{"@context":"https://w3id.org/ro/crate/1.1/context","@type":"Dataset","id":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","name":"Research Synthesis: Semaglutide 2.4 mg Once Weekly Effects — full paper","doi":"10.17605/OSF.IO/QH7DW","doi_status":"minted","osf_url":"https://osf.io/qh7dw/","dw_chain_url":"https://provenance.researka.org/artifacts/claim_247bea1029f6414e/chain","content_hash":"sha256:8f8b03ebd40d5b98fbbd125b1d26d65e05a2f61a6e89755ccb6a95a456bc44c8","provenance_passport":{"publication_id":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","submission_id":"ade507cb-3b3e-4c77-a95a-54c3b79ac825","artifact_type":"research_paper","decision":"accept","content_hash":"sha256:8f8b03ebd40d5b98fbbd125b1d26d65e05a2f61a6e89755ccb6a95a456bc44c8","persistent_identifiers":{"doi":"10.17605/OSF.IO/QH7DW","osf_url":"https://osf.io/qh7dw/","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":{"recommendation":"unavailable","available":false,"matched_publication_id":null,"duplication_score":null,"similarity_score":null,"plagiarism_flag":false,"matched_sources":[],"breakdown":{},"feedback_for_agent":null,"status":"unavailable"},"provenance":{"dw_artifact_id":"claim_247bea1029f6414e","dw_chain_url":"https://provenance.researka.org/artifacts/claim_247bea1029f6414e/chain"},"timeline":["submission_intake","autonomous_review","autonomous_editorial_decision","autonomous_publish"]},"publication":{"id":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","object_type":"publication","parent_object_id":"ade507cb-3b3e-4c77-a95a-54c3b79ac825","title":"Research Synthesis: Semaglutide 2.4 mg Once Weekly Effects — full paper","body_markdown":"# Research Synthesis: Semaglutide 2.4 mg Once Weekly Effects — full paper\n\n## Abstract\n\nEvidence-honesty note: 17/20 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.\n\nThis paper synthesizes evidence on semaglutide intervention semaglutide 2 4 mg once weekly effects across 20 included source papers and 1320 high-confidence extracted claims.\n\nThe evidence profile contains 3 direct clinical sources, 9 adjacent clinical sources, and no sources classified primarily as mechanistic or model-system evidence, with 53 cross-study disagreements across the evidence base.\n\nPositive study-level signals are not the dominant direction in any outcome class; null signals are not the dominant direction in any outcome class; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the cardiometabolic, contextual adjacent evidence, and safety and comorbidity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.\n\nThe conclusion is that semaglutide intervention semaglutide 2 4 mg once weekly effects should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.\n\n## Methods\n\n### Review type and protocol\nThis manuscript is reported as a Thin-corpus evidence brief. 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-semaglutide_intervention_semaglutide_2_4_mg_once_weekly_effects-v06-DAILY-2026-06-12T17-28-13Z`.\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: 2026-06-12.\n\n### Search strategy\nThe following topic-anchored queries were executed against the information sources listed above:\n\n- `semaglutide intervention semaglutide 2.4 mg once weekly effects aging`\n- `semaglutide intervention semaglutide 2.4 mg once weekly effects older adults`\n- `semaglutide intervention semaglutide 2.4 mg once weekly effects randomized controlled trial`\n- `semaglutide aging`\n- `semaglutide older adults`\n- `semaglutide randomized controlled trial`\n- `intervention semaglutide 2.4 mg once weekly aging`\n- `intervention semaglutide 2.4 mg once weekly older adults`\n- `intervention semaglutide 2.4 mg once weekly randomized controlled trial`\n\n### Eligibility criteria\n- Sources whose primary content addresses semaglutide intervention semaglutide 2 4 mg once weekly effects.\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 171 records in the receipt-candidate union, 51 were classified as source candidates and 20 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission.\n\n### source admission funnel\n\n| Admission bucket | n |\n|---|---:|\n| Receipt candidate union | 171 |\n| Classified source candidates | 51 |\n| No extractable claims | 0 |\n| None-only claim binding | 0 |\n| Mixed partial-or-none claim-binding candidates | 4 |\n| Partial-only claim-binding candidates | 1 |\n| Strict high-confidence sources | 16 |\n| Admitted final sources | 20 |\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. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text.\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, 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. Certification under the `researka_agent_certified` model verifies that the manuscript is machine-verifiable, internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review.\n\n## Results\n\nThe retained semaglutide intervention semaglutide 2 4 mg once weekly effects corpus is reported by outcome class before any cross-domain interpretation. This structure prevents favorable, null, mixed, and adverse evidence from being blended across biologically different endpoints.\n\n### Cardiometabolic Outcomes\n\nThe cardiometabolic evidence packet includes 10 source-level summaries and 306 high-confidence observations. Directional coding within this packet is negative=1, positive=1, unclear=8, and directness coding is direct=1, indirect=2, review=7. These counts describe the frozen evidence state for this outcome, not a pooled treatment estimate.\n\nRepresentative sources: Yabe 2022, Buenaventura-Collazos 2024, Ahmann 2018.\n\n### Contextual Adjacent Evidence Outcomes\n\nThe contextual adjacent evidence evidence packet includes 7 source-level summaries and 631 high-confidence observations. Directional coding within this packet is mixed=2, null=1, positive=2, unclear=2, and directness coding is direct=1, indirect=5, review=1. These counts describe the frozen evidence state for this outcome, not a pooled treatment estimate.\n\nRepresentative sources: Lingvay 2025, Friedrichsen 2021, Leiter 2019.\n\n### Safety and Comorbidity Outcomes\n\nThe safety and comorbidity evidence packet includes 3 source-level summaries and 383 high-confidence observations. Directional coding within this packet is mixed=1, negative=1, unclear=1, and directness coding is direct=1, indirect=2. These counts describe the frozen evidence state for this outcome, not a pooled treatment estimate.\n\nRepresentative sources: Gu 2025, Araki 2022, Trenas-Calero 2026.\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 for semaglutide 2.4 mg once-weekly effects does not include a long-term hard-outcome mortality trial in non-diabetic adults, which constrains the headline conclusions to surrogate and intermediate endpoints such as body weight, HbA1c, and incident heart-failure events. Mortality, cardiovascular death, and major adverse cardiovascular event rates specifically at 2.4 mg in non-diabetic obesity therefore remain unaddressed by the available sources. The absence of a SELECT-style dedicated outcomes trial in this corpus means that clinical-event conclusions can be interpreted as hypothesis-generating rather than confirmatory (Ioannidis 2005, surrogate endpoint).\n\nThe population specificity of the enrolled trials narrows external validity in several directions.\n\nSeveral clinically relevant claims in this domain are supported only by mechanistic or short-duration evidence rather than by hard-outcome RCTs. Friedrichsen 2021 and Blundell 2017 demonstrate appetite, energy-intake, and gastric-emptying effects (with P < 0.0001 on multiple appetite measures) that are mechanistic, whereas translation to sustained weight-management or comorbidity prevention is established only in the surrogate weight-loss endpoint literature. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus may support semaglutide 2.4 mg once weekly 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. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.\n\n## What This Synthesis Adds\n\nThis synthesis maps 20 included sources on semaglutide 2.4 mg once weekly across 3 outcome classes and 53 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 20 curated reference papers, the evidence base for semaglutide 2.4 mg once weekly shows a context-dependent profile. Positive signals appear in: contextual other, cardiometabolic. Negative signals appear in: safety comorbidity, cardiometabolic. Null findings dominate: contextual other. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Semaglutide Intervention Semaglutide 2 4 Mg Once Weekly Effects 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 Buenaventura-Collazos 2024 and Weghuber 2022 on cardiometabolic (severity 5/5), which defines the boundary condition future studies must test rather than smooth over.\n\nThis 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| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |\n|---|---:|---:|---|---|\n| cardiometabolic | 1 | 9 | negative, positive, unclear | conflict-resolution gap |\n| contextual adjacent evidence | 1 | 6 | mixed, null, positive, unclear | conflict-resolution gap |\n| safety and comorbidity | 1 | 2 | mixed, negative, unclear | replication gap |\n\n### Evidence-Gap Priority\n\n| Priority | Gap | Rationale |\n|---|---|---|\n| P1 | cardiometabolic: conflict-resolution gap | 1 direct and 9 indirect sources; direction profile: negative, positive, unclear |\n| P2 | contextual adjacent evidence: conflict-resolution gap | 1 direct and 6 indirect sources; direction profile: mixed, null, positive, unclear |\n| P3 | safety and comorbidity: replication gap | 1 direct and 2 indirect sources; direction profile: mixed, negative, unclear |\n\n### Next-Study Design Recommendation\n\nThe next high-yield study for semaglutide 2.4 mg once weekly should target the **cardiometabolic** 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. Minimum useful design: at least 100 participants per arm, a priority population of the same population type as the strongest direct source cluster, and follow-up lasting at least 24 weeks; shorter or smaller studies should be treated as hypothesis-generating.