Semaglutide — clinical evidence
Assessed outcomes with certainty ratings, contributing trials and the reasoning for each rating.
§3Clinical evidence
§3.1Atherosclerotic cardiovascular disease and cardiovascular risk reduction
Anchor outcome. Three-point major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke).
Effect as recorded. Three-point MACE hazard ratio 0.80 in adults with overweight or obesity and established cardiovascular disease without diabetes; HR 0.80 (95 % CI 0.72 to 0.90); 6.5 % versus 8.0 % over a mean 39.8 months.[1,2]
Certainty. High certainty SELECT randomised 17,604 participants and was event-driven with independent adjudication. The Institute grades event reduction as high certainty in the enrolled population and does not extrapolate to primary prevention.
Contributing trials. SELECT · SUSTAIN-6. Full structured abstracts are published for each.
Full evidence extract for atherosclerotic cardiovascular disease and cardiovascular risk reduction · Indication assessment
§3.2Chronic kidney disease in type 2 diabetes
Anchor outcome. Composite kidney outcome (kidney failure, sustained ≥50 % eGFR decline, kidney or cardiovascular death).
Effect as recorded. Composite kidney outcome hazard ratio 0.76 in type 2 diabetes with chronic kidney disease; HR 0.76 (95 % CI 0.66 to 0.88); annual eGFR slope difference 1.16 mL/min/1.73 m²/year.[2,3]
Certainty. High certainty FLOW was stopped early for efficacy on the recommendation of its independent data monitoring committee, which the Institute records as a source of modest effect-size inflation.
Contributing trials. FLOW. Full structured abstracts are published for each.
Full evidence extract for chronic kidney disease in type 2 diabetes · Indication assessment
§3.3Obesity and overweight in adults
Anchor outcome. Percentage change in body weight from baseline.
Effect as recorded. −14.9 % body weight at 68 weeks with semaglutide 2.4 mg versus −2.4 % with placebo; treatment difference −12.4 percentage points (95 % CI −13.4 to −11.5).[3,4]
Certainty. High certainty Consistent across five phase 3 trials with a common titration schedule and a common primary analysis timepoint. Effect is attenuated but preserved in the presence of type 2 diabetes.
Contributing trials. STEP-1 · STEP-3 · STEP-4 · STEP-5 · STEP-8. Full structured abstracts are published for each.
Full evidence extract for obesity and overweight in adults · Indication assessment
§3.4Type 2 diabetes mellitus
Anchor outcome. Change in HbA1c (%, mmol/mol).
Effect as recorded. −1.5 to −1.8 % HbA1c at 30–56 weeks versus placebo; superior to dulaglutide 1.5 mg in a head-to-head comparison; SUSTAIN 7 difference −0.41 % (95 % CI −0.57 to −0.25) for semaglutide 1.0 mg versus dulaglutide 1.5 mg.[4,5]
Certainty. High certainty Dose-dependent, reproducible across background therapies.
Contributing trials. SUSTAIN-1 · SUSTAIN-6 · SUSTAIN-7 · STEP-2. Full structured abstracts are published for each.
Full evidence extract for type 2 diabetes mellitus · Indication assessment
§3.5Heart failure with preserved ejection fraction and obesity
Anchor outcome. Change in Kansas City Cardiomyopathy Questionnaire clinical summary score.
Effect as recorded. KCCQ clinical summary score improvement of 7.8 points versus placebo at 52 weeks; estimated difference 7.8 points (95 % CI 4.8 to 10.9).[5,6]
Certainty. Moderate certainty Downgraded one level for risk of bias: weight change is visible to participants and the primary endpoint is patient-reported.
Contributing trials. STEP-HFpEF · STEP-HFpEF-DM. Full structured abstracts are published for each.
Full evidence extract for heart failure with preserved ejection fraction and obesity · Indication assessment
§3.6Hypertension in the context of adiposity
Anchor outcome. Change in systolic and diastolic blood pressure.
Effect as recorded. Systolic blood pressure −6.2 mmHg versus −1.1 mmHg with placebo (STEP 1); difference −5.1 mmHg (95 % CI −6.3 to −3.9).[6,7]
Certainty. Moderate certainty Reported as a secondary outcome; no dedicated antihypertensive programme exists.
Contributing trials. STEP-1 · SELECT. Full structured abstracts are published for each.
Full evidence extract for hypertension in the context of adiposity · Indication assessment
§3.7Metabolic dysfunction-associated steatohepatitis
Anchor outcome. Resolution of steatohepatitis without worsening of fibrosis.
Effect as recorded. Resolution of steatohepatitis without worsening of fibrosis in 62.9 % versus 34.3 % with placebo at 72 weeks; difference 28.7 percentage points (95 % CI 21.1 to 36.2).[7,8]
Certainty. Moderate certainty Part 1 of a two-part trial; the clinical-outcome part had not reported at this assessment cycle.
Contributing trials. ESSENCE. Full structured abstracts are published for each.
Full evidence extract for metabolic dysfunction-associated steatohepatitis · Indication assessment
§3.8Obesity in children and adolescents
Anchor outcome. Change in BMI (%, absolute, z-score).
Effect as recorded. −16.1 % BMI at 68 weeks versus +0.6 % with placebo; estimated difference −16.7 percentage points (95 % CI −20.3 to −13.2).[8,9]
Certainty. Moderate certainty Downgraded for imprecision in subgroups and absence of growth and bone-accrual follow-up.
Contributing trials. STEP-TEENS. Full structured abstracts are published for each.
Full evidence extract for obesity in children and adolescents · Indication assessment
§3.9Peripheral arterial disease with intermittent claudication
Anchor outcome. Maximum walking distance.
