[ { "slug": "surmount-1", "study_name": "SURMOUNT-1", "question": "Tirzepatide in adults with obesity or overweight", "nct": "NCT04184622", "doi": "10.1056/NEJMoa2206038", "pmid": null, "sponsor": "Eli Lilly and Company", "design": "Phase 3, randomised, double-blind, parallel-group, placebo-controlled", "population": "Adults with obesity (BMI 30 or above), or overweight (BMI 27 or above) with at least one weight-related complication, without type 2 diabetes", "sample_size": "2,539 randomised", "intervention": "Tirzepatide once weekly", "dose": "5 mg, 10 mg or 15 mg", "comparator": "Placebo", "duration": "72 weeks", "primary_endpoint": "Co-primary: percentage change in body weight from baseline at week 72, and the proportion achieving at least 5% weight reduction", "main_result": "Treatment-regimen estimand: \u221215.0% (5 mg), \u221219.5% (10 mg), \u221220.9% (15 mg) versus \u22123.1% placebo. Efficacy estimand: \u221216.0%, \u221221.4%, \u221222.5% versus \u22122.4%", "adverse_events": "At 15 mg: nausea 29%, diarrhoea 23%, constipation 17%, vomiting 13%, dyspepsia 10%. Mostly mild to moderate and concentrated during dose escalation", "discontinuations": "7% discontinued because of an adverse event at 15 mg", "limitations": "Industry-funded and industry-analysed. Excludes people with type 2 diabetes. Two estimands are published and are routinely conflated: the treatment-regimen estimand includes everyone regardless of adherence, the efficacy estimand assumes continued treatment. Marketing generally quotes the higher figure without saying which. Results are group means under trial conditions with structured lifestyle support, and describe an FDA-approved subcutaneous injection at studied doses.", "publication_date": "2022-06-04", "last_source_check": "2026-08-03", "evidence_status": "verified", "registry_search": "https://clinicaltrials.gov/search?term=SURMOUNT-1", "todo": null, "results_chart": [ [ "Tirzepatide 5 mg", 15.0 ], [ "Tirzepatide 10 mg", 19.5 ], [ "Tirzepatide 15 mg", 20.9 ], [ "Placebo", 3.1 ] ], "journal": "Jastreboff AM et al., N Engl J Med 2022;387(3). NCT04184622", "source_url": "https://www.nejm.org/doi/full/10.1056/NEJMoa2206038", "evidence_id": "EV-0101", "record_type": "single trial" }, { "slug": "surmount-3", "study_name": "SURMOUNT-3", "question": "Tirzepatide after intensive lifestyle intervention", "nct": "NCT04657016", "doi": null, "pmid": null, "sponsor": "Eli Lilly and Company", "design": "Phase 3 randomised placebo-controlled trial following an intensive lifestyle intervention lead-in", "population": "Adults with overweight or obesity who completed a 12-week intensive lifestyle intervention", "sample_size": "806 randomised", "intervention": null, "dose": "Maximum tolerated, 10 or 15 mg", "comparator": "Placebo", "duration": "72 weeks", "primary_endpoint": "Percentage change in body weight after a 12-week intensive lifestyle lead-in", "main_result": "\u221218.4% additional reduction versus +2.5% with placebo, on top of lead-in weight loss", "adverse_events": null, "discontinuations": null, "limitations": "Industry-funded. The lifestyle lead-in selects for people who already responded to lifestyle intervention, which limits generalisability.", "publication_date": null, "last_source_check": "2026-08-03", "evidence_status": "verified", "registry_search": "https://clinicaltrials.gov/search?term=SURMOUNT-3", "todo": null, "journal": "Wadden TA et al., Nature Medicine 2023. NCT04657016", "results_chart": [ [ "Tirzepatide, additional", 18.4 ] ], "evidence_id": "EV-0108", "record_type": "single trial" }, { "slug": "surmount-4", "study_name": "SURMOUNT-4", "question": "Continued tirzepatide versus withdrawal for weight maintenance", "nct": "NCT04660643", "doi": null, "pmid": null, "sponsor": "Eli Lilly and Company", "design": "Phase 3 randomised withdrawal trial", "population": "Adults with obesity who completed an open-label tirzepatide lead-in", "sample_size": "670 randomised", "intervention": null, "dose": "Maximum tolerated", "comparator": "Placebo, after withdrawal", "duration": "88 weeks total, 36-week open-label lead-in then 52-week randomised withdrawal", "primary_endpoint": "Percentage change in body weight during the randomised withdrawal period", "main_result": "Participants who continued lost a further 5.5%. Participants withdrawn to placebo regained 