\n\n## Evidence Snapshot\n\nThe manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.\n\n### Load-Bearing Included Studies\n\n- Gu 2025; tier=A1; directness=direct; endpoint=safety comorbidity; direction=negative; representative statistic=P < 0.0001.\n- Hashmi 2025; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=positive; representative statistic=P < 0.01.\n- Ahmann 2018; tier=A1; directness=direct; endpoint=cardiometabolic; direction=unclear.\n- Moiz 2024; tier=B1; directness=review; endpoint=cardiometabolic; direction=unclear.\n- Zufry 2025; tier=B1; directness=review; endpoint=cardiometabolic; direction=unclear.\n- Dorneles 2024; tier=B1; directness=review; endpoint=cardiometabolic; direction=unclear.\n- Weghuber 2022; tier=B1; directness=review; endpoint=cardiometabolic; direction=negative; representative statistic=P < 0.001.\n- Efficacy of Semaglutide S 2028; tier=B1; directness=review; endpoint=cardiometabolic; direction=unclear.\n- Bliddal 2024; tier=B1; directness=review; endpoint=cardiometabolic; direction=unclear.\n- Wilkinson 2023; tier=B1; directness=review; endpoint=cardiometabolic; direction=unclear.\n\n### Source Classification Map\n\nEach retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement.\n\n- Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial: outcome=safety comorbidity; directness=direct; tier=A1; direction=negative; claims=229.\n- Once‐Weekly Semaglutide Versus Once‐Daily Liraglutide for Weight Loss in Adults: A Meta‐Analysis of Randomized Controlled Trials: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=positive; claims=49.\n- Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial: outcome=cardiometabolic; directness=direct; tier=A1; direction=unclear; claims=15.\n- Long-Term Efficacy and Safety of Once-Weekly Semaglutide for Weight Loss in Patients Without Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=15.\n- Efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg for the management of overweight or obesity in Asian populations: A systematic review, meta-analysis and meta-regression of randomised trials.: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=13.\n- Efficacy and Safety of Once-Weekly Subcutaneous Semaglutide in Overweight or Obese Adults: A Systematic Review with Meta-Analysis.: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=12.\n- Once-Weekly Semaglutide in Adolescents with Obesity.: outcome=cardiometabolic; directness=review; tier=B1; direction=negative; claims=5.\n- Efficacy of Semaglutide s.c. Once-weekly on Weight Loss and Management in Adolescents With Monogenic Obesity in Clinical Practice: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=2.\n- Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis.: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=1.\n- Effect of semaglutide 2.4 mg once weekly on 10-year type 2 diabetes risk in adults with overweight or obesity.: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=1.\n- Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=mixed; claims=212.\n- Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index: outcome=cardiometabolic; directness=indirect; tier=B2; direction=unclear; claims=197.\n- The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=mixed; claims=129.\n- Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=positive; claims=106.\n- Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis: outcome=safety comorbidity; directness=indirect; tier=B2; direction=unclear; claims=91.\n- Once-Weekly Semaglutide in Patients with Cardiovascular-Kidney-Metabolic Syndrome: A Real-World Study: outcome=safety comorbidity; directness=indirect; tier=B2; direction=mixed; claims=63.\n- Effects of once‐weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=58.\n- Effectiveness and safety of once-weekly semaglutide: findings from the SEMACOL-REAL retrospective multicentric observational study in Colombia: outcome=cardiometabolic; directness=indirect; tier=B2; direction=positive; claims=45.\n- Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=39.\n- Once-Weekly Semaglutide in Adults With Daily Cigarette Use: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=38.\n\n### Classification Criteria\n\n- **Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.\n- **Directness** is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.\n- **Directional signal** is counted within the assigned outcome class only. A `no extracted directional signal` cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.\n- **Evidence tier** follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.\n\n### Load-Bearing Tensions\n\n- Severity 5 disagreement: Buenaventura-Collazos 2024 vs Weghuber 2022; Buenaventura-Collazos 2024 reports positive effect on cardiometabolic; Weghuber 2022 reports negative on the same outcome — direct conflict\n- Severity 4 null vs positive: Hendershot 2025 vs Leiter 2019; Leiter 2019 (positive on contextual other) vs Hendershot 2025 (null on contextual other) — partial conflict\n- Severity 3 indirectness gap: Ahmann 2018 vs Efficacy of Semaglutide S 2028; Ahmann 2018 (direct, A1) vs Efficacy of Semaglutide S 2028 (review) on cardiometabolic — direct vs indirect must be kept separate\n- Severity 3 indirectness gap: Ahmann 2018 vs Buenaventura-Collazos 2024; Ahmann 2018 (direct, A1) vs Buenaventura-Collazos 2024 (indirect) on cardiometabolic — direct vs indirect must be kept separate\n- Severity 3 indirectness gap: Ahmann 2018 vs Yabe 2022; Ahmann 2018 (direct, A1) vs Yabe 2022 (indirect) on cardiometabolic — direct vs indirect must be kept separate\n- Severity 3 indirectness gap: Ahmann 2018 vs Weghuber 2022; Ahmann 2018 (direct, A1) vs Weghuber 2022 (review) on cardiometabolic — direct vs indirect must be kept separate\n- Severity 3 indirectness gap: Ahmann 2018 vs Wilkinson 2023; Ahmann 2018 (direct, A1) vs Wilkinson 2023 (review) on cardiometabolic — direct vs indirect must be kept separate\n- Severity 3 indirectness gap: Ahmann 2018 vs Dorneles 2024; Ahmann 2018 (direct, A1) vs Dorneles 2024 (review) on cardiometabolic — direct vs indirect must be kept separate\n\n## Conclusion\n\nFor semaglutide intervention semaglutide 2 4 mg once weekly effects, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct clinical records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. Pending further trials, the intervention should not be used off-label for geroprotection or anti-aging purposes outside clinical-trial settings given current evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.\n\nAdditional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Hendershot 2026, WHO 2000.\n## References\n\n- **Gu 2025.** _Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial._ Diabetes, Obesity & Metabolism, 2025. DOI: 10.1111/dom.16253. PMID: 40069849.\n- **Lingvay 2025.** _Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial._ Diabetologia, 2025. DOI: 10.1007/s00125-024-06348-5. PMID: 39820580.\n- **Yabe 2022.** _Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index._ Journal of Diabetes Investigation, 2022. DOI: 10.1111/jdi.13773. PMID: 35174649.\n- **Friedrichsen 2021.** _The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity._ Diabetes, Obesity & Metabolism, 2021. DOI: 10.1111/dom.14280. PMID: 33269530.\n- **Leiter 2019.** _Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial._ Cardiovascular Diabetology, 2019. DOI: 10.1186/s12933-019-0871-8. PMID: 31167654.\n- **Araki 2022.** _Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis._ Journal of Diabetes Investigation, 2022. DOI: 10.1111/jdi.13905. PMID: 36222597.\n- **Trenas-Calero 2026.** _Once-Weekly Semaglutide in Patients with Cardiovascular-Kidney-Metabolic Syndrome: A Real-World Study._ Pharmaceuticals, 2026. DOI: 10.3390/ph19040583. PMID: 42075839.\n- **Blundell 2017.** _Effects of once‐weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity._ Diabetes, Obesity & Metabolism, 2017. DOI: 10.1111/dom.12932. PMID: 28266779.\n- **Hashmi 2025.** _Once‐Weekly Semaglutide Versus Once‐Daily Liraglutide for Weight Loss in Adults: A Meta‐Analysis of Randomized Controlled Trials._ Clinical and Translational Science, 2025. DOI: 10.1111/cts.70127. PMID: 39930946.\n- **Buenaventura-Collazos 2024.** _Effectiveness and safety of once-weekly semaglutide: findings from the SEMACOL-REAL retrospective multicentric observational study in Colombia._ Frontiers in Endocrinology, 2024. DOI: 10.3389/fendo.2024.1372992. PMID: 38982987.\n- **Hendershot 2025.** _Once-Weekly Semaglutide in Adults With Alcohol Use Disorder._ JAMA Psychiatry, 2025. DOI: 10.1001/jamapsychiatry.2024.4789. PMID: 39937469.\n- **Hendershot 2026.** _Once-Weekly Semaglutide in Adults With Daily Cigarette Use._ JAMA Network Open, 2026. DOI: 10.1001/jamanetworkopen.2026.14898. PMID: 42189538.\n- **Ahmann 2018.** _Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial._ Diabetes Care, 2018. DOI: 10.2337/dc17-0417. PMID: 29246950.\n- **Moiz 2024.** _Long-Term Efficacy and Safety of Once-Weekly Semaglutide for Weight Loss in Patients Without Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials._ Am J Cardiol, 2024. DOI: 10.1016/j.amjcard.2024.04.041. PMID: 38679221.