{"publication_id":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","content_hash":"sha256:0e45e7375edee63b96bdec3ba54bbf015588fa2f9c59e66af88b2ce1c3b62907","nodes":[{"id":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","type":"publication","title":"Research Synthesis: Semaglutide Intervention Semaglutide 2 4 Mg Rates — full paper"},{"id":"claim_1","type":"claim","text":"Evidence-honesty note: 23/29 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. Semaglutide 2.4 mg once weekly is now widely deployed for chronic weight management, yet synthesis of the evidence base is complicated by inconsistent reporting of 'rates' — operationalized here as rate of body-weight change, rate of HbA1c change, rate of cardiometabolic biomarker change, and rate of adverse events — across populations and trial designs. Among RCTs using the 2.4 mg dose, the STEP 5 extension reported co-primary endpoints achieved with P < 0.0001 and P = 0.0102 versus placebo over two years, while a network meta-analysis including semaglutide 2.4 mg showed P < 0.0001 for percent body-weight change alongside several p-values between 0.004 and 0.048 for cardiometabolic endpoints. Two verification-limited records (Efficacy of Semaglutide S n.d.; Primary Prevention and Uterine n.d.) lack persistent identifiers and are therefore held in a verification-limited annex, contributing to denominator counts but not to load-bearing clinical claims. We conclude that the 2."},{"id":"claim_2","type":"claim","text":"Evidence-honesty note: 23/29 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":"Semaglutide 2.4 mg once weekly is now widely deployed for chronic weight management, yet synthesis of the evidence base is complicated by inconsistent reporting of 'rates' — operationalized here as rate of body-weight change, rate of HbA1c change, rate of cardiometabolic biomarker change, and rate of adverse events — across populations and trial designs."},{"id":"claim_4","type":"claim","text":"We conclude that the 2.4 mg dose has convergent evidence for accelerating weight and HbA1c improvement over 6–24 months, but durable hard-outcome benefit, optimal rate-based dosing algorithms, and safety in underrepresented populations remain incompletely defined."},{"id":"claim_5","type":"claim","text":"Evidence-abstraction note.** The 29 retained reference papers are not 29 independent primary clinical trials: 23 are review, indirect, mechanistic, or registered-protocol source-level summaries, and 6 are classified as direct interventional evidence. Interpretation below therefore separates primary clinical-trial evidence from review-level, preclinical, and other indirect evidence."},{"id":"claim_6","type":"claim","text":"This synthesis evaluates evidence on semaglutide intervention semaglutide 2 4 mg rates across 29 included source papers and 2757 high-confidence extracted claims. The review is organized around the distinction between direct interventional hard-endpoint evidence, adjacent/review/context evidence, and mechanistic evidence so that biological plausibility is not confused with clinical certainty."},{"id":"claim_7","type":"claim","text":"The corpus contains 6 direct clinical sources, 23 adjacent, review, or context sources, and no sources classified primarily as mechanistic or model-system evidence. That distribution makes the synthesis appropriate for evaluating convergence, boundary conditions, and trial-design implications, while requiring caution around any conclusion that would exceed the direct human evidence."},{"id":"claim_8","type":"claim","text":"The introductory frame therefore treats the corpus as a set of evidence roles rather than a single directional verdict. Direct sources define the applied boundary, adjacent sources locate comparable clinical contexts, and mechanistic sources identify plausible bridges that still require endpoint-level confirmation."},{"id":"claim_9","type":"claim","text":"This distinction matters for publication because it makes the paper falsifiable. A future source can strengthen, weaken, or reverse the synthesis by changing the evidence tier, direction, or outcome-class balance."},{"id":"claim_10","type":"claim","text":"The mechanistic layer is most useful when it explains why a trial signal might appear or fail to appear. It is weaker when it is used as a replacement for outcome data, so this synthesis treats it as interpretive support rather than independent clinical proof."},{"id":"claim_11","type":"claim","text":"Null findings have a specific role in this evidence model. They do not erase mechanistic plausibility, but they do narrow the set of claims that can be made about effect consistency, target population, and endpoint selection."},{"id":"claim_12","type":"claim","text":"Adverse or negative signals are likewise retained in the main interpretation. For an aging intervention, the risk profile is part of the efficacy question because a plausible mechanism is not sufficient if the same corpus shows offsetting harm or tolerability constraints."},{"id":"claim_13","type":"claim","text":"The evidence base also distinguishes breadth from certainty. A broad corpus can cover many biological domains while still leaving the clinically decisive question unresolved if direct evidence is limited, heterogeneous, or endpoint-specific."},{"id":"claim_14","type":"claim","text":"For that reason, the manuscript does not collapse every source into a single recommendation. It presents the intervention as a set of linked claims whose strength depends on the evidence tier and the match between mechanism, population, and endpoint."},{"id":"claim_15","type":"claim","text":"The research value of the synthesis lies in making these boundaries explicit. It identifies which evidence streams are already aligned, which ones remain discordant, and which future studies would most directly test the unresolved bridge."},{"id":"claim_16","type":"claim","text":"The background evidence for semaglutide intervention semaglutide 2 4 mg rates is heterogeneous rather than uniformly confirmatory. Direct clinical sources such as Hamarsheh 2026, Buse 2025, Ganeshalingam 2026 are interpreted separately from mechanistic studies such as the retained evidence base, because these evidence roles answer different questions about aging biology and clinical translation."},{"id":"claim_17","type":"claim","text":"The direct evidence establishes what has been observed in human or adjacent clinical settings. The mechanistic evidence helps explain why an effect might be plausible, but it does not by itself establish the size, durability, or safety of a human healthspan effect."},{"id":"claim_18","type":"claim","text":"Across the retained sources, positive signals cluster around the cardiometabolic outcome class; null signals around the cardiometabolic, dosing and pharmacokinetics, contextual adjacent evidence outcome classes; and negative or adverse signals around the cardiometabolic outcome class. This pattern motivates a synthesis that keeps outcome domains separate before drawing cross-domain interpretation."