Tirzepatide for adults living with obesity.

rationaleObesity is a complex chronic condition linked to various comorbidities, such as hypertension, diabetes, and dyslipidaemia, with a significant global burden. Standard treatments, such as diet, exercise and behavioural changes, often have limited effects and poor compliance. Pharmacological options, including glucagon-like peptide receptor agonists (GLP-1RAs) and glucose-dependent insulinotropic polypeptide (GIP) dual agonists, show promise for individuals with obesity. This is one of three reviews investigating different GIP/GLP1-RAs for adults living with obesity.

objectivesTo assess the effects of the dual GIP/GLP-1 receptor agonist, tirzepatide, for adults living with obesity. SEARCH

methodsWe searched CENTRAL, MEDLINE, Embase, LILACS and two trials registries on 17 December 2024. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) on adults with obesity that compared tirzepatide at any dose with placebo, structured lifestyle modification programmes, another anti-obesity medication or other GLP-1RAs or GIP/GLP-1RAs, with a minimum follow-up of six months. OUTCOMES: Critical outcomes were weight, adverse events, major adverse cardiovascular events (MACE), quality of life, and mortality. Important outcomes included waist circumference and other obesity-related comorbidities. RISK OF BIAS: We used the original version of the Cochrane tool for assessing risk of bias (RoB 1). SYNTHESIS

methodsWe synthesised results for each outcome using meta-analysis with a random-effects model. Where this was not possible, we described the results narratively. We used GRADE to assess the certainty of evidence for each outcome. The main comparison of interest in the review is tirzepatide versus placebo. INCLUDED STUDIES: We included nine RCTs with 7111 participants, aged 36.1 to 65.25 years, primarily from middle- and high-income countries. The main comparison, tirzepatide versus placebo, is based on eight studies; one study compared tirzepatide with semaglutide. Studies included participants with weight-related comorbidities. Seven studies focused on specific subgroups, including type 2 diabetes, prediabetes, chronic heart failure, obstructive sleep apnoea (after a long pretreatment phase), and different racial populations. Tirzepatide was injected once a week, with dosing ranging from 5 mg to 15 mg. All the studies had medium-term follow-ups, and one had a long-term follow-up. All nine studies reported a major role of the drug manufacturer in their design, conduct, analysis, or writing. SYNTHESIS OF

resultsTirzepatide versus placebo (medium-term: 12 to 18 months) Tirzepatide likely results in a greater percentage reduction in body weight from baseline (mean difference (MD) -16.03, 95% confidence interval (CI) -18.91 to -13.14; 8 studies, 6317 participants; moderate-certainty evidence), and an increase in the number of people achieving a 5% weight reduction (risk ratio (RR) 3.60, 95% CI 2.44 to 5.30; I2 = 86%; 5 studies, 4455 participants; moderate-certainty evidence). Tirzepatide may result in an increase in non-serious adverse events (RR 1.33, 95% CI 1.03 to 1.71; 5 studies, 4582 participants; low-certainty evidence). The evidence is very uncertain about the effect on serious adverse events (RR 0.99, 95% CI 0.88 to 1.12; 8 studies, 6359 participants; very low-certainty evidence). Tirzepatide may result in little to no difference in adverse events leading to withdrawal (RR 2.06, 95% CI 1.21 to 3.52; 8 studies, 6359 participants; low-certainty evidence). Tirzepatide likely results in little to no difference in MACE (RR 0.75, 95% CI 0.34 to 1.66; I² = 0%; 7 studies, 5628 participants; moderate-certainty evidence). Tirzepatide likely results in little to no clinically important difference in quality of life as measured by the IWQOL-Lite-CT physical function domain (MD 9.91, 95% CI 7.81 to 12.02; 6 studies, 5020 participants; moderate-certainty evidence). Tirzepatide likely results in little to no difference in mortality (RR 0.79, 95% CI 0.34 to 1.83; 7 studies, 5628 participants; moderate-certainty evidence). Tirzepatide versus placebo (long-term: 3.5 years) Tirzepatide likely results in a greater percentage reduction in body weight from baseline (MD -15.66, 95% CI -19.14 to -12.18; 1 study, 1032 participants; moderate-certainty evidence), and an increase in the number of people achieving a 5% weight reduction (RR 2.81, 95% CI 2.33 to 3.38; 1 study, 1032 participants; moderate-certainty evidence). Tirzepatide may result in an increase in non-serious adverse events (RR 1.05, 95% CI 0.98 to 1.11; 1 study, 1032 participants; low-certainty evidence). The evidence is very uncertain about the effect on serious adverse events (RR 1.14, 95% CI 0.79 to 1.65; 1 study, 1032 participants; very low-certainty evidence). Tirzepatide may result in little to no difference in adverse events leading to withdrawal (RR 1.64, 95% CI 0.97 to 2.76; 1 study, 1032 participants; low-certainty evidence). Tirzepatide likely results in little to no difference in MACE (RR 0.56, 95% CI 0.22 to 1.42; 1 study, 1032 participants; moderate-certainty evidence). Tirzepatide may result in little to no clinically important difference in quality of life as measured by SF-36 physical component score (MD 2.70, 95% CI 0.00 to 5.40; 1 study, 1032 participants; low-certainty evidence). Tirzepatide may result in little to no difference in mortality (RR 0.83, 95% CI 0.22 to 3.17; 1 study, 1032 participants; low-certainty evidence). AUTHORS'

conclusionsTirzepatide likely results in weight loss at medium-term follow-up, and this initial weight loss is likely to be sustained at longer-term follow-up. The long-term impact on other patient-important outcomes may be limited or uncertain. The certainty of the evidence on events leading to withdrawal at medium- and long-term follow-up is low, which might further limit our understanding of the sustainability of the initial effects. All the included studies were funded by the drug manufacturer, raising concerns about potential conflicts of interest. Further independent studies are needed, particularly in underrepresented populations, to better understand the broader effects of tirzepatide in the management of obesity.

fundingWorld Health Organization (WHO) REGISTRATION: Protocol (2022) DOI: 10.1002/14651858.CD015092 Updated Protocol (2025): PROSPERO CRD420250654193.