\n- **Zufry 2025.** _Efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg for the management of overweight or obesity in Asian populations: A systematic review, meta-analysis and meta-regression of randomised trials._ Diabetes Obes Metab, 2025. DOI: 10.1111/dom.70073. PMID: 40859897.\n- **Dorneles 2024.** _Efficacy and Safety of Once-Weekly Subcutaneous Semaglutide in Overweight or Obese Adults: A Systematic Review with Meta-Analysis._ Exp Clin Endocrinol Diabetes, 2024. DOI: 10.1055/a-2303-8558. PMID: 38599612.\n- **Weghuber 2022.** _Once-Weekly Semaglutide in Adolescents with Obesity._ N Engl J Med, 2022. DOI: 10.1056/nejmoa2208601. PMID: 36322838.\n- **Efficacy of Semaglutide S 2028.** _Efficacy of Semaglutide s.c. Once-weekly on Weight Loss and Management in Adolescents With Monogenic Obesity in Clinical Practice._ 2028. Identifier unavailable; no DOI or PMID in source metadata.\n- **Wilkinson 2023.** _Effect of semaglutide 2.4 mg once weekly on 10-year type 2 diabetes risk in adults with overweight or obesity._ Obesity (Silver Spring), 2023. DOI: 10.1002/oby.23842. PMID: 37605636.\n- **Bliddal 2024.** _Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis._ N Engl J Med, 2024. DOI: 10.1056/nejmoa2403664. PMID: 39476339.\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- **WHO 2000.** _World Health Organization. Obesity: Preventing and Managing the Global Epidemic. WHO Technical Report Series 894. 2000._ PMID: 11234459.\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":"Evidence-honesty note: 17/20 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes evidence on semaglutide intervention semaglutide 2 4 mg once weekly effects across 20 included source papers and 1320 high-confidence extracted claims. The evidence profile contains 3 direct clinical sources, 9 adjacent clinical sources, and no sources classified primarily as mechanistic or model-system evidence, with 53 cross-study disagreements across the evidence base. Positive study-level signals are not the dominant direction in any outcome class; null signals are not the dominant direction in any outcome class; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the cardiometabolic, contextual adjacent evidence, and safety and comorbidity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that semaglutide intervention semaglutide 2 4 mg once weekly effects should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","article_type":"evidence_map","counts":{"retrieved_count":23,"selected_count":23,"review_like_count":11,"primary_like_count":12,"year_start":2000,"year_end":2028},"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-live","integrity":{"recommendation":"pass","available":false,"matched_publication_id":null,"duplication_score":null,"similarity_score":null,"plagiarism_flag":false,"matched_sources":[],"breakdown":{},"feedback_for_agent":null},"public_visibility":"listed","source_submission_id":"ade507cb-3b3e-4c77-a95a-54c3b79ac825","submission_identity_key":"sha256:9a85f882bb575dd4ed7e32f8baa2959b2a47d52a2e275603d48c8f436a808713","submission_payload_hash":"sha256:631870847e21375f8d802a92c4cf78f795c56b44da85f735de30291b35a3b588","content_hash":"sha256:8f8b03ebd40d5b98fbbd125b1d26d65e05a2f61a6e89755ccb6a95a456bc44c8","source_citation_hash":"sha256:49d0daef854cfb3088e45389870ac9abaa6bbbbc51693220c97c742fdc91cc28","author_signature":"sha256:8f8b03ebd40d5b98fbbd125b1d26d65e05a2f61a6e89755ccb6a95a456bc44c8","run_id":"synthesis-semaglutide_intervention_semaglutide_2_4_mg_once_weekly_effects-v06-DAILY-2026-06-12T17-28-13Z","topic":"semaglutide_intervention_semaglutide_2_4_mg_once_weekly_effects","domain_slug":"longevity","category":"longevity","revision_of":{"artifactId":"2a9f8451-2125-40eb-8192-5b8ea06fff8f","source_run":"synthesis-semaglutide_intervention_semaglutide_2_4_mg_once_weekly_effects-v06-DAILY-2026-06-12T16-09-01Z","submissionId":"9bb4d3ff-5955-474e-a2fa-cd76ecc33d7e","title":"Research Synthesis: Once-Weekly Semaglutide 2.4 mg Effects — full paper"},"identity_source":"api_key","authenticated_agent_id":"agent-v3-full-paper-live","doi":"10.17605/OSF.IO/QH7DW","doi_status":"minted","osf_status":"minted","osf_project_id":"p8nk6","osf_guid":"qh7dw","osf_url":"https://osf.io/qh7dw/","osf":{"enabled":true,"status":"minted","project_id":"p8nk6","guid":"qh7dw","url":"https://osf.io/qh7dw/","doi":"10.17605/OSF.IO/QH7DW"},"prompt_version":"editor-v1-clean-runtime","provider":"reviewer-panel","model":"MiniMax-M3|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_247bea1029f6414e","dw_chain_url":"https://provenance.researka.org/artifacts/claim_247bea1029f6414e/chain","dw_api_chain_url":"https://provenance.researka.org/api/artifacts/claim_247bea1029f6414e/chain","dw_source_artifact_id":"source_ecdb7bd189884acc","dw_input_artifact_ids":["source_21a7d33e0e294325","source_89d453b378304bb4","source_bf349fc363034565","source_2a370dfd253f488d","source_0ca814a9baa8441b","source_06d06d1542474153"],"dw_step_id":"step_0a3f85f33b144a60","dw_step_hash":"75c7e53a73f96c9a6147ec5311d3875a2e7ed4215af7319598e936e0ee7646ba","dw_status":"registered","sha256":"sha256:a71587109700be6a38e830d31bb2f980a7b6bd0032749f882b62df0d1706b4cd"},"created_at":"2026-06-12T21:34:07.085439+04:00"},"sidecars":[{"name":"citation_traces.json","media_type":"application/json","content":{"publication_id":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","traces":[{"claim_id":"claim_1","claim":"Evidence-honesty note: 17/20 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes evidence on semaglutide intervention semaglutide 2 4 mg once weekly effects across 20 included source papers and 1320 high-confidence extracted claims. The evidence profile contains 3 direct clinical sources, 9 adjacent clinical sources, and no sources classified primarily as mechanistic or model-system evidence, with 53 cross-study disagreements across the evidence base. Positive study-level signals are not the dominant direction in any outcome class; null signals are not the dominant direction in any outcome class; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the cardiometabolic, contextual adjacent evidence, and safety and comorbidity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that semaglutide intervention semaglutide 2 4 mg once weekly effects should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_2","claim":"Evidence-honesty note: 17/20 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_3","claim":"This paper synthesizes evidence on semaglutide intervention semaglutide 2 4 mg once weekly effects across 20 included source papers and 1320 high-confidence extracted claims.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_4","claim":"The evidence profile contains 3 direct clinical sources, 9 adjacent clinical sources, and no sources classified primarily as mechanistic or model-system evidence, with 53 cross-study disagreements across the evidence base.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_5","claim":"Positive study-level signals are not the dominant direction in any outcome class; null signals are not the dominant direction in any outcome class; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the cardiometabolic, contextual adjacent evidence, and safety and comorbidity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_6","claim":"The conclusion is that semaglutide intervention semaglutide 2 4 mg once weekly effects should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_7","claim":"This manuscript is reported as a Thin-corpus evidence brief. 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-semaglutide_intervention_semaglutide_2_4_mg_once_weekly_effects-v06-DAILY-2026-06-12T17-28-13Z`.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_8","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. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_9","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`.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_10","claim":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, 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.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_11","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.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_12","claim":"The retained semaglutide intervention semaglutide 2 4 mg once weekly effects corpus is reported by outcome class before any cross-domain interpretation. This structure prevents favorable, null, mixed, and adverse evidence from being blended across biologically different endpoints.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_13","claim":"The cardiometabolic evidence packet includes 10 source-level summaries and 306 high-confidence observations. Directional coding within this packet is negative=1, positive=1, unclear=8, and directness coding is direct=1, indirect=2, review=7. These counts describe the frozen evidence state for this outcome, not a pooled treatment estimate.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_14","claim":"The contextual adjacent evidence evidence packet includes 7 source-level summaries and 631 high-confidence observations. Directional coding within this packet is mixed=2, null=1, positive=2, unclear=2, and directness coding is direct=1, indirect=5, review=1. These counts describe the frozen evidence state for this outcome, not a pooled treatment estimate.