},{"id":"claim_19","type":"claim","text":"The study-level structure also prevents selective emphasis. Supportive, null, mixed, and adverse findings remain visible in the same manuscript, allowing the reader to distinguish evidential breadth from evidential certainty."},{"id":"claim_20","type":"claim","text":"The resulting paper is therefore a calibrated synthesis: it can identify plausible mechanisms, observed direct signals when present, unresolved tensions, and trial-design priorities without converting them into claims stronger than the retained corpus can support."},{"id":"claim_21","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 sidecar when populated, and claim registry) rather than from re-parsed full text."},{"id":"claim_22","type":"claim","text":"Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated `risk_of_bias.json` rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification."},{"id":"claim_23","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, longevity, skeletal, fracture, and bone); 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_24","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_25","type":"claim","text":"Topic-fit rationale: Sources are retained only when they operationalize semaglutide intervention semaglutide 2 4 mg rates directly or provide adjacent/contextual boundary evidence for the same construct. 6/29 retained sources are classified as direct; adjacent, contextual, review-level, or mechanistic sources are reclassified as boundary evidence rather than used for broad efficacy claims. Representative source-fit checks: Garvey 2022 (indirect; Cardiometabolic), Hamarsheh 2026 (direct; Cardiometabolic), Sillassen 2025 (review; Cardiometabolic), Buse 2025 (direct; Cardiometabolic), Ciudin 2026a (indirect; Cardiometabolic)."},{"id":"claim_26","type":"claim","text":"Source-scope annex note: Ganeshalingam 2026 (Semaglutide Effects on Insulin Sensitivity and β-Cell Function in Patients With Schizophrenia, Prediabetes, and Obesity Treated With Second-Generation Antipsychotics: Findings From the HISTORI Trial, a 30-Week Randomized, Placebo-Controlled Trial With Semaglutide 1.0 mg Weekly), Cortes 2024 (Effect of Semaglutide on Physical Function, Body Composition, and Biomarkers of Aging in Older Adults With Overweight and Insulin Resistance: Protocol for an Open-Labeled Randomized Controlled Trial), Buse 2025 (Long-term comparative effectiveness of once-weekly semaglutide versus alternative treatments in a real-world US adult population with type 2 diabetes: a randomized pragmatic clinical trial), Park 2025 (Semaglutide promotes bone marrow–derived progenitor cell flux towards an anti-inflammatory and pro-regenerative profile in high-risk patients: the SEMA-VR CardioLink-15 trial) are retained only as non-topic/contextual annex evidence when the manifest keeps them for boundary context, and are not pooled as direct evidence for the target outcome or as support for the primary directional conclusion."},{"id":"claim_27","type":"claim","text":"Findings Map accounting note: each outcome-class n, direction count, directness count, and source roster is computed from the same source-level rows listed in the detailed table. Receipt-level direction is not a statement that the source abstracts lack directional statistics; it is the conservative coded polarity used for synthesis accounting. Outcome-class roster: Cardiometabolic n=22 (direction: mixed=6; negative=1; null=5; positive=1; unclear=9; directness: direct=5; indirect=7; review=10; sources: Arslanian 2025; Buse 2025; Chrzanowski 2026; Ciudin 2026a; Ciudin 2026b; Cortes 2024; Efficacy of Semaglutide S n.d.; Elganyny 2026; Ganeshalingam 2026; Garvey 2022; Hamarsheh 2026; Harbi 2026; Jensen 2025; Lassen 2026; Lin 2024; Lu 2026; McGowan 2025; Primary Prevention and Uterine n.d.; Qin 2024; Sillassen 2025; Tan 2026; Zaccardi 2026); Contextual Adjacent Evidence n=4 (direction: mixed=1; null=1; unclear=2; directness: direct=1; indirect=1; review=2; sources: Alnaimi 2026; Hendershot 2026; Koychev 2024; Masson 2024); Dosing and Pharmacokinetics n=1 (direction: null=1; directness: protocol=1; sources: Sorum 2024); Longevity n=1 (direction: mixed=1; directness: review=1; sources: Abdullah 2025); Skeletal, Fracture, and Bone n=1 (direction: negative=1; directness: indirect=1; sources: Park 2025)."},{"id":"claim_28","type":"claim","text":"| Evidence domain | Source | Direction | Directness | Tier | Evidence role | Finding |"},{"id":"claim_29","type":"claim","text":"| Cardiometabolic | Arslanian 2025: Effect of Semaglutide on Insulin Sensitivity and Cardiometabolic Risk Factors in Adolescents With Obesity: The STEP TEENS Study | direction=mixed | directness=indirect | B2 | outcome=Cardiometabolic; direction=mixed | finding=representative statistic P = 0.0001; source-level statistic reported |"},{"id":"claim_30","type":"claim","text":"| Cardiometabolic | Chrzanowski 2026: Semaglutide-associated risk of nonarteritic anterior ischemic optic neuropathy in patients with type 2 diabetes: A systematic review and meta-analysis of observational studies | direction=unclear | directness=review | B2 | outcome=Cardiometabolic; direction=unclear | finding=representative statistic p < 0.001; source-level statistic reported |"},{"id":"source_1","type":"source","study":"Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial","year":2022,"doi":"10.1038/s41591-022-02026-4","url":"https://doi.org/10.1038/s41591-022-02026-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Garvey 2022","excerpt":"The STEP 5 trial assessed the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg versus placebo (both plus behavioral intervention) for long-term treatment of adults with obesity, or overweight with at least one weight-related comorbidity, without diabetes. The co-primary endpoints were the percentage change in body weight and achievement of weight loss of ≥5% at week 104. Efficacy was assessed among all randomized participants regardless of treatment discontinuation or rescue intervention. From 5 October 2018 to 1 February 2019, 304 participants were randomly assigned to semaglutide 2.4 mg (n = 152) or placebo (n = 152), 92.8% of whom completed the trial (attended the end-of-trial safety visit). Most participants were female (236 (77.6%)) and white (283 (93.1%)), with a mean (s.d.) age of 47.3 (11.0) years, body mass index of 38.5 (6.9) kg m -2 and weight of 106.0 (22.0) kg. The mean change in body weight from baseline to week 104 was -15.2% in the semaglutide group (n = 152) versus -2.6% with placebo (n = 152), for an estimated treatment difference of -12.6 %-points (95% confidence interval, -15.3 to -9.8; P < 0.0001)."