Effect as recorded. Maximum walking distance ratio to baseline 1.21 versus 1.08 with placebo at 52 weeks; estimated treatment ratio 1.13 (95 % CI 1.06 to 1.21).[9,10]
Certainty. Moderate certainty Single trial; functional endpoint in a population able to perceive weight change.
Contributing trials. STRIDE. Full structured abstracts are published for each.
Full evidence extract for peripheral arterial disease with intermittent claudication · Indication assessment
§3.10Prediabetes and progression to type 2 diabetes
Anchor outcome. Incident type 2 diabetes.
Effect as recorded. Reversion to normoglycaemia in 84.1 % of participants with prediabetes at baseline versus 47.8 % with placebo (STEP 1); not formally tested as a confirmatory endpoint.[10,11]
Certainty. Low certainty Exploratory subgroup analysis; no incident-diabetes outcome trial has reported.
Contributing trials. STEP-1 · STEP-5. Full structured abstracts are published for each.
Full evidence extract for prediabetes and progression to type 2 diabetes · Indication assessment
§3.11Sarcopenia and lean-mass preservation during weight reduction
Anchor outcome. Change in appendicular lean mass by DXA.
Effect as recorded. Approximately 39 % of total mass lost was lean mass in the DXA substudy; substudy n = 140; not powered for a comparative conclusion.[11,12]
Certainty. Low certainty The proportion is broadly consistent with dietary weight loss but the substudy is small and single-trial.
Contributing trials. STEP-1. Full structured abstracts are published for each.
Full evidence extract for sarcopenia and lean-mass preservation during weight reduction · Indication assessment
References cited on this page
References are numbered in order of first citation in this document. Each superscript in the text links to its entry below.
- Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF. Once-weekly semaglutide in adults with overweight or obesity. New England Journal of Medicine 2021;384(11):989–1002. doi:10.1056/NEJMoa2032183 · PMID 33567185
- Davies M, Færch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, Rosenstock J, Shimomura I, Viljoen A, Wadden TA, Lingvay I. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. The Lancet 2021;397(10278):971–984. doi:10.1016/S0140-6736(21)00213-0 · PMID 33667417
- Wadden TA, Bailey TS, Billings LK, Davies M, Frias JP, Koroleva A, Lingvay I, O’Neil PM, Rubino DM, Skovgaard D, Wallenstein SOR, Garvey WT. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA 2021;325(14):1403–1413. doi:10.1001/jama.2021.1831 · PMID 33625476
- Rubino D, Abrahamsson N, Davies M, Hesse D, Greenway FL, Jensen C, Lingvay I, Mosenzon O, Rosenstock J, Rubio MA, Rudofsky G, Tadayon S, Wadden TA, Dicker D. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA 2021;325(14):1414–1425. doi:10.1001/jama.2021.3224 · PMID 33755728
- Garvey WT, Batterham RL, Bhatta M, Buscemi S, Christensen LN, Frias JP, Jódar E, Kandler K, Rigas G, Wadden TA, Wharton S. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nature Medicine 2022;28(10):2083–2091. doi:10.1038/s41591-022-02026-4 · PMID 36216945
- Rubino DM, Greenway FL, Khalid U, O’Neil PM, Rosenstock J, Sørrig R, Wadden TA, Wizert A, Garvey WT. Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes: the STEP 8 randomized clinical trial. JAMA 2022;327(2):138–150. doi:10.1001/jama.2021.23619 · PMID 35015037
- Weghuber D, Barrett T, Barrientos-Pérez M, Gies I, Hesse D, Jeppesen OK, Kelly AS, Mastrandrea LD, Sørrig R, Arslanian S. Once-weekly semaglutide in adolescents with obesity. New England Journal of Medicine 2022;387(24):2245–2257. doi:10.1056/NEJMoa2208601 · PMID 36322838
- Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, Hardt-Lindberg S, Hovingh GK, Kahn SE, Kushner RF, Lingvay I, Oral TK, Michelsen MM, Plutzky J, Tornøe CW, Ryan DH. Semaglutide and cardiovascular outcomes in obesity without diabetes. New England Journal of Medicine 2023;389(24):2221–2232. doi:10.1056/NEJMoa2307563 · PMID 37952131
- Ryan DH, Lingvay I, Deanfield J, Kahn SE, Barrientos-Pérez M, Colhoun HM, Cercato C, Conway L, Kushner RF, Lincoff AM. Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. Nature Medicine 2024;30(7):2049–2057. doi:10.1038/s41591-024-02996-7 · PMID 38740993
- Perkovic V, Tuttle KR, Rossing P, Mahaffey KW, Mann JFE, Bakris G, Baeres FMM, Idorn T, Bosch-Traberg H, Lausvig NL, Pratley R. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. New England Journal of Medicine 2024;391(2):109–121. doi:10.1056/NEJMoa2403347 · PMID 38785209
- Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, Hovingh GK, Kitzman DW, Lindegaard ML, Møller DV, Shah SJ, Treppendahl MB, Verma S, Abhayaratna W, Ahmed FZ, Chopra V, Ezekowitz J, Fu M, Ito H, Petrie MC. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. New England Journal of Medicine 2023;389(12):1069–1084. doi:10.1056/NEJMoa2306963 · PMID 37622681
- Sanyal AJ, Newsome PN, Kliers I, Østergaard LH, Long MT, Kjær MS, Cali AMG, Bugianesi E, Rinella ME, Roden M, Ratziu V. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. New England Journal of Medicine 2025;392(21):2089–2099. doi:10.1056/NEJMoa2413258
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