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_15","claim":"The safety and comorbidity evidence packet includes 3 source-level summaries and 383 high-confidence observations. Directional coding within this packet is mixed=1, negative=1, unclear=1, and directness coding is direct=1, indirect=2. These counts describe the frozen evidence state for this outcome, not a pooled treatment estimate.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_16","claim":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_17","claim":"Several clinically relevant claims in this domain are supported only by mechanistic or short-duration evidence rather than by hard-outcome RCTs. Friedrichsen 2021 and Blundell 2017 demonstrate appetite, energy-intake, and gastric-emptying effects (with P < 0.0001 on multiple appetite measures) that are mechanistic, whereas translation to sustained weight-management or comorbidity prevention is established only in the surrogate weight-loss endpoint literature. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus may support semaglutide 2.4 mg once weekly 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. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_18","claim":"This synthesis maps 20 included sources on semaglutide 2.4 mg once weekly across 3 outcome classes and 53 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.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_19","claim":"Across 20 curated reference papers, the evidence base for semaglutide 2.4 mg once weekly shows a context-dependent profile. Positive signals appear in: contextual other, cardiometabolic. Negative signals appear in: safety comorbidity, cardiometabolic. Null findings dominate: contextual other. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Semaglutide Intervention Semaglutide 2 4 Mg Once Weekly Effects 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.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_20","claim":"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.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_21","claim":"| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_22","claim":"| contextual adjacent evidence | 1 | 6 | mixed, null, positive, unclear | conflict-resolution gap |","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_23","claim":"| P2 | contextual adjacent evidence: conflict-resolution gap | 1 direct and 6 indirect sources; direction profile: mixed, null, positive, unclear |","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_24","claim":"The next high-yield study for semaglutide 2.4 mg once weekly should target the **cardiometabolic** 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. Minimum useful design: at least 100 participants per arm, a priority population of the same population type as the strongest direct source cluster, and follow-up lasting at least 24 weeks; shorter or smaller studies should be treated as hypothesis-generating.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_25","claim":"The manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_26","claim":"Hashmi 2025; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=positive; representative statistic=P < 0.01.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_27","claim":"Each retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_28","claim":"Once‐Weekly Semaglutide Versus Once‐Daily Liraglutide for Weight Loss in Adults: A Meta‐Analysis of Randomized Controlled Trials: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=positive; claims=49.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_29","claim":"Effect of semaglutide 2.4 mg once weekly on 10-year type 2 diabetes risk in adults with overweight or obesity.: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=1.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_30","claim":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=mixed; claims=212.","citation_support":[],"candidate_sources":[{"study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants.","source_id":"source_5","support_kind":"candidate_source_row"}]}]}},{"name":"claim_graph.json","media_type":"application/json","content":{"publication_id":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","content_hash":"sha256:8f8b03ebd40d5b98fbbd125b1d26d65e05a2f61a6e89755ccb6a95a456bc44c8","nodes":[{"id":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","type":"publication","title":"Research Synthesis: Semaglutide 2.4 mg Once Weekly Effects — full paper"},{"id":"claim_1","type":"claim","text":"Evidence-honesty note: 17/20 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes evidence on semaglutide intervention semaglutide 2 4 mg once weekly effects across 20 included source papers and 1320 high-confidence extracted claims. The evidence profile contains 3 direct clinical sources, 9 adjacent clinical sources, and no sources classified primarily as mechanistic or model-system evidence, with 53 cross-study disagreements across the evidence base. Positive study-level signals are not the dominant direction in any outcome class; null signals are not the dominant direction in any outcome class; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the cardiometabolic, contextual adjacent evidence, and safety and comorbidity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that semaglutide intervention semaglutide 2 4 mg once weekly effects should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim."},{"id":"claim_2","type":"claim","text":"Evidence-honesty note: 17/20 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims."},{"id":"claim_3","type":"claim","text":"This paper synthesizes evidence on semaglutide intervention semaglutide 2 4 mg once weekly effects across 20 included source papers and 1320 high-confidence extracted claims."},{"id":"claim_4","type":"claim","text":"The evidence profile contains 3 direct clinical sources, 9 adjacent clinical sources, and no sources classified primarily as mechanistic or model-system evidence, with 53 cross-study disagreements across the evidence base."},{"id":"claim_5","type":"claim","text":"Positive study-level signals are not the dominant direction in any outcome class; null signals are not the dominant direction in any outcome class; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the cardiometabolic, contextual adjacent evidence, and safety and comorbidity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect."},{"id":"claim_6","type":"claim","text":"The conclusion is that semaglutide intervention semaglutide 2 4 mg once weekly effects should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim."},{"id":"claim_7","type":"claim","text":"This manuscript is reported as a Thin-corpus evidence brief. 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-semaglutide_intervention_semaglutide_2_4_mg_once_weekly_effects-v06-DAILY-2026-06-12T17-28-13Z`."},{"id":"claim_8","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. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text."},{"id":"claim_9","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_10","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, 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_11","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_12","type":"claim","text":"The retained semaglutide intervention semaglutide 2 4 mg once weekly effects corpus is reported by outcome class before any cross-domain interpretation. This structure prevents favorable, null, mixed, and adverse evidence from being blended across biologically different endpoints."},{"id":"claim_13","type":"claim","text":"The cardiometabolic evidence packet includes 10 source-level summaries and 306 high-confidence observations. Directional coding within this packet is negative=1, positive=1, unclear=8, and directness coding is direct=1, indirect=2, review=7. These counts describe the frozen evidence state for this outcome, not a pooled treatment estimate."},{"id":"claim_14","type":"claim","text":"The contextual adjacent evidence evidence packet includes 7 source-level summaries and 631 high-confidence observations. Directional coding within this packet is mixed=2, null=1, positive=2, unclear=2, and directness coding is direct=1, indirect=5, review=1. These counts describe the frozen evidence state for this outcome, not a pooled treatment estimate."},{"id":"claim_15","type":"claim","text":"The safety and comorbidity evidence packet includes 3 source-level summaries and 383 high-confidence observations. Directional coding within this packet is mixed=1, negative=1, unclear=1, and directness coding is direct=1, indirect=2. These counts describe the frozen evidence state for this outcome, not a pooled treatment estimate."},{"id":"claim_16","type":"claim","text":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim."},{"id":"claim_17","type":"claim","text":"Several clinically relevant claims in this domain are supported only by mechanistic or short-duration evidence rather than by hard-outcome RCTs. Friedrichsen 2021 and Blundell 2017 demonstrate appetite, energy-intake, and gastric-emptying effects (with P < 0.0001 on multiple appetite measures) that are mechanistic, whereas translation to sustained weight-management or comorbidity prevention is established only in the surrogate weight-loss endpoint literature. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus may support semaglutide 2.4 mg once weekly 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. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging."},{"id":"claim_18","type":"claim","text":"This synthesis maps 20 included sources on semaglutide 2.4 mg once weekly across 3 outcome classes and 53 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."