},{"id":"source_2","type":"source","study":"Comparative Effectiveness of CagriSegma , Semaglutide, Cagrilintide and Tirzepatide in the Management of Overweight and Obesity: A Network Meta‐Analysis of Randomized Clinical Trials","year":2026,"doi":"10.1002/edm2.70248","url":"https://doi.org/10.1002/edm2.70248","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":"direct","cited_as":"Hamarsheh 2026","excerpt":"BACKGROUND: Obesity is a chronic, progressive disease affecting over 1 billion adults worldwide, linked to serious comorbidities, including diabetes, hypertension, and cardiovascular disease and associated with increased mortality. Achieving clinically meaningful weight loss is critical to reducing cardiometabolic risk. Tirzepatide, semaglutide, cagrilintide and their combination (CagriSema) have demonstrated efficacy in clinical trials; however, no direct head-to-head studies have compared all advanced anti-obesity medications. This network meta-analysis examines their comparative efficacy and safety. METHODS: We systematically searched PubMed, Scopus and Cochrane Central for randomized controlled trials comparing these medications with placebo in adults with overweight or obesity. Outcomes included changes in percent body weight, absolute weight, waist circumference, BMI, patients achieving ≥ 5% to ≥ 20% weight loss, HDL-C and safety outcomes (AEs, serious AEs, gastrointestinal AEs and treatment discontinuation). Random-effects model and network meta-analysis methods were employed. RESULTS: Twenty-five trials involving 12 interventions met the inclusion criteria."},{"id":"source_3","type":"source","study":"The adverse effects associated with semaglutide use in patients at increased risk of cardiovascular events: a systematic review with meta-analysis and Trial Sequential Analysis","year":2025,"doi":"10.1186/s12916-025-04486-0","url":"https://doi.org/10.1186/s12916-025-04486-0","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review","cited_as":"Sillassen 2025","excerpt":"BACKGROUND: Semaglutide's disease-specific weight-reducing effects are well established, but its adverse effects, which may not be disease-specific, have not been systematically assessed. The aim of this review was to assess the adverse effects associated with semaglutide use compared with placebo in patients at increased risk of cardiovascular events. METHODS: We searched six electronic databases and other sources from inception to 31/03/2025. Randomized trials comparing semaglutide (oral or subcutaneous) with placebo in patients at increased risk of cardiovascular events were eligible. The search identified 8370 records. Two review authors independently screened all studies for eligibility. Data were synthesized using meta-analysis and Trial Sequential Analysis (TSA). Risk of bias was assessed with the Cochrane Risk of Bias tool - version 2; our eight-step procedure was used to assess if the thresholds for statistical significance were crossed, and the certainty of the evidence was assessed by the Grading of Recommendations, Assessment, Development and Evaluations. Primary outcomes were all-cause mortality and serious adverse events (SAEs)."},{"id":"source_4","type":"source","study":"Long-term comparative effectiveness of once-weekly semaglutide versus alternative treatments in a real-world US adult population with type 2 diabetes: a randomized pragmatic clinical trial","year":2025,"doi":"10.1136/bmjdrc-2025-005161","url":"https://doi.org/10.1136/bmjdrc-2025-005161","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":"direct","cited_as":"Buse 2025","excerpt":"INTRODUCTION: This study evaluated the long-term effectiveness of once-weekly subcutaneous semaglutide versus alternative treatment in adults with type 2 diabetes (T2D) in routine clinical practice. RESEARCH DESIGN AND METHODS: The SEmaglutide PRAgmatic (SEPRA) was a 2-year, randomized, open-label, pragmatic clinical trial (NCT03596450). Adults with T2D and inadequate glycemic control on one or two oral antidiabetic medications were randomized to receive once-weekly subcutaneous semaglutide or alternative treatment (chosen by the treating physician) as add-on therapy. Endpoints included proportion of participants achieving glycated hemoglobin (HbA 1c )<7.0% at year 1 (primary endpoint) and year 2; changes in HbA 1c (percentage point), body weight, and patient-reported outcomes (PROs) at years 1 and 2; and treatment changes (baseline to year 2). Missing data were imputed for some analyses. RESULTS: Participants were randomized to semaglutide (n=644) or alternative treatment (n=634). Proportions of participants achieving HbA 1c <7.0% were significantly higher with semaglutide versus alternative treatment at years 1 (53.1% vs 45.5%; OR (95% CI): 1.36 (1.03 to 1.79); p=0."},{"id":"source_5","type":"source","study":"Indirect Comparative Efficacy and Safety of Tirzepatide Versus Oral Semaglutide for the Treatment of Overweight and Obesity","year":2026,"doi":"10.1111/dom.70773","url":"https://doi.org/10.1111/dom.70773","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":"indirect","cited_as":"Ciudin 2026a","excerpt":"AIMS: Tirzepatide, an injectable glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA), is approved for weight management in several regions. Oral GLP-1 RAs, such as semaglutide, are under investigation to improve convenience, acceptance and adherence versus injectable formulations. Currently, no studies have compared the efficacy and safety of tirzepatide with oral semaglutide for weight management. This study aimed to indirectly compare the efficacy and safety of weekly injectable tirzepatide 5, 10 and 15 mg for weight management in obesity and overweight versus daily oral semaglutide 50 mg. MATERIALS AND METHODS: Pivotal trials SURMOUNT-1 (tirzepatide, Week 72) and OASIS 1 (oral semaglutide, Week 68) were compared using multilevel network meta-regression (ML-NMR) to adjust for differences in sex, ethnicity and outcome baselines between trial populations. Participants were adults without type 2 diabetes and with obesity (BMI ≥ 30 kg/m 2 ), or overweight (BMI ≥ 27 kg/m 2 ) with ≥ 1 obesity-related complication."},{"id":"source_6","type":"source","study":"Effect of Semaglutide on Insulin Sensitivity and Cardiometabolic Risk Factors in Adolescents With Obesity: The STEP TEENS Study","year":2025,"doi":"10.2337/dc25-0824","url":"https://doi.org/10.2337/dc25-0824","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":"indirect","cited_as":"Arslanian 2025","excerpt":"OBJECTIVE: This secondary analysis of the Semaglutide Treatment Effect in People with obesity (STEP) TEENS (NCT04102189) study investigated the effect of semaglutide 2.4 mg versus placebo on insulin sensitivity and cardiometabolic risk factors. RESEARCH DESIGN AND METHODS: The STEP TEENS phase 3a randomized study in adolescents (aged 12 to <18 years) with obesity demonstrated that once-weekly subcutaneous semaglutide 2.4 mg provided a significantly greater percentage reduction in BMI than placebo at week 68 (estimated difference -16.7 percentage points; P = 0.0001). This analysis investigated changes in insulin sensitivity and cardiometabolic risk factors from baseline to week 68. RESULTS: Overall, 193 participants without type 2 diabetes were included in the analysis. Participants receiving semaglutide 2.4 mg (n = 129) compared with those receiving placebo (n = 64) had greater reductions from baseline in fasting serum insulin (-33.6% vs. -10.1%; P = 0.0012), homeostatic model assessment for insulin resistance (HOMA-IR) score (-35.0% vs. -5.3%; P = 0.0002), glycemic measures (glycated hemoglobin: P < 0.0001; fasting plasma glucose: P = 0.0181), alanine aminotransferase (ALT; -17."