60s with high prevalence of hypertension, heart failure, or diabetes—while younger adults and those without comorbidity are largely absent. Two dosing-optimization studies recruited exclusively healthy Chinese volunteers (Mei 2025; Tian 2025), but these were pharmacokinetic bioequivalence trials, not clinical-efficacy studies, and thus do not inform the longevity question in healthy populations. External validity is further constrained by geographic concentration: multiple trials recruited from single centres or single countries (e.g., Japan, Singapore, Jordan), and none in the corpus is a multi-national, long-duration survival trial with diverse ethnic representation. Conclusions therefore cannot be generalized to younger, healthier, or non-Asian populations without additional evidence.\n\nNo source in the curated set reports a hard survival endpoint—total mortality or mortality-plus-hospitalisation—as a pre-specified primary outcome in a dedicated ARB-versus-placebo longevity trial. The longevity outcome class yields only three sources (Jin 2025; Murray-Thomas 2025; Wang 2026), all of which assess mortality as a secondary or exploratory outcome within heart-failure or acute-coronary-syndrome cohorts, not as a longevity-specific endpoint in the general population. Furthermore, the mechanistic evidence for anti-aging effects—such as Klotho/Wnt/β-catenin signaling modulation—is restricted to a single preclinical study in hypertensive rats with focal segmental glomerulosclerosis (Karanovic 2026), and the translation from rodent renal histology to human lifespan extension remains untested. The synthesis therefore cannot bridge the gap between plausible molecular mechanisms and demonstrated clinical survival benefit using the current corpus alone.\n\n### Conclusion\n\nThe final interpretation is deliberately tiered. Arbs Longevity has a biologically plausible geroscience rationale and selected clinical signals, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence.\n\nThe strongest interpretation is that positive signals in contextual adjacent evidence, safety and comorbidity, cardiometabolic coexist with null signals in contextual adjacent evidence, safety and comorbidity, cardiometabolic and negative signals in cardiometabolic, mortality and survival. That profile supports further targeted research and careful hypothesis refinement, not unqualified clinical or public-health claims.\n\nThe current corpus may support arbs longevity as a general health or lifestyle intervention where otherwise indicated, but does not justify marketing it as a standalone geroprotective or anti-aging intervention with proven hard-longevity effects. The safer translation path is a registered trial that specifies the endpoint layer in advance, pairs dosing with monitoring for metabolic and immune safety, and reports null or adverse signals with the same visibility as favorable results.\n\nAdditional corpus sources included animal/preclinical evidence; future work should prioritize studies that connect mechanistic studies (Karanovic 2026) to direct clinical outcomes represented by Yu 2025. Until that bridge is stronger, arbs longevity remains a promising but bounded geroscience case whose most useful contribution is to define the next trial rather than to justify current clinical adoption.\n\nThe decisive unresolved question is not whether the intervention can move selected biomarkers or pathway markers, but whether those changes improve durable human function without offsetting harm, adherence failure, or loss in another clinically relevant domain. That question should set the bar for future claims, clinical translation, future study design, and any public recommendation.\n\n### What This Synthesis Adds\n\nThis synthesis maps 71 included sources on ARBs longevity across 9 outcome classes and 665 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.\n\nAcross 71 curated reference papers, the evidence base for ARBs longevity shows a context-dependent profile. Positive signals appear in: contextual other, safety comorbidity. Negative signals appear in: cardiometabolic, mortality survival. Null findings dominate: contextual other, safety comorbidity. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The ARBs longevity anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.\n\nThe strongest unresolved contrast is the disagreement between Chung 2024 and Yamamoto 2024 on cardiometabolic (severity 5/5), which defines the boundary condition future studies must test rather than smooth over.\n\nPrior reviews in the corpus (Wang 2026, Filipova 2020, Abhari 2026, Silva 2026, Shubietah 2026) emphasize convergent signals on ARBs longevity. This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.\n\n#### Boundary-Condition Matrix\n\n| Outcome class | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |\n|---|---:|---:|---|---|\n| longevity | 0 | 4 | null, unclear | direct clinical gap |\n| cardiometabolic | 0 | 13 | mixed, negative, null, positive, unclear | conflict-resolution gap |\n| safety | 0 | 1 | unclear | direct clinical gap |\n| immune | 0 | 1 | unclear | direct clinical gap |\n| dosing and pharmacokinetics | 0 | 7 | null, unclear | direct clinical gap |\n| safety and comorbidity | 0 | 9 | null, positive | direct clinical gap |\n| immune and inflammation | 0 | 1 | null | direct clinical gap |\n| mortality and survival | 0 | 1 | negative | direct clinical gap |\n| contextual adjacent evidence | 1 | 33 | mixed, null, positive, unclear | conflict-resolution gap |\n\n#### Evidence-Gap Priority\n\n| Priority | Gap | Rationale |\n|---|---|---|\n| P1 | longevity: direct clinical gap | 0 direct and 4 indirect sources; direction profile: null, unclear |\n| P2 | cardiometabolic: conflict-resolution gap | 0 direct and 13 indirect sources; direction profile: mixed, negative, null, positive, unclear |\n| P3 | safety: direct clinical gap | 0 direct and 1 indirect source; direction profile: unclear |\n| P4 | immune: direct clinical gap | 0 direct and 1 indirect source; direction profile: unclear |\n| P5 | dosing and pharmacokinetics: direct clinical gap | 0 direct and 7 indirect sources; direction profile: null, unclear |\n\n#### Next-Study Design Recommendation\n\nThe next high-yield study for ARBs longevity should target the **longevity** evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction.\n\n### Structured Evidence Tables\n\n*The following tables present the structured evidence summary referenced throughout this paper. Numbers live in the tables; prose references them. Tables 1-3 cover included studies, per-study endpoint evidence, and cross-domain tensions; Table 4 is a supplemental design-level evidence weighting heuristic; Table 5 surfaces the underlying per-paper numeric index.*\n\n### Table 1: Included Studies\n\n| Citation | Design | Tier | N | Population | Endpoint | Direction | Directness | Trial ID | Representative p-value | n claims |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Solomon 2026 | Observational | B2 | — | adults | safety | unclear | indirect | — | P = 0.0038 | 336 |\n| Din 2026 | Observational | B2 | — | adults | cardiometabolic | null | review | — | P < 0.05 | 190 |\n| Li 2025 | Observational | B2 | — | — | contextual other | null | review | — | P = 0.001 | 163 |\n| Chung 2024 | Observational | B2 | — | adults | cardiometabolic | positive | indirect | — | P < 0.001 | 140 |\n| Mei 2025 | Observational | B2 | — | adults | dosing pharmacokinetics | null | indirect | — | — | 140 |\n| Taha 2025 | Observational | B2 | — | adults | contextual other | positive | review | — | P < 0.0001 | 115 |\n| Tian 2025 | Observational | B2 | — | adults | dosing pharmacokinetics | unclear | indirect | — | — | 113 |\n| Yamamoto 2024 | Observational | B2 | — | adults | cardiometabolic | negative | review | — | P = 0.003 | 105 |\n| Lee 2025 | Observational | B2 | — | adults | contextual other | mixed | indirect | — | P = 0.006 | 99 |\n| Senanayake 2026 | Observational | B2 | — | adults | contextual other | null | indirect | — | — | 93 |\n| Ahn 2026 | Observational | B2 | — | adults | dosing pharmacokinetics | null | indirect | — | P = 0.01 | 93 |\n| Yu 2025 | RCT (clinical) | A1 | — | adults | contextual other | null | direct | — | P = 0.002 | 88 |\n| Derington 2025 | Observational | B2 | — | adults | contextual other | unclear | indirect | — | — | 85 |\n| Campbell 2025 | Observational | B2 | — | adults | dosing pharmacokinetics | unclear | indirect | NCT00933231 | — | 84 |\n| Alqaisi 2025 | Observational | B2 | — | adults | contextual other | unclear | indirect | — | P < 0.001 | 82 |\n| Savarese 2026 | Observational | B2 | — | adults | contextual other | unclear | indirect | — | P = 0.01 | 80 |\n| Goh 2026 | Observational | B2 | — | adults | dosing pharmacokinetics | null | indirect | — | — | 78 |\n| Wang 2026 | Review / meta-analysis | B1 | — | — | longevity | unclear | review | — | — | 76 |\n| Albertini 2025 | Observational | B2 | — | adults | safety comorbidity | null | indirect | — | P < 0.001 | 74 |\n| Jo 2025 | Observational | B2 | — | adults | contextual other | unclear | indirect | — | P = 0.01 | 70 |\n| Nouhravesh 2025 | Observational | B2 | — | adults | contextual other | null | indirect | — | P = 0.015 | 70 |\n| Bavendiek 2025 | Observational | B2 | — | adults | safety comorbidity | null | review | — | — | 69 |\n| Mosepele 2025 | Observational | B2 | — | adults | cardiometabolic | null | indirect | — | P < 0.001 | 62 |\n| Takahashi 2025 | Observational | B2 | — | adults | contextual other | null | indirect | — | P = 0.016 | 61 |\n| Kehoe 2026 | Observational | B2 | — | adults | contextual other | unclear | indirect | NCT04212650 | — | 61 |\n| Filipova 2020 | Review / meta-analysis | B1 | — | adults | cardiometabolic | negative | review | — | P < 0.001 | 60 |\n| Wever 2025 | Observational | B2 | — | adults | cardiometabolic | unclear | indirect | — | — | 57 |\n| Pietro 2024 | Observational | B2 | — | adults | contextual other | null | indirect | — | P < 0.0001 | 55 |\n| Omland 2025 | Observational | B2 | — | adults | contextual other | null | indirect | — | — | 55 |\n| Humphreys 2025 | Observational | B2 | — | adults | contextual other | null | indirect | — | — | 55 |\n| Lu 2026 | Observational | B2 | — | adults | mortality survival | negative | review | — | P < 0.00001 | 54 |\n| Abhari 2026 | Review / meta-analysis | B1 | — | — | cardiometabolic | unclear | review | — | — | 53 |\n| Wang 2026b | Observational | B2 | — | — | contextual other | null | review | — | P < 0.001 | 53 |\n| Yang 2025 | Observational | B2 | — | adults | contextual other | unclear | indirect | — | P = 0.001 | 51 |\n| Yan 2025 | Observational | B2 | — | adults | cardiometabolic | mixed | indirect | — | P < 0.001 | 47 |\n| Han 2026 | Observational | B2 | — | adults | contextual other | null | indirect | — | P < 0.001 | 47 |\n| Hu 2025 | Observational | B2 | — | adults | dosing pharmacokinetics | null | indirect | — | — | 42 |\n| Tu 2026 | Observational | B2 | — | adults | safety comorbidity | positive | indirect | — | P < 0.001 | 42 |\n| Shaddy 2025 | Observational | B2 | — | adults | contextual other | null | indirect | — | P < 0.0001 | 41 |\n| Jia 2025 | Observational | B2 | — | adults | contextual other | null | indirect | — | — | 40 |\n| Kario 2024 | Observational | B2 | — | adults | cardiometabolic | null | review | — | — | 39 |\n| Schwartz 2025 | Observational | B2 | — | adults | contextual other | positive | indirect | — | P < 0.001 | 38 |\n| Kuang 2025 | Observational | B2 | — | — | safety comorbidity | null | review | — | P < 0.001 | 38 |\n| Jin 2025 | Observational | B2 | — | adults | longevity | unclear | indirect | — | — | 38 |\n| Murray-Thomas 2025 | Observational | B2 | — | adults | longevity | unclear | indirect | — | P < 0.001 | 36 |\n| Nouhravesh 2025b | Observational | B2 | — | adults | contextual other | null | indirect | — | P = 0.14 | 35 |\n| Kim 2025 | Observational | B2 | — | adults | contextual other | null | review | — | P = 0.527 | 35 |\n| Gomaz 2026 | Observational | B2 | — | adults | contextual other | mixed | indirect | — | P = 0.001 | 34 |\n| Chimura 2025 | Observational | B2 | — | adults | contextual other | unclear | indirect | — | P < 0.001 | 33 |\n| Silva 2026 | Review / meta-analysis | B1 | — | — | safety comorbidity | positive | review | — | P < 0.0001 | 33 |\n| Pepine 2026 | Observational | B2 | — | adults | contextual other | positive | review | — | P < 0.0001 | 32 |\n| Lu 2025 | Observational | B2 | — | adults | immune inflammation | null | indirect | — | P < 0.0001 | 30 |\n| Fumarulo 2025 | Observational | B2 | — | adults | contextual other | null | indirect | — | — | 27 |\n| Dou 2025 | Observational | B2 | — | — | contextual other | unclear | review | — | P = 0.001 | 27 |\n| Ngai 2025 | Observational | B2 | — | adults | safety comorbidity | null | indirect | NCT03643965 | — | 26 |\n| Rezazadeh 2025 | Observational | B2 | — | adults | contextual other | unclear | indirect | — | — | 25 |\n| Nazari-Robati 2025 | Observational | B2 | — | adults | contextual other | null | indirect | — | P < 0.001 | 24 |\n| Asim 2025 | Observational | B2 | — | adults | cardiometabolic | negative | indirect | — | P = 0.0004 | 24 |\n| Odeh 2026 | Observational | B2 | — | adults | contextual other | null | indirect | — | P = 0.001 | 22 |\n| Wang 2025 | Observational | B2 | — | adults | safety comorbidity | null | indirect | — | — | 20 |\n| Ramaswamy 2025 | Observational | B2 | — | adults | contextual other | null | indirect | — | P > 0.05 | 19 |\n| Yang 2025b | Observational | B2 | — | — | cardiometabolic | negative | review | — | P < 0.00001 | 17 |\n| Kato 2025 | Observational | B2 | — | adults | dosing pharmacokinetics | unclear | indirect | — | P < 0.001 | 16 |\n| Agarwal 2025 | Observational | B2 | — | adults | longevity | null | indirect | — | — | 15 |\n| Wang 2025b | Observational | B2 | — | — | cardiometabolic | null | review | — | — | 13 |\n| Zhao 2025 | Observational | B2 | — | adults | contextual other | null | review | — | P < 0.05 | 12 |\n| Karanovic 2026 | Preclinical (animal/in vitro) | C1 | — | adults | contextual other | null | mechanistic | — | — | 12 |\n| Wang 2025c | Observational | B2 | — | adults | safety comorbidity | null | indirect | — | — | 6 |\n| Shubietah 2026 | Review / meta-analysis | B1 | — | adults | cardiometabolic | null | review | — | — | 6 |\n| Al-Omari 2026 | Observational | B2 | — | adults | safety comorbidity | null | indirect | — | — | 3 |\n| Gomaz 2025 | Review / meta-analysis | B1 | — | adults | immune | unclear | review | — | — | 2 |\n\n### Table 2: Per-Study Endpoint Evidence\n\nAdditional corpus sources included animal/preclinical evidence; | Endpoint | Study | p/CI | Direction | Directness | Tier | Interpretation |\n| --- | --- | --- | --- | --- | --- | --- |\n| safety | Solomon 2026 | P = 0.0038 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| safety | Solomon 2026 | P = 0.0038 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| cardiometabolic | Din 2026 | P < 0.05 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| cardiometabolic | Din 2026 | P < 0.05 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| cardiometabolic | Din 2026 | P > 0.05 | null summary | review | B2 | reported statistic; source summary remains null |\n| cardiometabolic | Din 2026 | P < 0.05 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| cardiometabolic | Din 2026 | P < 0.05 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| cardiometabolic | Din 2026 | P < 0.05 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| contextual other | Li 2025 | P = 0.001 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| contextual other | Li 2025 | P < 0.001 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| contextual other | Li 2025 | P = 0.001 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| contextual other | Li 2025 | P < 0.001 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| contextual other | Li 2025 | P = 0.016 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| contextual other | Li 2025 | P = 0.017 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| cardiometabolic | Chung 2024 | P < 0.001 | positive summary | indirect | B2 | reported statistic; source summary remains positive |\n| cardiometabolic | Chung 2024 | P < 0.001 | positive summary | indirect | B2 | reported statistic; source summary remains positive |\n| cardiometabolic | Chung 2024 | P < 0.001 | positive summary | indirect | B2 | reported statistic; source summary remains positive |\n| cardiometabolic | Chung 2024 | P = 0.126 | positive summary | indirect | B2 | reported statistic; source summary remains positive |\n| cardiometabolic | Chung 2024 | P = 0.307 | positive summary | indirect | B2 | reported statistic; source summary remains positive |\n| cardiometabolic | Chung 2024 | P = 0.35 | positive summary | indirect | B2 | reported statistic; source summary remains positive |\n| dosing pharmacokinetics | Mei 2025 | — | null | indirect | B2 | no significant effect on dosing pharmacokinetics |\n| contextual other | Taha 2025 | P < 0.01 | positive summary | review | B2 | reported statistic; source summary remains positive |\n| contextual other | Taha 2025 | P = 0.01 | positive summary | review | B2 | reported statistic; source summary remains positive |\n| contextual other | Taha 2025 | P = 0.048 | positive summary | review | B2 | reported statistic; source summary remains positive |\n| contextual other | Taha 2025 | P < 0.0001 | positive summary | review | B2 | reported statistic; source summary remains positive |\n| contextual other | Taha 2025 | P = 0.0001 | positive summary | review | B2 | reported statistic; source summary remains positive |\n| contextual other | Taha 2025 | P = 0.024 | positive summary | review | B2 | reported statistic; source summary remains positive |\n| dosing pharmacokinetics | Tian 2025 | — | unclear | indirect | B2 | unclear effect on dosing pharmacokinetics |\n| cardiometabolic | Yamamoto 2024 | P = 0.003 | negative summary | review | B2 | reported statistic; source summary remains negative |\n| cardiometabolic | Yamamoto 2024 | P = 0.637 | negative summary | review | B2 | reported statistic; source summary remains negative |\n| cardiometabolic | Yamamoto 2024 | P = 0.003 | negative summary | review | B2 | reported statistic; source summary remains negative |\n| contextual other | Lee 2025 | P = 0.762 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed |\n| contextual other | Lee 2025 | P = 0.006 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed |\n| contextual other | Lee 2025 | P = 0.571 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed |\n| contextual other | Lee 2025 | P = 0.006 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed |\n| contextual other | Lee 2025 | P = 0.016 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed |\n| contextual other | Lee 2025 | P = 0.014 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed |\n| contextual other | Senanayake 2026 | — | null | indirect | B2 | no significant effect on contextual other |\n| dosing pharmacokinetics | Ahn 2026 | P = 0.01 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| dosing pharmacokinetics | Ahn 2026 | P < 0.01 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| dosing pharmacokinetics | Ahn 2026 | P = 0.01 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| dosing pharmacokinetics | Ahn 2026 | P < 0.01 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| dosing pharmacokinetics | Ahn 2026 | P < 0.05 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| dosing pharmacokinetics | Ahn 2026 | P < 0.01 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Yu 2025 | P = 0.02 | significant statistic | direct | A1 | significant statistic; source-level direction remains null |\n| contextual other | Yu 2025 | P = 0.03 | significant statistic | direct | A1 | significant statistic; source-level direction remains null |\n| contextual other | Yu 2025 | P = 0.002 | significant statistic | direct | A1 | significant statistic; source-level direction remains null |\n| contextual other | Yu 2025 | P = 0.02 | significant statistic | direct | A1 | significant statistic; source-level direction remains null |\n| contextual other | Yu 2025 | P = 0.03 | significant statistic | direct | A1 | significant statistic; source-level direction remains null |\n| contextual other | Yu 2025 | P = 0.045 | significant statistic | direct | A1 | significant statistic; source-level direction remains null |\n| contextual other | Derington 2025 | — | unclear | indirect | B2 | unclear effect on contextual other |\n| dosing pharmacokinetics | Campbell 2025 | — | unclear | indirect | B2 | unclear effect on dosing pharmacokinetics |\n| contextual other | Alqaisi 2025 | P = 0.03 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Alqaisi 2025 | P = 0.03 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Alqaisi 2025 | P = 0.003 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Alqaisi 2025 | P = 0.53 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Alqaisi 2025 | P < 0.001 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Alqaisi 2025 | P = 0.86 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Savarese 2026 | P = 0.01 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Savarese 2026 | P = 0.1 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Savarese 2026 | P = 0.04 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| dosing pharmacokinetics | Goh 2026 | — | null | indirect | B2 | no significant effect on dosing pharmacokinetics |\n| longevity | Wang 2026 | — | unclear | review | B1 | unclear effect on longevity |\n| safety comorbidity | Albertini 2025 | P = 0.04 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| safety comorbidity | Albertini 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| safety comorbidity | Albertini 2025 | P = 0.02 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| safety comorbidity | Albertini 2025 | P = 0.04 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| safety comorbidity | Albertini 2025 | P = 0.04 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| safety comorbidity | Albertini 2025 | P = 0.12 | null summary | indirect | B2 | reported statistic; source summary remains null |\n| contextual other | Jo 2025 | P = 0.01 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Jo 2025 | P = 0.42 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Jo 2025 | P = 0.02 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Jo 2025 | P = 0.56 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Jo 2025 | P < 0.05 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Jo 2025 | P > 0.05 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Nouhravesh 2025 | P = 0.24 | null summary | indirect | B2 | reported statistic; source summary remains null |\n| contextual other | Nouhravesh 2025 | P = 0.37 | null summary | indirect | B2 | reported statistic; source summary remains null |\n| contextual other | Nouhravesh 2025 | P = 0.015 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Nouhravesh 2025 | P = 0.59 | null summary | indirect | B2 | reported statistic; source summary remains null |\n| safety comorbidity | Bavendiek 2025 | — | null | review | B2 | no significant effect on safety comorbidity |\n| cardiometabolic | Mosepele 2025 | P = 0.036 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| cardiometabolic | Mosepele 2025 | P = 0.008 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| cardiometabolic | Mosepele 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Takahashi 2025 | P = 0.048 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Takahashi 2025 | P = 0.016 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Takahashi 2025 | P = 0.048 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Takahashi 2025 | P = 0.016 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Takahashi 2025 | P = 0.047 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Takahashi 2025 | P = 0.039 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Kehoe 2026 | — | unclear | indirect | B2 | unclear effect on contextual other |\n| cardiometabolic | Filipova 2020 | P < 0.001 | negative summary | review | B1 | reported statistic; source summary remains negative |\n| cardiometabolic | Filipova 2020 | P = 0.0016 | negative summary | review | B1 | reported statistic; source summary remains negative |\n| cardiometabolic | Wever 2025 | — | unclear | indirect | B2 | unclear effect on cardiometabolic |\n| contextual other | Pietro 2024 | P < 0.0001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Pietro 2024 | P < 0.0001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Pietro 2024 | P < 0.0001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Pietro 2024 | P = 0.0009 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Pietro 2024 | P < 0.0001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Pietro 2024 | P = 0.0009 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Omland 2025 | — | null | indirect | B2 | no significant effect on contextual other |\n| contextual other | Humphreys 2025 | — | null | indirect | B2 | no significant effect on contextual other |\n| mortality survival | Lu 2026 | P = 0.11 | negative summary | review | B2 | reported statistic; source summary remains negative |\n| mortality survival | Lu 2026 | P = 0.56 | negative summary | review | B2 | reported statistic; source summary remains negative |\n| mortality survival | Lu 2026 | P = 0.89 | negative summary | review | B2 | reported statistic; source summary remains negative |\n| mortality survival | Lu 2026 | P = 0.02 | negative summary | review | B2 | reported statistic; source summary remains negative |\n| mortality