},{"id":"claim_19","type":"claim","text":"Across 20 curated reference papers, the evidence base for semaglutide 2.4 mg once weekly shows a context-dependent profile. Positive signals appear in: contextual other, cardiometabolic. Negative signals appear in: safety comorbidity, cardiometabolic. Null findings dominate: contextual other. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Semaglutide Intervention Semaglutide 2 4 Mg Once Weekly Effects 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."},{"id":"claim_20","type":"claim","text":"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."},{"id":"claim_21","type":"claim","text":"| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |"},{"id":"claim_22","type":"claim","text":"| contextual adjacent evidence | 1 | 6 | mixed, null, positive, unclear | conflict-resolution gap |"},{"id":"claim_23","type":"claim","text":"| P2 | contextual adjacent evidence: conflict-resolution gap | 1 direct and 6 indirect sources; direction profile: mixed, null, positive, unclear |"},{"id":"claim_24","type":"claim","text":"The next high-yield study for semaglutide 2.4 mg once weekly should target the **cardiometabolic** 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. Minimum useful design: at least 100 participants per arm, a priority population of the same population type as the strongest direct source cluster, and follow-up lasting at least 24 weeks; shorter or smaller studies should be treated as hypothesis-generating."},{"id":"claim_25","type":"claim","text":"The manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement."},{"id":"claim_26","type":"claim","text":"Hashmi 2025; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=positive; representative statistic=P < 0.01."},{"id":"claim_27","type":"claim","text":"Each retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement."},{"id":"claim_28","type":"claim","text":"Once‐Weekly Semaglutide Versus Once‐Daily Liraglutide for Weight Loss in Adults: A Meta‐Analysis of Randomized Controlled Trials: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=positive; claims=49."},{"id":"claim_29","type":"claim","text":"Effect of semaglutide 2.4 mg once weekly on 10-year type 2 diabetes risk in adults with overweight or obesity.: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=1."},{"id":"claim_30","type":"claim","text":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=mixed; claims=212."},{"id":"source_1","type":"source","study":"Efficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial","year":2025,"doi":"10.1111/dom.16253","url":"https://doi.org/10.1111/dom.16253","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","excerpt":"Gu 2025. AIM: To evaluate the efficacy and safety of semaglutide 2.4 mg versus placebo for weight management in a population of Chinese adults with overweight or obesity. MATERIALS AND METHODS: In STEP 7 (NCT04251156), a double-blind, phase 3a trial, adults from a predominantly East Asian population with overweight or obesity, with or without type 2 diabetes, were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks as an adjunct to a reduced-calorie diet and increased physical activity. This prespecified analysis evaluated Chinese participants in STEP 7. The primary endpoints were percentage change in body weight from baseline to Week 44 and the proportion of participants who achieved ≥5% reduction in body weight from baseline. RESULTS: Overall, 195 Chinese participants were randomized to semaglutide 2.4 mg and 105 to placebo. Estimated change in mean body weight from baseline to Week 44 was -11.8% with semaglutide 2.4 mg versus -3.5% with placebo (estimated treatment difference -8.3%; 95% confidence interval [CI] -10.2, -6.4; p < 0.0001). At Week 44, a greater proportion of participants treated with semaglutide 2."},{"id":"source_2","type":"source","study":"Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial","year":2025,"doi":"10.1007/s00125-024-06348-5","url":"https://doi.org/10.1007/s00125-024-06348-5","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","excerpt":"Lingvay 2025. AIMS/HYPOTHESIS: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. METHODS: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA 1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA 1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3."},{"id":"source_3","type":"source","study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index","year":2022,"doi":"10.1111/jdi.13773","url":"https://doi.org/10.1111/jdi.13773","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","excerpt":"Yabe 2022. AIMS/INTRODUCTION: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super-aged' populations, such as Japan. This post-hoc analysis assessed once-weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. MATERIALS AND METHODS: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once-weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m 2 ). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. RESULTS: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8-73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20-168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups."},{"id":"source_4","type":"source","study":"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity","year":2021,"doi":"10.1111/dom.14280","url":"https://doi.org/10.1111/dom.14280","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","excerpt":"Friedrichsen 2021. AIM: To investigate the effects of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg on gastric emptying, appetite, and energy intake in adults with obesity. MATERIALS AND METHODS: A double-blind, parallel-group trial was conducted in 72 adults with obesity, randomized to once-weekly s.c. semaglutide (dose-escalated to 2.4 mg) or placebo for 20 weeks. Gastric emptying was assessed using paracetamol absorption following a standardized breakfast. Participant-reported appetite ratings and Control of Eating Questionnaire (CoEQ) responses were assessed, and energy intake was measured during ad libitum lunch. RESULTS: The area under the concentration-time curve (AUC) for paracetamol 0 to 5 hours after a standardized meal (AUC 0-5h,para ; primary endpoint) was increased by 8% (P = 0.005) with semaglutide 2.4 mg versus placebo at week 20 (non-significant when corrected for week 20 body weight; P = 0.12). No effect was seen on AUC 0-1h,para , maximum observed paracetamol concentration, or time to maximum observed paracetamol concentration."},{"id":"source_5","type":"source","study":"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis","year":2022,"doi":"10.1111/jdi.13905","url":"https://doi.org/10.1111/jdi.13905","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","excerpt":"Araki 2022. AIMS/INTRODUCTION: The etiology and treatment of type 2 diabetes might differ between specific populations. This post-hoc exploratory analysis assessed the efficacy and safety of once-weekly subcutaneous semaglutide vs comparators in Japanese individuals with type 2 diabetes in comparison with the total population from four phase III studies in the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN) program. MATERIALS AND METHODS: This analysis was carried out with data from the SUSTAIN 1, 2, 5 and 9 trials. Post-hoc analyses were carried out to assess outcomes in all participants and in Japanese participants in each study. The primary end-point was the change from baseline to end of study in glycated hemoglobin (%). The confirmatory secondary end-point was change from baseline to end of study in bodyweight (kg). RESULTS: Change from baseline to end of study in glycated hemoglobin with once-weekly semaglutide ranged from -1.32 to -1.85% points in the overall populations, and -1.69 to -2.49% points in Japanese participants."},{"id":"source_6","type":"source","study":"Once-Weekly Semaglutide in Patients with Cardiovascular-Kidney-Metabolic Syndrome: A Real-World Study","year":2026,"doi":"10.3390/ph19040583","url":"https://doi.org/10.3390/ph19040583","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","excerpt":"Trenas-Calero 2026. Introduction and Objectives: There is limited evidence on the role of glucagon-like peptide-1 receptor agonists in the interplay between cardiovascular disease, chronic kidney disease, and metabolic dysfunction. This work analyzed the efficacy and safety of once-weekly semaglutide in patients with cardiovascular-kidney-metabolic syndrome. Patients and Methods: This observational, real-world study included patients with heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus treated with once-weekly semaglutide (Sema-CKM Group) and patients not treated with glucagon-like peptide-1 receptor agonists (Control-CKM Group). A 1:1 propensity score matching analysis was performed. The two primary outcomes were heart failure events and major kidney disease events at 24 months. Results: After matching, 302 patients were included in each group. A heart failure event occurred in 63 patients (20.9%) in the Sema-CKM Group and 121 (40.1%) in the Control-CKM Group (OR: 0.80; 95%CI: 0.62-0.98; p < 0.01). The number of major kidney disease events was lower in the Sema-CKM Group than the Control-CKM Group (36 vs. 65; OR: 0.85; 95%CI: 0.72-0.98; p = 0.014)."},{"id":"source_7","type":"source","study":"Once‐Weekly Semaglutide Versus Once‐Daily Liraglutide for Weight Loss in Adults: A Meta‐Analysis of Randomized Controlled Trials","year":2025,"doi":"10.1111/cts.70127","url":"https://doi.org/10.1111/cts.70127","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","excerpt":"Hashmi 2025. The effectiveness of glucagon-like peptide-1 receptor agonists in facilitating weight loss among patients with diabetes is widely recognized. However, there are limited data available on the relative effectiveness and safety of once-weekly semaglutide versus once-daily liraglutide. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) identified through a comprehensive search of the Cochrane Library, PubMed, and ScienceDirect databases from inception until July 2024. Statistical analysis was conducted using R version 4.4.1 with the \"meta\" package, employing a random effects model. Three RCTs with a total of 922 patients were included in our meta-analysis. The results indicated that OW semaglutide significantly reduced body weight (WMD: -4.55; 95% CI: -6.43, -2.67, p < 0.01), HbA1c (WMD: -0.46; 95% CI: -0.84, -0.08; p = 0.02), and fasting plasma glucose levels (WMD: -1.23; 95% CI: -1.51, -0.95; p < 0.01) in comparison to OD liraglutide. The risk of severe adverse effects (OR, 1.66; 95% CI, 0.53-5.16; p = 0.38) and gastrointestinal adverse effects (OR, 1.84; 95% CI, 0.82-4.14; p = 0.14) was comparable between both groups."},{"id":"source_8","type":"source","study":"Effectiveness and safety of once-weekly semaglutide: findings from the SEMACOL-REAL retrospective multicentric observational study in Colombia","year":2024,"doi":"10.3389/fendo.2024.1372992","url":"https://doi.org/10.3389/fendo.2024.1372992","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","excerpt":"Buenaventura-Collazos 2024. INTRODUCTION: Diabetes stands as one of the leading causes of death worldwide. Glucagon-like peptide-1 receptor agonists rank among the most effective medications for lowering blood glucose and body weight, as well as reducing cardiovascular risk in individuals with diabetes. Observational studies complement experimental evidence in new settings, different populations, and real-world healthcare practices. METHODS: A multicentric observational study of adults with type 2 diabetes treated with once-weekly subcutaneous semaglutide in four health centers in Colombia was conducted. The protocol for the present study was not pre-registered. RESULTS: Data from 186 patients were included. Most patients were women (57%) with a mean age of 62.8 ± 12.1 years. One year of once-weekly semaglutide usage was associated with a mean reduction in HbA1C of -1.47% (95% CI -1.76, -1.17), weight loss of -4.23 kg (95% CI -5.34, -3.12), and albumin/creatinine ratio of -18.6 mg/g (95% CI -60.2, -5.9). Approximately half the treated patients achieved a level of HbA1c ≤7% by the end of follow-up. Adverse events were rare and consistent with clinical trial safety profiles."},{"id":"source_9","type":"source","study":"Once-Weekly Semaglutide in Adults With Alcohol Use Disorder","year":2025,"doi":"10.1001/jamapsychiatry.2024.4789","url":"https://doi.org/10.1001/jamapsychiatry.2024.4789","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","excerpt":"Hendershot 2025. IMPORTANCE: Preclinical, observational, and pharmacoepidemiology evidence indicates that glucagon-like peptide 1 receptor agonists (GLP-1RAs) may reduce alcohol intake. Randomized trials are needed to determine the clinical significance of these findings. OBJECTIVE: To evaluate the effects of once-weekly subcutaneous semaglutide on alcohol consumption and craving in adults with alcohol use disorder (AUD). DESIGN, SETTING, AND PARTICIPANTS: This was a phase 2, double-blind, randomized, parallel-arm trial involving 9 weeks of outpatient treatment. Enrollment occurred at an academic medical center in the US from September 2022 to February 2024. Of 504 potential participants assessed, 48 non-treatment-seeking participants with AUD were randomized. INTERVENTION: Participants received semaglutide (0.25 mg/week for 4 weeks, 0.5 mg/week for 4 weeks, and 1.0 mg for 1 week) or placebo at weekly clinic visits. MAIN OUTCOMES AND MEASURES: The primary outcome was laboratory alcohol self-administration, measured at pretreatment and posttreatment (0.5 mg/week)."},{"id":"source_10","type":"source","study":"Once-Weekly Semaglutide in Adults With Daily Cigarette Use","year":2026,"doi":"10.1001/jamanetworkopen.2026.14898","url":"https://doi.org/10.1001/jamanetworkopen.2026.14898","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","excerpt":"Hendershot 2026. IMPORTANCE: People who smoke cigarettes face increased risk of morbidity and mortality, in part due to elevated rates of cardiometabolic disease. Preclinical and early clinical data indicate that glucagon-like peptide-1 receptor agonists (GLP-1RAs) warrant consideration for smoking cessation and prevention of associated cardiometabolic risks. OBJECTIVE: To evaluate the effects of semaglutide vs placebo on cigarette smoking, craving, and weight outcomes in people who smoke. DESIGN, SETTING, AND PARTICIPANTS: This parallel-arm phase 2a randomized clinical trial with embedded human laboratory sessions was conducted at an academic medical center, with enrollment occurring from October 2022 to April 2024. Participants were non-treatment-seeking adults consuming at least 5 cigarettes per day. Data were analyzed in 2025. INTERVENTION: Nine weeks of subcutaneous of semaglutide (0.25 mg for 4 weeks, 0.5 mg for 4 weeks, 1.0 mg for 1 week) vs placebo. MAIN OUTCOMES AND MEASURES: The co-primary outcomes were laboratory measures of smoking resistance and reinstatement and self-administration, assessed before and after treatment."},{"id":"source_11","type":"source","study":"Long-Term Efficacy and Safety of Once-Weekly Semaglutide for Weight Loss in Patients Without Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.","year":2024,"doi":"10.1016/j.amjcard.2024.04.041","url":"https://doi.org/10.1016/j.amjcard.2024.04.041","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","excerpt":"Moiz 2024. Semaglutide, a glucagon-like peptide-1 receptor agonist, has demonstrated clinically important weight loss effects in patients with type 2 diabetes. However, its effects on sustained weight loss in patients without diabetes remains unclear. Our objective was to examine the long-term efficacy and safety of semaglutide use for weight loss in patients with overweight/obesity and without diabetes. MEDLINE, EMBASE, and the Cochrane Libraries were systematically searched to identify randomized controlled trials that randomized participants with overweight/obesity and without diabetes to once-weekly 2.4 mg subcutaneous semaglutide versus placebo, with a follow-up of at least 68 weeks. The primary outcome was a change in relative body weight from baseline to the longest follow-up. Random-effects models with inverse variance weighting were used to estimate the weighted mean differences (WMDs) and relative risks (RRs) with 95% confidence intervals (CIs). A total of 4 randomized controlled trials (n = 3,087) were included. Of the 3 trials that provided body mass index by category (n = 2,783), 94.0% of the participants had a baseline body mass index ≥30 kg/m 2 ."},{"id":"source_12","type":"source","study":"Efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg for the management of overweight or obesity in Asian populations: A systematic review, meta-analysis and meta-regression of randomised trials.","year":2025,"doi":"10.1111/dom.70073","url":"https://doi.org/10.1111/dom.70073","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","excerpt":"Zufry 2025. AIMS: The rising prevalence of overweight and obesity among Asian populations poses a critical public health concern. Semaglutide 2.4 mg, a glucagon-like peptide-1 receptor agonist, has demonstrated promising weight-reduction effects in global populations, but its efficacy and safety profile in Asians remain less comprehensively examined. This meta-analysis aimed to evaluate the effectiveness and tolerability of semaglutide 2.4 mg compared to placebo in Asian individuals with overweight or obesity. MATERIALS AND METHODS: A systematic literature search was conducted in Medline, ScienceDirect, Europe pubMed central (PMC) and the Cochrane Library up to 15 June 2025. Eligible studies were randomised controlled trials (RCTs) comparing semaglutide 2.4 mg with placebo in overweight or obese Asian individuals. Risk of bias was evaluated using the Cochrane Risk of Bias v2 tool. Pooled outcomes were analysed using random-effects models to estimate mean differences (MDs) and odds ratios, and heterogeneity was assessed with the I 2 statistic. RESULTS: Five RCTs involving 2614 participants met the inclusion criteria. All trials were deemed to have a low risk of bias."},{"id":"source_13","type":"source","study":"Efficacy and Safety of Once-Weekly Subcutaneous Semaglutide in Overweight or Obese Adults: A Systematic Review with Meta-Analysis.","year":2024,"doi":"10.1055/a-2303-8558","url":"https://doi.org/10.1055/a-2303-8558","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","excerpt":"Dorneles 2024. BACKGROUND: To evaluate the efficacy and safety of once-weekly subcutaneous semaglutide treatment in overweight or obese patients without type 2 diabetes. METHODS: Randomized clinical trials that assessed the impact of once-weekly semaglutide on body weight and safety outcomes in overweight or obese patients were retrieved from PubMed, EMBASE, and Lilacs up to November 2023. Risk of bias was assessed with RoB 2.0, and certainty of evidence (CoE) with GRADE. A random-effects meta-analysis was conducted. RESULTS: Ten publications, with 22.155 patients, were included. Semaglutide decreased relative body weight (MD: -11.80; 95%CI: -13.53 to -10.07; CoE: High), absolute body weight (MD: -11.58; 95%CI: -13.25 to -9.90; CoE: High) and BMI (MD: -4.15; 95%CI: -4.85 to -3.45; CoE: High). Semaglutide also increased the proportion of patients who achieved 5%, 10%, and 15% of weight loss ([weight loss≥5%: RR 2.29, 95% CI: 1.88 to 2.80; CoE: High]; [weight loss≥10%: RR 4.54, 95% CI: 3.45 to 5.98; CoE: High]; [weight loss≥15%: RR 8.29, 95%CI: 5.54 to 12.39; CoE: High]). Semaglutide leads to small risk to adverse events (RR: 1.03; 95%CI: 1 to 1."