},{"id":"source_7","type":"source","study":"A systematic review and meta-analysis of the efficacy and safety of pharmacological treatments for obesity in adults","year":2025,"doi":"10.1038/s41591-025-03978-z","url":"https://doi.org/10.1038/s41591-025-03978-z","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","cited_as":"McGowan 2025","excerpt":"This systematic review and network meta-analysis evaluated the efficacy and safety of obesity management medications (OMMs) in terms of reducing body weight and impact on obesity-related complications. Here a Medline and Embase search was performed up to 31 January 2025 for randomized controlled trials comparing OMMs versus placebo/active comparators in adults. Primary endpoint was percentage of total body weight loss (TBWL%) at the end of the study. Secondary endpoints were TBWL% at 1, 2 and ≥3 years, lipid profile, blood pressure, hemoglobin A1c, fasting plasma glucose, mental health, serious adverse events, quality of life, cardiovascular morbidity and mortality, remission of obesity-related complications and all-cause mortality. Fifty-six clinical trials were identified-orlistat (22), semaglutide (14), liraglutide (11), tirzepatide (6), naltrexone/bupropion (5) and phentermine/topiramate (2)-enrolling 60,307 patients (32,598 OMM and 27,709 placebo). All OMMs showed a significantly greater TBWL% versus placebo (P < 0.0001), more than 10% for semaglutide and tirzepatide."},{"id":"source_8","type":"source","study":"Cardiometabolic and Renal Outcomes in Semaglutide Users with Type 2 Diabetes Achieving Glycemic and Weight Goals: An Observational Cohort Study","year":2026,"doi":"10.1007/s12325-026-03610-7","url":"https://doi.org/10.1007/s12325-026-03610-7","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":"indirect","cited_as":"Tan 2026","excerpt":"INTRODUCTION: Within the cardiovascular-kidney-metabolic syndrome (CKM) framework, semaglutide has demonstrated benefits beyond glycemic control and weight loss in clinical trials. However, most real-world studies in type 2 diabetes (T2D) have limited assessment of broader cardiometabolic and renal outcomes. We evaluated CKM-relevant outcomes among individuals with T2D who achieved substantial hemoglobin A1c (HbA1c) and weight improvements after initiating semaglutide in real-world settings. METHODS: This observational pre-post study used Optum's de-identified Market Clarity Data from January 1, 2007, to June 30, 2024. The primary cohort comprised individuals with T2D who achieved glycemic control (HbA1c < 7%) and weight loss (≥ 5%) goals after semaglutide initiation. We compared baseline (1 year before initiation) with 1st-year and 2nd-year follow-up for cardiometabolic endpoints (3-point and 5-point major adverse cardiovascular events [MACE]), cardiometabolic risk factors, and renal outcomes. Sensitivity analysis was performed in an exploratory cohort of patients in the top tertile of Hb1Ac reduction and weight loss."},{"id":"source_9","type":"source","study":"Comparison of Clinical Efficacy and Safety of Tirzepatide, Liraglutide and Semaglutide in Patients with Obesity and Without T2D: A Bayesian Network Meta-Analysis of Randomised Controlled Trials","year":2026,"doi":"10.1007/s12325-026-03523-5","url":"https://doi.org/10.1007/s12325-026-03523-5","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","cited_as":"Ciudin 2026b","excerpt":"INTRODUCTION: Recent pharmacological options for weight management include the glucagon-like peptide 1 (GLP-1) receptor agonists semaglutide and liraglutide, and the glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist tirzepatide, but head-to-head comparisons of all three of these interventions are lacking. METHODS: Based on a systematic literature review (SLR) and Bayesian network meta-analysis (NMA), the efficacy and safety of semaglutide 2.4 mg, liraglutide 3 mg and tirzepatide 5, 10 and 15 mg were compared in adults without type 2 diabetes, and with either obesity (body mass index [BMI] ≥ 30 kg/m 2 ) or overweight (BMI ≥ 27 kg/m 2 ) with ≥ 1 obesity-related complication. RESULTS: Following a stringent heterogeneity assessment, six of 42 randomised controlled trials identified in the SLR were included in the NMA. Efficacy estimand results showed all tirzepatide doses were associated with statistically greater improvements in weight reduction outcomes versus liraglutide, and for tirzepatide 10 and 15 mg versus semaglutide: including percentage weight reduction (- 12.86% for tirzepatide 10 mg and - 13.95% for tirzepatide 15 mg versus liraglutide; - 4."},{"id":"source_10","type":"source","study":"Safety and Efficacy of Semaglutide in Patients With Chronic Kidney Disease, With or Without Type 2 Diabetes: A Systematic Review and Meta‐Analysis","year":2025,"doi":"10.1002/edm2.70136","url":"https://doi.org/10.1002/edm2.70136","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","cited_as":"Abdullah 2025","excerpt":"BACKGROUND: Chronic kidney disease (CKD) affects over half a billion people globally and significantly increases the risk of cardiovascular complications, particularly in those with type 2 diabetes mellitus (T2DM). Although semaglutide, a glucagon-like peptide-1 receptor agonist, has shown favourable cardiorenal effects in T2DM patients, prior meta-analyses were limited by small sample sizes and few studies. This updated meta-analysis includes both diabetic and non-diabetic CKD patients, incorporates recently published RCTs and addresses gaps in the literature to enhance result generalizability. METHODS: MEDLINE, Embase and Cochrane CENTRAL were searched from inception to May 2025 following PRISMA and AMSTAR guidelines. Studies comparing semaglutide with placebo or standard care in adults (≥ 18 years) with CKD, with or without T2DM were included. Primary outcomes included cardiovascular mortality, major adverse cardiovascular events (MACE), major kidney-related adverse events, nonfatal myocardial infarction and nonfatal stroke. Risk of bias was assessed using Cochrane RoB 2.0. RESULTS: Five RCTs involving 12,785 participants were included."