14.0%", "adverse_events": null, "discontinuations": null, "limitations": "The lead-in selects for people who tolerated and responded to the drug, so both arms are a responder population. Says nothing about tapering strategies, which were not tested.", "publication_date": null, "last_source_check": "2026-08-03", "evidence_status": "verified", "registry_search": "https://clinicaltrials.gov/search?term=SURMOUNT-4", "todo": null, "journal": "Aronne LJ et al., JAMA 2024. NCT04660643", "source_url": "https://jamanetwork.com/journals/jama/fullarticle/2812936", "evidence_id": "EV-0109", "results_chart": [ [ "Continued tirzepatide, further loss", 5.5 ], [ "Withdrawn to placebo, regain", 14.0 ] ], "record_type": "single trial" }, { "slug": "surmount-5", "study_name": "SURMOUNT-5", "question": "Tirzepatide versus semaglutide, head to head", "nct": "NCT05822830", "doi": "10.1056/NEJMoa2416394", "pmid": null, "sponsor": "Eli Lilly and Company", "design": "Phase 3b, randomised, open-label, active-controlled head-to-head", "population": "Adults with obesity but without type 2 diabetes; BMI 30 or above, or 27 or above with at least one obesity-related complication. 32 sites in the United States and Puerto Rico, April 2023 to November 2024", "sample_size": "751 randomised 1:1", "intervention": "Tirzepatide once weekly at maximum tolerated dose", "dose": "10 mg or 15 mg", "comparator": "Semaglutide once weekly at maximum tolerated dose, 1.7 mg or 2.4 mg", "duration": "72 weeks", "primary_endpoint": "Percentage change in body weight from baseline at week 72", "main_result": "Least-squares mean weight change of \u221220.2% with tirzepatide versus \u221213.7% with semaglutide (P<0.001); \u221222.8 kg versus \u221215.0 kg; waist circumference \u221218.4 cm versus \u221213.0 cm", "adverse_events": "Most adverse events were gastrointestinal and mild to moderate. Serious adverse events occurred in 4.8% of the tirzepatide group and 3.5% of the semaglutide group", "discontinuations": "Six participants in each group discontinued because of adverse events", "limitations": "Open-label, so neither participants nor investigators were blinded. Industry-funded. Compares maximum tolerated doses, not fixed doses, and more semaglutide participants reached their top dose than tirzepatide participants in some real-world analyses. Excludes people with type 2 diabetes.", "publication_date": "2025-05-11", "last_source_check": "2026-08-03", "evidence_status": "verified", "registry_search": "https://clinicaltrials.gov/search?term=SURMOUNT-5", "todo": null, "results_chart": [ [ "Tirzepatide, % weight change", 20.2 ], [ "Semaglutide, % weight change", 13.7 ] ], "journal": "New England Journal of Medicine 2025;393(1):26-36", "source_url": "https://www.nejm.org/doi/full/10.1056/NEJMoa2416394", "evidence_id": "EV-0102", "record_type": "single trial" }, { "slug": "surmount-osa", "study_name": "SURMOUNT-OSA", "question": "Tirzepatide in obstructive sleep apnoea with obesity", "nct": "NCT05412004", "doi": "10.1056/NEJMoa2404881", "pmid": "38912654", "sponsor": "Eli Lilly and Company", "design": "Two phase 3, randomised, double-blind, placebo-controlled trials under one master protocol", "population": "Adults with moderate-to-severe obstructive sleep apnoea and obesity. Trial 1 enrolled participants not using positive airway pressure; trial 2 enrolled participants using PAP at baseline", "sample_size": null, "intervention": "Tirzepatide once weekly at maximum tolerated dose", "dose": "10 mg or 15 mg", "comparator": "Placebo", "duration": "52 weeks", "primary_endpoint": "Change in apnoea-hypopnoea index from baseline", "main_result": "Tirzepatide reduced the apnoea-hypopnoea index, body weight, hypoxic burden, hsCRP and systolic blood pressure, and improved sleep-related patient-reported outcomes", "adverse_events": null, "discontinuations": null, "limitations": "Industry-funded. PAP was withdrawn before assessment in trial 2, which complicates comparison with continued PAP therapy. Reduction in AHI is not the same as resolution of sleep apnoea, and tirzepatide is not a substitute for PAP in every patient.", "publication_date": "2024-06-21", "last_source_check": "2026-08-03", "evidence_status": "verified", "registry_search": "https://clinicaltrials.gov/search?term=SURMOUNT-OSA", "todo": null, "results_chart": null, "journal": "New England Journal of Medicine 