survival | Lu 2026 | P < 0.00001 | negative summary | review | B2 | reported statistic; source summary remains negative |\n| mortality survival | Lu 2026 | P = 0.02 | negative summary | review | B2 | reported statistic; source summary remains negative |\n| cardiometabolic | Abhari 2026 | — | unclear | review | B1 | unclear effect on cardiometabolic |\n| contextual other | Wang 2026b | P = 0.006 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| contextual other | Wang 2026b | P = 0.003 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| contextual other | Wang 2026b | P = 0.005 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| contextual other | Wang 2026b | P < 0.001 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| contextual other | Wang 2026b | P = 0.006 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| contextual other | Wang 2026b | P = 0.003 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| contextual other | Yang 2025 | P = 0.06 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Yang 2025 | P = 0.005 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Yang 2025 | P = 0.037 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Yang 2025 | P = 0.001 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| cardiometabolic | Yan 2025 | P < 0.001 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed |\n| cardiometabolic | Yan 2025 | P < 0.001 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed |\n| cardiometabolic | Yan 2025 | P < 0.001 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed |\n| cardiometabolic | Yan 2025 | P < 0.001 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed |\n| cardiometabolic | Yan 2025 | P < 0.01 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed |\n| cardiometabolic | Yan 2025 | P = 0.11 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed |\n| contextual other | Han 2026 | P = 0.58 | null summary | indirect | B2 | reported statistic; source summary remains null |\n| contextual other | Han 2026 | P = 0.017 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Han 2026 | P = 0.004 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Han 2026 | P = 0.99 | null summary | indirect | B2 | reported statistic; source summary remains null |\n| contextual other | Han 2026 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Han 2026 | P = 0.032 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| dosing pharmacokinetics | Hu 2025 | — | null | indirect | B2 | no significant effect on dosing pharmacokinetics |\n| safety comorbidity | Tu 2026 | P = 0.12 | positive summary | indirect | B2 | reported statistic; source summary remains positive |\n| safety comorbidity | Tu 2026 | P = 0.57 | positive summary | indirect | B2 | reported statistic; source summary remains positive |\n| safety comorbidity | Tu 2026 | P < 0.001 | positive summary | indirect | B2 | reported statistic; source summary remains positive |\n| safety comorbidity | Tu 2026 | P = 0.008 | positive summary | indirect | B2 | reported statistic; source summary remains positive |\n| safety comorbidity | Tu 2026 | P = 0.12 | positive summary | indirect | B2 | reported statistic; source summary remains positive |\n| safety comorbidity | Tu 2026 | P = 0.44 | positive summary | indirect | B2 | reported statistic; source summary remains positive |\n| contextual other | Shaddy 2025 | P < 0.0001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Shaddy 2025 | P = 0.0004 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Jia 2025 | — | null | indirect | B2 | no significant effect on contextual other |\n| cardiometabolic | Kario 2024 | — | null | review | B2 | no significant effect on cardiometabolic |\n| contextual other | Schwartz 2025 | P < 0.001 | positive summary | indirect | B2 | reported statistic; source summary remains positive |\n| contextual other | Schwartz 2025 | P < 0.016 | positive summary | indirect | B2 | reported statistic; source summary remains positive |\n| contextual other | Schwartz 2025 | P < 0.001 | positive summary | indirect | B2 | reported statistic; source summary remains positive |\n| contextual other | Schwartz 2025 | P = 0.46 | positive summary | indirect | B2 | reported statistic; source summary remains positive |\n| contextual other | Schwartz 2025 | P > 0.05 | positive summary | indirect | B2 | reported statistic; source summary remains positive |\n| contextual other | Schwartz 2025 | P = 0.023 | positive summary | indirect | B2 | reported statistic; source summary remains positive |\n| safety comorbidity | Kuang 2025 | P < 0.001 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| safety comorbidity | Kuang 2025 | P < 0.001 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| safety comorbidity | Kuang 2025 | P = 0.049 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| safety comorbidity | Kuang 2025 | P = 0.19 | null summary | review | B2 | reported statistic; source summary remains null |\n| safety comorbidity | Kuang 2025 | P = 0.049 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| safety comorbidity | Kuang 2025 | P = 0.573 | null summary | review | B2 | reported statistic; source summary remains null |\n| longevity | Jin 2025 | — | unclear | indirect | B2 | unclear effect on longevity |\n| longevity | Murray-Thomas 2025 | P < 0.001 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| longevity | Murray-Thomas 2025 | P < 0.001 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Nouhravesh 2025b | P = 0.14 | null summary | indirect | B2 | reported statistic; source summary remains null |\n| contextual other | Nouhravesh 2025b | P = 0.22 | null summary | indirect | B2 | reported statistic; source summary remains null |\n| contextual other | Kim 2025 | P = 0.713 | null summary | review | B2 | reported statistic; source summary remains null |\n| contextual other | Kim 2025 | P = 0.527 | null summary | review | B2 | reported statistic; source summary remains null |\n| contextual other | Gomaz 2026 | P = 0.001 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed |\n| contextual other | Gomaz 2026 | P = 0.90 | mixed summary | indirect | B2 | reported statistic; source summary remains mixed |\n| contextual other | Chimura 2025 | P < 0.001 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Chimura 2025 | P = 0.36 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Chimura 2025 | P = 0.004 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| contextual other | Chimura 2025 | P < 0.001 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| safety comorbidity | Silva 2026 | P < 0.0001 | positive summary | review | B1 | reported statistic; source summary remains positive |\n| safety comorbidity | Silva 2026 | P = 0.0019 | positive summary | review | B1 | reported statistic; source summary remains positive |\n| safety comorbidity | Silva 2026 | P < 0.0001 | positive summary | review | B1 | reported statistic; source summary remains positive |\n| safety comorbidity | Silva 2026 | P < 0.0001 | positive summary | review | B1 | reported statistic; source summary remains positive |\n| safety comorbidity | Silva 2026 | P < 0.0001 | positive summary | review | B1 | reported statistic; source summary remains positive |\n| safety comorbidity | Silva 2026 | P = 0.0561 | positive summary | review | B1 | reported statistic; source summary remains positive |\n| contextual other | Pepine 2026 | P = 0.20 | positive summary | review | B2 | reported statistic; source summary remains positive |\n| contextual other | Pepine 2026 | P = 0.20 | positive summary | review | B2 | reported statistic; source summary remains positive |\n| contextual other | Pepine 2026 | P = 0.92 | positive summary | review | B2 | reported statistic; source summary remains positive |\n| contextual other | Pepine 2026 | P < 0.0001 | positive summary | review | B2 | reported statistic; source summary remains positive |\n| contextual other | Pepine 2026 | P = 0.037 | positive summary | review | B2 | reported statistic; source summary remains positive |\n| contextual other | Pepine 2026 | P = 0.38 | positive summary | review | B2 | reported statistic; source summary remains positive |\n| immune inflammation | Lu 2025 | P = 0.06 | null summary | indirect | B2 | reported statistic; source summary remains null |\n| immune inflammation | Lu 2025 | P > 0.05 | null summary | indirect | B2 | reported statistic; source summary remains null |\n| immune inflammation | Lu 2025 | P = 0.24 | null summary | indirect | B2 | reported statistic; source summary remains null |\n| immune inflammation | Lu 2025 | P > 0.05 | null summary | indirect | B2 | reported statistic; source summary remains null |\n| immune inflammation | Lu 2025 | P < 0.0001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| immune inflammation | Lu 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Fumarulo 2025 | — | null | indirect | B2 | no significant effect on contextual other |\n| contextual other | Dou 2025 | P = 0.001 | unclear summary | review | B2 | reported statistic; source summary remains unclear |\n| contextual other | Dou 2025 | P = 0.001 | unclear summary | review | B2 | reported statistic; source summary remains unclear |\n| safety comorbidity | Ngai 2025 | — | null | indirect | B2 | no significant effect on safety comorbidity |\n| contextual other | Rezazadeh 2025 | — | unclear | indirect | B2 | unclear effect on contextual other |\n| contextual other | Nazari-Robati 2025 | P < 0.05 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Nazari-Robati 2025 | P < 0.05 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Nazari-Robati 2025 | P > 0.05 | null summary | indirect | B2 | reported statistic; source summary remains null |\n| contextual other | Nazari-Robati 2025 | P < 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Nazari-Robati 2025 | P = 0.014 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Nazari-Robati 2025 | P = 0.044 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| cardiometabolic | Asim 2025 | P = 0.008 | negative summary | indirect | B2 | reported statistic; source summary remains negative |\n| cardiometabolic | Asim 2025 | P = 0.0004 | negative summary | indirect | B2 | reported statistic; source summary remains negative |\n| cardiometabolic | Asim 2025 | P = 0.41 | negative summary | indirect | B2 | reported statistic; source summary remains negative |\n| contextual other | Odeh 2026 | P < 0.05 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Odeh 2026 | P < 0.05 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Odeh 2026 | P = 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Odeh 2026 | P = 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| contextual other | Odeh 2026 | P = 0.001 | significant statistic | indirect | B2 | significant statistic; source-level direction remains null |\n| safety comorbidity | Wang 2025 | — | null | indirect | B2 | no significant effect on safety comorbidity |\n| contextual other | Ramaswamy 2025 | P > 0.05 | null summary | indirect | B2 | reported statistic; source summary remains null |\n| cardiometabolic | Yang 2025b | P < 0.00001 | negative summary | review | B2 | reported statistic; source summary remains negative |\n| cardiometabolic | Yang 2025b | P < 0.00001 | negative summary | review | B2 | reported statistic; source summary remains negative |\n| cardiometabolic | Yang 2025b | P < 0.00001 | negative summary | review | B2 | reported statistic; source summary remains negative |\n| cardiometabolic | Yang 2025b | P < 0.00001 | negative summary | review | B2 | reported statistic; source summary remains negative |\n| cardiometabolic | Yang 2025b | P = 0.0001 | negative summary | review | B2 | reported statistic; source summary remains negative |\n| cardiometabolic | Yang 2025b | P = 0.24 | negative summary | review | B2 | reported statistic; source summary remains negative |\n| dosing pharmacokinetics | Kato 2025 | P < 0.05 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| dosing pharmacokinetics | Kato 2025 | P < 0.001 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| dosing pharmacokinetics | Kato 2025 | P < 0.05 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| dosing pharmacokinetics | Kato 2025 | P < 0.001 | unclear summary | indirect | B2 | reported statistic; source summary remains unclear |\n| longevity | Agarwal 2025 | — | null | indirect | B2 | no significant effect on longevity |\n| cardiometabolic | Wang 2025b | — | null | review | B2 | no significant effect on cardiometabolic |\n| contextual other | Zhao 2025 | P < 0.05 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| contextual other | Zhao 2025 | P > 0.05 | null summary | review | B2 | reported statistic; source summary remains null |\n| contextual other | Zhao 2025 | P < 0.05 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| contextual other | Zhao 2025 | P < 0.05 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| contextual other | Zhao 2025 | P < 0.05 | significant statistic | review | B2 | significant statistic; source-level direction remains null |\n| contextual other | Karanovic 2026 | — | null | mechanistic | C1 | no significant effect on contextual other |\n| safety comorbidity | Wang 2025c | — | null | indirect | B2 | no significant effect on safety comorbidity |\n| cardiometabolic | Shubietah 2026 | — | null | review | B1 | no significant effect on cardiometabolic |\n| safety comorbidity | Al-Omari 2026 | — | null | indirect | B2 | no significant effect on safety comorbidity |\n| immune | Gomaz 2025 | — | unclear | review | B1 | unclear effect on immune |\n\n### Table 3: Cross-Domain Tensions\n\nAdditional corpus sources included animal/preclinical evidence; | Tension kind | Severity | source A | source B | Outcome class | Summary | Practical implication |\n| --- | --- | --- | --- | --- | --- | --- |\n| agreement | 1 | Campbell 2025 | Tian 2025 | dosing pharmacokinetics | Campbell 2025 (unclear) vs Tian 2025 (unclear) on dosing pharmacokinetics | agreement (minor) |\n| null vs positive | 3 | Campbell 2025 | Hu 2025 | dosing pharmacokinetics | Campbell 2025 (unclear) vs Hu 2025 (null) on dosing pharmacokinetics | null vs positive (notable) |\n| agreement | 1 | Campbell 2025 | Kato 2025 | dosing pharmacokinetics | Campbell 2025 (unclear) vs Kato 2025 (unclear) on dosing pharmacokinetics | agreement (minor) |\n| null vs positive | 3 | Campbell 2025 | Mei 2025 | dosing pharmacokinetics | Campbell 2025 (unclear) vs Mei 2025 (null) on dosing pharmacokinetics | null vs positive (notable) |\n| null vs positive | 3 | Campbell 2025 | Ahn 2026 | dosing pharmacokinetics | Campbell 2025 (unclear) vs Ahn 2026 (null) on dosing pharmacokinetics | null vs positive (notable) |\n| null vs positive | 3 | Campbell 2025 | Goh 2026 | dosing pharmacokinetics | Campbell 2025 (unclear) vs Goh 2026 (null) on dosing pharmacokinetics | null vs positive (notable) |\n| null vs positive | 3 | Tian 2025 | Hu 2025 | dosing pharmacokinetics | Tian 2025 (unclear) vs Hu 2025 (null) on dosing pharmacokinetics | null vs positive (notable) |\n| agreement | 1 | Tian 2025 | Kato 2025 | dosing pharmacokinetics | Tian 2025 (unclear) vs Kato 2025 (unclear) on dosing pharmacokinetics | agreement (minor) |\n| null vs positive | 3 | Tian 2025 | Mei 2025 | dosing pharmacokinetics | Tian 2025 (unclear) vs Mei 2025 (null) on dosing pharmacokinetics | null vs positive (notable) |\n| null vs positive | 3 | Tian 2025 | Ahn 2026 | dosing pharmacokinetics | Tian 2025 (unclear) vs Ahn 2026 (null) on dosing pharmacokinetics | null vs positive (notable) |\n| null vs positive | 3 | Tian 2025 | Goh 2026 | dosing pharmacokinetics | Tian 2025 (unclear) vs Goh 2026 (null) on dosing pharmacokinetics | null vs positive (notable) |\n| disagreement | 5 | Chung 2024 | Yamamoto 2024 | cardiometabolic | Chung 2024 (positive) vs Yamamoto 2024 (negative) on cardiometabolic | disagreement (load-bearing) |\n| disagreement | 4 | Chung 2024 | Yan 2025 | cardiometabolic | Chung 2024 (positive) vs Yan 2025 (mixed) on cardiometabolic | disagreement (load-bearing) |\n| null vs positive | 3 | Chung 2024 | Kario 2024 | cardiometabolic | Chung 2024 (positive) vs Kario 2024 (null) on cardiometabolic | null vs positive (notable) |\n| disagreement | 5 | Chung 2024 | Yang 2025b | cardiometabolic | Chung 2024 (positive) vs Yang 2025b (negative) on cardiometabolic | disagreement (load-bearing) |\n| null vs positive | 3 | Chung 2024 | Mosepele 2025 | cardiometabolic | Chung 2024 (positive) vs Mosepele 2025 (null) on cardiometabolic | null vs positive (notable) |\n| null vs positive | 3 | Chung 2024 | Wang 2025b | cardiometabolic | Chung 2024 (positive) vs Wang 2025b (null) on cardiometabolic | null vs positive (notable) |\n| disagreement | 5 | Chung 2024 | Asim 2025 | cardiometabolic | Chung 2024 (positive) vs Asim 2025 (negative) on cardiometabolic | disagreement (load-bearing) |\n| null vs positive | 3 | Chung 2024 | Din 2026 | cardiometabolic | Chung 2024 (positive) vs Din 2026 (null) on cardiometabolic | null vs positive (notable) |\n| disagreement | 5 | Chung 2024 | Filipova 2020 | cardiometabolic | Chung 2024 (positive) vs Filipova 2020 (negative) on cardiometabolic | disagreement (load-bearing) |\n| null vs positive | 3 | Chung 2024 | Shubietah 2026 | cardiometabolic | Chung 2024 (positive) vs Shubietah 2026 (null) on cardiometabolic | null vs positive (notable) |\n| disagreement | 4 | Yamamoto 2024 | Yan 2025 | cardiometabolic | Yamamoto 2024 (negative) vs Yan 2025 (mixed) on cardiometabolic | disagreement (load-bearing) |\n| null vs positive | 3 | Yamamoto 2024 | Kario 2024 | cardiometabolic | Yamamoto 2024 (negative) vs Kario 2024 (null) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Yamamoto 2024 | Yang 2025b | cardiometabolic | Yamamoto 2024 (negative) vs Yang 2025b (negative) on cardiometabolic | agreement (minor) |\n| null vs positive | 3 | Yamamoto 2024 | Mosepele 2025 | cardiometabolic | Yamamoto 2024 (negative) vs Mosepele 2025 (null) on cardiometabolic | null vs positive (notable) |\n| null vs positive | 3 | Yamamoto 2024 | Wang 2025b | cardiometabolic | Yamamoto 2024 (negative) vs Wang 2025b (null) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Yamamoto 2024 | Asim 2025 | cardiometabolic | Yamamoto 2024 (negative) vs Asim 2025 (negative) on cardiometabolic | agreement (minor) |\n| null vs positive | 3 | Yamamoto 2024 | Din 2026 | cardiometabolic | Yamamoto 2024 (negative) vs Din 2026 (null) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Yamamoto 2024 | Filipova 2020 | cardiometabolic | Yamamoto 2024 (negative) vs Filipova 2020 (negative) on cardiometabolic | agreement (minor) |\n| null vs positive | 3 | Yamamoto 2024 | Shubietah 2026 | cardiometabolic | Yamamoto 2024 (negative) vs Shubietah 2026 (null) on cardiometabolic | null vs positive (notable) |\n| disagreement | 4 | Yan 2025 | Kario 2024 | cardiometabolic | Yan 2025 (mixed) vs Kario 2024 (null) on cardiometabolic | disagreement (load-bearing) |\n| disagreement | 4 | Yan 2025 | Yang 2025b | cardiometabolic | Yan 2025 (mixed) vs Yang 2025b (negative) on cardiometabolic | disagreement (load-bearing) |\n| disagreement | 4 | Yan 2025 | Mosepele 2025 | cardiometabolic | Yan 2025 (mixed) vs Mosepele 2025 (null) on cardiometabolic | disagreement (load-bearing) |\n| disagreement | 4 | Yan 2025 | Wever 2025 | cardiometabolic | Yan 2025 (mixed) vs Wever 2025 (unclear) on cardiometabolic | disagreement (load-bearing) |\n| disagreement | 4 | Yan 2025 | Wang 2025b | cardiometabolic | Yan 2025 (mixed) vs Wang 2025b (null) on cardiometabolic | disagreement (load-bearing) |\n| disagreement | 4 | Yan 2025 | Asim 2025 | cardiometabolic | Yan 2025 (mixed) vs Asim 2025 (negative) on cardiometabolic | disagreement (load-bearing) |\n| disagreement | 4 | Yan 2025 | Abhari 2026 | cardiometabolic | Yan 2025 (mixed) vs Abhari 2026 (unclear) on cardiometabolic | disagreement (load-bearing) |\n| disagreement | 4 | Yan 2025 | Din 2026 | cardiometabolic | Yan 2025 (mixed) vs Din 2026 (null) on cardiometabolic | disagreement (load-bearing) |\n| disagreement | 4 | Yan 2025 | Filipova 2020 | cardiometabolic | Yan 2025 (mixed) vs Filipova 2020 (negative) on cardiometabolic | disagreement (load-bearing) |\n| disagreement | 4 | Yan 2025 | Shubietah 2026 | cardiometabolic | Yan 2025 (mixed) vs Shubietah 2026 (null) on cardiometabolic | disagreement (load-bearing) |\n| null vs positive | 3 | Kario 2024 | Yang 2025b | cardiometabolic | Kario 2024 (null) vs Yang 2025b (negative) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Kario 2024 | Mosepele 2025 | cardiometabolic | Kario 2024 (null) vs Mosepele 2025 (null) on cardiometabolic | agreement (minor) |\n| null vs positive | 3 | Kario 2024 | Wever 2025 | cardiometabolic | Kario 2024 (null) vs Wever 2025 (unclear) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Kario 2024 | Wang 2025b | cardiometabolic | Kario 2024 (null) vs Wang 2025b (null) on cardiometabolic | agreement (minor) |\n| null vs positive | 3 | Kario 2024 | Asim 2025 | cardiometabolic | Kario 2024 (null) vs Asim 2025 (negative) on cardiometabolic | null vs positive (notable) |\n| null vs positive | 3 | Kario 2024 | Abhari 2026 | cardiometabolic | Kario 2024 (null) vs Abhari 2026 (unclear) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Kario 2024 | Din 2026 | cardiometabolic | Kario 2024 (null) vs Din 2026 (null) on cardiometabolic | agreement (minor) |\n| null vs positive | 3 | Kario 2024 | Filipova 2020 | cardiometabolic | Kario 2024 (null) vs Filipova 2020 (negative) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Kario 2024 | Shubietah 2026 | cardiometabolic | Kario 2024 (null) vs Shubietah 2026 (null) on cardiometabolic | agreement (minor) |\n| null vs positive | 3 | Yang 2025b | Mosepele 2025 | cardiometabolic | Yang 2025b (negative) vs Mosepele 2025 (null) on cardiometabolic | null vs positive (notable) |\n| null vs positive | 3 | Yang 2025b | Wang 2025b | cardiometabolic | Yang 2025b (negative) vs Wang 2025b (null) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Yang 2025b | Asim 2025 | cardiometabolic | Yang 2025b (negative) vs Asim 2025 (negative) on cardiometabolic | agreement (minor) |\n| null vs positive | 3 | Yang 2025b | Din 2026 | cardiometabolic | Yang 2025b (negative) vs Din 2026 (null) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Yang 2025b | Filipova 2020 | cardiometabolic | Yang 2025b (negative) vs Filipova 2020 (negative) on cardiometabolic | agreement (minor) |\n| null vs positive | 3 | Yang 2025b | Shubietah 2026 | cardiometabolic | Yang 2025b (negative) vs Shubietah 2026 (null) on cardiometabolic | null vs positive (notable) |\n| null vs positive | 3 | Mosepele 2025 | Wever 2025 | cardiometabolic | Mosepele 2025 (null) vs Wever 2025 (unclear) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Mosepele 2025 | Wang 2025b | cardiometabolic | Mosepele 2025 (null) vs Wang 2025b (null) on cardiometabolic | agreement (minor) |\n| null vs positive | 3 | Mosepele 2025 | Asim 2025 | cardiometabolic | Mosepele 2025 (null) vs Asim 2025 (negative) on cardiometabolic | null vs positive (notable) |\n| null vs positive | 3 | Mosepele 2025 | Abhari 2026 | cardiometabolic | Mosepele 2025 (null) vs Abhari 2026 (unclear) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Mosepele 2025 | Din 2026 | cardiometabolic | Mosepele 2025 (null) vs Din 2026 (null) on cardiometabolic | agreement (minor) |\n| null vs positive | 3 | Mosepele 2025 | Filipova 2020 | cardiometabolic | Mosepele 2025 (null) vs Filipova 2020 (negative) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Mosepele 2025 | Shubietah 2026 | cardiometabolic | Mosepele 2025 (null) vs Shubietah 2026 (null) on cardiometabolic | agreement (minor) |\n| null vs positive | 3 | Pietro 2024 | Alqaisi 2025 | contextual other | Pietro 2024 (null) vs Alqaisi 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Pietro 2024 | Zhao 2025 | contextual other | Pietro 2024 (null) vs Zhao 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Pietro 2024 | Jia 2025 | contextual other | Pietro 2024 (null) vs Jia 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Pietro 2024 | Nouhravesh 2025b | contextual other | Pietro 2024 (null) vs Nouhravesh 2025b (null) on contextual other | agreement (minor) |\n| agreement | 1 | Pietro 2024 | Ramaswamy 2025 | contextual other | Pietro 2024 (null) vs Ramaswamy 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Pietro 2024 | Schwartz 2025 | contextual other | Pietro 2024 (null) vs Schwartz 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Pietro 2024 | Fumarulo 2025 | contextual other | Pietro 2024 (null) vs Fumarulo 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Pietro 2024 | Derington 2025 | contextual other | Pietro 2024 (null) vs Derington 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Pietro 2024 | Shaddy 2025 | contextual other | Pietro 2024 (null) vs Shaddy 2025 (null) on contextual other | agreement (minor) |\n| disagreement | 4 | Pietro 2024 | Lee 2025 | contextual other | Pietro 2024 (null) vs Lee 2025 (mixed) on contextual other | disagreement (load-bearing) |\n| agreement | 1 | Pietro 2024 | Li 2025 | contextual other | Pietro 2024 (null) vs Li 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Pietro 2024 | Chimura 2025 | contextual other | Pietro 2024 (null) vs Chimura 2025 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Pietro 2024 | Jo 2025 | contextual other | Pietro 2024 (null) vs Jo 2025 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Pietro 2024 | Dou 2025 | contextual other | Pietro 2024 (null) vs Dou 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Pietro 2024 | Nouhravesh 2025 | contextual other | Pietro 2024 (null) vs Nouhravesh 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Pietro 2024 | Nazari-Robati 2025 | contextual other | Pietro 2024 (null) vs Nazari-Robati 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Pietro 2024 | Yu 2025 | contextual other | Pietro 2024 (null) vs Yu 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Pietro 2024 | Omland 2025 | contextual other | Pietro 2024 (null) vs Omland 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Pietro 2024 | Rezazadeh 2025 | contextual other | Pietro 2024 (null) vs Rezazadeh 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Pietro 2024 | Takahashi 2025 | contextual other | Pietro 2024 (null) vs Takahashi 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Pietro 2024 | Humphreys 2025 | contextual other | Pietro 2024 (null) vs Humphreys 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Pietro 2024 | Yang 2025 | contextual other | Pietro 2024 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Pietro 2024 | Kim 2025 | contextual other | Pietro 2024 (null) vs Kim 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Pietro 2024 | Taha 2025 | contextual other | Pietro 2024 (null) vs Taha 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Pietro 2024 | Karanovic 2026 | contextual other | Pietro 2024 (null) vs Karanovic 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Pietro 2024 | Odeh 2026 | contextual other | Pietro 2024 (null) vs Odeh 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Pietro 2024 | Han 2026 | contextual other | Pietro 2024 (null) vs Han 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Pietro 2024 | Senanayake 2026 | contextual other | Pietro 2024 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Pietro 2024 | Wang 2026b | contextual other | Pietro 2024 (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Pietro 2024 | Pepine 2026 | contextual other | Pietro 2024 (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Pietro 2024 | Gomaz 2026 | contextual other | Pietro 2024 (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Pietro 2024 | Savarese 2026 | contextual other | Pietro 2024 (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Pietro 2024 | Kehoe 2026 | contextual other | Pietro 2024 (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Alqaisi 2025 | Zhao 2025 | contextual other | Alqaisi 2025 (unclear) vs Zhao 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Alqaisi 2025 | Jia 2025 | contextual other | Alqaisi 2025 (unclear) vs Jia 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Alqaisi 2025 | Nouhravesh 2025b | contextual other | Alqaisi 2025 (unclear) vs Nouhravesh 2025b (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Alqaisi 2025 | Ramaswamy 2025 | contextual other | Alqaisi 2025 (unclear) vs Ramaswamy 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Alqaisi 2025 | Fumarulo 2025 | contextual other | Alqaisi 2025 (unclear) vs Fumarulo 2025 (null) on contextual other | null vs positive (notable) |\n| agreement | 1 | Alqaisi 2025 | Derington 2025 | contextual other | Alqaisi 2025 (unclear) vs Derington 2025 (unclear) on contextual other | agreement (minor) |\n| null vs positive | 3 | Alqaisi 2025 | Shaddy 2025 | contextual other | Alqaisi 2025 (unclear) vs Shaddy 2025 (null) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Alqaisi 2025 | Lee 2025 | contextual other | Alqaisi 2025 (unclear) vs Lee 2025 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Alqaisi 2025 | Li 2025 | contextual other | Alqaisi 2025 (unclear) vs Li 2025 (null) on contextual other | null vs positive (notable) |\n| agreement | 1 | Alqaisi 2025 | Chimura 2025 | contextual other | Alqaisi 2025 (unclear) vs Chimura 2025 (unclear) on contextual other | agreement (minor) |\n| agreement | 1 | Alqaisi 2025 | Jo 2025 | contextual other | Alqaisi 2025 (unclear) vs Jo 2025 (unclear) on contextual other | agreement (minor) |\n| agreement | 1 | Alqaisi 2025 | Dou 2025 | contextual other | Alqaisi 2025 (unclear) vs Dou 2025 (unclear) on contextual other | agreement (minor) |\n| null vs positive | 3 | Alqaisi 2025 | Nouhravesh 2025 | contextual other | Alqaisi 2025 (unclear) vs Nouhravesh 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Alqaisi 2025 | Nazari-Robati 2025 | contextual other | Alqaisi 2025 (unclear) vs Nazari-Robati 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Alqaisi 2025 | Yu 2025 | contextual other | Alqaisi 2025 (unclear) vs Yu 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Alqaisi 2025 | Omland 2025 | contextual other | Alqaisi 2025 (unclear) vs Omland 2025 (null) on contextual other | null vs positive (notable) |\n| agreement | 1 | Alqaisi 2025 | Rezazadeh 2025 | contextual other | Alqaisi 2025 (unclear) vs Rezazadeh 2025 (unclear) on contextual other | agreement (minor) |\n| null vs positive | 3 | Alqaisi 2025 | Takahashi 2025 | contextual other | Alqaisi 2025 (unclear) vs Takahashi 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Alqaisi 2025 | Humphreys 2025 | contextual other | Alqaisi 2025 (unclear) vs Humphreys 2025 (null) on contextual other | null vs positive (notable) |\n| agreement | 1 | Alqaisi 2025 | Yang 2025 | contextual other | Alqaisi 2025 (unclear) vs Yang 2025 (unclear) on contextual other | agreement (minor) |\n| null vs positive | 3 | Alqaisi 2025 | Kim 2025 | contextual other | Alqaisi 2025 (unclear) vs Kim 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Alqaisi 2025 | Karanovic 2026 | contextual other | Alqaisi 2025 (unclear) vs Karanovic 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Alqaisi 2025 | Odeh 2026 | contextual other | Alqaisi 2025 (unclear) vs Odeh 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Alqaisi 2025 | Han 2026 | contextual other | Alqaisi 2025 (unclear) vs Han 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Alqaisi 2025 | Senanayake 2026 | contextual other | Alqaisi 2025 (unclear) vs Senanayake 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Alqaisi 2025 | Wang 2026b | contextual other | Alqaisi 2025 (unclear) vs Wang 2026b (null) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Alqaisi 2025 | Gomaz 2026 | contextual other | Alqaisi 2025 (unclear) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| agreement | 1 | Alqaisi 2025 | Savarese 2026 | contextual other | Alqaisi 2025 (unclear) vs Savarese 2026 (unclear) on contextual other | agreement (minor) |\n| agreement | 1 | Alqaisi 2025 | Kehoe 2026 | contextual other | Alqaisi 2025 (unclear) vs Kehoe 2026 (unclear) on contextual other | agreement (minor) |\n| agreement | 1 | Zhao 2025 | Jia 2025 | contextual other | Zhao 2025 (null) vs Jia 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Zhao 2025 | Nouhravesh 2025b | contextual other | Zhao 2025 (null) vs Nouhravesh 2025b (null) on contextual other | agreement (minor) |\n| agreement | 1 | Zhao 2025 | Ramaswamy 2025 | contextual other | Zhao 2025 (null) vs Ramaswamy 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Zhao 2025 | Schwartz 2025 | contextual other | Zhao 2025 (null) vs Schwartz 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Zhao 2025 | Fumarulo 2025 | contextual other | Zhao 2025 (null) vs Fumarulo 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Zhao 2025 | Derington 2025 | contextual other | Zhao 2025 (null) vs Derington 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Zhao 2025 | Shaddy 2025 | contextual other | Zhao 2025 (null) vs Shaddy 2025 (null) on contextual other | agreement (minor) |\n| disagreement | 4 | Zhao 2025 | Lee 2025 | contextual other | Zhao 2025 (null) vs Lee 2025 (mixed) on contextual other | disagreement (load-bearing) |\n| agreement | 1 | Zhao 2025 | Li 2025 | contextual other | Zhao 2025 (null) vs Li 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Zhao 2025 | Chimura 2025 | contextual other | Zhao 2025 (null) vs Chimura 2025 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Zhao 2025 | Jo 2025 | contextual other | Zhao 2025 (null) vs Jo 2025 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Zhao 2025 | Dou 2025 | contextual other | Zhao 2025 (null) vs Dou 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Zhao 2025 | Nouhravesh 2025 | contextual other | Zhao 2025 (null) vs Nouhravesh 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Zhao 2025 | Nazari-Robati 2025 | contextual other | Zhao 2025 (null) vs Nazari-Robati 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Zhao 2025 | Yu 2025 | contextual other | Zhao 2025 (null) vs Yu 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Zhao 2025 | Omland 2025 | contextual other | Zhao 2025 (null) vs Omland 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Zhao 2025 | Rezazadeh 2025 | contextual other | Zhao 2025 (null) vs Rezazadeh 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Zhao 2025 | Takahashi 2025 | contextual other | Zhao 2025 (null) vs Takahashi 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Zhao 2025 | Humphreys 2025 | contextual other | Zhao 2025 (null) vs Humphreys 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Zhao 2025 | Yang 2025 | contextual other | Zhao 2025 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Zhao 2025 | Kim 2025 | contextual other | Zhao 2025 (null) vs Kim 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Zhao 2025 | Taha 2025 | contextual other | Zhao 2025 (null) vs Taha 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Zhao 2025 | Karanovic 2026 | contextual other | Zhao 2025 (null) vs Karanovic 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Zhao 2025 | Odeh 2026 | contextual other | Zhao 2025 (null) vs Odeh 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Zhao 2025 | Han 2026 | contextual other | Zhao 2025 (null) vs Han 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Zhao 2025 | Senanayake 2026 | contextual other | Zhao 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Zhao 2025 | Wang 2026b | contextual other | Zhao 2025 (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Zhao 2025 | Pepine 2026 | contextual other | Zhao 2025 (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Zhao 2025 | Gomaz 2026 | contextual other | Zhao 2025 (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Zhao 2025 | Savarese 2026 | contextual other | Zhao 2025 (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Zhao 2025 | Kehoe 2026 | contextual other | Zhao 2025 (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Jia 2025 | Nouhravesh 2025b | contextual other | Jia 2025 (null) vs Nouhravesh 2025b (null) on contextual other | agreement (minor) |\n| agreement | 1 | Jia 2025 | Ramaswamy 2025 | contextual other | Jia 2025 (null) vs Ramaswamy 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Jia 2025 | Schwartz 2025 | contextual other | Jia 2025 (null) vs Schwartz 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Jia 2025 | Fumarulo 2025 | contextual other | Jia 2025 (null) vs Fumarulo 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Jia 2025 | Derington 2025 | contextual other | Jia 2025 (null) vs Derington 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Jia 2025 | Shaddy 2025 | contextual other | Jia 2025 (null) vs Shaddy 2025 (null) on contextual other | agreement (minor) |\n| disagreement | 4 | Jia 2025 | Lee 2025 | contextual other | Jia 2025 (null) vs Lee 2025 (mixed) on contextual other | disagreement (load-bearing) |\n| agreement | 1 | Jia 2025 | Li 2025 | contextual other | Jia 2025 (null) vs Li 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Jia 2025 | Chimura 2025 | contextual other | Jia 2025 (null) vs Chimura 2025 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Jia 2025 | Jo 2025 | contextual other | Jia 2025 (null) vs Jo 2025 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Jia 2025 | Dou 2025 | contextual other | Jia 2025 (null) vs Dou 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Jia 2025 | Nouhravesh 2025 | contextual other | Jia 2025 (null) vs Nouhravesh 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Jia 2025 | Nazari-Robati 2025 | contextual other | Jia 2025 (null) vs Nazari-Robati 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Jia 2025 | Yu 2025 | contextual other | Jia 2025 (null) vs Yu 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Jia 2025 | Omland 2025 | contextual other | Jia 2025 (null) vs Omland 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Jia 2025 | Rezazadeh 2025 | contextual other | Jia 2025 (null) vs Rezazadeh 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Jia 2025 | Takahashi 2025 | contextual other | Jia 2025 (null) vs Takahashi 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Jia 2025 | Humphreys 2025 | contextual other | Jia 2025 (null) vs Humphreys 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Jia 2025 | Yang 2025 | contextual other | Jia 2025 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Jia 2025 | Kim 2025 | contextual other | Jia 2025 (null) vs Kim 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Jia 2025 | Taha 2025 | contextual other | Jia 2025 (null) vs Taha 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Jia 2025 | Karanovic 2026 | contextual other | Jia 2025 (null) vs Karanovic 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Jia 2025 | Odeh 2026 | contextual other | Jia 2025 (null) vs Odeh 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Jia 2025 | Han 2026 | contextual other | Jia 2025 (null) vs Han 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Jia 2025 | Senanayake 2026 | contextual other | Jia 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Jia 2025 | Wang 2026b | contextual other | Jia 2025 (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Jia 2025 | Pepine 2026 | contextual other | Jia 2025 (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Jia 2025 | Gomaz 2026 | contextual other | Jia 2025 (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Jia 2025 | Savarese 2026 | contextual other | Jia 2025 (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Jia 2025 | Kehoe 2026 | contextual other | Jia 2025 (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Hu 2025 | Kato 2025 | dosing pharmacokinetics | Hu 2025 (null) vs Kato 2025 (unclear) on dosing pharmacokinetics | null vs positive (notable) |\n| agreement | 1 | Hu 2025 | Mei 2025 | dosing pharmacokinetics | Hu 2025 (null) vs Mei 2025 (null) on dosing pharmacokinetics | agreement (minor) |\n| agreement | 1 | Hu 2025 | Ahn 2026 | dosing pharmacokinetics | Hu 2025 (null) vs Ahn 2026 (null) on dosing pharmacokinetics | agreement (minor) |\n| agreement | 1 | Hu 2025 | Goh 2026 | dosing pharmacokinetics | Hu 2025 (null) vs Goh 2026 (null) on dosing pharmacokinetics | agreement (minor) |\n| agreement | 1 | Nouhravesh 2025b | Ramaswamy 2025 | contextual other | Nouhravesh 2025b (null) vs Ramaswamy 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Nouhravesh 2025b | Schwartz 2025 | contextual other | Nouhravesh 2025b (null) vs Schwartz 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Nouhravesh 2025b | Fumarulo 2025 | contextual other | Nouhravesh 2025b (null) vs Fumarulo 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Nouhravesh 2025b | Derington 2025 | contextual other | Nouhravesh 2025b (null) vs Derington 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Nouhravesh 2025b | Shaddy 2025 | contextual other | Nouhravesh 2025b (null) vs Shaddy 2025 (null) on contextual other | agreement (minor) |\n| disagreement | 4 | Nouhravesh 2025b | Lee 2025 | contextual other | Nouhravesh 2025b (null) vs Lee 2025 (mixed) on contextual other | disagreement (load-bearing) |\n| agreement | 1 | Nouhravesh 2025b | Li 2025 | contextual other | Nouhravesh 2025b (null) vs Li 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Nouhravesh 2025b | Chimura 2025 | contextual other | Nouhravesh 2025b (null) vs Chimura 2025 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Nouhravesh 2025b | Jo 2025 | contextual other | Nouhravesh 2025b (null) vs Jo 2025 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Nouhravesh 2025b | Dou 2025 | contextual other | Nouhravesh 2025b (null) vs Dou 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Nouhravesh 2025b | Nouhravesh 2025 | contextual other | Nouhravesh 2025b (null) vs Nouhravesh 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nouhravesh 2025b | Nazari-Robati 2025 | contextual other | Nouhravesh 2025b (null) vs Nazari-Robati 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nouhravesh 2025b | Yu 2025 | contextual other | Nouhravesh 2025b (null) vs Yu 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nouhravesh 2025b | Omland 2025 | contextual other | Nouhravesh 2025b (null) vs Omland 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Nouhravesh 2025b | Rezazadeh 2025 | contextual other | Nouhravesh 2025b (null) vs Rezazadeh 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Nouhravesh 2025b | Takahashi 2025 | contextual other | Nouhravesh 2025b (null) vs Takahashi 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nouhravesh 2025b | Humphreys 2025 | contextual other | Nouhravesh 2025b (null) vs Humphreys 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Nouhravesh 2025b | Yang 2025 | contextual other | Nouhravesh 2025b (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Nouhravesh 2025b | Kim 2025 | contextual other | Nouhravesh 2025b (null) vs Kim 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Nouhravesh 2025b | Taha 2025 | contextual other | Nouhravesh 2025b (null) vs Taha 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Nouhravesh 2025b | Karanovic 2026 | contextual other | Nouhravesh 2025b (null) vs Karanovic 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nouhravesh 2025b | Odeh 2026 | contextual other | Nouhravesh 2025b (null) vs Odeh 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nouhravesh 2025b | Han 2026 | contextual other | Nouhravesh 2025b (null) vs Han 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nouhravesh 2025b | Senanayake 2026 | contextual other | Nouhravesh 2025b (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nouhravesh 2025b | Wang 2026b | contextual other | Nouhravesh 2025b (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Nouhravesh 2025b | Pepine 2026 | contextual other | Nouhravesh 2025b (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Nouhravesh 2025b | Gomaz 2026 | contextual other | Nouhravesh 2025b (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Nouhravesh 2025b | Savarese 2026 | contextual other | Nouhravesh 2025b (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Nouhravesh 2025b | Kehoe 2026 | contextual other | Nouhravesh 2025b (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Ramaswamy 2025 | Schwartz 2025 | contextual other | Ramaswamy 2025 (null) vs Schwartz 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Ramaswamy 2025 | Fumarulo 2025 | contextual other | Ramaswamy 2025 (null) vs Fumarulo 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Ramaswamy 2025 | Derington 2025 | contextual other | Ramaswamy 2025 (null) vs Derington 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Ramaswamy 2025 | Shaddy 2025 | contextual other | Ramaswamy 2025 (null) vs Shaddy 2025 (null) on contextual other | agreement (minor) |\n| disagreement | 4 | Ramaswamy 2025 | Lee 2025 | contextual other | Ramaswamy 2025 (null) vs Lee 2025 (mixed) on contextual other | disagreement (load-bearing) |\n| agreement | 1 | Ramaswamy 2025 | Li 2025 | contextual other | Ramaswamy 2025 (null) vs Li 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Ramaswamy 2025 | Chimura 2025 | contextual other | Ramaswamy 2025 (null) vs Chimura 2025 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Ramaswamy 2025 | Jo 2025 | contextual other | Ramaswamy 2025 (null) vs Jo 2025 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Ramaswamy 2025 | Dou 2025 | contextual other | Ramaswamy 2025 (null) vs Dou 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Ramaswamy 2025 | Nouhravesh 2025 | contextual other | Ramaswamy 2025 (null) vs Nouhravesh 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Ramaswamy 2025 | Nazari-Robati 2025 | contextual other | Ramaswamy 2025 (null) vs Nazari-Robati 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Ramaswamy 2025 | Yu 2025 | contextual other | Ramaswamy 2025 (null) vs Yu 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Ramaswamy 2025 | Omland 2025 | contextual other | Ramaswamy 2025 (null) vs Omland 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Ramaswamy 2025 | Rezazadeh 2025 | contextual other | Ramaswamy 2025 (null) vs Rezazadeh 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Ramaswamy 2025 | Takahashi 2025 | contextual other | Ramaswamy 2025 (null) vs Takahashi 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Ramaswamy 2025 | Humphreys 2025 | contextual other | Ramaswamy 2025 (null) vs Humphreys 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Ramaswamy 2025 | Yang 2025 | contextual other | Ramaswamy 2025 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Ramaswamy 2025 | Kim 2025 | contextual other | Ramaswamy 2025 (null) vs Kim 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Ramaswamy 2025 | Taha 2025 | contextual other | Ramaswamy 2025 (null) vs Taha 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Ramaswamy 2025 | Karanovic 2026 | contextual other | Ramaswamy 2025 (null) vs Karanovic 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Ramaswamy 2025 | Odeh 2026 | contextual other | Ramaswamy 2025 (null) vs Odeh 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Ramaswamy 2025 | Han 2026 | contextual other | Ramaswamy 2025 (null) vs Han 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Ramaswamy 2025 | Senanayake 2026 | contextual other | Ramaswamy 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Ramaswamy 2025 | Wang 2026b | contextual other | Ramaswamy 2025 (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Ramaswamy 2025 | Pepine 2026 | contextual other | Ramaswamy 2025 (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Ramaswamy 2025 | Gomaz 2026 | contextual other | Ramaswamy 2025 (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Ramaswamy 2025 | Savarese 2026 | contextual other | Ramaswamy 2025 (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Ramaswamy 2025 | Kehoe 2026 | contextual other | Ramaswamy 2025 (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Schwartz 2025 | Fumarulo 2025 | contextual other | Schwartz 2025 (positive) vs Fumarulo 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Schwartz 2025 | Shaddy 2025 | contextual other | Schwartz 2025 (positive) vs Shaddy 2025 (null) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Schwartz 2025 | Lee 2025 | contextual other | Schwartz 2025 (positive) vs Lee 2025 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Schwartz 2025 | Li 2025 | contextual other | Schwartz 2025 (positive) vs Li 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Schwartz 2025 | Nouhravesh 2025 | contextual other | Schwartz 2025 (positive) vs Nouhravesh 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Schwartz 2025 | Nazari-Robati 2025 | contextual other | Schwartz 2025 (positive) vs Nazari-Robati 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Schwartz 2025 | Yu 2025 | contextual other | Schwartz 2025 (positive) vs Yu 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Schwartz 2025 | Omland 2025 | contextual other | Schwartz 2025 (positive) vs Omland 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Schwartz 2025 | Takahashi 2025 | contextual other | Schwartz 2025 (positive) vs Takahashi 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Schwartz 2025 | Humphreys 2025 | contextual other | Schwartz 2025 (positive) vs Humphreys 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Schwartz 2025 | Kim 2025 | contextual other | Schwartz 2025 (positive) vs Kim 2025 (null) on contextual other | null vs positive (notable) |\n| agreement | 1 | Schwartz 2025 | Taha 2025 | contextual other | Schwartz 2025 (positive) vs Taha 2025 (positive) on contextual other | agreement (minor) |\n| null vs positive | 3 | Schwartz 2025 | Karanovic 2026 | contextual other | Schwartz 2025 (positive) vs Karanovic 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Schwartz 2025 | Odeh 2026 | contextual other | Schwartz 2025 (positive) vs Odeh 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Schwartz 2025 | Han 2026 | contextual other | Schwartz 2025 (positive) vs Han 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Schwartz 2025 | Senanayake 2026 | contextual other | Schwartz 2025 (positive) vs Senanayake 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Schwartz 2025 | Wang 2026b | contextual other | Schwartz 2025 (positive) vs Wang 2026b (null) on contextual other | null vs positive (notable) |\n| agreement | 1 | Schwartz 2025 | Pepine 2026 | contextual other | Schwartz 2025 (positive) vs Pepine 2026 (positive) on contextual other | agreement (minor) |\n| disagreement | 4 | Schwartz 2025 | Gomaz 2026 | contextual other | Schwartz 2025 (positive) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Fumarulo 2025 | Derington 2025 | contextual other | Fumarulo 2025 (null) vs Derington 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Fumarulo 2025 | Shaddy 2025 | contextual other | Fumarulo 2025 (null) vs Shaddy 2025 (null) on contextual other | agreement (minor) |\n| disagreement | 4 | Fumarulo 2025 | Lee 2025 | contextual other | Fumarulo 2025 (null) vs Lee 2025 (mixed) on contextual other | disagreement (load-bearing) |\n| agreement | 1 | Fumarulo 2025 | Li 2025 | contextual other | Fumarulo 2025 (null) vs Li 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Fumarulo 2025 | Chimura 2025 | contextual other | Fumarulo 2025 (null) vs Chimura 2025 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Fumarulo 2025 | Jo 2025 | contextual other | Fumarulo 2025 (null) vs