Tirzepatide — clinical evidence
Assessed outcomes with certainty ratings, contributing trials and the reasoning for each rating.
§3Clinical evidence
§3.1Obesity and overweight in adults
Anchor outcome. Percentage change in body weight from baseline.
Effect as recorded. −20.9 % body weight at 72 weeks with 15 mg versus −3.1 % with placebo (SURMOUNT-1); treatment difference −17.8 percentage points (95 % CI −19.3 to −16.3).[1,2]
Certainty. High certainty The largest placebo-subtracted weight effect of any approved agent at the date of this cycle. SURMOUNT-5 reported superiority over semaglutide 2.4 mg (−20.2 % versus −13.7 %).
Contributing trials. SURMOUNT-1 · SURMOUNT-2 · SURMOUNT-3 · SURMOUNT-4 · SURMOUNT-5. Full structured abstracts are published for each.
Full evidence extract for obesity and overweight in adults · Indication assessment
§3.2Obstructive sleep apnoea with obesity
Anchor outcome. Change in apnoea–hypopnoea index (events/hour).
Effect as recorded. Apnoea–hypopnoea index reduced by 25.3 events/hour versus 5.3 with placebo in participants not using positive airway pressure; estimated difference −20.0 events/hour (95 % CI −25.8 to −14.2).[2,3]
Certainty. High certainty Objective, centrally scored polysomnographic endpoint; two parallel trials with consistent results.
Contributing trials. SURMOUNT-OSA-1 · SURMOUNT-OSA-2. Full structured abstracts are published for each.
Full evidence extract for obstructive sleep apnoea with obesity · Indication assessment
§3.3Type 2 diabetes mellitus
Anchor outcome. Change in HbA1c (%, mmol/mol).
Effect as recorded. −1.87 to −2.59 % HbA1c across doses and backgrounds; superior to semaglutide 1.0 mg, insulin degludec and insulin glargine; SURPASS-2 difference versus semaglutide 1.0 mg −0.45 % (95 % CI −0.57 to −0.32) at 15 mg.[3,4]
Certainty. High certainty Five-trial programme with active comparators throughout, an unusually strong design feature.
Contributing trials. SURPASS-1 · SURPASS-2 · SURPASS-3 · SURPASS-4 · SURPASS-5. Full structured abstracts are published for each.
Full evidence extract for type 2 diabetes mellitus · Indication assessment
§3.4Atherosclerotic 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. MACE hazard ratio 0.92 versus dulaglutide 1.5 mg in an active-controlled non-inferiority design; HR 0.92 (95 % CI 0.83 to 1.01).[4,5]
Certainty. Moderate certainty An active-controlled non-inferiority result establishes that tirzepatide is not inferior to an agent of proven benefit. It does not establish superiority to placebo directly, and the Institute states that distinction explicitly.
Contributing trials. SURPASS-CVOT. Full structured abstracts are published for each.
Full evidence extract for atherosclerotic cardiovascular disease and cardiovascular risk reduction · 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. Composite of cardiovascular death or worsening heart failure hazard ratio 0.62; HR 0.62 (95 % CI 0.41 to 0.95); KCCQ difference 6.9 points (95 % CI 3.3 to 10.6).[5,6]
Certainty. Moderate certainty Downgraded for imprecision — the composite was driven by heart-failure events with wide confidence limits.
Contributing trials. SUMMIT. Full structured abstracts are published for each.
Full evidence extract for heart failure with preserved ejection fraction and obesity · Indication assessment
§3.6Prediabetes and progression to type 2 diabetes
Anchor outcome. Incident type 2 diabetes.
Effect as recorded. Progression to type 2 diabetes at 176 weeks reduced by 94 % in the prediabetes cohort; HR 0.06 (95 % CI 0.03 to 0.14).[6,7]
Certainty. Moderate certainty Prespecified extension of one trial; the very large effect partly reflects glycaemic masking during treatment, which the Institute notes explicitly.
Contributing trials. SURMOUNT-1. Full structured abstracts are published for each.
Full evidence extract for prediabetes and progression to type 2 diabetes · Indication assessment
§3.7Knee osteoarthritis with obesity
Anchor outcome. WOMAC pain subscale.
Effect as recorded. WOMAC pain score improvement exceeding placebo at 68 weeks; reported difference of approximately 8 points on a 0–100 scale.[7,8]
Certainty. Low certainty Mechanical unloading cannot be separated from any direct effect.