2024;391(13)", "source_url": "https://www.nejm.org/doi/10.1056/NEJMoa2404881", "evidence_id": "EV-0103", "record_type": "single trial" }, { "slug": "summit-hfpef", "study_name": "SUMMIT", "question": "Tirzepatide in heart failure with preserved ejection fraction and obesity", "nct": "NCT04847557", "doi": null, "pmid": null, "sponsor": "Eli Lilly and Company", "design": "Phase 3, randomised, double-blind, parallel-group, placebo-controlled, multicentre", "population": "Adults with heart failure with preserved ejection fraction and obesity (BMI 30 or above), with or without type 2 diabetes", "sample_size": "731 randomised 1:1", "intervention": "Tirzepatide once weekly at maximum tolerated dose", "dose": "5 mg, 10 mg or 15 mg", "comparator": "Placebo", "duration": "52 weeks to the symptom endpoint, with event follow-up", "primary_endpoint": "Co-primary: time to first occurrence of a heart-failure outcome, and change in heart-failure symptoms and physical limitations at 52 weeks", "main_result": "A 38% reduction in the combined endpoint of cardiovascular death and worsening heart-failure events, with improvement in symptoms, physical limitations and exercise capacity", "adverse_events": null, "discontinuations": null, "limitations": "Industry-funded. Restricted to obesity-related HFpEF, a specific phenotype, so the result should not be generalised to heart failure broadly or to HFpEF without obesity. Relative risk reduction without the absolute event rate overstates the effect to most readers.", "publication_date": "2024-11-16", "last_source_check": "2026-08-03", "evidence_status": "verified", "registry_search": "https://clinicaltrials.gov/search?term=SUMMIT", "todo": null, "results_chart": null, "journal": "Presented at AHA 2024; SUMMIT substudies in JACC and Nature Medicine", "source_url": "https://www.jacc.org/doi/10.1016/j.jacc.2024.11.001", "evidence_id": "EV-0106", "record_type": "single trial" }, { "slug": "tirzepatide-diabetes-prevention", "study_name": "SURMOUNT-1, three-year prediabetes analysis", "question": "Progression to type 2 diabetes", "nct": "NCT04184622", "doi": "10.1056/NEJMoa2410819", "pmid": null, "sponsor": "Eli Lilly and Company", "design": "Prespecified analysis of a phase 3 randomised double-blind placebo-controlled trial", "population": "The 1,032 SURMOUNT-1 participants who had both obesity and prediabetes", "sample_size": "1,032 of 2,539", "intervention": "Tirzepatide once weekly", "dose": "5 mg, 10 mg or 15 mg", "comparator": "Placebo", "duration": "176 weeks of treatment followed by a 17-week off-treatment period", "primary_endpoint": "Progression to type 2 diabetes, plus three-year weight change and safety", "main_result": "Three years of tirzepatide produced substantial sustained weight reduction and a markedly lower risk of progression to type 2 diabetes than placebo", "adverse_events": null, "discontinuations": null, "limitations": "Industry-funded. Applies to people with both obesity and prediabetes, not to the general population. The 17-week off-treatment period is short relative to a chronic condition, and delaying progression is not the same as preventing it permanently.", "publication_date": "2024-11-13", "last_source_check": "2026-08-03", "evidence_status": "verified", "registry_search": "https://clinicaltrials.gov/search?term=SURMOUNT-1+prediabetes+extension", "todo": null, "results_chart": null, "journal": "New England Journal of Medicine, published 13 November 2024, updated 6 March 2025", "source_url": "https://www.nejm.org/doi/abs/10.1056/NEJMoa2410819", "evidence_id": "EV-0104", "record_type": "single trial" }, { "slug": "surpass-2", "study_name": "SURPASS-2", "question": "Tirzepatide versus semaglutide in type 2 diabetes", "nct": "NCT03987919", "doi": null, "pmid": null, "sponsor": "Eli Lilly and Company", "design": "Phase 3, randomised, active-controlled, in type 2 diabetes", "population": null, "sample_size": "1,879 randomised", "intervention": null, "dose": "5, 10 or 15 mg", "comparator": "Semaglutide 1 mg", "duration": "40 weeks", "primary_endpoint": "Change in HbA1c", "main_result": "HbA1c reduction of 2.01% to 2.30% with tirzepatide versus 1.86% with semaglutide 1 mg", "adverse_events": null, "discontinuations": null, "limitations": "Compares against semaglutide 1 mg, which is below the 2.4 mg dose used for weight management. A glycaemic trial in diabetes; do not read it as a weight-loss