Jo 2025 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Fumarulo 2025 | Dou 2025 | contextual other | Fumarulo 2025 (null) vs Dou 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Fumarulo 2025 | Nouhravesh 2025 | contextual other | Fumarulo 2025 (null) vs Nouhravesh 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Fumarulo 2025 | Nazari-Robati 2025 | contextual other | Fumarulo 2025 (null) vs Nazari-Robati 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Fumarulo 2025 | Yu 2025 | contextual other | Fumarulo 2025 (null) vs Yu 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Fumarulo 2025 | Omland 2025 | contextual other | Fumarulo 2025 (null) vs Omland 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Fumarulo 2025 | Rezazadeh 2025 | contextual other | Fumarulo 2025 (null) vs Rezazadeh 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Fumarulo 2025 | Takahashi 2025 | contextual other | Fumarulo 2025 (null) vs Takahashi 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Fumarulo 2025 | Humphreys 2025 | contextual other | Fumarulo 2025 (null) vs Humphreys 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Fumarulo 2025 | Yang 2025 | contextual other | Fumarulo 2025 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Fumarulo 2025 | Kim 2025 | contextual other | Fumarulo 2025 (null) vs Kim 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Fumarulo 2025 | Taha 2025 | contextual other | Fumarulo 2025 (null) vs Taha 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Fumarulo 2025 | Karanovic 2026 | contextual other | Fumarulo 2025 (null) vs Karanovic 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Fumarulo 2025 | Odeh 2026 | contextual other | Fumarulo 2025 (null) vs Odeh 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Fumarulo 2025 | Han 2026 | contextual other | Fumarulo 2025 (null) vs Han 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Fumarulo 2025 | Senanayake 2026 | contextual other | Fumarulo 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Fumarulo 2025 | Wang 2026b | contextual other | Fumarulo 2025 (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Fumarulo 2025 | Pepine 2026 | contextual other | Fumarulo 2025 (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Fumarulo 2025 | Gomaz 2026 | contextual other | Fumarulo 2025 (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Fumarulo 2025 | Savarese 2026 | contextual other | Fumarulo 2025 (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Fumarulo 2025 | Kehoe 2026 | contextual other | Fumarulo 2025 (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Albertini 2025 | Kuang 2025 | safety comorbidity | Albertini 2025 (null) vs Kuang 2025 (null) on safety comorbidity | agreement (minor) |\n| agreement | 1 | Albertini 2025 | Bavendiek 2025 | safety comorbidity | Albertini 2025 (null) vs Bavendiek 2025 (null) on safety comorbidity | agreement (minor) |\n| agreement | 1 | Albertini 2025 | Wang 2025 | safety comorbidity | Albertini 2025 (null) vs Wang 2025 (null) on safety comorbidity | agreement (minor) |\n| agreement | 1 | Albertini 2025 | Wang 2025c | safety comorbidity | Albertini 2025 (null) vs Wang 2025c (null) on safety comorbidity | agreement (minor) |\n| agreement | 1 | Albertini 2025 | Ngai 2025 | safety comorbidity | Albertini 2025 (null) vs Ngai 2025 (null) on safety comorbidity | agreement (minor) |\n| null vs positive | 3 | Albertini 2025 | Tu 2026 | safety comorbidity | Albertini 2025 (null) vs Tu 2026 (positive) on safety comorbidity | null vs positive (notable) |\n| null vs positive | 3 | Albertini 2025 | Silva 2026 | safety comorbidity | Albertini 2025 (null) vs Silva 2026 (positive) on safety comorbidity | null vs positive (notable) |\n| agreement | 1 | Albertini 2025 | Al-Omari 2026 | safety comorbidity | Albertini 2025 (null) vs Al-Omari 2026 (null) on safety comorbidity | agreement (minor) |\n| null vs positive | 3 | Agarwal 2025 | Jin 2025 | longevity | Agarwal 2025 (null) vs Jin 2025 (unclear) on longevity | null vs positive (notable) |\n| null vs positive | 3 | Agarwal 2025 | Murray-Thomas 2025 | longevity | Agarwal 2025 (null) vs Murray-Thomas 2025 (unclear) on longevity | null vs positive (notable) |\n| null vs positive | 3 | Agarwal 2025 | Wang 2026 | longevity | Agarwal 2025 (null) vs Wang 2026 (unclear) on longevity | null vs positive (notable) |\n| null vs positive | 3 | Derington 2025 | Shaddy 2025 | contextual other | Derington 2025 (unclear) vs Shaddy 2025 (null) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Derington 2025 | Lee 2025 | contextual other | Derington 2025 (unclear) vs Lee 2025 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Derington 2025 | Li 2025 | contextual other | Derington 2025 (unclear) vs Li 2025 (null) on contextual other | null vs positive (notable) |\n| agreement | 1 | Derington 2025 | Chimura 2025 | contextual other | Derington 2025 (unclear) vs Chimura 2025 (unclear) on contextual other | agreement (minor) |\n| agreement | 1 | Derington 2025 | Jo 2025 | contextual other | Derington 2025 (unclear) vs Jo 2025 (unclear) on contextual other | agreement (minor) |\n| agreement | 1 | Derington 2025 | Dou 2025 | contextual other | Derington 2025 (unclear) vs Dou 2025 (unclear) on contextual other | agreement (minor) |\n| null vs positive | 3 | Derington 2025 | Nouhravesh 2025 | contextual other | Derington 2025 (unclear) vs Nouhravesh 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Derington 2025 | Nazari-Robati 2025 | contextual other | Derington 2025 (unclear) vs Nazari-Robati 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Derington 2025 | Yu 2025 | contextual other | Derington 2025 (unclear) vs Yu 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Derington 2025 | Omland 2025 | contextual other | Derington 2025 (unclear) vs Omland 2025 (null) on contextual other | null vs positive (notable) |\n| agreement | 1 | Derington 2025 | Rezazadeh 2025 | contextual other | Derington 2025 (unclear) vs Rezazadeh 2025 (unclear) on contextual other | agreement (minor) |\n| null vs positive | 3 | Derington 2025 | Takahashi 2025 | contextual other | Derington 2025 (unclear) vs Takahashi 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Derington 2025 | Humphreys 2025 | contextual other | Derington 2025 (unclear) vs Humphreys 2025 (null) on contextual other | null vs positive (notable) |\n| agreement | 1 | Derington 2025 | Yang 2025 | contextual other | Derington 2025 (unclear) vs Yang 2025 (unclear) on contextual other | agreement (minor) |\n| null vs positive | 3 | Derington 2025 | Kim 2025 | contextual other | Derington 2025 (unclear) vs Kim 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Derington 2025 | Karanovic 2026 | contextual other | Derington 2025 (unclear) vs Karanovic 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Derington 2025 | Odeh 2026 | contextual other | Derington 2025 (unclear) vs Odeh 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Derington 2025 | Han 2026 | contextual other | Derington 2025 (unclear) vs Han 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Derington 2025 | Senanayake 2026 | contextual other | Derington 2025 (unclear) vs Senanayake 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Derington 2025 | Wang 2026b | contextual other | Derington 2025 (unclear) vs Wang 2026b (null) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Derington 2025 | Gomaz 2026 | contextual other | Derington 2025 (unclear) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| agreement | 1 | Derington 2025 | Savarese 2026 | contextual other | Derington 2025 (unclear) vs Savarese 2026 (unclear) on contextual other | agreement (minor) |\n| agreement | 1 | Derington 2025 | Kehoe 2026 | contextual other | Derington 2025 (unclear) vs Kehoe 2026 (unclear) on contextual other | agreement (minor) |\n| disagreement | 4 | Shaddy 2025 | Lee 2025 | contextual other | Shaddy 2025 (null) vs Lee 2025 (mixed) on contextual other | disagreement (load-bearing) |\n| agreement | 1 | Shaddy 2025 | Li 2025 | contextual other | Shaddy 2025 (null) vs Li 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Shaddy 2025 | Chimura 2025 | contextual other | Shaddy 2025 (null) vs Chimura 2025 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Shaddy 2025 | Jo 2025 | contextual other | Shaddy 2025 (null) vs Jo 2025 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Shaddy 2025 | Dou 2025 | contextual other | Shaddy 2025 (null) vs Dou 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Shaddy 2025 | Nouhravesh 2025 | contextual other | Shaddy 2025 (null) vs Nouhravesh 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Shaddy 2025 | Nazari-Robati 2025 | contextual other | Shaddy 2025 (null) vs Nazari-Robati 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Shaddy 2025 | Yu 2025 | contextual other | Shaddy 2025 (null) vs Yu 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Shaddy 2025 | Omland 2025 | contextual other | Shaddy 2025 (null) vs Omland 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Shaddy 2025 | Rezazadeh 2025 | contextual other | Shaddy 2025 (null) vs Rezazadeh 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Shaddy 2025 | Takahashi 2025 | contextual other | Shaddy 2025 (null) vs Takahashi 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Shaddy 2025 | Humphreys 2025 | contextual other | Shaddy 2025 (null) vs Humphreys 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Shaddy 2025 | Yang 2025 | contextual other | Shaddy 2025 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Shaddy 2025 | Kim 2025 | contextual other | Shaddy 2025 (null) vs Kim 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Shaddy 2025 | Taha 2025 | contextual other | Shaddy 2025 (null) vs Taha 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Shaddy 2025 | Karanovic 2026 | contextual other | Shaddy 2025 (null) vs Karanovic 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Shaddy 2025 | Odeh 2026 | contextual other | Shaddy 2025 (null) vs Odeh 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Shaddy 2025 | Han 2026 | contextual other | Shaddy 2025 (null) vs Han 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Shaddy 2025 | Senanayake 2026 | contextual other | Shaddy 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Shaddy 2025 | Wang 2026b | contextual other | Shaddy 2025 (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Shaddy 2025 | Pepine 2026 | contextual other | Shaddy 2025 (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Shaddy 2025 | Gomaz 2026 | contextual other | Shaddy 2025 (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Shaddy 2025 | Savarese 2026 | contextual other | Shaddy 2025 (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Shaddy 2025 | Kehoe 2026 | contextual other | Shaddy 2025 (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Lee 2025 | Li 2025 | contextual other | Lee 2025 (mixed) vs Li 2025 (null) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Chimura 2025 | contextual other | Lee 2025 (mixed) vs Chimura 2025 (unclear) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Jo 2025 | contextual other | Lee 2025 (mixed) vs Jo 2025 (unclear) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Dou 2025 | contextual other | Lee 2025 (mixed) vs Dou 2025 (unclear) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Nouhravesh 2025 | contextual other | Lee 2025 (mixed) vs Nouhravesh 2025 (null) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Nazari-Robati 2025 | contextual other | Lee 2025 (mixed) vs Nazari-Robati 2025 (null) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Yu 2025 | contextual other | Lee 2025 (mixed) vs Yu 2025 (null) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Omland 2025 | contextual other | Lee 2025 (mixed) vs Omland 2025 (null) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Rezazadeh 2025 | contextual other | Lee 2025 (mixed) vs Rezazadeh 2025 (unclear) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Takahashi 2025 | contextual other | Lee 2025 (mixed) vs Takahashi 2025 (null) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Humphreys 2025 | contextual other | Lee 2025 (mixed) vs Humphreys 2025 (null) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Yang 2025 | contextual other | Lee 2025 (mixed) vs Yang 2025 (unclear) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Kim 2025 | contextual other | Lee 2025 (mixed) vs Kim 2025 (null) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Taha 2025 | contextual other | Lee 2025 (mixed) vs Taha 2025 (positive) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Karanovic 2026 | contextual other | Lee 2025 (mixed) vs Karanovic 2026 (null) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Odeh 2026 | contextual other | Lee 2025 (mixed) vs Odeh 2026 (null) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Han 2026 | contextual other | Lee 2025 (mixed) vs Han 2026 (null) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Senanayake 2026 | contextual other | Lee 2025 (mixed) vs Senanayake 2026 (null) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Wang 2026b | contextual other | Lee 2025 (mixed) vs Wang 2026b (null) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Pepine 2026 | contextual other | Lee 2025 (mixed) vs Pepine 2026 (positive) on contextual other | disagreement (load-bearing) |\n| agreement | 1 | Lee 2025 | Gomaz 2026 | contextual other | Lee 2025 (mixed) vs Gomaz 2026 (mixed) on contextual other | agreement (minor) |\n| disagreement | 4 | Lee 2025 | Savarese 2026 | contextual other | Lee 2025 (mixed) vs Savarese 2026 (unclear) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Lee 2025 | Kehoe 2026 | contextual other | Lee 2025 (mixed) vs Kehoe 2026 (unclear) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Li 2025 | Chimura 2025 | contextual other | Li 2025 (null) vs Chimura 2025 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Li 2025 | Jo 2025 | contextual other | Li 2025 (null) vs Jo 2025 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Li 2025 | Dou 2025 | contextual other | Li 2025 (null) vs Dou 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Li 2025 | Nouhravesh 2025 | contextual other | Li 2025 (null) vs Nouhravesh 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Li 2025 | Nazari-Robati 2025 | contextual other | Li 2025 (null) vs Nazari-Robati 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Li 2025 | Yu 2025 | contextual other | Li 2025 (null) vs Yu 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Li 2025 | Omland 2025 | contextual other | Li 2025 (null) vs Omland 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Li 2025 | Rezazadeh 2025 | contextual other | Li 2025 (null) vs Rezazadeh 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Li 2025 | Takahashi 2025 | contextual other | Li 2025 (null) vs Takahashi 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Li 2025 | Humphreys 2025 | contextual other | Li 2025 (null) vs Humphreys 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Li 2025 | Yang 2025 | contextual other | Li 2025 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Li 2025 | Kim 2025 | contextual other | Li 2025 (null) vs Kim 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Li 2025 | Taha 2025 | contextual other | Li 2025 (null) vs Taha 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Li 2025 | Karanovic 2026 | contextual other | Li 2025 (null) vs Karanovic 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Li 2025 | Odeh 2026 | contextual other | Li 2025 (null) vs Odeh 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Li 2025 | Han 2026 | contextual other | Li 2025 (null) vs Han 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Li 2025 | Senanayake 2026 | contextual other | Li 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Li 2025 | Wang 2026b | contextual other | Li 2025 (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Li 2025 | Pepine 2026 | contextual other | Li 2025 (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Li 2025 | Gomaz 2026 | contextual other | Li 2025 (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Li 2025 | Savarese 2026 | contextual other | Li 2025 (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Li 2025 | Kehoe 2026 | contextual other | Li 2025 (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Chimura 2025 | Jo 2025 | contextual other | Chimura 2025 (unclear) vs Jo 2025 (unclear) on contextual other | agreement (minor) |\n| agreement | 1 | Chimura 2025 | Dou 2025 | contextual other | Chimura 2025 (unclear) vs Dou 2025 (unclear) on contextual other | agreement (minor) |\n| null vs positive | 3 | Chimura 2025 | Nouhravesh 2025 | contextual other | Chimura 2025 (unclear) vs Nouhravesh 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Chimura 2025 | Nazari-Robati 2025 | contextual other | Chimura 2025 (unclear) vs Nazari-Robati 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Chimura 2025 | Yu 2025 | contextual other | Chimura 2025 (unclear) vs Yu 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Chimura 2025 | Omland 2025 | contextual other | Chimura 2025 (unclear) vs Omland 2025 (null) on contextual other | null vs positive (notable) |\n| agreement | 1 | Chimura 2025 | Rezazadeh 2025 | contextual other | Chimura 2025 (unclear) vs Rezazadeh 2025 (unclear) on contextual other | agreement (minor) |\n| null vs positive | 3 | Chimura 2025 | Takahashi 2025 | contextual other | Chimura 2025 (unclear) vs Takahashi 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Chimura 2025 | Humphreys 2025 | contextual other | Chimura 2025 (unclear) vs Humphreys 2025 (null) on contextual other | null vs positive (notable) |\n| agreement | 1 | Chimura 2025 | Yang 2025 | contextual other | Chimura 2025 (unclear) vs Yang 2025 (unclear) on contextual other | agreement (minor) |\n| null vs positive | 3 | Chimura 2025 | Kim 2025 | contextual other | Chimura 2025 (unclear) vs Kim 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Chimura 2025 | Karanovic 2026 | contextual other | Chimura 2025 (unclear) vs Karanovic 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Chimura 2025 | Odeh 2026 | contextual other | Chimura 2025 (unclear) vs Odeh 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Chimura 2025 | Han 2026 | contextual other | Chimura 2025 (unclear) vs Han 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Chimura 2025 | Senanayake 2026 | contextual other | Chimura 2025 (unclear) vs Senanayake 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Chimura 2025 | Wang 2026b | contextual other | Chimura 2025 (unclear) vs Wang 2026b (null) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Chimura 2025 | Gomaz 2026 | contextual other | Chimura 2025 (unclear) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| agreement | 1 | Chimura 2025 | Savarese 2026 | contextual other | Chimura 2025 (unclear) vs Savarese 2026 (unclear) on contextual other | agreement (minor) |\n| agreement | 1 | Chimura 2025 | Kehoe 2026 | contextual other | Chimura 2025 (unclear) vs Kehoe 2026 (unclear) on contextual other | agreement (minor) |\n| agreement | 1 | Kuang 2025 | Bavendiek 2025 | safety comorbidity | Kuang 2025 (null) vs Bavendiek 2025 (null) on safety comorbidity | agreement (minor) |\n| agreement | 1 | Kuang 2025 | Wang 2025 | safety comorbidity | Kuang 2025 (null) vs Wang 2025 (null) on safety comorbidity | agreement (minor) |\n| agreement | 1 | Kuang 2025 | Wang 2025c | safety comorbidity | Kuang 2025 (null) vs Wang 2025c (null) on safety comorbidity | agreement (minor) |\n| agreement | 1 | Kuang 2025 | Ngai 2025 | safety comorbidity | Kuang 2025 (null) vs Ngai 2025 (null) on safety comorbidity | agreement (minor) |\n| null vs positive | 3 | Kuang 2025 | Tu 2026 | safety comorbidity | Kuang 2025 (null) vs Tu 2026 (positive) on safety comorbidity | null vs positive (notable) |\n| null vs positive | 3 | Kuang 2025 | Silva 2026 | safety comorbidity | Kuang 2025 (null) vs Silva 2026 (positive) on safety comorbidity | null vs positive (notable) |\n| agreement | 1 | Kuang 2025 | Al-Omari 2026 | safety comorbidity | Kuang 2025 (null) vs Al-Omari 2026 (null) on safety comorbidity | agreement (minor) |\n| agreement | 1 | Bavendiek 2025 | Wang 2025 | safety comorbidity | Bavendiek 2025 (null) vs Wang 2025 (null) on safety comorbidity | agreement (minor) |\n| agreement | 1 | Bavendiek 2025 | Wang 2025c | safety comorbidity | Bavendiek 2025 (null) vs Wang 2025c (null) on safety comorbidity | agreement (minor) |\n| agreement | 1 | Bavendiek 2025 | Ngai 2025 | safety comorbidity | Bavendiek 2025 (null) vs Ngai 2025 (null) on safety comorbidity | agreement (minor) |\n| null vs positive | 3 | Bavendiek 2025 | Tu 2026 | safety comorbidity | Bavendiek 2025 (null) vs Tu 2026 (positive) on safety comorbidity | null vs positive (notable) |\n| null vs positive | 3 | Bavendiek 2025 | Silva 2026 | safety comorbidity | Bavendiek 2025 (null) vs Silva 2026 (positive) on safety comorbidity | null vs positive (notable) |\n| agreement | 1 | Bavendiek 2025 | Al-Omari 2026 | safety comorbidity | Bavendiek 2025 (null) vs Al-Omari 2026 (null) on safety comorbidity | agreement (minor) |\n| null vs positive | 3 | Kato 2025 | Mei 2025 | dosing pharmacokinetics | Kato 2025 (unclear) vs Mei 2025 (null) on dosing pharmacokinetics | null vs positive (notable) |\n| null vs positive | 3 | Kato 2025 | Ahn 2026 | dosing pharmacokinetics | Kato 2025 (unclear) vs Ahn 2026 (null) on dosing pharmacokinetics | null vs positive (notable) |\n| null vs positive | 3 | Kato 2025 | Goh 2026 | dosing pharmacokinetics | Kato 2025 (unclear) vs Goh 2026 (null) on dosing pharmacokinetics | null vs positive (notable) |\n| null vs positive | 3 | Wever 2025 | Wang 2025b | cardiometabolic | Wever 2025 (unclear) vs Wang 2025b (null) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Wever 2025 | Abhari 2026 | cardiometabolic | Wever 2025 (unclear) vs Abhari 2026 (unclear) on cardiometabolic | agreement (minor) |\n| null vs positive | 3 | Wever 2025 | Din 2026 | cardiometabolic | Wever 2025 (unclear) vs Din 2026 (null) on cardiometabolic | null vs positive (notable) |\n| null vs positive | 3 | Wever 2025 | Shubietah 2026 | cardiometabolic | Wever 2025 (unclear) vs Shubietah 2026 (null) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Jin 2025 | Murray-Thomas 2025 | longevity | Jin 2025 (unclear) vs Murray-Thomas 2025 (unclear) on longevity | agreement (minor) |\n| agreement | 1 | Jin 2025 | Wang 2026 | longevity | Jin 2025 (unclear) vs Wang 2026 (unclear) on longevity | agreement (minor) |\n| agreement | 1 | Jo 2025 | Dou 2025 | contextual other | Jo 2025 (unclear) vs Dou 2025 (unclear) on contextual other | agreement (minor) |\n| null vs positive | 3 | Jo 2025 | Nouhravesh 2025 | contextual other | Jo 2025 (unclear) vs Nouhravesh 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Jo 2025 | Nazari-Robati 2025 | contextual other | Jo 2025 (unclear) vs Nazari-Robati 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Jo 2025 | Yu 2025 | contextual other | Jo 2025 (unclear) vs Yu 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Jo 2025 | Omland 2025 | contextual other | Jo 2025 (unclear) vs Omland 2025 (null) on contextual other | null vs positive (notable) |\n| agreement | 1 | Jo 2025 | Rezazadeh 2025 | contextual other | Jo 2025 (unclear) vs Rezazadeh 2025 (unclear) on contextual other | agreement (minor) |\n| null vs positive | 3 | Jo 2025 | Takahashi 2025 | contextual other | Jo 2025 (unclear) vs Takahashi 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Jo 2025 | Humphreys 2025 | contextual other | Jo 2025 (unclear) vs Humphreys 2025 (null) on contextual other | null vs positive (notable) |\n| agreement | 1 | Jo 2025 | Yang 2025 | contextual other | Jo 2025 (unclear) vs Yang 2025 (unclear) on contextual other | agreement (minor) |\n| null vs positive | 3 | Jo 2025 | Kim 2025 | contextual other | Jo 2025 (unclear) vs Kim 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Jo 2025 | Karanovic 2026 | contextual other | Jo 2025 (unclear) vs Karanovic 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Jo 2025 | Odeh 2026 | contextual other | Jo 2025 (unclear) vs Odeh 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Jo 2025 | Han 2026 | contextual other | Jo 2025 (unclear) vs Han 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Jo 2025 | Senanayake 2026 | contextual other | Jo 2025 (unclear) vs Senanayake 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Jo 2025 | Wang 2026b | contextual other | Jo 2025 (unclear) vs Wang 2026b (null) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Jo 2025 | Gomaz 2026 | contextual other | Jo 2025 (unclear) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| agreement | 1 | Jo 2025 | Savarese 2026 | contextual other | Jo 2025 (unclear) vs Savarese 2026 (unclear) on contextual other | agreement (minor) |\n| agreement | 1 | Jo 2025 | Kehoe 2026 | contextual other | Jo 2025 (unclear) vs Kehoe 2026 (unclear) on contextual other | agreement (minor) |\n| agreement | 1 | Murray-Thomas 2025 | Wang 2026 | longevity | Murray-Thomas 2025 (unclear) vs Wang 2026 (unclear) on longevity | agreement (minor) |\n| null vs positive | 3 | Dou 2025 | Nouhravesh 2025 | contextual other | Dou 2025 (unclear) vs Nouhravesh 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Dou 2025 | Nazari-Robati 2025 | contextual other | Dou 2025 (unclear) vs Nazari-Robati 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Dou 2025 | Yu 2025 | contextual other | Dou 2025 (unclear) vs Yu 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Dou 2025 | Omland 2025 | contextual other | Dou 2025 (unclear) vs Omland 2025 (null) on contextual other | null vs positive (notable) |\n| agreement | 1 | Dou 2025 | Rezazadeh 2025 | contextual other | Dou 2025 (unclear) vs Rezazadeh 2025 (unclear) on contextual other | agreement (minor) |\n| null vs positive | 3 | Dou 2025 | Takahashi 2025 | contextual other | Dou 2025 (unclear) vs Takahashi 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Dou 2025 | Humphreys 2025 | contextual other | Dou 2025 (unclear) vs Humphreys 2025 (null) on contextual other | null vs positive (notable) |\n| agreement | 1 | Dou 2025 | Yang 2025 | contextual other | Dou 2025 (unclear) vs Yang 2025 (unclear) on contextual other | agreement (minor) |\n| null vs positive | 3 | Dou 2025 | Kim 2025 | contextual other | Dou 2025 (unclear) vs Kim 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Dou 2025 | Karanovic 2026 | contextual other | Dou 2025 (unclear) vs Karanovic 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Dou 2025 | Odeh 2026 | contextual other | Dou 2025 (unclear) vs Odeh 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Dou 2025 | Han 2026 | contextual other | Dou 2025 (unclear) vs Han 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Dou 2025 | Senanayake 2026 | contextual other | Dou 2025 (unclear) vs Senanayake 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Dou 2025 | Wang 2026b | contextual other | Dou 2025 (unclear) vs Wang 2026b (null) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Dou 2025 | Gomaz 2026 | contextual other | Dou 2025 (unclear) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| agreement | 1 | Dou 2025 | Savarese 2026 | contextual other | Dou 2025 (unclear) vs Savarese 2026 (unclear) on contextual other | agreement (minor) |\n| agreement | 1 | Dou 2025 | Kehoe 2026 | contextual other | Dou 2025 (unclear) vs Kehoe 2026 (unclear) on contextual other | agreement (minor) |\n| agreement | 1 | Nouhravesh 2025 | Nazari-Robati 2025 | contextual other | Nouhravesh 2025 (null) vs Nazari-Robati 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nouhravesh 2025 | Yu 2025 | contextual other | Nouhravesh 2025 (null) vs Yu 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nouhravesh 2025 | Omland 2025 | contextual other | Nouhravesh 2025 (null) vs Omland 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Nouhravesh 2025 | Rezazadeh 2025 | contextual other | Nouhravesh 2025 (null) vs Rezazadeh 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Nouhravesh 2025 | Takahashi 2025 | contextual other | Nouhravesh 2025 (null) vs Takahashi 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nouhravesh 2025 | Humphreys 2025 | contextual other | Nouhravesh 2025 (null) vs Humphreys 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Nouhravesh 2025 | Yang 2025 | contextual other | Nouhravesh 2025 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Nouhravesh 2025 | Kim 2025 | contextual other | Nouhravesh 2025 (null) vs Kim 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Nouhravesh 2025 | Taha 2025 | contextual other | Nouhravesh 2025 (null) vs Taha 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Nouhravesh 2025 | Karanovic 2026 | contextual other | Nouhravesh 2025 (null) vs Karanovic 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nouhravesh 2025 | Odeh 2026 | contextual other | Nouhravesh 2025 (null) vs Odeh 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nouhravesh 2025 | Han 2026 | contextual other | Nouhravesh 2025 (null) vs Han 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nouhravesh 2025 | Senanayake 2026 | contextual other | Nouhravesh 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nouhravesh 2025 | Wang 2026b | contextual other | Nouhravesh 2025 (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Nouhravesh 2025 | Pepine 2026 | contextual other | Nouhravesh 2025 (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Nouhravesh 2025 | Gomaz 2026 | contextual other | Nouhravesh 2025 (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Nouhravesh 2025 | Savarese 2026 | contextual other | Nouhravesh 2025 (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Nouhravesh 2025 | Kehoe 2026 | contextual other | Nouhravesh 2025 (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Nazari-Robati 2025 | Yu 2025 | contextual other | Nazari-Robati 2025 (null) vs Yu 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nazari-Robati 2025 | Omland 2025 | contextual other | Nazari-Robati 2025 (null) vs Omland 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Nazari-Robati 2025 | Rezazadeh 2025 | contextual other | Nazari-Robati 2025 (null) vs Rezazadeh 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Nazari-Robati 2025 | Takahashi 2025 | contextual other | Nazari-Robati 2025 (null) vs Takahashi 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nazari-Robati 2025 | Humphreys 2025 | contextual other | Nazari-Robati 2025 (null) vs Humphreys 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Nazari-Robati 2025 | Yang 2025 | contextual other | Nazari-Robati 2025 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Nazari-Robati 2025 | Kim 2025 | contextual other | Nazari-Robati 2025 (null) vs Kim 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Nazari-Robati 2025 | Taha 2025 | contextual other | Nazari-Robati 2025 (null) vs Taha 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Nazari-Robati 2025 | Karanovic 2026 | contextual other | Nazari-Robati 2025 (null) vs Karanovic 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nazari-Robati 2025 | Odeh 2026 | contextual other | Nazari-Robati 2025 (null) vs Odeh 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nazari-Robati 2025 | Han 2026 | contextual other | Nazari-Robati 2025 (null) vs Han 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nazari-Robati 2025 | Senanayake 2026 | contextual other | Nazari-Robati 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Nazari-Robati 2025 | Wang 2026b | contextual other | Nazari-Robati 2025 (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Nazari-Robati 2025 | Pepine 2026 | contextual other | Nazari-Robati 2025 (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Nazari-Robati 2025 | Gomaz 2026 | contextual other | Nazari-Robati 2025 (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Nazari-Robati 2025 | Savarese 2026 | contextual other | Nazari-Robati 2025 (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Nazari-Robati 2025 | Kehoe 2026 | contextual other | Nazari-Robati 2025 (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Wang 2025 | Wang 2025c | safety comorbidity | Wang 2025 (null) vs Wang 2025c (null) on safety comorbidity | agreement (minor) |\n| agreement | 1 | Wang 2025 | Ngai 2025 | safety comorbidity | Wang 2025 (null) vs Ngai 2025 (null) on safety comorbidity | agreement (minor) |\n| null vs positive | 3 | Wang 2025 | Tu 2026 | safety comorbidity | Wang 2025 (null) vs Tu 2026 (positive) on safety comorbidity | null vs positive (notable) |\n| null vs positive | 3 | Wang 2025 | Silva 2026 | safety comorbidity | Wang 2025 (null) vs Silva 2026 (positive) on safety comorbidity | null vs positive (notable) |\n| agreement | 1 | Wang 2025 | Al-Omari 2026 | safety comorbidity | Wang 2025 (null) vs Al-Omari 2026 (null) on safety comorbidity | agreement (minor) |\n| agreement | 1 | Yu 2025 | Omland 2025 | contextual other | Yu 2025 (null) vs Omland 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Yu 2025 | Rezazadeh 2025 | contextual other | Yu 2025 (null) vs Rezazadeh 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Yu 2025 | Takahashi 2025 | contextual other | Yu 2025 (null) vs Takahashi 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Yu 2025 | Humphreys 2025 | contextual other | Yu 2025 (null) vs Humphreys 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Yu 2025 | Yang 2025 | contextual other | Yu 2025 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Yu 2025 | Kim 2025 | contextual other | Yu 2025 (null) vs Kim 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Yu 2025 | Taha 2025 | contextual other | Yu 2025 (null) vs Taha 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Yu 2025 | Karanovic 2026 | contextual other | Yu 2025 (null) vs Karanovic 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Yu 2025 | Odeh 2026 | contextual other | Yu 2025 (null) vs Odeh 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Yu 2025 | Han 2026 | contextual other | Yu 2025 (null) vs Han 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Yu 2025 | Senanayake 2026 | contextual other | Yu 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Yu 2025 | Wang 2026b | contextual other | Yu 2025 (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Yu 2025 | Pepine 2026 | contextual other | Yu 2025 (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Yu 2025 | Gomaz 2026 | contextual other | Yu 2025 (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Yu 2025 | Savarese 2026 | contextual other | Yu 2025 (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Yu 2025 | Kehoe 2026 | contextual other | Yu 2025 (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Omland 2025 | Rezazadeh 2025 | contextual other | Omland 2025 (null) vs Rezazadeh 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Omland 2025 | Takahashi 2025 | contextual other | Omland 2025 (null) vs Takahashi 2025 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Omland 2025 | Humphreys 2025 | contextual other | Omland 2025 (null) vs Humphreys 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Omland 2025 | Yang 2025 | contextual other | Omland 2025 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Omland 2025 | Kim 2025 | contextual other | Omland 2025 (null) vs Kim 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Omland 2025 | Taha 2025 | contextual other | Omland 2025 (null) vs Taha 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Omland 2025 | Karanovic 2026 | contextual other | Omland 2025 (null) vs Karanovic 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Omland 2025 | Odeh 2026 | contextual other | Omland 2025 (null) vs Odeh 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Omland 2025 | Han 2026 | contextual other | Omland 2025 (null) vs Han 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Omland 2025 | Senanayake 2026 | contextual other | Omland 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Omland 2025 | Wang 2026b | contextual other | Omland 2025 (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Omland 2025 | Pepine 2026 | contextual other | Omland 2025 (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Omland 2025 | Gomaz 2026 | contextual other | Omland 2025 (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Omland 2025 | Savarese 2026 | contextual other | Omland 2025 (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Omland 2025 | Kehoe 2026 | contextual other | Omland 2025 (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Rezazadeh 2025 | Takahashi 2025 | contextual other | Rezazadeh 2025 (unclear) vs Takahashi 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Rezazadeh 2025 | Humphreys 2025 | contextual other | Rezazadeh 2025 (unclear) vs Humphreys 2025 (null) on contextual other | null vs positive (notable) |\n| agreement | 1 | Rezazadeh 2025 | Yang 2025 | contextual other | Rezazadeh 2025 (unclear) vs Yang 2025 (unclear) on contextual other | agreement (minor) |\n| null vs positive | 3 | Rezazadeh 2025 | Kim 2025 | contextual other | Rezazadeh 2025 (unclear) vs Kim 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Rezazadeh 2025 | Karanovic 2026 | contextual other | Rezazadeh 2025 (unclear) vs Karanovic 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Rezazadeh 2025 | Odeh 2026 | contextual other | Rezazadeh 2025 (unclear) vs Odeh 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Rezazadeh 2025 | Han 2026 | contextual other | Rezazadeh 2025 (unclear) vs Han 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Rezazadeh 2025 | Senanayake 2026 | contextual other | Rezazadeh 2025 (unclear) vs Senanayake 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Rezazadeh 2025 | Wang 2026b | contextual other | Rezazadeh 2025 (unclear) vs Wang 2026b (null) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Rezazadeh 2025 | Gomaz 2026 | contextual other | Rezazadeh 2025 (unclear) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| agreement | 1 | Rezazadeh 2025 | Savarese 2026 | contextual other | Rezazadeh 2025 (unclear) vs Savarese 2026 (unclear) on contextual other | agreement (minor) |\n| agreement | 1 | Rezazadeh 2025 | Kehoe 2026 | contextual other | Rezazadeh 2025 (unclear) vs Kehoe 2026 (unclear) on contextual other | agreement (minor) |\n| agreement | 1 | Takahashi 2025 | Humphreys 2025 | contextual other | Takahashi 2025 (null) vs Humphreys 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Takahashi 2025 | Yang 2025 | contextual other | Takahashi 2025 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Takahashi 2025 | Kim 2025 | contextual other | Takahashi 2025 (null) vs Kim 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Takahashi 2025 | Taha 2025 | contextual other | Takahashi 2025 (null) vs Taha 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Takahashi 2025 | Karanovic 2026 | contextual other | Takahashi 2025 (null) vs Karanovic 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Takahashi 2025 | Odeh 2026 | contextual other | Takahashi 2025 (null) vs Odeh 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Takahashi 2025 | Han 2026 | contextual other | Takahashi 2025 (null) vs Han 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Takahashi 2025 | Senanayake 2026 | contextual other | Takahashi 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Takahashi 2025 | Wang 2026b | contextual other | Takahashi 2025 (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Takahashi 2025 | Pepine 2026 | contextual other | Takahashi 2025 (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Takahashi 2025 | Gomaz 2026 | contextual other | Takahashi 2025 (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Takahashi 2025 | Savarese 2026 | contextual other | Takahashi 2025 (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Takahashi 2025 | Kehoe 2026 | contextual other | Takahashi 2025 (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Humphreys 2025 | Yang 2025 | contextual other | Humphreys 2025 (null) vs Yang 2025 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Humphreys 2025 | Kim 2025 | contextual other | Humphreys 2025 (null) vs Kim 2025 (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Humphreys 2025 | Taha 2025 | contextual other | Humphreys 2025 (null) vs Taha 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Humphreys 2025 | Karanovic 2026 | contextual other | Humphreys 2025 (null) vs Karanovic 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Humphreys 2025 | Odeh 2026 | contextual other | Humphreys 2025 (null) vs Odeh 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Humphreys 2025 | Han 2026 | contextual other | Humphreys 2025 (null) vs Han 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Humphreys 2025 | Senanayake 2026 | contextual other | Humphreys 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Humphreys 2025 | Wang 2026b | contextual other | Humphreys 2025 (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Humphreys 2025 | Pepine 2026 | contextual other | Humphreys 2025 (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Humphreys 2025 | Gomaz 2026 | contextual other | Humphreys 2025 (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Humphreys 2025 | Savarese 2026 | contextual other | Humphreys 2025 (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Humphreys 2025 | Kehoe 2026 | contextual other | Humphreys 2025 (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Yang 2025 | Kim 2025 | contextual other | Yang 2025 (unclear) vs Kim 2025 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Yang 2025 | Karanovic 2026 | contextual other | Yang 2025 (unclear) vs Karanovic 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Yang 2025 | Odeh 2026 | contextual other | Yang 2025 (unclear) vs Odeh 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Yang 2025 | Han 2026 | contextual other | Yang 2025 (unclear) vs Han 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Yang 2025 | Senanayake 2026 | contextual other | Yang 2025 (unclear) vs Senanayake 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Yang 2025 | Wang 2026b | contextual other | Yang 2025 (unclear) vs Wang 2026b (null) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Yang 2025 | Gomaz 2026 | contextual other | Yang 2025 (unclear) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| agreement | 1 | Yang 2025 | Savarese 2026 | contextual other | Yang 2025 (unclear) vs Savarese 2026 (unclear) on contextual other | agreement (minor) |\n| agreement | 1 | Yang 2025 | Kehoe 2026 | contextual other | Yang 2025 (unclear) vs Kehoe 2026 (unclear) on contextual other | agreement (minor) |\n| null vs positive | 3 | Wang 2025b | Asim 2025 | cardiometabolic | Wang 2025b (null) vs Asim 2025 (negative) on cardiometabolic | null vs positive (notable) |\n| null vs positive | 3 | Wang 2025b | Abhari 2026 | cardiometabolic | Wang 2025b (null) vs Abhari 2026 (unclear) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Wang 2025b | Din 2026 | cardiometabolic | Wang 2025b (null) vs Din 2026 (null) on cardiometabolic | agreement (minor) |\n| null vs positive | 3 | Wang 2025b | Filipova 2020 | cardiometabolic | Wang 2025b (null) vs Filipova 2020 (negative) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Wang 2025b | Shubietah 2026 | cardiometabolic | Wang 2025b (null) vs Shubietah 2026 (null) on cardiometabolic | agreement (minor) |\n| null vs positive | 3 | Kim 2025 | Taha 2025 | contextual other | Kim 2025 (null) vs Taha 2025 (positive) on contextual other | null vs positive (notable) |\n| agreement | 1 | Kim 2025 | Karanovic 2026 | contextual other | Kim 2025 (null) vs Karanovic 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Kim 2025 | Odeh 2026 | contextual other | Kim 2025 (null) vs Odeh 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Kim 2025 | Han 2026 | contextual other | Kim 2025 (null) vs Han 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Kim 2025 | Senanayake 2026 | contextual other | Kim 2025 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Kim 2025 | Wang 2026b | contextual other | Kim 2025 (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Kim 2025 | Pepine 2026 | contextual other | Kim 2025 (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Kim 2025 | Gomaz 2026 | contextual other | Kim 2025 (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Kim 2025 | Savarese 2026 | contextual other | Kim 2025 (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Kim 2025 | Kehoe 2026 | contextual other | Kim 2025 (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Wang 2025c | Ngai 2025 | safety comorbidity | Wang 2025c (null) vs Ngai 2025 (null) on safety comorbidity | agreement (minor) |\n| null vs positive | 3 | Wang 2025c | Tu 2026 | safety comorbidity | Wang 2025c (null) vs Tu 2026 (positive) on safety comorbidity | null vs positive (notable) |\n| null vs positive | 3 | Wang 2025c | Silva 2026 | safety comorbidity | Wang 2025c (null) vs Silva 2026 (positive) on safety comorbidity | null vs positive (notable) |\n| agreement | 1 | Wang 2025c | Al-Omari 2026 | safety comorbidity | Wang 2025c (null) vs Al-Omari 2026 (null) on safety comorbidity | agreement (minor) |\n| null vs positive | 3 | Asim 2025 | Din 2026 | cardiometabolic | Asim 2025 (negative) vs Din 2026 (null) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Asim 2025 | Filipova 2020 | cardiometabolic | Asim 2025 (negative) vs Filipova 2020 (negative) on cardiometabolic | agreement (minor) |\n| null vs positive | 3 | Asim 2025 | Shubietah 2026 | cardiometabolic | Asim 2025 (negative) vs Shubietah 2026 (null) on cardiometabolic | null vs positive (notable) |\n| null vs positive | 3 | Ngai 2025 | Tu 2026 | safety comorbidity | Ngai 2025 (null) vs Tu 2026 (positive) on safety comorbidity | null vs positive (notable) |\n| null vs positive | 3 | Ngai 2025 | Silva 2026 | safety comorbidity | Ngai 2025 (null) vs Silva 2026 (positive) on safety comorbidity | null vs positive (notable) |\n| agreement | 1 | Ngai 2025 | Al-Omari 2026 | safety comorbidity | Ngai 2025 (null) vs Al-Omari 2026 (null) on safety comorbidity | agreement (minor) |\n| null vs positive | 3 | Taha 2025 | Karanovic 2026 | contextual other | Taha 2025 (positive) vs Karanovic 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Taha 2025 | Odeh 2026 | contextual other | Taha 2025 (positive) vs Odeh 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Taha 2025 | Han 2026 | contextual other | Taha 2025 (positive) vs Han 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Taha 2025 | Senanayake 2026 | contextual other | Taha 2025 (positive) vs Senanayake 2026 (null) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Taha 2025 | Wang 2026b | contextual other | Taha 2025 (positive) vs Wang 2026b (null) on contextual other | null vs positive (notable) |\n| agreement | 1 | Taha 2025 | Pepine 2026 | contextual other | Taha 2025 (positive) vs Pepine 2026 (positive) on contextual other | agreement (minor) |\n| disagreement | 4 | Taha 2025 | Gomaz 2026 | contextual other | Taha 2025 (positive) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| agreement | 1 | Mei 2025 | Ahn 2026 | dosing pharmacokinetics | Mei 2025 (null) vs Ahn 2026 (null) on dosing pharmacokinetics | agreement (minor) |\n| agreement | 1 | Mei 2025 | Goh 2026 | dosing pharmacokinetics | Mei 2025 (null) vs Goh 2026 (null) on dosing pharmacokinetics | agreement (minor) |\n| agreement | 1 | Karanovic 2026 | Odeh 2026 | contextual other | Karanovic 2026 (null) vs Odeh 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Karanovic 2026 | Han 2026 | contextual other | Karanovic 2026 (null) vs Han 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Karanovic 2026 | Senanayake 2026 | contextual other | Karanovic 2026 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Karanovic 2026 | Wang 2026b | contextual other | Karanovic 2026 (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Karanovic 2026 | Pepine 2026 | contextual other | Karanovic 2026 (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Karanovic 2026 | Gomaz 2026 | contextual other | Karanovic 2026 (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Karanovic 2026 | Savarese 2026 | contextual other | Karanovic 2026 (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Karanovic 2026 | Kehoe 2026 | contextual other | Karanovic 2026 (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Tu 2026 | Silva 2026 | safety comorbidity | Tu 2026 (positive) vs Silva 2026 (positive) on safety comorbidity | agreement (minor) |\n| null vs positive | 3 | Tu 2026 | Al-Omari 2026 | safety comorbidity | Tu 2026 (positive) vs Al-Omari 2026 (null) on safety comorbidity | null vs positive (notable) |\n| agreement | 1 | Odeh 2026 | Han 2026 | contextual other | Odeh 2026 (null) vs Han 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Odeh 2026 | Senanayake 2026 | contextual other | Odeh 2026 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Odeh 2026 | Wang 2026b | contextual other | Odeh 2026 (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Odeh 2026 | Pepine 2026 | contextual other | Odeh 2026 (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Odeh 2026 | Gomaz 2026 | contextual other | Odeh 2026 (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Odeh 2026 | Savarese 2026 | contextual other | Odeh 2026 (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Odeh 2026 | Kehoe 2026 | contextual other | Odeh 2026 (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| agreement | 1 | Han 2026 | Senanayake 2026 | contextual other | Han 2026 (null) vs Senanayake 2026 (null) on contextual other | agreement (minor) |\n| agreement | 1 | Han 2026 | Wang 2026b | contextual other | Han 2026 (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Han 2026 | Pepine 2026 | contextual other | Han 2026 (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Han 2026 | Gomaz 2026 | contextual other | Han 2026 (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Han 2026 | Savarese 2026 | contextual other | Han 2026 (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Han 2026 | Kehoe 2026 | contextual other | Han 2026 (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Abhari 2026 | Din 2026 | cardiometabolic | Abhari 2026 (unclear) vs Din 2026 (null) on cardiometabolic | null vs positive (notable) |\n| null vs positive | 3 | Abhari 2026 | Shubietah 2026 | cardiometabolic | Abhari 2026 (unclear) vs Shubietah 2026 (null) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Senanayake 2026 | Wang 2026b | contextual other | Senanayake 2026 (null) vs Wang 2026b (null) on contextual other | agreement (minor) |\n| null vs positive | 3 | Senanayake 2026 | Pepine 2026 | contextual other | Senanayake 2026 (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Senanayake 2026 | Gomaz 2026 | contextual other | Senanayake 2026 (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Senanayake 2026 | Savarese 2026 | contextual other | Senanayake 2026 (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Senanayake 2026 | Kehoe 2026 | contextual other | Senanayake 2026 (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Din 2026 | Filipova 2020 | cardiometabolic | Din 2026 (null) vs Filipova 2020 (negative) on cardiometabolic | null vs positive (notable) |\n| agreement | 1 | Din 2026 | Shubietah 2026 | cardiometabolic | Din 2026 (null) vs Shubietah 2026 (null) on cardiometabolic | agreement (minor) |\n| agreement | 1 | Ahn 2026 | Goh 2026 | dosing pharmacokinetics | Ahn 2026 (null) vs Goh 2026 (null) on dosing pharmacokinetics | agreement (minor) |\n| null vs positive | 3 | Silva 2026 | Al-Omari 2026 | safety comorbidity | Silva 2026 (positive) vs Al-Omari 2026 (null) on safety comorbidity | null vs positive (notable) |\n| null vs positive | 3 | Wang 2026b | Pepine 2026 | contextual other | Wang 2026b (null) vs Pepine 2026 (positive) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Wang 2026b | Gomaz 2026 | contextual other | Wang 2026b (null) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| null vs positive | 3 | Wang 2026b | Savarese 2026 | contextual other | Wang 2026b (null) vs Savarese 2026 (unclear) on contextual other | null vs positive (notable) |\n| null vs positive | 3 | Wang 2026b | Kehoe 2026 | contextual other | Wang 2026b (null) vs Kehoe 2026 (unclear) on contextual other | null vs positive (notable) |\n| disagreement | 4 | Pepine 2026 | Gomaz 2026 | contextual other | Pepine 2026 (positive) vs Gomaz 2026 (mixed) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Gomaz 2026 | Savarese 2026 | contextual other | Gomaz 2026 (mixed) vs Savarese 2026 (unclear) on contextual other | disagreement (load-bearing) |\n| disagreement | 4 | Gomaz 2026 | Kehoe 2026 | contextual other | Gomaz 2026 (mixed) vs Kehoe 2026 (unclear) on contextual other | disagreement (load-bearing) |\n| agreement | 1 | Savarese 2026 | Kehoe 2026 | contextual other | Savarese 2026 (unclear) vs Kehoe 2026 (unclear) on contextual other | agreement (minor) |\n| null vs positive | 3 | Filipova 2020 | Shubietah 2026 | cardiometabolic | Filipova 2020 (negative) vs Shubietah 2026 (null) on cardiometabolic | null vs positive (notable) |\n\n### Table 4 (supplemental): Design-Level Evidence Weighting Heuristic\n\n*Per-domain grades are derived from each study's evidence tier (A1/A2/B1/B2/C1/C2) — they capture design-level limitations, NOT a formal per-paper risk-of-bias assessment from the source text. Domains follow design-family categories for randomized, observational, animal, and systematic-review evidence; `n/a` indicates the domain is not meaningful for that design (e.g. blinding for an observational cohort). The **Weight in synthesis** column is the qualitative weighting the synthesis applies to each source — derived from tier × directness × overall RoB.