},{"id":"source_11","type":"source","study":"Efficacy of 12 months therapy with glucagon-like peptide-1 receptor agonists liraglutide and semaglutide on weight regain after bariatric surgery: a real-world retrospective observational study","year":2025,"doi":"10.1186/s12902-025-01913-4","url":"https://doi.org/10.1186/s12902-025-01913-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"indirect","cited_as":"Jensen 2025","excerpt":"BACKGROUND: The role of glucagon-like peptide-1 receptor agonists (GLP1-RAs) in patients with weight regain after bariatric surgery remains unclear. The objective of this study was to determine the efficacy and safety of 12 months of GLP1-RA treatment in a real-world patient population with weight regain after bariatric surgery. METHODS: A single-centre retrospective observational study. Patients with post-bariatric weight regain subsequently treated with GLP1-RA were identified, and the effect on weight after 12 months of treatment was determined. Data are presented as medians (interquartile ranges) or frequencies (%), and Wilcoxon signed-rank tests and Mann-Whitney U tests were used for paired and nonpaired group comparisons, respectively. RESULTS: Forty patients (80% female) were included in the analysis. Liraglutide (3.0 mg, daily subcutaneous injection, n = 22) or semaglutide (1.0 mg, weekly subcutaneous injection, n = 18) was started 74.5 (51.0, 108.3) months after surgery following a weight regain of 14.7 (10.3, 19.6)%. After 12 months of GLP1-RA treatment, a total body weight, BMI, and percentage excess body weight reduction of 10.5 (6.1, 14.7) kg, 3.7 (2.5, 5."},{"id":"source_12","type":"source","study":"Semaglutide promotes bone marrow–derived progenitor cell flux towards an anti-inflammatory and pro-regenerative profile in high-risk patients: the SEMA-VR CardioLink-15 trial","year":2025,"doi":"10.1093/eurheartj/ehaf690","url":"https://doi.org/10.1093/eurheartj/ehaf690","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":"indirect","cited_as":"Park 2025","excerpt":"BACKGROUND AND AIMS: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major atherosclerotic cardiovascular events in individuals living with either diabetes or obesity. Since the turnover of vascular regenerative (VR) stem and progenitor cells has been demonstrated to modulate vessel repair and atherothrombotic risk, this study aimed to determine the effect of the GLP-1RA semaglutide on the levels of circulating VR cells. METHODS: SEMA-VR CardioLink-15 was a randomized translational trial of usual care vs semaglutide for 6 months in 46 participants with either type 2 diabetes and/or obesity plus atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk factors. Vascular regenerative cells were enumerated using multi-parametric flow cytometry for high aldehyde dehydrogenase activity (ALDHhi) and lineage-specific cell surface marker expression. The primary endpoint was the 6-month change in VR cell content. RESULTS: Compared with usual care (n = 24), semaglutide (n = 22) led to a greater increase in the number of VR cells [high aldehyde dehydrogenase 1A1 activity and low side scatter (ALDHhiSSClow): +0.8% vs +34.8%; P = ."},{"id":"source_13","type":"source","study":"Cardiometabolic Profiles of Oral and Subcutaneous Glucagon‐Like Peptide‐1 Receptor Mono‐Agonists in Adults With Overweight or Obesity: A Systematic Review and Network Meta‐Analysis","year":2026,"doi":"10.1111/dom.70742","url":"https://doi.org/10.1111/dom.70742","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","cited_as":"Lu 2026","excerpt":"AIMS: To characterize the cardiometabolic profiles of oral and subcutaneous glucagon-like peptide-1 (GLP-1) receptor mono-agonists in adults with overweight or obesity, with or without type 2 diabetes (T2D), using network meta-analysis (NMA). MATERIALS AND METHODS: PubMed, Embase and CENTRAL were searched (January 2014-November 2025) for randomized controlled trials (RCTs) evaluating GLP-1 receptor mono-agonists (semaglutide, liraglutide and orforglipron) in adults with overweight or obesity. The primary outcome was the cardiometabolic efficacy index (CEI), a ranking-based composite (0 to 1) summarizing performance across seven cardiometabolic endpoints: total body weight loss percentage, triglycerides, HDL cholesterol-C, LDL-C, waist circumference, HbA1c and systolic blood pressure. Secondary outcomes included treatment effects for each individual CEI component. RESULTS: Nineteen RCTs (N = 13 117) were analysed. Semaglutide 7.2 mg achieved the highest CEI (0.86), followed by orforglipron 36 mg (bioequivalent to Foundayo 17.2 mg tablet) (0.68) and semaglutide 2.4 mg (0.66), all exhibiting placebo-adjusted weight reductions ≥ 10%."},{"id":"source_14","type":"source","study":"Semaglutide Effects on Insulin Sensitivity and β-Cell Function in Patients With Schizophrenia, Prediabetes, and Obesity Treated With Second-Generation Antipsychotics: Findings From the HISTORI Trial, a 30-Week Randomized, Placebo-Controlled Trial With Semaglutide 1.0 mg Weekly","year":2026,"doi":"10.2337/dc25-2041","url":"https://doi.org/10.2337/dc25-2041","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":"direct","cited_as":"Ganeshalingam 2026","excerpt":"OBJECTIVE: To examine the effects of semaglutide on insulin sensitivity, insulin resistance, and β-cell function and explore whether these changes were mediated by weight loss in overweight or obese individuals with schizophrenia and prediabetes receiving second-generation antipsychotics. RESEARCH DESIGN AND METHODS: In this 30-week, double-blind trial, 154 participants were randomized to semaglutide (n = 77) or placebo (n = 77); 141 (91.5%) completed the study. Baseline and end-of-study assessments included fasting glucose, insulin, C-peptide, HOMA2 of β-cell function, HOMA2 of insulin sensitivity, HOMA of insulin resistance, and body weight. RESULTS: Participants (56% women, mean age 38.3 years) provided complete insulin data in 131 cases. Compared with placebo, semaglutide significantly reduced fasting glucose (-0.87 mmol/L [95% CI -1.15, -0.59]; P < 0.001), improved insulin sensitivity (8.60 [5.82, 13.65]; P = 0.001), and lowered insulin resistance (-0.69 [-1.00, -0.20]; P = 0.006). Mean weight loss was 9.2 kg and mediated improvements in insulin sensitivity (estimate 7.82; P = 0.01) and insulin resistance (estimate -0.75; P = 0.01)."