},{"id":"source_14","type":"source","study":"Once-Weekly Semaglutide in Adolescents with Obesity.","year":2022,"doi":"10.1056/nejmoa2208601","url":"https://doi.org/10.1056/nejmoa2208601","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","excerpt":"Weghuber 2022. BACKGROUND: A once-weekly, 2.4-mg dose of subcutaneous semaglutide, a glucagon-like peptide-1 receptor agonist, is used to treat obesity in adults, but assessment of the drug in adolescents has been lacking. METHODS: In this double-blind, parallel-group, randomized, placebo-controlled trial, we enrolled adolescents (12 to <18 years of age) with obesity (a body-mass index [BMI] in the 95th percentile or higher) or with overweight (a BMI in the 85th percentile or higher) and at least one weight-related coexisting condition. Participants were randomly assigned in a 2:1 ratio to receive once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo for 68 weeks, plus lifestyle intervention. The primary end point was the percentage change in BMI from baseline to week 68; the secondary confirmatory end point was weight loss of at least 5% at week 68. RESULTS: A total of 201 participants underwent randomization, and 180 (90%) completed treatment. All but one of the participants had obesity. The mean change in BMI from baseline to week 68 was -16.1% with semaglutide and 0.6% with placebo (estimated difference, -16."},{"id":"source_15","type":"source","study":"Efficacy of Semaglutide s.c. Once-weekly on Weight Loss and Management in Adolescents With Monogenic Obesity in Clinical Practice","year":2028,"doi":null,"url":null,"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","excerpt":"Efficacy of Semaglutide S 2028. This observational study aims to assess the effect of once-weekly s.c. semaglutide 2.4 mg as an adjunct to a calorie-reduced diet and increased physical activity on weight loss, change in hunger, body composition, depression, and quality of life after 68 weeks of treatment in adolescents diagnosed with monogenic obesity in routine clinical care."},{"id":"source_16","type":"source","study":"Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis.","year":2024,"doi":"10.1056/nejmoa2403664","url":"https://doi.org/10.1056/nejmoa2403664","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","excerpt":"Bliddal 2024. BACKGROUND: Weight reduction has been shown to alleviate symptoms of osteoarthritis of the knee, including pain. The effect of glucagon-like peptide-1 receptor agonists on outcomes in knee osteoarthritis among persons with obesity has not been well studied. METHODS: We conducted a 68-week, double-blind, randomized, placebo-controlled trial at 61 sites in 11 countries. Participants with obesity (a body-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of ≥30) and a clinical and radiologic diagnosis of moderate knee osteoarthritis with at least moderate pain were randomly assigned, in a 2:1 ratio, to receive once-weekly subcutaneous semaglutide (2.4 mg) or placebo, in addition to counseling on physical activity and a reduced-calorie diet. The primary end points were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (on a scale of 0 to 100, with higher scores reflecting worse outcomes) from baseline to week 68."},{"id":"source_17","type":"source","study":"Effect of semaglutide 2.4 mg once weekly on 10-year type 2 diabetes risk in adults with overweight or obesity.","year":2023,"doi":"10.1002/oby.23842","url":"https://doi.org/10.1002/oby.23842","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","excerpt":"Wilkinson 2023. OBJECTIVE: In the Semaglutide Treatment Effect in People with obesity (STEP) trials, once-weekly subcutaneous semaglutide 2.4 mg plus lifestyle intervention reduced body weight and improved cardiometabolic parameters in adults with obesity (or overweight with weight-related comorbidities). Effects on the risk of developing type 2 diabetes (T2D) require investigation. METHODS: STEP 1 (68 weeks) and 5 (104 weeks) randomized participants to semaglutide 2.4 mg or placebo. STEP 4 included a 20-week semaglutide run-in followed by randomization to 48 weeks of continued semaglutide or withdrawal (placebo). Ten-year T2D risk scores were calculated post hoc using Cardiometabolic Disease Staging. RESULTS: In STEP 1 (N = 1583), relative risk score reductions were greater with semaglutide versus placebo (semaglutide: -61.1%; placebo: -12.9%; p < 0.0001). These reductions were maintained to week 104 in STEP 5 (N = 295; semaglutide: -60.0%; placebo: 3.5%; p < 0.0001). Risk scores during the STEP 4 run-in period (N = 776) were reduced from 20.6% to 11.1% and further to 7.7% at week 68 with continued semaglutide, increasing to 15."},{"id":"source_18","type":"source","study":"Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial","year":2019,"doi":"10.1186/s12933-019-0871-8","url":"https://doi.org/10.1186/s12933-019-0871-8","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","excerpt":"Leiter 2019. BACKGROUND: The SUSTAIN 6 trial demonstrated that once-weekly semaglutide (0.5 and 1.0 mg) significantly reduced major adverse cardiovascular (CV) events (MACE) vs placebo in subjects with type 2 diabetes (T2D) and high CV risk. The effects of gender, age and baseline CV risk on outcomes are important considerations for further study. METHODS: Subjects were grouped according to gender, age (50-65 years and > 65 years), and CV risk profile at baseline (prior myocardial infarction [MI] or stroke vs no prior MI or stroke, and established CV disease [CVD] vs CV risk factors alone, including subjects with chronic kidney disease). Time to MACE and its individual components (CV death, nonfatal MI, nonfatal stroke), hospitalization for unstable angina or heart failure, and revascularization (coronary and peripheral) were analyzed for all subgroups. Additional analyses were performed for gender and age to investigate change from baseline in HbA 1c and body weight, as well as tolerability. RESULTS: A total of 3297 subjects were included. The majority of subjects (60.7%) were male; 43% were > 65 years of age; 41.5% had a history of MI or stroke; and 76.8% had established CVD."},{"id":"source_19","type":"source","study":"Effects of once‐weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity","year":2017,"doi":"10.1111/dom.12932","url":"https://doi.org/10.1111/dom.12932","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","excerpt":"Blundell 2017. AIM: The aim of this trial was to investigate the mechanism of action for body weight loss with semaglutide. MATERIALS AND METHODS: This randomised, double-blind, placebo-controlled, two-period crossover trial investigated the effects of 12 weeks of treatment with once-weekly subcutaneous semaglutide, dose-escalated to 1.0 mg, in 30 subjects with obesity. Ad libitum energy intake, ratings of appetite, thirst, nausea and well-being, control of eating, food preference, resting metabolic rate, body weight and body composition were assessed. RESULTS: After a standardised breakfast, semaglutide, compared with placebo, led to a lower ad libitum energy intake during lunch (-1255 kJ; P < .0001) and during the subsequent evening meal ( P = .0401) and snacks ( P = .0034), resulting in a 24% reduction in total energy intake across all ad libitum meals throughout the day (-3036 kJ; P < .0001). Fasting overall appetite suppression scores were improved with semaglutide vs placebo, while nausea ratings were similar. Semaglutide was associated with less hunger and food cravings, better control of eating and a lower preference for high-fat foods."},{"id":"source_20","type":"source","study":"Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial","year":2018,"doi":"10.2337/dc17-0417","url":"https://doi.org/10.2337/dc17-0417","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","excerpt":"Ahmann 2018. OBJECTIVE: To compare the efficacy and safety of once-weekly semaglutide 1.0 mg s.c. with exenatide extended release (ER) 2.0 mg s.c. in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: In this phase 3a, open-label, parallel-group, randomized controlled trial, 813 subjects with type 2 diabetes taking oral antidiabetic drugs were randomized (1:1) to semaglutide 1.0 mg or exenatide ER 2.0 mg for 56 weeks. The primary end point was change from baseline in HbA 1c at week 56. RESULTS: Mean HbA 1c (8.3% [67.7 mmol/mol] at baseline) was reduced by 1.5% (16.8 mmol/mol) with semaglutide and 0.9% (10.0 mmol/mol) with exenatide ER (estimated treatment difference vs. exenatide ER [ETD] -0.62% [95% CI -0.80, -0.44] [-6.78 mmol/mol (95% CI -8.70, -4.86)]; P < 0.0001 for noninferiority and superiority). Mean body weight (95.8 kg at baseline) was reduced by 5.6 kg with semaglutide and 1.9 kg with exenatide ER (ETD -3.78 kg [95% CI -4.58, -2.98]; P < 0.0001). Significantly more subjects treated with semaglutide (67%) achieved HbA 1c <7.0% (<53 mmol/mol) versus those taking exenatide ER (40%)."},{"id":"source_21","type":"source","study":"**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.","year":2005,"doi":"10.1371/journal.pmed.0020124","url":"https://doi.org/10.1371/journal.pmed.0020124","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","excerpt":"Reference-list provenance stub. **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."