*\n\n| Citation | Tier | Tool | Allocation | Blinding | Attrition | Outcome measurement | Reporting | Confounding control | Generalizability | Overall RoB | Weight in synthesis | Effect direction notes |\n| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |\n| Solomon 2026 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | signed claims without significance signal |\n| Din 2026 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Li 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Chung 2024 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | positive effect — see Tables 1/2 |\n| Mei 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Taha 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | positive effect — see Tables 1/2 |\n| Tian 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | signed claims without significance signal |\n| Yamamoto 2024 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | negative effect — see Tables 1/2 |\n| Lee 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | internal contradiction across endpoints |\n| Senanayake 2026 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Ahn 2026 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Yu 2025 | A1 | Cochrane RoB-2 | low | low | moderate | low | low | low | moderate | low | **load-bearing** (direct clinical RCT) | primary endpoint did not reach significance |\n| Derington 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | signed claims without significance signal |\n| Campbell 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | signed claims without significance signal |\n| Alqaisi 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | signed claims without significance signal |\n| Savarese 2026 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | signed claims without significance signal |\n| Goh 2026 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Wang 2026 | B1 | AMSTAR-2 (review) | unclear | unclear | unclear | unclear | moderate | moderate | moderate | unclear | **supporting** (synthesis evidence) | signed claims without significance signal |\n| Albertini 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Jo 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | signed claims without significance signal |\n| Nouhravesh 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Bavendiek 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Mosepele 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Takahashi 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Kehoe 2026 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | signed claims without significance signal |\n| Filipova 2020 | B1 | AMSTAR-2 (review) | unclear | unclear | unclear | unclear | moderate | moderate | moderate | unclear | **supporting** (synthesis evidence) | negative effect — see Tables 1/2 |\n| Wever 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | signed claims without significance signal |\n| Pietro 2024 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Omland 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Humphreys 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Lu 2026 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | negative effect — see Tables 1/2 |\n| Abhari 2026 | B1 | AMSTAR-2 (review) | unclear | unclear | unclear | unclear | moderate | moderate | moderate | unclear | **supporting** (synthesis evidence) | signed claims without significance signal |\n| Wang 2026b | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Yang 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | signed claims without significance signal |\n| Yan 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | internal contradiction across endpoints |\n| Han 2026 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Hu 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Tu 2026 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | positive effect — see Tables 1/2 |\n| Shaddy 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Jia 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Kario 2024 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Schwartz 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | positive effect — see Tables 1/2 |\n| Kuang 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Jin 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | signed claims without significance signal |\n| Murray-Thomas 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | signed claims without significance signal |\n| Nouhravesh 2025b | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Kim 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Gomaz 2026 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | internal contradiction across endpoints |\n| Chimura 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | signed claims without significance signal |\n| Silva 2026 | B1 | AMSTAR-2 (review) | unclear | unclear | unclear | unclear | moderate | moderate | moderate | unclear | **supporting** (synthesis evidence) | positive effect — see Tables 1/2 |\n| Pepine 2026 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | positive effect — see Tables 1/2 |\n| Lu 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Fumarulo 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Dou 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | signed claims without significance signal |\n| Ngai 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Rezazadeh 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | signed claims without significance signal |\n| Nazari-Robati 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Asim 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | negative effect — see Tables 1/2 |\n| Odeh 2026 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Wang 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Ramaswamy 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Yang 2025b | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | negative effect — see Tables 1/2 |\n| Kato 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | signed claims without significance signal |\n| Agarwal 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Wang 2025b | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Zhao 2025 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Karanovic 2026 | C1 | SYRCLE (animal) | low | n/a | low | moderate | moderate | n/a | high | low | **hypothesis-generating** (preclinical mechanism) | primary endpoint did not reach significance |\n| Wang 2025c | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Shubietah 2026 | B1 | AMSTAR-2 (review) | unclear | unclear | unclear | unclear | moderate | moderate | moderate | unclear | **supporting** (synthesis evidence) | primary endpoint did not reach significance |\n| Al-Omari 2026 | B2 | ROBINS-I | n/a | n/a | moderate | moderate | moderate | high | moderate | moderate | **contextual** (observational signal) | primary endpoint did not reach significance |\n| Gomaz 2025 | B1 | AMSTAR-2 (review) | unclear | unclear | unclear | unclear | moderate | moderate | moderate | unclear | **supporting** (synthesis evidence) | signed claims without significance signal |\n\n### Table 5 (supplemental): Per-Paper Numeric Index\n\n*Top-N quantitative claims per paper — the underlying corpus numerics that power Q2 trace and Q9 density. One row per (paper × claim) tuple, prioritised by claim type (p-value > percentage > ratio > unit-value).*\n\n| Citation | Section | Type | Value | Units |\n| --- | --- | --- | --- | --- |\n| Chung 2024 | abstract | unit value | 55 years | years |\n| Chung 2024 | abstract | unit value | 140 mmHg | mmHg |\n| Chung 2024 | abstract | unit value | 80 mg | mg |\n| Chung 2024 | abstract | unit value | 8 mg | mg |\n| Chung 2024 | discussion | unit value | 140 mmHg | mmHg |\n| Tian 2025 | results | sample size | N=35 | — |\n| Tian 2025 | results | sample size | N=35 | — |\n| Yu 2025 | abstract | p-value | P = 0.002 | — |\n| Yu 2025 | abstract | percentage | 87.8% | % |\n| Yu 2025 | abstract | unit value | 13.80 mmHg | mmHg |\n| Yu 2025 | abstract | unit value | 16.85 mmHg | mmHg |\n| Yu 2025 | abstract | unit value | 10.18 mmHg | mmHg |\n| Campbell 2025 | abstract | unit value | 5 years | years |\n| Alqaisi 2025 | results | percentage | 86% | % |\n| Alqaisi 2025 | results | percentage | 71% | % |\n| Alqaisi 2025 | results | percentage | 64% | % |\n| Alqaisi 2025 | results | percentage | 50% | % |\n| Alqaisi 2025 | results | percentage | 79% | % |\n| Wang 2026 | abstract | percentage | 13% | % |\n| Wang 2026 | abstract | percentage | 27% | % |\n| Wang 2026 | results | risk ratio | RR = 0.88 | — |\n| Wang 2026 | results | percentage | 95% | % |\n| Wang 2026 | results | risk ratio | RR = 0.86 | — |\n| Jo 2025 | results | unit value | 6 months | months |\n| Jo 2025 | results | mean ± SD | 128.5±17.8 | — |\n| Jo 2025 | results | mean ± SD | 76.4±12.9 | — |\n| Jo 2025 | results | unit value | 12.9 mm | mm |\n| Jo 2025 | results | mean ± SD | 112.8±13.7 | — |\n| Kehoe 2026 | methods | unit value | 6 years | years |\n| Filipova 2020 | results | unit value | 80 mmHg | mmHg |\n| Filipova 2020 | results | mean ± SD | 153.7 ± 14.4 | — |\n| Filipova 2020 | results | unit value | 90 mmHg | mmHg |\n| Filipova 2020 | results | mean ± SD | 153.5 ± 15.1 | — |\n| Filipova 2020 | results | mean ± SD | 101.5 ± 4.9 | — |\n| Abhari 2026 | results | percentage | 0.47% | % |\n| Abhari 2026 | results | confidence interval | 95% CI: -0.75, -0.20 | 95%CI |\n| Yang 2025 | introduction | p-value | P = 0.06 | — |\n| Yang 2025 | introduction | percentage | 95% | % |\n| Yang 2025 | abstract | hazard ratio | HR: 0.87 | — |\n| Yang 2025 | abstract | confidence interval | 95%CI: 0.75-1.00 | 95%CI |\n| Yang 2025 | abstract | confidence interval | 95%CI: 0.71-0.90 | 95%CI |\n| Yan 2025 | results | p-value | P < 0.001 | — |\n| Yan 2025 | discussion | percentage | 20.92% | % |\n| Yan 2025 | results | unit value | 80 mmHg | mmHg |\n| Yan 2025 | results | p-value | P < 0.001 | — |\n| Yan 2025 | results | p-value | P < 0.01 | — |\n| Jin 2025 | results | hazard ratio | HR: 0.51 | — |\n| Jin 2025 | results | confidence interval | 95% CI: 0.40 to 0.67 | 95%CI |\n| Jin 2025 | results | hazard ratio | HR: 1.10 | — |\n| Jin 2025 | results | confidence interval | 95% CI: 0.89 to 1.35 | 95%CI |\n| Jin 2025 | results | risk ratio | RR: 0.62 | — |\n| Gomaz 2026 | abstract | p-value | P = 0.001 | — |\n| Gomaz 2026 | abstract | unit value | 12 weeks | weeks |\n| Chimura 2025 | abstract | percentage | 95% | % |\n| Chimura 2025 | abstract | percentage | 95% | % |\n| Silva 2026 | abstract | p-value | P = 0.0019 | — |\n| Silva 2026 | abstract | percentage | 95% | % |\n| Silva 2026 | abstract | percentage | 86% | % |\n| Silva 2026 | abstract | percentage | 95% | % |\n| Silva 2026 | abstract | p-value | P < 0.0001 | — |\n| Lu 2025 | results | p-value | P > 0.05 | — |\n| Lu 2025 | results | unit value | 10 mg/dL | mg/dL |\n| Lu 2025 | results | unit value | 50 mg/dL | mg/dL |\n| Lu 2025 | results | unit value | 1.95 mg/dL | mg/dL |\n| Lu 2025 | results | unit value | 0.8 mg/dL | mg/dL |\n| Shubietah 2026 | abstract | percentage | 95% | % |\n| Shubietah 2026 | abstract | unit value | 6 weeks | weeks |\n| Shubietah 2026 | abstract | unit value | 8.84 mmHg | mmHg |\n| Shubietah 2026 | abstract | unit value | 12 weeks | weeks |\n| Shubietah 2026 | abstract | unit value | 5.52 mmHg | mmHg |\n| Gomaz 2025 | abstract | unit value | 3.4 mg | mg |\n| Gomaz 2025 | abstract | unit value | 1.8 mg | mg |\n\nAdditional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: ADA 2024, Ioannidis 2005.\n### References\n\n- **Solomon 2026.** _The NPR1 agonist antibody XXB750 in heart failure: a phase 2 randomized trial._ Nature Medicine, 2026. 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PMID: 39473218.\n- **Omland 2025.** _Sacubitril/Valsartan and Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy: The PRADA II Randomized Clinical Trial._ Circulation, 2025. DOI: 10.1161/CIRCULATIONAHA.125.076616. PMID: 40884047.\n- **Humphreys 2025.** _Long-term effectiveness of ACE inhibitors or angiotensin receptor blockers in myocardial infarction with preserved left ventricular ejection fraction._ European Heart Journal. Cardiovascular Pharmacotherapy, 2025. DOI: 10.1093/ehjcvp/pvaf051. PMID: 40886074.\n- **Lu 2026.** _The Effect of Medical Therapies for Subthreshold Abdominal Aortic Aneurysm Growth and Mortality: A Network Meta-Analysis of Randomized Controlled Trials._ Interdisciplinary Cardiovascular and Thoracic Surgery, 2026. DOI: 10.1093/icvts/ivag088. PMID: 41875387.\n- **Abhari 2026.** _Metabolic alterations associated with sacubitril/valsartan treatment: a systematic review and meta-analysis._ BMC Cardiovascular Disorders, 2026. 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PMID: 39826131.\n- **Han 2026.** _Vasopressin and angiotensin II pathways differentially modulate human fear response dynamics to looming threats._ PLOS Biology, 2026. DOI: 10.1371/journal.pbio.3003668. PMID: 41734211.\n- **Hu 2025.** _Bioequivalence and Food Effect Assessment of Two Fixed‐Dose Combination Formulations of Telmisartan‐Hydrochlorothiazide Tablets in Chinese Healthy Subjects._ Clinical and Translational Science, 2025. DOI: 10.1111/cts.70228. PMID: 40279189.\n- **Tu 2026.** _The effectiveness and safety of sacubitril/valsartan in real-world dialysis patients with heart failure reduced ejection fraction._ Medicine, 2026. DOI: 10.1097/MD.0000000000046866. PMID: 41630233.\n- **Shaddy 2025.** _Association between NT‐proBNP changes and clinical outcomes in paediatric patients with heart failure: Insights from PANORAMA‐HF and PARADIGM‐HF._ ESC Heart Failure, 2025. DOI: 10.1002/ehf2.15326. PMID: 40353367.\n- **Jia 2025.** _Efficacy of Chinese traditional quadruple single pill combination versus valsartan/hydrochlorothiazide for the treatment of hypertension (COSPQ-BP): study protocol for randomised controlled study._ BMJ Open, 2025. DOI: 10.1136/bmjopen-2024-092109. PMID: 39920071.\n- **Kario 2024.** _Rationale and Design of a Randomized, Open‐Label, Parallel‐Group Study of Esaxerenone Versus Angiotensin Receptor Blockers in Older Patients With Uncontrolled Hypertension on Calcium Channel Blocker Monotherapy (ESCORT‐HT)._ The Journal of Clinical Hypertension, 2024. DOI: 10.1111/jch.14947. PMID: 39584450.\n- **Schwartz 2025.** _Oral Losartan Treatment Improves Microvascular Endothelial Function via Nitric Oxide-Dependent Mechanisms in Women With a History of Preeclampsia._ American Journal of Hypertension, 2025. DOI: 10.1093/ajh/hpaf033. PMID: 40077915.\n- **Kuang 2025.** _Impact of s acubitril/valsartan on chronic heart failure patients with sleep-disordered breathing: a systematic review and meta-analysis._ Scientific Reports, 2025. DOI: 10.1038/s41598-025-14458-2. PMID: 40796619.\n- **Jin 2025.** _Guideline-directed medical therapy and in-hospital mortality in acute coronary syndrome patients with advanced renal dysfunction: analysis of two nationwide retrospective cohort studies._ BMJ Open, 2025. DOI: 10.1136/bmjopen-2024-098195. PMID: 40858368.\n- **Murray-Thomas 2025.** _Non-adherence to medications prescribed to patients with heart failure in general practice: prevalence, risk factors and association with mortality and hospitalisation._ Open Heart, 2025. DOI: 10.1136/openhrt-2025-003373. PMID: 40992794.\n- **Nouhravesh 2025b.** _In‐Hospital or Out‐of‐Hospital Initiation of Sacubitril/Valsartan Versus Valsartan in Patients With Mildly Reduced or Preserved Ejection Fraction After A Worsening Heart Failure Event: The PARAGLIDE‐HF Trial._ Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 2025. DOI: 10.1161/JAHA.124.037899. PMID: 39968788.\n- **Kim 2025.** _Intraoperative hypotension after remimazolam or propofol induction with sevoflurane maintenance in angiotensin II receptor blockers-treated patients: a randomized controlled trial._ Scientific Reports, 2025. DOI: 10.1038/s41598-025-23469-y. PMID: 41233396.\n- **Gomaz 2026.** _Telmisartan vs. other antihypertensives on cardiometabolic and vascular outcomes in diabetic hypertension: A randomised trial._ The Indian Journal of Medical Research, 2026. DOI: 10.25259/IJMR_1859_2025. PMID: 41934432.\n- **Chimura 2025.** _Comprehensive Analysis of the Effects of Sacubitril/Valsartan According to Sex Among Patients With Heart Failure and Reduced Ejection Fraction in PARADIGM ‐ HF._ Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 2025. DOI: 10.1161/JAHA.124.038249. PMID: 40265590.\n- **Silva 2026.** _Efficacy and safety of sacubitril/valsartan in patients on peritoneal dialysis: a systematic review and meta-analysis._ Jornal Brasileiro de Nefrologia, 2026. DOI: 10.1590/2175-8239-JBN-2025-0318en. PMID: 41931676.\n- **Pepine 2026.** _Women’s IschemiA TRial to Reduce Events In Non-ObstRuctive CAD (WARRIOR): a randomised controlled trial._ Open Heart, 2026. DOI: 10.1136/openhrt-2026-004115. PMID: 41932694.\n- **Lu 2025.** _Telmisartan reduces systemic inflammation and alters the renin-angiotensin system in mild COVID-19._ Scientific Reports, 2025. DOI: 10.1038/s41598-025-30304-x. PMID: 41339688.\n- **Fumarulo 2025.** _Evaluation of the Effects of the Sodium–Glucose Cotransporter 2 Inhibitors and Sacubitril/Valsartan Combined Therapy in Patients with HFrEF: An Echocardiographic Study._ International Journal of Molecular Sciences, 2025. DOI: 10.3390/ijms26125651. PMID: 40565116.\n- **Dou 2025.** _Withholding vs. continuing angiotensin-converting enzyme inhibitors or angiotensin receptor blockers before surgery: a systematic review and meta-analysis of randomized controlled trials._ Annals of Medicine, 2025. DOI: 10.1080/07853890.2025.2566873. PMID: 41017370.\n- **Ngai 2025.** _Matching-adjusted indirect comparison of kidney function in patients with immunoglobulin A nephropathy treated with nefecon or sparsentan._ Journal of Comparative Effectiveness Research, 2025. DOI: 10.57264/cer-2025-0045. PMID: 41263371.\n- **Rezazadeh 2025.** _Impact of hypertension and angiotensin receptor blockers on colorectal cancer: A retrospective study._ Medicine, 2025. DOI: 10.1097/MD.0000000000045372. PMID: 41137259.\n- **Nazari-Robati 2025.** _Effects of a polypill on circulating levels of resistin and visfatin in men with non-alcoholic fatty liver disease: A five-year clinical trial._ PLOS One, 2025. DOI: 10.1371/journal.pone.0331121. PMID: 41060939.\n- **Asim 2025.** _Dual‐Targeted Therapy in Cardiometabolic Risk: A Meta‐Analysis of Telmisartan‐Based Combinations for Hypertension and Dyslipidemia._ Clinical Cardiology, 2025. DOI: 10.1002/clc.70211. PMID: 41292423.\n- **Odeh 2026.** _Association between angiotensin receptor-neprilysin inhibitor use and clinical outcomes in patients with heart failure: a 1-year prospective cohort study from Jordan._ BMJ Open, 2026. DOI: 10.1136/bmjopen-2025-111865. PMID: 41730558.\n- **Wang 2025.** _A real-world pharmacovigilance analysis of acute renal failure associated with sacubitril/valsartan based on FDA Adverse Event Reporting System (FAERS)._ PLOS One, 2025. DOI: 10.1371/journal.pone.0334402. PMID: 41091778.\n- **Ramaswamy 2025.** _Efficacy of losartan plus modified FOLFIRINOX versus modified FOLFIRINOX in advanced pancreatic cancers: A randomized clinical trial (AFPAC Study)._ Cancer, 2025. DOI: 10.1002/cncr.35945. PMID: 40542713.\n- **Yang 2025b.** _The efficacy of Shenyankangfu tablets in combination with valsartan in diabetic nephropathy: A systematic review and meta-analysis._ Medicine, 2025. DOI: 10.1097/MD.0000000000041518. PMID: 40020136.\n- **Kato 2025.** _Dose-dependent renoprotective effects of sacubitril/valsartan in heart failure: a retrospective study._ Renal Failure, 2025. DOI: 10.1080/0886022X.2025.2538830. PMID: 40841853.\n- **Agarwal 2025.** _Heart failure with reduced ejection fraction polypill implementation strategy in Sri Lanka: design and protocol of a pilot type I hybrid randomised clinical trial._ BMJ Open, 2025. DOI: 10.1136/bmjopen-2025-100952. PMID: 40664424.\n- **Wang 2025b.** _Angiotensin converting enzyme inhibitors and angiotensin receptor blockers impact on the gut microbiome: a systematic review._ Frontiers in Endocrinology, 2025. DOI: 10.3389/fendo.2025.1685424. PMID: 41199864.\n- **Zhao 2025.** _Clinical efficacy of sacubitril/valsartan combined with cardiac rehabilitation in patients with heart failure after acute myocardial infarction: a single-center randomized trial._ BMC Cardiovascular Disorders, 2025. DOI: 10.1186/s12872-025-04682-z. PMID: 40175938.\n- **Karanovic 2026.** _Olive Leaf Extract Added to Losartan Treatment Improved Klotho/Wnt/β-Catenin Signaling in Hypertensive Rats with Focal Segmental Glomerulosclerosis._ Antioxidants, 2026. DOI: 10.3390/antiox15010146. PMID: 41596204.\n- **Wang 2025c.** _Effect of angiotensin II receptor blockers on efficacy and safety of Camrelizumab plus chemotherapy in the first-line therapy for advanced non-small cell lung cancer (ARMOR I): a protocol for a prospective, real-world, multicenter, intervention clinical trial._ Frontiers in Immunology, 2025. DOI: 10.3389/fimmu.2025.1668782. PMID: 41306970.\n- **Shubietah 2026.** _Low-Dose Triple-Pill of Telmisartan, Amlodipine, and Indapamide for Initial Hypertension Treatment: A GRADE-Assessed Meta-analysis of Randomized Trials._ High Blood Press Cardiovasc Prev, 2026. DOI: 10.1007/s40292-025-00751-8. PMID: 41222871.\n- **Al-Omari 2026.** _Bleeding Disorder, A Newly Recognized Adverse Event Following Sacubitril/Valsartan Therapy._ European Journal of Case Reports in Internal Medicine, 2026. DOI: 10.12890/2026_006178. PMID: 41988551.\n- **Gomaz 2025.** _Anti-inflammatory potential of telmisartan compared to other antihypertensives: secondary outcomes from a randomized trial._ Inflammopharmacology, 2025. DOI: 10.1007/s10787-025-01995-5. PMID: 41046489.\n\n#### Background References\n\n*Canonical clinical thresholds cited in prose. Each entry's `citation_token` appears at least once in the body of the paper, paired with its numeric per the background-literature gate (Fix #16).*\n\n- **ADA 2024.** _American Diabetes Association. Standards of Care in Diabetes. Diabetes Care. 2024;47(Suppl 1)._ DOI: 10.2337/dc24-S006.\n- **Ioannidis 2005.** _Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124._ DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.\n","metadata":{"abstract":"This synthesis tests the thesis that evidence for ARBs longevity is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation. This paper synthesizes arbs longevity as an aging-related intervention across 71 included source papers and 4116 high-confidence extracted claims. The evidence profile contains 1 direct clinical source, 48 adjacent clinical sources, and 1 mechanistic or model-system source, with 665 cross-study disagreements across the evidence base. Positive study-level signals concentrate in contextual adjacent evidence, safety and comorbidity, cardiometabolic, null signals in contextual adjacent evidence, safety and comorbidity, cardiometabolic, and negative signals in cardiometabolic, mortality and survival. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that arbs longevity remains a bounded geroscience case: mechanistic plausibility and selected clinical signals justify further targeted testing, while mixed and null findings limit any unqualified anti-aging claim. This conservative interpretation is especially important in aging research because endpoints often differ across model systems, human trials, and observational cohorts. A signal in one domain does not automatically establish the same signal in","article_type":"rapid_evidence_synthesis","counts":{"retrieved_count":71,"selected_count":71,"review_like_count":70,"primary_like_count":1,"year_start":2020,"year_end":2026},"gates":[{"name":"leakage_blocker","passed":true,"reason":"final body must not contain reviewer or pipeline leakage"},{"name":"count_reconciliation","passed":true,"reason":"selected count must equal review-like + primary-like counts"},{"name":"core_claims_resolved","passed":true,"reason":"title/abstract/conclusion claims must not remain unresolved"}],"author_agent_id":"agent-v3-full-paper","doi":"10.17605/OSF.IO/DS49N","doi_status":"minted","osf_status":"minted","osf_project_id":"p8nk6","osf_guid":"ds49n","osf_url":"https://osf.io/ds49n/","osf":{"enabled":true,"status":"minted","project_id":"p8nk6","guid":"ds49n","url":"https://osf.io/ds49n/","doi":"10.17605/OSF.IO/DS49N"},"prompt_version":"editor-v1-clean-runtime","provider":"reviewer-panel","model":"mimo-v2.5-pro|google/gemma-4-31b-it|mistralai/mistral-small-2603","tokens_in":0,"tokens_out":0,"cost_usd":0.0,"osf_auth_source":"oauth_agent_token","dw_artifact_id":"claim_447bda30fe9f4d77","dw_chain_url":"https://provenance.researka.org/artifacts/claim_447bda30fe9f4d77/chain","dw_api_chain_url":"https://provenance.researka.org/api/artifacts/claim_447bda30fe9f4d77/chain","dw_source_artifact_id":"source_e6c6dde203b54903","dw_input_artifact_ids":["source_b971bc684cd34453","source_4225870f31584672","source_16649e8b45144733","source_d103f85637b24eed","source_3674b1a1e9944966","source_81475b6c904f498b"],"dw_step_id":"step_cb5f6ad75057446c","dw_step_hash":"e635999ffec4b51853a11eda97a06d4c00e65a202d38825d011e3a8d16c7a4c1","dw_status":"registered","content_hash":"sha256:3fd5cb574764d77dc6199b9c4b2670ba2e545a066d673bdb50013b46e197e54b","sha256":"sha256:3fd5cb574764d77dc6199b9c4b2670ba2e545a066d673bdb50013b46e197e54b"},"created_at":"2026-05-28T13:07:23.883309+04:00"},"sidecars":[{"name":"citation_traces.json","media_type":"application/json","content":{"publication_id":"edeb045d-18ed-49dc-95b6-57f76783ce2b","traces":[{"claim_id":"claim_1","claim":"What does the current evidence establish about Arbs Longevity and human geroscience? This synthesis tests the thesis that evidence for ARBs longevity is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation. This paper synthesizes arbs longevity as an aging-related intervention across 71 included source papers and 4116 high-confidence extracted claims. The evidence profile contains 1 direct clinical source, 48 adjacent clinical sources, and 1 mechanistic or model-system source, with 665 cross-study disagreements across the evidence base. Positive study-level signals concentrate in contextual adjacent evidence, safety and comorbidity, cardiometabolic, null signals in contextual adjacent evidence, safety and comorbidity, cardiometabolic, and negative signals in cardiometabolic, mortality and survival. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that arbs longevity remains a bounded geroscience case: mechanistic plausibility and selected clinical signals justify further targeted testing, while mixed and null findings limit any unqualified anti-aging claim. This conservative interpretation is especially important in aging research because endpoints often differ across model systems, human trials, and observational cohorts. A signal in one domain does not automatically establish the same signal in","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_2","claim":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating.","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_3","claim":"Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`.","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_4","claim":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, immune, immune and inflammation, longevity, mortality and survival, safety, safety and comorbidity); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_5","claim":"Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_6","claim":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence.","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_7","claim":"| Contextual Adjacent Evidence | n=34; claims=1839 | null signal in 20/34 sources | 1 direct; 25 indirect; 1 mechanistic; 7 review | limited corpus depth in this outcome class |","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_8","claim":"| Cardiometabolic | n=13; claims=813 | null signal in 5/13 sources | 5 indirect; 8 review | limited corpus depth in this outcome class |","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_9","claim":"| Safety and Comorbidity | n=9; claims=311 | null signal in 7/9 sources | 6 indirect; 3 review | limited corpus depth in this outcome class |","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_10","claim":"| Dosing and Pharmacokinetics | n=7; claims=566 | null signal in 4/7 sources | 7 indirect | limited corpus depth in this outcome class |","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_11","claim":"| Immune and Inflammation | n=1; claims=30 | null signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_12","claim":"Mechanistically, the blood pressure-lowering effects of ARBs are well-established through blockade of the angiotensin II type 1 receptor, leading to vasodilation and reduced aldosterone secretion. The PARASOL study's findings align with this pathway, where sacubitril/valsartan's combined neprilysin inhibition and AT1 receptor blockade showed efficacy in hypertensive Japanese adults (Yamamoto 2024). Preclinical and mechanistic data suggest that ARBs may influence metabolic pathways, as indicated by the significant HbA1c and glucose reductions with sacubitril/valsartan treatment (Abhari 2026). Furthermore, the observed renal hemodynamic effects, such as changes in intrarenal blood flow, may contribute to the variable outcomes seen in CKD populations (Wever 2025).","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_13","claim":"Mechanistically, the evidence reveals that ARBs and ARNI operate through distinct but overlapping pathways that extend beyond blood pressure lowering to affect cardiac remodeling, endothelial function, and metabolic regulation.","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_14","claim":"Gomaz 2026 randomized trial of telmisartan versus other antihypertensives in diabetic hypertension reported P = 0.001 for cardiometabolic and vascular outcome differences, suggesting ARB-specific pleiotropic metabolic effects.","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_15","claim":"Quantitative findings from this trial are characterized by a mixture of null and highly significant results across different measured endpoints. However, other endpoints demonstrated strong statistical significance, with P < 0.0001 and P < 0.001 reported. The full distribution of per-study endpoint evidence, including the specific biomarkers associated with these p-values, is detailed in Table 2.","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_16","claim":"Mechanistically, the observation that telmisartan alters systemic inflammation and the renin-angiotensin system aligns with the proposed pathway whereby ARBs could modulate aging-related processes. The renin-angiotensin system is a key regulator of vascular tone, inflammation, and oxidative stress, all of which are implicated in cellular senescence and organismal aging. This clinical RCT provides human evidence that an ARB intervention can impact these pathways, offering a plausible link between the pharmacological action of telmisartan and potential longevity-related benefits mediated through immune and inflammatory modulation.","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_17","claim":"A tension within this outcome class arises from the mixed pattern of statistical results observed in a single trial. While some endpoints reached high statistical significance, others did not, suggesting that the anti-inflammatory effect of telmisartan may be context-dependent or specific to certain biomarkers. The absence of corroborating large-scale human RCTs for this specific outcome class means the evidence remains preliminary, with the boundary conditions for a consistent immunomodulatory effect yet to be fully established.","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_18","claim":"The evidence base for angiotensin receptor blockers (ARBs) and longevity is derived from indirect sources, including a systematic review and meta-analysis on heart failure therapies (Wang 2026), observational cohort studies on medication adherence (Murray-Thomas 2025) and guideline-directed medical therapy (Jin 2025), and a pilot trial protocol for a polypill strategy (Agarwal 2025). No direct, randomized controlled trials isolating ARB monotherapy for a primary longevity endpoint were identified within this curated corpus. The population examined across these studies is adults with cardiovascular conditions such as heart failure or acute coronary syndrome, with outcomes typically assessed over hospital or follow-up periods rather than lifespan durations (Jin 2025; Murray-Thomas 2025). The primary endpoint across the relevant studies is mortality, encompassing in-hospital death and all-cause mortality linked to medication use (Jin 2025; Murray-Thomas 2025). The dosing of ARBs in these contexts is part of broader guideline-directed medical therapy regimens, not evaluated in isolation for longevity effects (Agarwal 2025; Jin 2025).","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_19","claim":"Quantitative findings from the observational data show a strong association between medication non-adherence and adverse outcomes. This suggests that consistent use of guideline-directed therapy, which often incorporates ARBs, is critical for survival benefits. However, the specific contribution of ARBs cannot be disentangled from the multi-drug regimens studied (Murray-Thomas 2025). The Wang 2026 meta-analysis reports that SGLT2 inhibitors, a drug class often used alongside ARBs, significantly reduced cardiovascular death compared to placebo, but ARB-specific mortality effects within this comparison were not separately quantified in the provided excerpts (Wang 2026).","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_20","claim":"Mechanistically, the rationale linking ARBs to longevity centers on mitigating pathological angiotensin II signaling, which contributes to inflammation, fibrosis, and organ damage, thereby theoretically slowing age-related decline. The mechanistic substrate underlying this potential benefit is supported by the broader evidence on RAAS inhibition in cardiovascular disease, which forms the biological plausibility for trials like the HFrEF polypill pilot (Agarwal 2025). This pilot trial protocol (Agarwal 2025) includes losartan, an ARB, as one component of a multi-drug intervention aimed at improving heart failure outcomes, which are a major determinant of mortality. The systematic review by Wang 2026 synthesizes evidence on several advanced heart failure therapies, positioning ARBs as part of a foundational treatment landscape where survival benefits are mediated through integrated cardiovascular protection (Wang 2026). The evidence therefore points to a context-dependent effect, where ARBs may contribute to longevity by reducing mortality in specific high-risk cardiovascular populations as part of comprehensive care (Jin 2025; Murray-Thomas 2025).","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_21","claim":"Within the corpus, tensions in the longevity outcome class arise primarily from differences in effect certainty and directness. By contrast, the Agarwal 2025 polypill protocol represents a future interventional approach but does not yet report a definitive null or positive effect on longevity, reflecting an anticipated rather than an observed outcome (Agarwal 2025). In contrast, the observational cohort by Murray-Thomas 2025 demonstrates a clear, statistically significant negative consequence of ARB non-adherence on mortality (Murray-Thomas 2025). The Jin 2025 cohort study on guideline-directed therapy in acute coronary syndrome patients with renal dysfunction provides corroborating observational evidence for the importance of therapy adherence, aligning with Murray-Thomas 2025 in highlighting the role of medication use in survival, though specific effect sizes for ARBs remain unclear (Jin 2025). The Wang 2026 meta-analysis adds a layer of complexity by situating ARBs within a multi-therapy landscape where newer agents like SGLT2i show strong mortality benefits, potentially challenging the incremental longevity value of ARBs alone (Wang 2026).","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_22","claim":"A tension exists in the broader interpretation of this safety data. The statistically significant P-value of 0.0038 points to a measurable difference between groups, yet the effect direction for this observational cohort was classified as unclear. This suggests that while a statistical association was detected, the clinical implication—whether the effect represents a beneficial safety profile or a concerning adverse signal—requires further elucidation through dedicated long-term outcome trials.","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_23","claim":"The evidence base for safety and comorbidity outcomes associated with renin-angiotensin system modulation encompasses diverse study designs and patient populations. Observational cohort studies, including the DAPA-SRV trial, evaluated dapagliflozin in adults with systemic right ventricular dysfunction (Albertini 2025). The DIGIT-HHF trial characterized baseline characteristics of patients with advanced chronic heart failure in a randomized, double-blind, placebo-controlled design (Bavendiek 2025). Real-world analyses examined sacubitril/valsartan effectiveness in dialysis patients with heart failure with reduced ejection fraction, reporting on hospitalization and mortality endpoints (Tu 2026). Systematic reviews synthesized evidence on sacubitril/valsartan's impact on sleep-disordered breathing in chronic heart failure patients (Kuang 2025) and its efficacy in peritoneal dialysis populations (Silva 2026). Pharmacovigilance analyses based on the FDA Adverse Event Reporting System assessed renal failure risk (Wang 2025), while prospective protocols investigated ARBs in oncology contexts (Wang 2025c).","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_24","claim":"Mechanistically, the observed functional and hemodynamic benefits align with pathways of neurohormonal modulation and cardiac remodeling. Reductions in AHI and improvements in oxygen saturation point to a potential role in mitigating comorbid sleep-disordered breathing, a common condition in heart failure (Kuang 2025). The significant decrease in NT-proBNP, a biomarker of cardiac wall stress, corroborates the hemodynamic benefits observed in dialysis populations (Silva 2026). These mechanistic human studies and clinical trial data provide a plausible substrate for the safety signals. However, the clinical significance of these changes for long-term survival and comorbidity reduction requires further contextualization.","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_25","claim":"Within the corpus, a notable tension exists regarding the net clinical benefit, particularly in advanced renal disease. Furthermore, pharmacovigilance reporting identified bleeding disorders as a newly recognized adverse event, with elevated PT/INR values observed within 14 days to four months of therapy initiation, even without anticoagulant medication (Al-Omari 2026). The contrast between positive signals from pooled analyses of selected trials and null or safety-concern signals from real-world cohorts and adverse event reports underscores the complexity of applying these therapies across heterogeneous patient populations. These disagreements highlight the need for careful patient selection and monitoring in clinical practice.","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_26","claim":"Mechanistically, the pharmacokinetic data from these studies support the development of fixed-dose combinations to improve patient adherence and simplify treatment regimens. The bioequivalence studies by Mei 2025, Tian 2025, Hu 2025, and Goh 2026 provide the foundational evidence for such formulations, ensuring comparable systemic exposure to the individual components (Mei 2025, Tian 2025, Hu 2025, Goh 2026). Preclinical and human data suggest that optimized dosing can achieve target receptor blockade while potentially minimizing off-target effects, a principle supported by the dose-dependent findings reported in the retrospective analysis by Kato 2025 on sacubitril/valsartan in heart failure (Kato 2025).","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_27","claim":"By contrast, the bioequivalence studies by Mei 2025 and Goh 2026 are designed to demonstrate pharmacokinetic similarity rather than clinical superiority, reporting effect directions as null (Mei 2025, Goh 2026).","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_28","claim":"Dosing and Pharmacokinetics is retained as a separate Results slice (n=7; null signal in 4/7 sources; 7 indirect; no direct clinical anchor) and is not pooled into adjacent endpoint classes.","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_29","claim":"Despite these positive mechanistic signals, the evidence base for immune-related longevity outcomes remains limited and contextual. The reviewed findings are derived from secondary endpoint analyses in trials not primarily designed to assess longevity, and the clinical significance of the magnitude of biomarker change is not established (Gomaz 2025). Furthermore, the broader synthesis indicates that positive signals for ARBs in longevity are often context-dependent and may not translate to hard clinical endpoints like mortality, highlighting the tension between biomarker improvement and definitive survival benefit.","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]},{"claim_id":"claim_30","claim":"The evidence base for immune and inflammatory outcomes in the context of ARBs and longevity is anchored by a single randomized, double-blinded, placebo-controlled pilot clinical trial. Lu 2025 reported. The trial population consisted of adults in an observational cohort design, assessing changes in systemic inflammation and the renin-angiotensin system. This study provides the primary direct evidence from a controlled human intervention relevant to this outcome class.","candidate_sources":[{"study":"Solomon 2026","doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w"},{"study":"Din 2026","doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2"},{"study":"Li 2025","doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275"},{"study":"Mei 2025","doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9"},{"study":"Chung 2024","doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929"}]}]}},{"name":"claim_graph.json","media_type":"application/json","content":{"publication_id":"edeb045d-18ed-49dc-95b6-57f76783ce2b","content_hash":"sha256:3fd5cb574764d77dc6199b9c4b2670ba2e545a066d673bdb50013b46e197e54b","nodes":[{"id":"edeb045d-18ed-49dc-95b6-57f76783ce2b","type":"publication","title":"Research Synthesis: ARBs Longevity — full paper"},{"id":"claim_1","type":"claim","text":"What does the current evidence establish about Arbs Longevity and human geroscience? This synthesis tests the thesis that evidence for ARBs longevity is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation. This paper synthesizes arbs longevity as an aging-related intervention across 71 included source papers and 4116 high-confidence extracted claims. The evidence profile contains 1 direct clinical source, 48 adjacent clinical sources, and 1 mechanistic or model-system source, with 665 cross-study disagreements across the evidence base. Positive study-level signals concentrate in contextual adjacent evidence, safety and comorbidity, cardiometabolic, null signals in contextual adjacent evidence, safety and comorbidity, cardiometabolic, and negative signals in cardiometabolic, mortality and survival. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that arbs longevity remains a bounded geroscience case: mechanistic plausibility and selected clinical signals justify further targeted testing, while mixed and null findings limit any unqualified anti-aging claim. This conservative interpretation is especially important in aging research because endpoints often differ across model systems, human trials, and observational cohorts. A signal in one domain does not automatically establish the same signal in"},{"id":"claim_2","type":"claim","text":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating."},{"id":"claim_3","type":"claim","text":"Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`."},{"id":"claim_4","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, immune, immune and inflammation, longevity, mortality and survival, safety, safety and comorbidity); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates."},{"id":"claim_5","type":"claim","text":"Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified."},{"id":"claim_6","type":"claim","text":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence."},{"id":"claim_7","type":"claim","text":"| Contextual Adjacent Evidence | n=34; claims=1839 | null signal in 20/34 sources | 1 direct; 25 indirect; 1 mechanistic; 7 review | limited corpus depth in this outcome class |"},{"id":"claim_8","type":"claim","text":"| Cardiometabolic | n=13; claims=813 | null signal in 5/13 sources | 5 indirect; 8 review | limited corpus depth in this outcome class |"},{"id":"claim_9","type":"claim","text":"| Safety and Comorbidity | n=9; claims=311 | null signal in 7/9 sources | 6 indirect; 3 review | limited corpus depth in this outcome class |"},{"id":"claim_10","type":"claim","text":"| Dosing and Pharmacokinetics | n=7; claims=566 | null signal in 4/7 sources | 7 indirect | limited corpus depth in this outcome class |"},{"id":"claim_11","type":"claim","text":"| Immune and Inflammation | n=1; claims=30 | null signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |"},{"id":"claim_12","type":"claim","text":"Mechanistically, the blood pressure-lowering effects of ARBs are well-established through blockade of the angiotensin II type 1 receptor, leading to vasodilation and reduced aldosterone secretion. The PARASOL study's findings align with this pathway, where sacubitril/valsartan's combined neprilysin inhibition and AT1 receptor blockade showed efficacy in hypertensive Japanese adults (Yamamoto 2024). Preclinical and mechanistic data suggest that ARBs may influence metabolic pathways, as indicated by the significant HbA1c and glucose reductions with sacubitril/valsartan treatment (Abhari 2026). Furthermore, the observed renal hemodynamic effects, such as changes in intrarenal blood flow, may contribute to the variable outcomes seen in CKD populations (Wever 2025)."},{"id":"claim_13","type":"claim","text":"Mechanistically, the evidence reveals that ARBs and ARNI operate through distinct but overlapping pathways that extend beyond blood pressure lowering to affect cardiac remodeling, endothelial function, and metabolic regulation."},{"id":"claim_14","type":"claim","text":"Gomaz 2026 randomized trial of telmisartan versus other antihypertensives in diabetic hypertension reported P = 0.001 for cardiometabolic and vascular outcome differences, suggesting ARB-specific pleiotropic metabolic effects."},{"id":"claim_15","type":"claim","text":"Quantitative findings from this trial are characterized by a mixture of null and highly significant results across different measured endpoints. However, other endpoints demonstrated strong statistical significance, with P < 0.0001 and P < 0.001 reported. The full distribution of per-study endpoint evidence, including the specific biomarkers associated with these p-values, is detailed in Table 2."},{"id":"claim_16","type":"claim","text":"Mechanistically, the observation that telmisartan alters systemic inflammation and the renin-angiotensin system aligns with the proposed pathway whereby ARBs could modulate aging-related processes. The renin-angiotensin system is a key regulator of vascular tone, inflammation, and oxidative stress, all of which are implicated in cellular senescence and organismal aging. This clinical RCT provides human evidence that an ARB intervention can impact these pathways, offering a plausible link between the pharmacological action of telmisartan and potential longevity-related benefits mediated through immune and inflammatory modulation."},{"id":"claim_17","type":"claim","text":"A tension within this outcome class arises from the mixed pattern of statistical results observed in a single trial. While some endpoints reached high statistical significance, others did not, suggesting that the anti-inflammatory effect of telmisartan may be context-dependent or specific to certain biomarkers. The absence of corroborating large-scale human RCTs for this specific outcome class means the evidence remains preliminary, with the boundary conditions for a consistent immunomodulatory effect yet to be fully established."