Contributing trials. SURMOUNT-KOA. Full structured abstracts are published for each.
Full evidence extract for knee osteoarthritis with obesity · Indication assessment
§3.8Metabolic dysfunction-associated steatohepatitis
Anchor outcome. Resolution of steatohepatitis without worsening of fibrosis.
Effect as recorded. Resolution of steatohepatitis without worsening fibrosis in 44–62 % across doses versus 10 % with placebo at 52 weeks; phase 2; 10 mg difference 44.4 percentage points (95 % CI 25.6 to 63.2).[8,9]
Certainty. Low certainty Phase 2 only, wide confidence limits, no phase 3 histological result at this cycle.
Contributing trials. SYNERGY-NASH. Full structured abstracts are published for each.
Full evidence extract for metabolic dysfunction-associated steatohepatitis · Indication assessment
§3.9Sarcopenia and lean-mass preservation during weight reduction
Anchor outcome. Change in appendicular lean mass by DXA.
Effect as recorded. Approximately 25 % of total mass lost was lean mass in the body-composition substudy; substudy n = 160.[9,10]
Certainty. Low certainty Lower lean-mass fraction than reported for dietary weight loss in the same programme, but the substudy is small.
Contributing trials. SURMOUNT-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.
- Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A. Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine 2022;387(3):205–216. doi:10.1056/NEJMoa2206038 · PMID 35658024
- Garvey WT, Frias JP, Jastreboff AM, le Roux CW, Sattar N, Aizenberg D, Mao H, Zhang S, Ahmad NN, Bunck MC, Benabbad I, Zhang XM. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. The Lancet 2023;402(10402):613–626. doi:10.1016/S0140-6736(23)01200-X · PMID 37385275
- Wadden TA, Chao AM, Machineni S, Kushner R, Ard J, Srivastava G, Halpern B, Zhang S, Chen J, Bunck MC, Ahmad NN, Forrester T. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial. Nature Medicine 2023;29(11):2909–2918. doi:10.1038/s41591-023-02597-w · PMID 37840095
- Aronne LJ, Sattar N, Horn DB, Bays HE, Wharton S, Lin WY, Ahmad NN, Zhang S, Liao R, Bunck MC, Jouravskaya I, Murphy MA. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA 2024;331(1):38–48. doi:10.1001/jama.2023.24945 · PMID 38078870
- Aronne LJ, Horn DB, le Roux CW, Ho W, Falcon BL, Gomez Valderas E, Das S, Stefanski A, Sapin H, Rodriguez Flores M. Tirzepatide as compared with semaglutide for the treatment of obesity. New England Journal of Medicine 2025;392(1):45–57. doi:10.1056/NEJMoa2416394
- Malhotra A, Grunstein RR, Fietze I, Weaver TE, Redline S, Azarbarzin A, Sands SA, Schwab RJ, Dunn JP, Chakladar S, Bunck MC, Bednarik J. Tirzepatide for the treatment of obstructive sleep apnea and obesity. New England Journal of Medicine 2024;391(13):1193–1205. doi:10.1056/NEJMoa2404881 · PMID 38912654
- Packer M, Zile MR, Kramer CM, Baum SJ, Litwin SE, Menon V, Ge J, Weerakkody GJ, Ou Y, Bunck MC, Hurt KC, Murakami M, Borlaug BA. Tirzepatide for heart failure with preserved ejection fraction and obesity. New England Journal of Medicine 2025;392(5):427–437. doi:10.1056/NEJMoa2410027
- Rosenstock J, Wysham C, Frías JP, Kaneko S, Lee CJ, Fernández Landó L, Mao H, Cui X, Karanikas CA, Thieu VT. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. The Lancet 2021;398(10295):143–155. doi:10.1016/S0140-6736(21)01324-6 · PMID 34186022
- Frías JP, Davies MJ, Rosenstock J, Pérez Manghi FC, Fernández Landó L, Bergman BK, Liu B, Cui X, Brown K. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. New England Journal of Medicine 2021;385(6):503–515. doi:10.1056/NEJMoa2107519 · PMID 34170647
- Ludvik B, Giorgino F, Jódar E, Frias JP, Fernández Landó L, Brown K, Bray R, Rodríguez Á. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. The Lancet 2021;398(10300):583–598. doi:10.1016/S0140-6736(21)01443-4 · PMID 34370970
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