},{"id":"source_15","type":"source","study":"Semaglutide Treatment in Young Adults Living With Type 2 Diabetes: A Post Hoc Analysis From the SUSTAIN and PIONEER Clinical Trials","year":2026,"doi":"10.1111/dom.70770","url":"https://doi.org/10.1111/dom.70770","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":"indirect","cited_as":"Zaccardi 2026","excerpt":"AIMS: Young adults (aged ≤ 40 years) are underrepresented in clinical trials that investigate interventions for those living with Type 2 diabetes (T2D). This study evaluated the efficacy of semaglutide treatment in young adults with T2D by examining the effects on HbA 1c and body weight (BW) during the SUSTAIN and PIONEER programmes compared to placebo and active comparators, according to age at study enrolment. This study also assessed aggregated safety data across age subgroups. MATERIALS AND METHODS: This post hoc analysis of the SUSTAIN (once-weekly subcutaneous administration) and PIONEER (once-daily oral administration) programmes assessed the efficacy of semaglutide treatment in different age subgroups by comparing change in HbA 1c and BW between young adults with T2D (≤ 40 years), middle-aged adults with T2D (> 40- ≤ 50 years), and middle older-aged adults with T2D (> 50 years). Selected safety outcomes were assessed, focusing on serious adverse events (SAEs) and gastrointestinal SAEs from the programmes."},{"id":"source_16","type":"source","study":"Semaglutide-associated risk of nonarteritic anterior ischemic optic neuropathy in patients with type 2 diabetes: A systematic review and meta-analysis of observational studies","year":2026,"doi":"10.1371/journal.pmed.1005064","url":"https://doi.org/10.1371/journal.pmed.1005064","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","cited_as":"Chrzanowski 2026","excerpt":"BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist, is widely used for the management of type 2 diabetes (T2DM). Recent case reports have raised concerns about a potential association between semaglutide use and the development of nonarteritic anterior ischemic optic neuropathy (NAION), a rare but vision-threatening condition. We aimed to evaluate whether semaglutide use is associated with an increased risk of NAION in patients with T2DM. METHODS AND FINDINGS: We conducted a systematic review and meta-analysis of observational studies comparing patients with T2DM aged ≥12 years treated with semaglutide to those receiving other glucose-lowering therapies. We searched PubMed, Scopus, and Web of Science databases from January 2023 to November 2025. Two reviewers independently extracted data on study design, population characteristics, and outcomes. Risk of bias was assessed using the Newcastle-Ottawa Scale, and ROBINS-I v.2. Certainty of the evidence was graded according to the GRADE framework."},{"id":"source_17","type":"source","study":"Anti-inflammatory effect of semaglutide: updated systematic review and meta-analysis","year":2024,"doi":"10.3389/fcvm.2024.1379189","url":"https://doi.org/10.3389/fcvm.2024.1379189","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","cited_as":"Masson 2024","excerpt":"BACKGROUND: The anti-inflammatory effect could be one of the mechanisms by which semaglutide reduces cardiovascular risk in patients with type 2 diabetes mellitus (T2DM) and/or obesity. Determining the anti-inflammatory effect of semaglutide was the objective of this systematic review and meta-analysis. METHODS: This meta-analysis was performed according to the PRISMA guidelines. A literature search was performed to detect randomised clinical trials that have quantified the effect of semaglutide on C-reactive protein (CRP) levels compared to placebo or a control group (other glucose-lowering drugs). The primary outcome was CRP index (final CRP/basal CRP). A random-effects model was used. RESULTS: Thirteen randomised clinical trials were considered eligible ( n = 26,131). Overall, semaglutide therapy was associated with lower CRP index values compared to the placebo group (SMD -0.56; 95% CI -0.69 to -0.43, I 2 92%) or the control group (SMD -0.45; 95% CI -0.68 to -0.23, I 2 82%).Such an association was similarly observed when different treatment regimens (subcutaneous vs. oral) or different populations (patients with or without T2DM) were analysed."},{"id":"source_18","type":"source","study":"Effect of Semaglutide on Physical Function, Body Composition, and Biomarkers of Aging in Older Adults With Overweight and Insulin Resistance: Protocol for an Open-Labeled Randomized Controlled Trial","year":2024,"doi":"10.2196/62667","url":"https://doi.org/10.2196/62667","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":"direct","cited_as":"Cortes 2024","excerpt":"BACKGROUND: Older adults with type 2 diabetes mellitus (T2DM) or prediabetes are at increased risk of adverse changes in body composition, physical function, and aging-related biomarkers compared to those with normal glucose tolerance. Semaglutide is a glucagon-like peptide 1 receptor agonist that has been approved for T2DM and chronic weight management. Although semaglutide is effective for weight loss and T2DM management, its effects on lean body mass, physical function, and biomarkers of aging are understudied in older adults. OBJECTIVE: This study aims to compare the effects of lifestyle counseling with and that without semaglutide on body composition, physical function, and biomarkers of aging in older adults. METHODS: This is an open-label randomized controlled trial. A total of 20 adults (aged 65 years and older) with elevated BMI (27-40 kg/m 2 ) and prediabetes or well-controlled T2DM (hemoglobin A 1c 5.7%-7.5%) are recruited, stratified by sex, and randomized 1:1 to one of 2 groups (semaglutide plus lifestyle counseling vs lifestyle counseling alone) and followed up for 5 months. Those in the semaglutide group are titrated to 1 mg weekly, as tolerated, for 12 weeks."},{"id":"source_19","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":"indirect","cited_as":"Hendershot 2026","excerpt":"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_20","type":"source","study":"Semaglutide combined with empagliflozin vs. monotherapy for non-alcoholic fatty liver disease in type 2 diabetes: Study protocol for a randomized clinical trial","year":2024,"doi":"10.1371/journal.pone.0302155","url":"https://doi.org/10.1371/journal.pone.0302155","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":"direct","cited_as":"Lin 2024","excerpt":"BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is strongly associated with type 2 diabetes mellitus (T2DM). Lifestyle intervention remains a preferred treatment modality for NAFLD. The glucagon-like peptide (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been developed as new glucose-lowering drugs, which can improve fatty liver via an insulin-independent glucose-lowering effect. However, studies exploring the efficacy of GLP-1 receptor agonists combined with SGLT-2 inhibitors in patients with NAFLD and T2DM are scanty. Thus, the present randomised controlled trial aims at comparing the efficacy and safety of semaglutide plus empagliflozin with each treatment alone in patients with NAFLD and T2DM. METHODS: This 52-week double-blinded, randomised, parallel-group, active-controlled trial evaluates the effects of semaglutide, empagliflozin and semaglutide + empagliflozin in 105 eligible overweight/obese subjects with NAFLD and T2DM. The primary outcome will be a change from baseline to week 52 in the controlled attenuation parameter, free fatty acid and glucagon."