},{"id":"claim_18","type":"claim","text":"The evidence base for angiotensin receptor blockers (ARBs) and longevity is derived from indirect sources, including a systematic review and meta-analysis on heart failure therapies (Wang 2026), observational cohort studies on medication adherence (Murray-Thomas 2025) and guideline-directed medical therapy (Jin 2025), and a pilot trial protocol for a polypill strategy (Agarwal 2025). No direct, randomized controlled trials isolating ARB monotherapy for a primary longevity endpoint were identified within this curated corpus. The population examined across these studies is adults with cardiovascular conditions such as heart failure or acute coronary syndrome, with outcomes typically assessed over hospital or follow-up periods rather than lifespan durations (Jin 2025; Murray-Thomas 2025). The primary endpoint across the relevant studies is mortality, encompassing in-hospital death and all-cause mortality linked to medication use (Jin 2025; Murray-Thomas 2025). The dosing of ARBs in these contexts is part of broader guideline-directed medical therapy regimens, not evaluated in isolation for longevity effects (Agarwal 2025; Jin 2025)."},{"id":"claim_19","type":"claim","text":"Quantitative findings from the observational data show a strong association between medication non-adherence and adverse outcomes. This suggests that consistent use of guideline-directed therapy, which often incorporates ARBs, is critical for survival benefits. However, the specific contribution of ARBs cannot be disentangled from the multi-drug regimens studied (Murray-Thomas 2025). The Wang 2026 meta-analysis reports that SGLT2 inhibitors, a drug class often used alongside ARBs, significantly reduced cardiovascular death compared to placebo, but ARB-specific mortality effects within this comparison were not separately quantified in the provided excerpts (Wang 2026)."},{"id":"claim_20","type":"claim","text":"Mechanistically, the rationale linking ARBs to longevity centers on mitigating pathological angiotensin II signaling, which contributes to inflammation, fibrosis, and organ damage, thereby theoretically slowing age-related decline. The mechanistic substrate underlying this potential benefit is supported by the broader evidence on RAAS inhibition in cardiovascular disease, which forms the biological plausibility for trials like the HFrEF polypill pilot (Agarwal 2025). This pilot trial protocol (Agarwal 2025) includes losartan, an ARB, as one component of a multi-drug intervention aimed at improving heart failure outcomes, which are a major determinant of mortality. The systematic review by Wang 2026 synthesizes evidence on several advanced heart failure therapies, positioning ARBs as part of a foundational treatment landscape where survival benefits are mediated through integrated cardiovascular protection (Wang 2026). The evidence therefore points to a context-dependent effect, where ARBs may contribute to longevity by reducing mortality in specific high-risk cardiovascular populations as part of comprehensive care (Jin 2025; Murray-Thomas 2025)."},{"id":"claim_21","type":"claim","text":"Within the corpus, tensions in the longevity outcome class arise primarily from differences in effect certainty and directness. By contrast, the Agarwal 2025 polypill protocol represents a future interventional approach but does not yet report a definitive null or positive effect on longevity, reflecting an anticipated rather than an observed outcome (Agarwal 2025). In contrast, the observational cohort by Murray-Thomas 2025 demonstrates a clear, statistically significant negative consequence of ARB non-adherence on mortality (Murray-Thomas 2025). The Jin 2025 cohort study on guideline-directed therapy in acute coronary syndrome patients with renal dysfunction provides corroborating observational evidence for the importance of therapy adherence, aligning with Murray-Thomas 2025 in highlighting the role of medication use in survival, though specific effect sizes for ARBs remain unclear (Jin 2025). The Wang 2026 meta-analysis adds a layer of complexity by situating ARBs within a multi-therapy landscape where newer agents like SGLT2i show strong mortality benefits, potentially challenging the incremental longevity value of ARBs alone (Wang 2026)."},{"id":"claim_22","type":"claim","text":"A tension exists in the broader interpretation of this safety data. The statistically significant P-value of 0.0038 points to a measurable difference between groups, yet the effect direction for this observational cohort was classified as unclear. This suggests that while a statistical association was detected, the clinical implication—whether the effect represents a beneficial safety profile or a concerning adverse signal—requires further elucidation through dedicated long-term outcome trials."},{"id":"claim_23","type":"claim","text":"The evidence base for safety and comorbidity outcomes associated with renin-angiotensin system modulation encompasses diverse study designs and patient populations. Observational cohort studies, including the DAPA-SRV trial, evaluated dapagliflozin in adults with systemic right ventricular dysfunction (Albertini 2025). The DIGIT-HHF trial characterized baseline characteristics of patients with advanced chronic heart failure in a randomized, double-blind, placebo-controlled design (Bavendiek 2025). Real-world analyses examined sacubitril/valsartan effectiveness in dialysis patients with heart failure with reduced ejection fraction, reporting on hospitalization and mortality endpoints (Tu 2026). Systematic reviews synthesized evidence on sacubitril/valsartan's impact on sleep-disordered breathing in chronic heart failure patients (Kuang 2025) and its efficacy in peritoneal dialysis populations (Silva 2026). Pharmacovigilance analyses based on the FDA Adverse Event Reporting System assessed renal failure risk (Wang 2025), while prospective protocols investigated ARBs in oncology contexts (Wang 2025c)."},{"id":"claim_24","type":"claim","text":"Mechanistically, the observed functional and hemodynamic benefits align with pathways of neurohormonal modulation and cardiac remodeling. Reductions in AHI and improvements in oxygen saturation point to a potential role in mitigating comorbid sleep-disordered breathing, a common condition in heart failure (Kuang 2025). The significant decrease in NT-proBNP, a biomarker of cardiac wall stress, corroborates the hemodynamic benefits observed in dialysis populations (Silva 2026). These mechanistic human studies and clinical trial data provide a plausible substrate for the safety signals. However, the clinical significance of these changes for long-term survival and comorbidity reduction requires further contextualization."},{"id":"claim_25","type":"claim","text":"Within the corpus, a notable tension exists regarding the net clinical benefit, particularly in advanced renal disease. Furthermore, pharmacovigilance reporting identified bleeding disorders as a newly recognized adverse event, with elevated PT/INR values observed within 14 days to four months of therapy initiation, even without anticoagulant medication (Al-Omari 2026). The contrast between positive signals from pooled analyses of selected trials and null or safety-concern signals from real-world cohorts and adverse event reports underscores the complexity of applying these therapies across heterogeneous patient populations. These disagreements highlight the need for careful patient selection and monitoring in clinical practice."},{"id":"claim_26","type":"claim","text":"Mechanistically, the pharmacokinetic data from these studies support the development of fixed-dose combinations to improve patient adherence and simplify treatment regimens. The bioequivalence studies by Mei 2025, Tian 2025, Hu 2025, and Goh 2026 provide the foundational evidence for such formulations, ensuring comparable systemic exposure to the individual components (Mei 2025, Tian 2025, Hu 2025, Goh 2026). Preclinical and human data suggest that optimized dosing can achieve target receptor blockade while potentially minimizing off-target effects, a principle supported by the dose-dependent findings reported in the retrospective analysis by Kato 2025 on sacubitril/valsartan in heart failure (Kato 2025)."},{"id":"claim_27","type":"claim","text":"By contrast, the bioequivalence studies by Mei 2025 and Goh 2026 are designed to demonstrate pharmacokinetic similarity rather than clinical superiority, reporting effect directions as null (Mei 2025, Goh 2026)."},{"id":"claim_28","type":"claim","text":"Dosing and Pharmacokinetics is retained as a separate Results slice (n=7; null signal in 4/7 sources; 7 indirect; no direct clinical anchor) and is not pooled into adjacent endpoint classes."},{"id":"claim_29","type":"claim","text":"Despite these positive mechanistic signals, the evidence base for immune-related longevity outcomes remains limited and contextual. The reviewed findings are derived from secondary endpoint analyses in trials not primarily designed to assess longevity, and the clinical significance of the magnitude of biomarker change is not established (Gomaz 2025). Furthermore, the broader synthesis indicates that positive signals for ARBs in longevity are often context-dependent and may not translate to hard clinical endpoints like mortality, highlighting the tension between biomarker improvement and definitive survival benefit."},{"id":"claim_30","type":"claim","text":"The evidence base for immune and inflammatory outcomes in the context of ARBs and longevity is anchored by a single randomized, double-blinded, placebo-controlled pilot clinical trial. Lu 2025 reported. The trial population consisted of adults in an observational cohort design, assessing changes in systemic inflammation and the renin-angiotensin system. This study provides the primary direct evidence from a controlled human intervention relevant to this outcome class."},{"id":"source_1","type":"source","study":"Solomon 2026","year":2026,"doi":"10.1038/s41591-026-04313-w","url":"https://doi.org/10.1038/s41591-026-04313-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_2","type":"source","study":"Din 2026","year":2026,"doi":"10.1038/s41598-026-40790-2","url":"https://doi.org/10.1038/s41598-026-40790-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_3","type":"source","study":"Li 2025","year":2025,"doi":"10.3389/fphar.2025.1543275","url":"https://doi.org/10.3389/fphar.2025.1543275","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_4","type":"source","study":"Mei 2025","year":2025,"doi":"10.1038/s41598-025-32576-9","url":"https://doi.org/10.1038/s41598-025-32576-9","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_5","type":"source","study":"Chung 2024","year":2024,"doi":"10.1111/jch.14929","url":"https://doi.org/10.1111/jch.14929","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_6","type":"source","study":"Taha 2025","year":2025,"doi":"10.1080/14796678.2025.2535218","url":"https://doi.org/10.1080/14796678.2025.2535218","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_7","type":"source","study":"Tian 2025","year":2025,"doi":"10.2147/DDDT.S485851","url":"https://doi.org/10.2147/DDDT.S485851","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_8","type":"source","study":"Yamamoto 2024","year":2024,"doi":"10.1111/jch.14938","url":"https://doi.org/10.1111/jch.14938","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_9","type":"source","study":"Lee 2025","year":2025,"doi":"10.1038/s41467-025-62203-0","url":"https://doi.org/10.1038/s41467-025-62203-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_10","type":"source","study":"Senanayake 2026","year":2026,"doi":"10.1136/bmjopen-2025-107127","url":"https://doi.org/10.1136/bmjopen-2025-107127","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_11","type":"source","study":"Ahn 2026","year":2026,"doi":"10.1161/HYPERTENSIONAHA.125.25810","url":"https://doi.org/10.1161/HYPERTENSIONAHA.125.25810","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_12","type":"source","study":"Yu 2025","year":2025,"doi":"10.2196/63350","url":"https://doi.org/10.2196/63350","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_13","type":"source","study":"Derington 2025","year":2025,"doi":"10.1093/gerona/glaf028","url":"https://doi.org/10.1093/gerona/glaf028","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_14","type":"source","study":"Campbell 2025","year":2025,"doi":"10.1111/ctr.70067","url":"https://doi.org/10.1111/ctr.70067","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_15","type":"source","study":"Alqaisi 2025","year":2025,"doi":"10.1158/1078-0432.CCR-24-3128","url":"https://doi.org/10.1158/1078-0432.CCR-24-3128","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_16","type":"source","study":"Savarese 2026","year":2026,"doi":"10.1093/eschf/xvag095","url":"https://doi.org/10.1093/eschf/xvag095","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_17","type":"source","study":"Goh 2026","year":2026,"doi":"10.1007/s00210-025-04903-4","url":"https://doi.org/10.1007/s00210-025-04903-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_18","type":"source","study":"Wang 2026","year":2026,"doi":"10.3389/fphar.2026.1644757","url":"https://doi.org/10.3389/fphar.2026.1644757","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_19","type":"source","study":"Albertini 2025","year":2025,"doi":"10.1161/JAHA.124.040302","url":"https://doi.org/10.1161/JAHA.124.040302","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"id":"source_20","type":"source","study":"Jo 2025","year":2025,"doi":"10.1161/JAHA.125.041406","url":"https://doi.org/10.1161/JAHA.125.041406","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not 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candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]}}},{"name":"contradiction_map.json","media_type":"application/json","content":{"publication_id":"edeb045d-18ed-49dc-95b6-57f76783ce2b","screening":{"identified":71,"screened":71,"excluded":0,"included":71,"included_or_retained":71,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"71 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]},"limitations":["This is an agent-assisted evidence map, not a PRISMA-complete systematic review or clinical guideline.","It is not PROSPERO-registered and should not be read as medical advice.","Public sidecars expose citation traces and extraction status; empty fields mean not extracted, not assumed absent."],"contradictions":["What does the current evidence establish about Arbs Longevity and human geroscience? This synthesis tests the thesis that evidence for ARBs longevity is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation. This paper synthesizes arbs longevity as an aging-related intervention across 71 included source papers and 4116 high-confidence extracted claims. The evidence profile contains 1 direct clinical source, 48 adjacent clinical sources, and 1 mechanistic or model-system source, with 665 cross-study disagreements across the evidence base. Positive study-level signals concentrate in contextual adjacent evidence, safety and comorbidity, cardiometabolic, null signals in contextual adjacent evidence, safety and comorbidity, cardiometabolic, and negative signals in cardiometabolic, mortality and survival. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that arbs longevity remains a bounded geroscience case: mechanistic plausibility and selected clinical signals justify further targeted testing, while mixed and null findings limit any unqualified anti-aging claim. This conservative interpretation is especially important in aging research because endpoints often differ across model systems, human trials, and observational cohorts. A signal in one domain does not automatically establish the same signal in","Mechanistically, the blood pressure-lowering effects of ARBs are well-established through blockade of the angiotensin II type 1 receptor, leading to vasodilation and reduced aldosterone secretion. The PARASOL study's findings align with this pathway, where sacubitril/valsartan's combined neprilysin inhibition and AT1 receptor blockade showed efficacy in hypertensive Japanese adults (Yamamoto 2024). Preclinical and mechanistic data suggest that ARBs may influence metabolic pathways, as indicated by the significant HbA1c and glucose reductions with sacubitril/valsartan treatment (Abhari 2026). Furthermore, the observed renal hemodynamic effects, such as changes in intrarenal blood flow, may contribute to the variable outcomes seen in CKD populations (Wever 2025).","Mechanistically, the evidence reveals that ARBs and ARNI operate through distinct but overlapping pathways that extend beyond blood pressure lowering to affect cardiac remodeling, endothelial function, and metabolic regulation.","Quantitative findings from this trial are characterized by a mixture of null and highly significant results across different measured endpoints. However, other endpoints demonstrated strong statistical significance, with P < 0.0001 and P < 0.001 reported. The full distribution of per-study endpoint evidence, including the specific biomarkers associated with these p-values, is detailed in Table 2.","A tension within this outcome class arises from the mixed pattern of statistical results observed in a single trial. While some endpoints reached high statistical significance, others did not, suggesting that the anti-inflammatory effect of telmisartan may be context-dependent or specific to certain biomarkers. The absence of corroborating large-scale human RCTs for this specific outcome class means the evidence remains preliminary, with the boundary conditions for a consistent immunomodulatory effect yet to be fully established.","Quantitative findings from the observational data show a strong association between medication non-adherence and adverse outcomes. This suggests that consistent use of guideline-directed therapy, which often incorporates ARBs, is critical for survival benefits. However, the specific contribution of ARBs cannot be disentangled from the multi-drug regimens studied (Murray-Thomas 2025). The Wang 2026 meta-analysis reports that SGLT2 inhibitors, a drug class often used alongside ARBs, significantly reduced cardiovascular death compared to placebo, but ARB-specific mortality effects within this comparison were not separately quantified in the provided excerpts (Wang 2026).","Mechanistically, the rationale linking ARBs to longevity centers on mitigating pathological angiotensin II signaling, which contributes to inflammation, fibrosis, and organ damage, thereby theoretically slowing age-related decline. The mechanistic substrate underlying this potential benefit is supported by the broader evidence on RAAS inhibition in cardiovascular disease, which forms the biological plausibility for trials like the HFrEF polypill pilot (Agarwal 2025). This pilot trial protocol (Agarwal 2025) includes losartan, an ARB, as one component of a multi-drug intervention aimed at improving heart failure outcomes, which are a major determinant of mortality. The systematic review by Wang 2026 synthesizes evidence on several advanced heart failure therapies, positioning ARBs as part of a foundational treatment landscape where survival benefits are mediated through integrated cardiovascular protection (Wang 2026). The evidence therefore points to a context-dependent effect, where ARBs may contribute to longevity by reducing mortality in specific high-risk cardiovascular populations as part of comprehensive care (Jin 2025; Murray-Thomas 2025).","Within the corpus, tensions in the longevity outcome class arise primarily from differences in effect certainty and directness. By contrast, the Agarwal 2025 polypill protocol represents a future interventional approach but does not yet report a definitive null or positive effect on longevity, reflecting an anticipated rather than an observed outcome (Agarwal 2025). In contrast, the observational cohort by Murray-Thomas 2025 demonstrates a clear, statistically significant negative consequence of ARB non-adherence on mortality (Murray-Thomas 2025). The Jin 2025 cohort study on guideline-directed therapy in acute coronary syndrome patients with renal dysfunction provides corroborating observational evidence for the importance of therapy adherence, aligning with Murray-Thomas 2025 in highlighting the role of medication use in survival, though specific effect sizes for ARBs remain unclear (Jin 2025). The Wang 2026 meta-analysis adds a layer of complexity by situating ARBs within a multi-therapy landscape where newer agents like SGLT2i show strong mortality benefits, potentially challenging the incremental longevity value of ARBs alone (Wang 2026).","A tension exists in the broader interpretation of this safety data. The statistically significant P-value of 0.0038 points to a measurable difference between groups, yet the effect direction for this observational cohort was classified as unclear. This suggests that while a statistical association was detected, the clinical implication—whether the effect represents a beneficial safety profile or a concerning adverse signal—requires further elucidation through dedicated long-term outcome trials.","The evidence base for safety and comorbidity outcomes associated with renin-angiotensin system modulation encompasses diverse study designs and patient populations. Observational cohort studies, including the DAPA-SRV trial, evaluated dapagliflozin in adults with systemic right ventricular dysfunction (Albertini 2025). The DIGIT-HHF trial characterized baseline characteristics of patients with advanced chronic heart failure in a randomized, double-blind, placebo-controlled design (Bavendiek 2025). Real-world analyses examined sacubitril/valsartan effectiveness in dialysis patients with heart failure with reduced ejection fraction, reporting on hospitalization and mortality endpoints (Tu 2026). Systematic reviews synthesized evidence on sacubitril/valsartan's impact on sleep-disordered breathing in chronic heart failure patients (Kuang 2025) and its efficacy in peritoneal dialysis populations (Silva 2026). Pharmacovigilance analyses based on the FDA Adverse Event Reporting System assessed renal failure risk (Wang 2025), while prospective protocols investigated ARBs in oncology contexts (Wang 2025c).","Mechanistically, the observed functional and hemodynamic benefits align with pathways of neurohormonal modulation and cardiac remodeling. Reductions in AHI and improvements in oxygen saturation point to a potential role in mitigating comorbid sleep-disordered breathing, a common condition in heart failure (Kuang 2025). The significant decrease in NT-proBNP, a biomarker of cardiac wall stress, corroborates the hemodynamic benefits observed in dialysis populations (Silva 2026). These mechanistic human studies and clinical trial data provide a plausible substrate for the safety signals. However, the clinical significance of these changes for long-term survival and comorbidity reduction requires further contextualization.","Mechanistically, the pharmacokinetic data from these studies support the development of fixed-dose combinations to improve patient adherence and simplify treatment regimens. The bioequivalence studies by Mei 2025, Tian 2025, Hu 2025, and Goh 2026 provide the foundational evidence for such formulations, ensuring comparable systemic exposure to the individual components (Mei 2025, Tian 2025, Hu 2025, Goh 2026). Preclinical and human data suggest that optimized dosing can achieve target receptor blockade while potentially minimizing off-target effects, a principle supported by the dose-dependent findings reported in the retrospective analysis by Kato 2025 on sacubitril/valsartan in heart failure (Kato 2025)."]}},{"name":"evidence_table.csv","media_type":"text/csv","content":"study,population,intervention_or_exposure,comparator,endpoint,effect,risk_of_bias,directness\r\nSolomon 2026,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nDin 2026,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nLi 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nMei 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nChung 2024,not 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extracted,not extracted,not appraised in public sidecar,review-level\r\nNouhravesh 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nBavendiek 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nMosepele 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nKehoe 2026,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nTakahashi 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nFilipova 2020,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nWever 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nOmland 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extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nLu 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nFumarulo 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nDou 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nNgai 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nRezazadeh 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nNazari-Robati 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nAsim 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public 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extracted,not extracted,not appraised in public sidecar,review-level\r\nZhao 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nShubietah 2026,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nWang 2025c,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nAl-Omari 2026,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nGomaz 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nADA 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,citation\r\nIoannidis 2005,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public 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