comparison.", "publication_date": null, "last_source_check": "2026-08-03", "evidence_status": "verified", "registry_search": "https://clinicaltrials.gov/search?term=SURPASS-2", "todo": null, "journal": "Fr\u00edas JP et al., N Engl J Med 2021. NCT03987919", "evidence_id": "EV-0110", "record_type": "single trial" }, { "slug": "tirzepatide-lean-mass", "study_name": "Body-composition analyses", "question": "Lean mass change during tirzepatide treatment", "nct": null, "doi": null, "pmid": null, "sponsor": null, "design": null, "population": null, "sample_size": null, "intervention": null, "dose": null, "comparator": null, "duration": null, "primary_endpoint": null, "main_result": null, "adverse_events": null, "discontinuations": null, "limitations": "Body-composition findings come from imaging sub-studies of the main trials, not from trials powered for that endpoint. Sample sizes are small, methods differ between studies, and the long-term functional consequence \u2014 strength, mobility, fall risk \u2014 is not established.", "publication_date": null, "last_source_check": "2026-08-03", "evidence_status": "pending", "registry_search": "https://clinicaltrials.gov/search?term=Body-composition+analyses", "todo": "Capture NCT ID, DOI, PMID, sponsor, design, N, dose, comparator, duration, endpoint, result, adverse events and limitations from the registry entry and the peer-reviewed publication. Do not summarise from a press release or a secondary article.", "record_type": "evidence summary" }, { "slug": "tirzepatide-kidney-disease", "study_name": "Renal outcome analyses", "question": "Kidney endpoints with tirzepatide", "nct": null, "doi": null, "pmid": null, "sponsor": null, "design": null, "population": null, "sample_size": null, "intervention": null, "dose": null, "comparator": null, "duration": null, "primary_endpoint": null, "main_result": null, "adverse_events": null, "discontinuations": null, "limitations": "Renal findings are secondary or exploratory analyses of trials whose primary endpoints were weight or glycaemia. No trial on this site was powered for kidney outcomes as a primary endpoint, so these are hypothesis-generating rather than confirmatory.", "publication_date": null, "last_source_check": "2026-08-03", "evidence_status": "pending", "registry_search": "https://clinicaltrials.gov/search?term=Renal+outcome+analyses", "todo": "Capture NCT ID, DOI, PMID, sponsor, design, N, dose, comparator, duration, endpoint, result, adverse events and limitations from the registry entry and the peer-reviewed publication. Do not summarise from a press release or a secondary article.", "record_type": "evidence summary" }, { "slug": "tirzepatide-fatty-liver-mash", "study_name": "SYNERGY-NASH", "question": "Tirzepatide in MASH with fibrosis", "nct": null, "doi": null, "pmid": null, "sponsor": null, "design": null, "population": null, "sample_size": null, "intervention": null, "dose": null, "comparator": null, "duration": null, "primary_endpoint": null, "main_result": null, "adverse_events": null, "discontinuations": null, "limitations": "SYNERGY-NASH used histological endpoints in a phase 2 population. Phase 2 results in liver disease have repeatedly failed to replicate at phase 3, and no outcome data on cirrhosis, decompensation or mortality exists for this indication.", "publication_date": null, "last_source_check": "2026-08-03", "evidence_status": "pending", "registry_search": "https://clinicaltrials.gov/search?term=SYNERGY-NASH", "todo": "Capture NCT ID, DOI, PMID, sponsor, design, N, dose, comparator, duration, endpoint, result, adverse events and limitations from the registry entry and the peer-reviewed publication. Do not summarise from a press release or a secondary article.", "record_type": "evidence summary" }, { "slug": "tirzepatide-pcos", "study_name": "PCOS evidence base", "question": "Tirzepatide in polycystic ovary syndrome", "nct": null, "doi": null, "pmid": null, "sponsor": null, "design": null, "population": null, "sample_size": null, "intervention": null, "dose": null, "comparator": null, "duration": null, "primary_endpoint": null, "main_result": null, "adverse_events": null, "discontinuations": null, "limitations": "The PCOS evidence base is small studies and secondary analyses. No GLP-1 is approved for PCOS, no trial was powered for PCOS-specific endpoints, and weight loss confounds every reported improvement because