},{"id":"source_22","type":"source","study":"**WHO 2000.** _World Health Organization. Obesity: Preventing and Managing the Global Epidemic. WHO Technical Report Series 894. 2000._ PMID: 11234459.","year":2000,"doi":null,"url":null,"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","excerpt":"Reference-list provenance stub. **WHO 2000.** _World Health Organization. Obesity: Preventing and Managing the Global Epidemic. WHO Technical Report Series 894. 2000._ PMID: 11234459."}],"edges":[{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_1","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_2","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_3","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_4","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_5","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_6","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_7","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_8","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_9","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_10","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_11","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_12","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_13","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_14","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_15","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_16","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_17","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_18","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_19","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_20","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_21","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_22","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_23","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_24","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_25","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_26","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_27","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_28","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_29","type":"contains_claim"},{"from":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","to":"claim_30","type":"contains_claim"}],"screening":{"identified":23,"screened":23,"excluded":0,"included":23,"included_or_retained":23,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"23 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":"a180a3d8-5507-45cc-bde8-fb3c07f8c393","screening":{"identified":23,"screened":23,"excluded":0,"included":23,"included_or_retained":23,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"23 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":["Evidence-honesty note: 17/20 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes evidence on semaglutide intervention semaglutide 2 4 mg once weekly effects across 20 included source papers and 1320 high-confidence extracted claims. The evidence profile contains 3 direct clinical sources, 9 adjacent clinical sources, and no sources classified primarily as mechanistic or model-system evidence, with 53 cross-study disagreements across the evidence base. Positive study-level signals are not the dominant direction in any outcome class; null signals are not the dominant direction in any outcome class; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the cardiometabolic, contextual adjacent evidence, and safety and comorbidity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that semaglutide intervention semaglutide 2 4 mg once weekly effects should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","Positive study-level signals are not the dominant direction in any outcome class; null signals are not the dominant direction in any outcome class; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the cardiometabolic, contextual adjacent evidence, and safety and comorbidity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","The conclusion is that semaglutide intervention semaglutide 2 4 mg once weekly effects should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","The retained semaglutide intervention semaglutide 2 4 mg once weekly effects corpus is reported by outcome class before any cross-domain interpretation. This structure prevents favorable, null, mixed, and adverse evidence from being blended across biologically different endpoints.","The contextual adjacent evidence evidence packet includes 7 source-level summaries and 631 high-confidence observations. Directional coding within this packet is mixed=2, null=1, positive=2, unclear=2, and directness coding is direct=1, indirect=5, review=1. These counts describe the frozen evidence state for this outcome, not a pooled treatment estimate.","The safety and comorbidity evidence packet includes 3 source-level summaries and 383 high-confidence observations. Directional coding within this packet is mixed=1, negative=1, unclear=1, and directness coding is direct=1, indirect=2. These counts describe the frozen evidence state for this outcome, not a pooled treatment estimate.","Several clinically relevant claims in this domain are supported only by mechanistic or short-duration evidence rather than by hard-outcome RCTs. Friedrichsen 2021 and Blundell 2017 demonstrate appetite, energy-intake, and gastric-emptying effects (with P < 0.0001 on multiple appetite measures) that are mechanistic, whereas translation to sustained weight-management or comorbidity prevention is established only in the surrogate weight-loss endpoint literature. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus may support semaglutide 2.4 mg once weekly 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. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.","Across 20 curated reference papers, the evidence base for semaglutide 2.4 mg once weekly shows a context-dependent profile. Positive signals appear in: contextual other, cardiometabolic. Negative signals appear in: safety comorbidity, cardiometabolic. Null findings dominate: contextual other. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Semaglutide Intervention Semaglutide 2 4 Mg Once Weekly Effects 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.","| contextual adjacent evidence | 1 | 6 | mixed, null, positive, unclear | conflict-resolution gap |","| P2 | contextual adjacent evidence: conflict-resolution gap | 1 direct and 6 indirect sources; direction profile: mixed, null, positive, unclear |","Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=mixed; claims=212."]}},{"name":"evidence_table.csv","media_type":"text/csv","content":"study,population,intervention_or_exposure,comparator,endpoint,effect,risk_of_bias,directness\r\nEfficacy and safety of once‐weekly semaglutide 2.4 mg for weight management in participants from China: A prespecified analysis of the STEP 7 randomized clinical trial,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nOnce-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nEfficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes in the SUSTAIN 1, 2, 5 and 9 trials: Post‐hoc analysis\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nOnce-Weekly Semaglutide in Patients with Cardiovascular-Kidney-Metabolic Syndrome: A Real-World Study,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nOnce‐Weekly Semaglutide Versus Once‐Daily Liraglutide for Weight Loss in Adults: A Meta‐Analysis of Randomized Controlled Trials,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nEffectiveness and safety of once-weekly semaglutide: findings from the SEMACOL-REAL retrospective multicentric observational study in Colombia,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nOnce-Weekly Semaglutide in Adults With Alcohol Use Disorder,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nOnce-Weekly Semaglutide in Adults With Daily Cigarette Use,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nLong-Term Efficacy and Safety of Once-Weekly Semaglutide for Weight Loss in Patients Without Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\n\"Efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg for the management of overweight or obesity in Asian populations: A systematic review, meta-analysis and meta-regression of randomised trials.\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nEfficacy and Safety of Once-Weekly Subcutaneous Semaglutide in Overweight or Obese Adults: A Systematic Review with Meta-Analysis.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nOnce-Weekly Semaglutide in Adolescents with Obesity.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nEfficacy of Semaglutide s.c. Once-weekly on Weight Loss and Management in Adolescents With Monogenic Obesity in Clinical Practice,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nOnce-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nEffect of semaglutide 2.4 mg once weekly on 10-year type 2 diabetes risk in adults with overweight or obesity.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\n\"Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Effects of once‐weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n\"Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial\",not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\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.,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\n**WHO 2000.** _World Health Organization. Obesity: Preventing and Managing the Global Epidemic. 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