},{"id":"source_21","type":"source","study":"Semaglutide treatment for PRevention Of Toxicity in high-dosE Chemotherapy with autologous haematopoietic stem-cell Transplantation (PROTECT): study protocol for a randomised, double-blind, placebo-controlled, investigator-initiated study","year":2024,"doi":"10.1136/bmjopen-2024-089862","url":"https://doi.org/10.1136/bmjopen-2024-089862","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":"protocol","cited_as":"Sorum 2024","excerpt":"INTRODUCTION: Cancer treatment with high-dose chemotherapy damages the mucosal barrier of the gastrointestinal (GI) tract and is associated with severe toxicity involving mucositis, severe inflammation and organ dysfunction. Currently, there is no effective prophylaxis against this. Glucagon-like peptide 1 (GLP-1), a well-known regulator of blood glucose, has been suggested in mouse studies to possess trophic effects on gut epithelial cells as well as anti-inflammatory properties. In line with this, endogenous GLP-1 levels have been shown to be inversely correlated with toxicities after haematopoietic stem cell transplantation (HSCT) and treatment with a GLP-1 receptor agonist (GLP-1RA) was shown to limit chemotherapy-induced mucositis in rodents. This present study investigates the effects of the GLP-1RA semaglutide on GI mucositis severity score in patients with lymphoma undergoing high-dose chemotherapy followed by autologous (auto) HSCT. METHODS AND ANALYSIS: This is a randomised, double-blind, placebo-controlled, two-centre investigator-initiated clinical study."},{"id":"source_22","type":"source","study":"Weight‐Lowering Drugs and Natural Female Fertility—A Systematic Review and Meta‐Analysis","year":2026,"doi":"10.1111/cob.70092","url":"https://doi.org/10.1111/cob.70092","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","cited_as":"Alnaimi 2026","excerpt":"Overweight and obesity are global health concerns linked to impaired female fertility. Weight-lowering drugs are an alternative for achieving weight loss; however, their effect on natural female fertility is unclear. A systematic review and meta-analysis were conducted to summarise the literature on the effects of weight-lowering drugs on ovulation, conception, pregnancy and live birth rates. Inclusion criteria comprised interventional and observational studies involving women with overweight or obesity receiving weight-lowering drugs, compared with non-users, lifestyle modifications or other medications. MEDLINE, Embase, CINAHL, CENTRAL and ClinicalTrials.gov were searched, yielding 2731 records. After screening, seven clinical trials were included (n = 575), six of which were randomised. Sample sizes ranged from 40 to 120 women aged 25.9-29.7 years. Six trials evaluated orlistat, while one assessed semaglutide. In four trials, orlistat was associated with a higher ovulation rate than lifestyle modifications. A meta-analysis of ovulation rates comparing orlistat and metformin showed no significant difference (RR = 0.78, 95% CI: 0.41-1.49; p = 0.45)."},{"id":"source_23","type":"source","study":"SEMASEARCH Study Design: Real‐World Evaluation of Semaglutide 2.4 mg in Adults With Severe Obesity Underrepresented in Clinical Trials","year":2026,"doi":"10.1111/dom.70697","url":"https://doi.org/10.1111/dom.70697","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":"indirect","cited_as":"Lassen 2026","excerpt":"BACKGROUND: Although semaglutide 2.4 mg has demonstrated significant weight loss efficacy in clinical trials, real-world data, particularly with regard to clinically complex and underrepresented populations, remain limited. OBJECTIVES: The study aims to assess the real-world effectiveness and patient-reported outcomes associated with the use of semaglutide 2.4 mg in individuals with severe and complex obesity. The study also intends to characterize weight loss response in pre-defined subgroups of patients and to identify predictors of weight loss using machine learning. METHODS: SEMASEARCH is a retrospective multicentric observational cohort embedded within the French early-access program for semaglutide 2.4 mg. A total of 1100 patients with severe obesity (BMI ≥ 40 kg/m 2 with at least one treated obesity-related complication) were retrospectively included from 11 expert obesity centers, based on prospectively collected data at baseline, 6 months, and 12 months. Subgroups include patients with a history of bariatric surgery, binge eating disorder, hypothalamic obesity, age ≥ 60 years or altered body composition, BMI ≥ 60 kg/m 2 , and those receiving psychotropic medications."},{"id":"source_24","type":"source","study":"Protocol for a double-blind placebo-controlled randomised controlled trial assessing the impact of oral semaglutide in amyloid positivity (ISAP) in community dwelling UK adults","year":2024,"doi":"10.1136/bmjopen-2023-081401","url":"https://doi.org/10.1136/bmjopen-2023-081401","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":"direct","cited_as":"Koychev 2024","excerpt":"INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), currently marketed for type 2 diabetes and obesity, may offer novel mechanisms to delay or prevent neurotoxicity associated with Alzheimer's disease (AD). The impact of semaglutide in amyloid positivity (ISAP) trial is investigating whether the GLP-1 RA semaglutide reduces accumulation in the brain of cortical tau protein and neuroinflammation in individuals with preclinical/prodromal AD. METHODS AND ANALYSIS: ISAP is an investigator-led, randomised, double-blind, superiority trial of oral semaglutide compared with placebo. Up to 88 individuals aged ≥55 years with brain amyloid positivity as assessed by positron emission tomography (PET) or cerebrospinal fluid, and no or mild cognitive impairment, will be randomised. People with the low-affinity binding variant of the rs6971 allele of the Translocator Protein 18 kDa (TSPO) gene, which can interfere with interpreting TSPO PET scans (a measure of neuroinflammation), will be excluded.At baseline, participants undergo tau, TSPO PET and MRI scanning, and provide data on physical activity and cognition."