weight loss improves PCOS independently of how it was achieved.", "publication_date": null, "last_source_check": "2026-08-03", "evidence_status": "pending", "registry_search": "https://clinicaltrials.gov/search?term=PCOS+evidence+base", "todo": "Capture NCT ID, DOI, PMID, sponsor, design, N, dose, comparator, duration, endpoint, result, adverse events and limitations from the registry entry and the peer-reviewed publication. Do not summarise from a press release or a secondary article.", "record_type": "evidence summary" }, { "slug": "tirzepatide-cardiovascular-outcomes", "study_name": "SURPASS-CVOT", "question": "Cardiovascular outcomes with tirzepatide", "nct": "NCT04255433", "doi": null, "pmid": null, "sponsor": "Eli Lilly and Company", "design": "Phase 3 cardiovascular outcomes trial", "population": null, "sample_size": "13,299 randomised", "intervention": null, "dose": "Maximum tolerated", "comparator": "Dulaglutide", "duration": "Approximately 4.5 years", "primary_endpoint": "Major adverse cardiovascular events", "main_result": "Non-inferior to dulaglutide for MACE. This is not a demonstration of superiority over placebo", "adverse_events": null, "discontinuations": null, "limitations": "An active-comparator non-inferiority design. Non-inferiority to another GLP-1 is a different claim from cardiovascular benefit versus placebo, and the two are frequently conflated.", "publication_date": null, "last_source_check": "2026-08-03", "evidence_status": "verified", "registry_search": "https://clinicaltrials.gov/search?term=SURPASS-CVOT", "todo": null, "journal": "SURPASS-CVOT, 2024. NCT04255433", "evidence_id": "EV-0111", "record_type": "single trial" }, { "slug": "tirzepatide-type-2-diabetes", "study_name": "SURPASS programme", "question": "Glycaemic outcomes with tirzepatide", "nct": null, "doi": null, "pmid": null, "sponsor": null, "design": null, "population": null, "sample_size": null, "intervention": null, "dose": null, "comparator": null, "duration": null, "primary_endpoint": null, "main_result": null, "adverse_events": null, "discontinuations": null, "limitations": "The SURPASS programme measured glycaemic and weight endpoints, not cardiovascular events against placebo. SURPASS-CVOT used an active comparator, which supports a weaker claim than a placebo-controlled outcomes trial.", "publication_date": null, "last_source_check": "2026-08-03", "evidence_status": "pending", "registry_search": "https://clinicaltrials.gov/search?term=SURPASS+programme", "todo": "Capture NCT ID, DOI, PMID, sponsor, design, N, dose, comparator, duration, endpoint, result, adverse events and limitations from the registry entry and the peer-reviewed publication. Do not summarise from a press release or a secondary article.", "record_type": "evidence summary" }, { "slug": "retatrutide-phase-3", "study_name": "Retatrutide (TRIUMPH programme)", "question": "Retatrutide phase 3 results", "nct": null, "doi": "10.1056/NEJMoa2301972", "pmid": null, "sponsor": "Eli Lilly and Company", "design": "Phase 3 programme; the published phase 2 trial was randomised, double-blind and placebo-controlled", "population": "Adults with obesity, or overweight with weight-related complications", "sample_size": null, "intervention": "Retatrutide, a GLP-1, GIP and glucagon triple receptor agonist", "dose": null, "comparator": null, "duration": null, "primary_endpoint": null, "main_result": null, "adverse_events": null, "discontinuations": null, "limitations": "Retatrutide is investigational. It is not approved by the FDA or EMA for any indication, and it is not legally available from any telehealth provider or compounder.", "publication_date": null, "last_source_check": "2026-08-03", "evidence_status": "reported", "registry_search": "https://clinicaltrials.gov/search?term=TRIUMPH+programme", "todo": "Phase 3 figures circulating online (28.3% at 80 weeks, TRIUMPH-1) trace only to commercial secondary sources, several of which sell peptides or carry provider advertising. Do not publish any phase 3 number until it is confirmed against the NEJM paper or the registry record.", "journal": "Phase 2 results: New England Journal of Medicine, 2023", "record_type": "single trial" }, { "slug": "attain-1", "study_name": "ATTAIN-1", "question": "Orforglipron for chronic weight management", "nct": "NCT05869903", "doi": null, "pmid": null, "sponsor": "Eli Lilly and Company", "design": "Phase 3, randomised, double-blind, placebo-controlled", "population": "Adults with obesity, or overweight with weight-related comorbidities. Over 1,600 randomised across the US, Argentina, Australia, Brazil, China, Czechia, Germany, Greece, India, South Korea and Puerto Rico", "sample_size": "Over 1,600 randomised", "intervention": "Orforglipron, once-daily oral non-peptide GLP-1 receptor agonist", "dose": "Up to 17.2 mg once daily", "comparator": "Placebo", "duration": "72 weeks", "primary_endpoint": "Mean percentage change in body weight from baseline at 72 weeks", "main_result": "Approximately 11% to 12.4% mean weight reduction at the highest dose over 72 weeks. Lilly states 12.4% at the highest dose; secondary coverage cites approximately 11%", "results_chart": [ [ "Orforglipron 17.2 mg", 12.4 ] ], "adverse_events": "Predominantly gastrointestinal \u2014 nausea, vomiting, diarrhoea, constipation, abdominal pain. Boxed warning for thyroid C-cell tumours including medullary thyroid carcinoma", "discontinuations": null, "limitations": "Industry-funded. The published figure varies between sources (11% to 12.4%) depending on the analysis quoted; the estimand behind each is not consistently stated. Substantially lower mean reduction than injectable tirzepatide or either semaglutide formulation, which matters when the drug is compared on price alone.", "publication_date": "2026-04-01", "last_source_check": "2026-08-03", "evidence_status": "reported", "journal": "FDA approval announced 1 April 2026; ATTAIN-1 publication details not yet captured", "registry_search": "ClinicalTrials.gov NCT05869903", "source_url": "https://investor.lilly.com/news-releases/news-release-details/fda-approves-lillys-foundayotm-orforglipron-only-glp-1-pill", "evidence_id": "EV-0113", "todo": "Capture the NCT identifier, the peer-reviewed publication, the estimand behind each reported figure, and discontinuation rates. Do not chart a single efficacy number until the estimand is established.", "record_type": "single trial" }, { "slug": "oasis-4", "study_name": "OASIS 4", "question": "Oral semaglutide 25 mg for weight management", "nct": "NCT05564117", "doi": "10.1056/NEJMoa2500969", "pmid": null, "sponsor": "Novo Nordisk", "design": "Phase 3, randomised, double-blind, placebo-controlled", "population": "307 adults with obesity (BMI 30 or above) or overweight (BMI 27\u201329.9) with at least one weight-related comorbidity, excluding people with diabetes. Mean baseline weight 106 kg, mean BMI 38", "sample_size": "307 randomised 2:1 (205 active, 102 placebo)", "intervention": "Oral semaglutide 25 mg once daily, with a 12-week dose escalation", "dose": "25 mg once daily", "comparator": "Placebo", "duration": "64 weeks of treatment plus a 7-week off-treatment follow-up", "primary_endpoint": "Co-primary: percentage change in body weight and the proportion achieving at least 5% reduction at week 64", "main_result": "13.6% mean weight reduction on the treatment-policy estimand versus 2.2% placebo; 16.6% versus 2.7% among those who remained on treatment. One in three adherent participants achieved 20% or greater reduction", "results_chart": [ [ "Oral semaglutide, treatment-policy", 13.6 ], [ "Oral semaglutide, adherent", 16.6 ], [ "Placebo", 2.2 ] ], "adverse_events": "Serious adverse events occurred less frequently with oral semaglutide than with placebo, 3.9% against 8.8%", "discontinuations": null, "limitations": "Industry-funded. Small by the standards of this field at 307 participants, against 2,539 in SURMOUNT-1. Excludes people with diabetes. Two estimands are published and differ by three percentage points. The 7-week off-treatment period is too short to establish durability.", "publication_date": "2025-12-22", "last_source_check": "2026-08-03", "evidence_status": "verified", "journal": "Wharton S, Lingvay I, Bogdanski P, et al. N Engl J Med 2025;393(11):1077-1087", "registry_search": "https://clinicaltrials.gov/study/NCT05564117", "source_url": "https://doi.org/10.1056/NEJMoa2500969", "evidence_id": "EV-0114", "todo": null, "record_type": "single trial" }, { "slug": "synergy-nash", "study_name": "SYNERGY-NASH", "question": "Tirzepatide for MASH with liver fibrosis", "nct": "NCT04166773", "doi": "10.1056/NEJMoa2401943", "pmid": "38856224", "sponsor": "Eli Lilly and Company", "design": "Phase 