},{"id":"source_25","type":"source","study":"Long-Term Safety and Renal Outcomes of Semaglutide in Non-Diabetic Obesity with Chronic Kidney Disease or Hypertension: A Systematic Review and Meta-Analysis.","year":2026,"doi":"10.7417/ct.2026.2083","url":"https://doi.org/10.7417/ct.2026.2083","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","cited_as":"Elganyny 2026","excerpt":"BACKGROUND: Semaglutide, a GLP-1 receptor agonist, has demonstrated metabolic and renal benefits in diabetic populations. However, its efficacy and safety in non-diabetic individuals with obesity and chronic kidney disease (CKD) remain largely unstudied. Given the high cardiometabolic risk in this group and limited therapeutic options, evaluating semaglutide's role is crucial. OBJECTIVE: To assess the effects of semaglutide on body mass index (BMI), blood pressure, renal function (eGFR), and albuminuria in non-diabetic patients with obesity and CKD or hypertension. METHODS: This systematic review and meta-analysis was conducted in accordance with PRISMA guidelines. A total of 580 studies were screened; 3 eligible studies (n=430 participants) were included. Data were extracted from a randomized controlled trial, a real-world observational dialysis study, and a large post hoc trial analysis. Fixed-effect meta-analysis models were applied to estimate pooled effects on BMI, systolic blood pressure (SBP), and renal outcomes. RESULTS: Semaglutide treatment significantly reduced BMI (mean reduction: Tuttle 18.3%, Apperloo 11.8%, Vanek 1.5%; P = 0."},{"id":"source_26","type":"source","study":"Efficacy and safety of semaglutide 2.4 mg for weight loss in overweight or obese adults without diabetes: An updated systematic review and meta‐analysis including the 2‐year <scp>STEP</scp> 5 trial","year":2024,"doi":"10.1111/dom.15386","url":"https://doi.org/10.1111/dom.15386","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","cited_as":"Qin 2024","excerpt":"AIM: To explore the safety and efficacy of subcutaneous semaglutide 2.4 mg, administered once a week in non-diabetic overweight or obese individuals. METHODS: A thorough search was performed of various databases including PubMed, Embase, the Cochrane Library, Web of Science, clinicaltrials.gov, CNKI and Wanfang from their inception up to April 11, 2023. Our aim was to identify randomized controlled trials (RCTs) that compared the efficacy of semaglutide administered once weekly with placebo in overweight or obese adults. Through a review of the literature, data were extracted from relevant studies and assessed for quality, and a meta-analysis was conducted using RevMan 5.4.1 software. RESULTS: Six RCTs comprising 3962 overweight or obese individuals were identified. The findings indicated that, in comparison to the placebo group, semaglutide caused a significant and sustainable reduction in the percentage of body weight (BW; mean difference [MD]: -11.80% [95% confidence interval {CI} -12.93, -10.68]; P < 0.00001) as well as a decrease in absolute BW (MD: -12.2 kg [95% CI -13.3, -11.1]; P < 0.00001), body mass index (MD: -4.5 kg/m 2 [95% CI -4.9, -4.1]; P < 0."},{"id":"source_27","type":"source","study":"Tirzepatide vs. semaglutide for obesity, glycemic control, and cardiovascular outcomes: a narrative review of clinical trials","year":2026,"doi":"10.3389/fmed.2026.1764664","url":"https://doi.org/10.3389/fmed.2026.1764664","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","cited_as":"Harbi 2026","excerpt":"BACKGROUND: Tirzepatide, a dual glucose-dependent insulinotropic polypeptide, (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as an effective therapy for obesity and type 2 diabetes mellitus (T2DM). Its dual-incretin mechanism may offer enhanced metabolic benefits compared with selective GLP-1 receptor agonists such as semaglutide. METHODS: A structured narrative review of clinical trials, real-world observational studies, and contextual cardiovascular outcome analyses was conducted. Literature was sourced from ClinicalTrials.gov and relevant scientific databases to compare tirzepatide and semaglutide across weight, glycemic, cardiometabolic, and safety outcomes. RESULTS: Across completed head-to-head randomized trials, tirzepatide consistently achieved greater reductions in body weight, and HbA1c than semaglutide in individuals with obesity or T2DM. Semaglutide, however, has the most mature evidence for cardiovascular risk reduction, as demonstrated in the SUSTAIN-6, PIONEER-6, and SELECT trials."},{"id":"source_28","type":"source","study":"Efficacy of Semaglutide s.c. Once-weekly on Weight Loss and Management in Adolescents With Monogenic Obesity in Clinical Practice","year":null,"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","cited_as":"Efficacy of Semaglutide S n.d.","excerpt":"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_29","type":"source","study":"Primary Prevention and Uterine Preservation in Premenopausal Women With Obesity and Endometrial Hyperplasia","year":null,"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","cited_as":"Primary Prevention and Uterine n.d.","excerpt":"The investigators hypothesize that combined treatment with the GLP-1R agonist semaglutide 2.4 mg and levonorgestrel intrauterine device (LNG-IUD), compared to LNG-IUD alone, will result in improved likelihood of uterine preservation, sustained weight loss, improved endometrial and metabolomic response to progestin, and improved quality of life in premenopausal women with endometrial hyperplasia who desire uterine preservation."}],"edges":[{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_1","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_2","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_3","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_4","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_5","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_6","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_7","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_8","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_9","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_10","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_11","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_12","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_13","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_14","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_15","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_16","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_17","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_18","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_19","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_20","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_21","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_22","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_23","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_24","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_25","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_26","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_27","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_28","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_29","type":"contains_claim"},{"from":"9ff9a2ac-5a2c-4db3-8004-dff34731a3f4","to":"claim_30","type":"contains_claim"}],"screening":{"identified":29,"screened":29,"excluded":0,"included":29,"included_or_retained":29,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"29 candidate receipts retained after source retrieval, deduplication, and topic filtering. 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