2, dose-finding, multicentre, double-blind, randomised, placebo-controlled, 130 sites in 10 countries", "population": "Adults 18-80 with biopsy-confirmed MASH, stage F2 or F3 fibrosis, BMI 27-50, with or without type 2 diabetes, NAFLD activity score of 4 or above", "sample_size": "Randomised 1:1:1:1", "intervention": "Tirzepatide, once-weekly subcutaneous", "dose": "5 mg, 10 mg or 15 mg", "comparator": "Placebo", "duration": "52 weeks", "primary_endpoint": "MASH resolution without worsening of fibrosis on liver histology at 52 weeks", "main_result": "Tirzepatide was superior to placebo for MASH resolution without worsening of fibrosis. Reported resolution rates differ between secondary sources: one gives 51.8%, 62.8% and 73.3% at 5, 10 and 15 mg against 13.2% placebo; another gives 62% at 15 mg against 10% placebo", "results_chart": null, "adverse_events": "Nausea, diarrhoea, decreased appetite, constipation and weight loss, generally mild to moderate. No new safety signals against the SURMOUNT and SURPASS programmes", "discontinuations": null, "limitations": "Phase 2 and dose-finding rather than confirmatory. Fibrosis improvement was less pronounced than MASH resolution at 52 weeks. No head-to-head against semaglutide for liver endpoints. Secondary sources report materially different resolution figures, so we have not charted a single number.", "publication_date": "2024-07-25", "last_source_check": "2026-08-03", "evidence_status": "verified", "journal": "Loomba R, Hartman ML, Lawitz EJ, et al. N Engl J Med 2024;391(4):299-310", "registry_search": "https://clinicaltrials.gov/study/NCT04166773", "source_url": "https://clinicaltrials.gov/study/NCT04166773", "capture_date": "2026-07-24", "reviewer": "Editorial research desk", "evidence_id": "EV-1001", "todo": "Obtain the NEJM full text and record the exact resolution rate per arm with its estimand. Two secondary sources conflict at the 15 mg arm (73.3% vs 62%).", "record_type": "single trial" }, { "slug": "select", "study_name": "SELECT", "question": "Does semaglutide reduce cardiovascular events in people with obesity and established cardiovascular disease, without diabetes?", "nct": "NCT03574597", "doi": "10.1056/NEJMoa2307563", "pmid": "37952131", "sponsor": "Novo Nordisk", "design": "Randomised, double-blind, placebo-controlled, event-driven outcomes trial", "population": "Adults 45 and over with overweight or obesity and established cardiovascular disease, without diabetes", "sample_size": 17604, "intervention": "Semaglutide", "dose": "2.4 mg weekly, subcutaneous", "comparator": "Placebo", "duration": "Mean follow-up approximately 40 months", "primary_endpoint": "Composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke", "main_result": "Approximately a 20% relative reduction in the primary composite; event rate fell from roughly 8.0% to roughly 6.5%", "adverse_events": "Gastrointestinal effects more common on semaglutide; discontinuation for adverse events higher than placebo", "discontinuations": "Higher on semaglutide, driven by gastrointestinal effects", "limitations": "Participants all had established cardiovascular disease, so nothing transfers to primary prevention. Diabetes was excluded. The mechanism is unsettled: benefit appeared earlier than weight change alone explains. Relative and absolute reductions differ substantially.", "publication_date": "2023-11-11", "last_source_check": "2026-08-03", "evidence_status": "published, peer-reviewed", "registry_search": "ClinicalTrials.gov NCT03574597", "todo": null, "results_chart": [ [ "Semaglutide 2.4 mg", 6.5 ], [ "Placebo", 8.0 ] ], "journal": "New England Journal of Medicine", "source_url": "https://www.nejm.org/doi/full/10.1056/NEJMoa2307563", "evidence_id": "EV-5101", "record_type": "single trial" }, { "slug": "step-1", "study_name": "STEP-1", "question": "How much weight does semaglutide 2.4 mg produce in adults with obesity and without diabetes?", "nct": "NCT03548935", "doi": "10.1056/NEJMoa2032183", "pmid": "33567185", "sponsor": "Novo Nordisk", "design": "Randomised, double-blind, placebo-controlled, phase 3", "population": "Adults with BMI 30 or above, or 27 or above with at least one weight-related comorbidity, without diabetes", "sample_size": 1961, "intervention": "Semaglutide", "dose": "2.4 mg weekly, subcutaneous", "comparator": "Placebo, both arms with lifestyle intervention", "duration": "68 weeks", "primary_endpoint": "Percentage change in body weight", "main_result": "Mean weight change of \u221214.9% against \u22122.4% on placebo; about 86% reached 5% or more, about 51% reached 15% or more", "adverse_events": "Nausea approximately 44%, diarrhoea approximately 30%, vomiting approximately 24%", "discontinuations": "Approximately 7% for adverse events against approximately 3% on placebo", "limitations": "Both arms received diet and activity counselling, so the figure is drug plus programme. The mean conceals a wide distribution. The extension reported about two-thirds of lost weight returned within a year of stopping.", "publication_date": "2021-02-10", "last_source_check": "2026-08-03", "evidence_status": "published, peer-reviewed", "registry_search": "ClinicalTrials.gov NCT03548935", "todo": null, "results_chart": [ [ "Semaglutide 2.4 mg", 14.9 ], [ "Placebo", 2.4 ] ], "journal": "New England Journal of Medicine", "source_url": "https://www.nejm.org/doi/full/10.1056/NEJMoa2032183", "evidence_id": "EV-5102", "record_type": "single trial" }, { "slug": "surpass-cvot", "study_name": "SURPASS-CVOT", "question": "Is tirzepatide non-inferior to dulaglutide for cardiovascular outcomes in type 2 diabetes?", "nct": "NCT04255433", "doi": null, "pmid": null, "sponsor": "Eli Lilly", "design": "Randomised, double-blind, ACTIVE-COMPARATOR controlled outcomes trial", "population": "Adults with type 2 diabetes and established atherosclerotic cardiovascular disease", "sample_size": 13299, "intervention": "Tirzepatide", "dose": "Up to 15 mg weekly, subcutaneous", "comparator": "Dulaglutide 1.5 mg weekly \u2014 an active drug with existing cardiovascular evidence", "duration": "Event-driven", "primary_endpoint": "Composite of cardiovascular death, myocardial infarction, or stroke, tested for non-inferiority", "main_result": "Designed to establish non-inferiority against an active comparator, not superiority against placebo", "adverse_events": "Gastrointestinal effects consistent with the class", "discontinuations": "Reported within the trial publication", "limitations": "An active-comparator design cannot support the claim a placebo-controlled trial supports. 'Not worse than a drug that works' is weaker evidence than 'reduces events against no treatment', and the two are routinely conflated. The population is diabetes; SELECT excluded diabetes, so neither trial transfers to the other's population.", "publication_date": null, "last_source_check": "2026-08-03", "evidence_status": "reported; confirm the primary publication", "registry_search": "ClinicalTrials.gov NCT04255433", "todo": "Confirm the primary publication and its reported effect estimate before citing a figure", "results_chart": null, "journal": null, "source_url": "https://clinicaltrials.gov/study/NCT04255433", "evidence_id": "EV-5103", "record_type": "single trial" }, { "slug": "step-8", "study_name": "STEP-8", "question": "How does weekly semaglutide compare with daily liraglutide for weight loss?", "nct": "NCT04074161", "doi": "10.1001/jama.2021.23619", "pmid": "35015037", "sponsor": "Novo Nordisk", "design": "Randomised, open-label, active-comparator, phase 3b", "population": "Adults with BMI 30 or above, or 27 or above with a comorbidity, without diabetes", "sample_size": 338, "intervention": "Semaglutide 2.4 mg weekly", "dose": "2.4 mg weekly", "comparator": "Liraglutide 3.0 mg daily, and placebo", "duration": "68 weeks", "primary_endpoint": "Percentage change in body weight", "main_result": "Mean weight change approximately \u221215.8% on semaglutide against approximately \u22126.4% on liraglutide and \u22121.9% on placebo", "adverse_events": "Gastrointestinal effects common in both active arms", "discontinuations": "Higher on liraglutide than semaglutide in the reported analysis", "limitations": "Open-label, and smaller than the main STEP trials. Establishes the gap between the two molecules but not against tirzepatide, which was not in the trial.", "publication_date": "2022-01-11", "last_source_check": "2026-08-03", "evidence_status": "published, peer-reviewed", "registry_search": "ClinicalTrials.gov NCT04074161", "todo": null, "results_chart": [ [ "Semaglutide 2.4 mg", 15.8 ], [ "Liraglutide 3.0 mg", 6.4 ], [ "Placebo", 1.9 ] ], "journal": "JAMA", "source_url": "https://jamanetwork.com/journals/jama/fullarticle/2787907", "evidence_id": "EV-5104", "record_type": "single trial" } ]