Semaglutide for adults living with obesity.

RATIONALE: Obesity is a complex chronic condition linked to various comorbidities, such as hypertension, diabetes, and dyslipidaemia, with a significant global burden. Semaglutide, a widely used glucagon-like peptide-1 receptor agonist (GLP-1RA), can aid in weight loss by reducing appetite. However, its efficacy remains unclear. OBJECTIVES: To assess the effects of semaglutide on adults living with obesity. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, and two trials registries. The latest search date was 17 December 2024. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) that compared semaglutide with placebo, structured lifestyle modification programmes, other anti-obesity medications or other GLP-1RAs in adults living with obesity, with a minimum of six months' follow-up. OUTCOMES: Critical outcomes were weight, adverse events, major adverse cardiovascular events (MACE), quality of life, and mortality. Important outcomes were waist circumference, heart failure, diabetes-related outcomes, blood pressure-related outcomes, liver disease-related outcomes, obstructive sleep apnoea, and lipid metabolism-related outcomes. RISK OF BIAS: We used the original version of the Cochrane tool for assessing risk of bias in RCTs (RoB 1). SYNTHESIS METHODS: We 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 semaglutide versus placebo. INCLUDED STUDIES: We included 18 RCTs (27,949 participants), with a mean age ranging from 41.0 to 69.5 years, and an average BMI between 31.9 kg/mand 40.3 kg/m. Seventeen RCTs reported that the drug manufacturer had a major role in their design, conduct, analysis, or writing. Seventeen RCTs compared semaglutide versus placebo, at medium- (16 RCTs) or long-term (2 RCTs) follow-up. Other comparators were liraglutide (2 RCTs) and tirzepatide (1 RCT). SYNTHESIS OF RESULTS: Semaglutide versus placebo (medium term: 6 months to 17 months) At medium-term follow-up, semaglutide reduces percentage body weight (mean difference (MD) -10.73, 95% confidence interval (CI) -12.24 to -9.21; 15 studies, 8651 participants; high-certainty evidence) and increases the proportion of people achieving 5% weight loss (risk ratio (RR) 2.68, 95% CI 2.30 to 3.12; 12 studies, 7458 participants; high-certainty evidence). Semaglutide may increase non-serious adverse events (RR 1.11, 95% CI 1.01 to 1.22; 13 studies, 8443 participants; low-certainty evidence), likely results in little to no absolute difference in adverse events leading to withdrawal (RR 1.84, 95% CI 1.53 to 2.21; 15 studies, 9054 participants; moderate-certainty evidence), and has very uncertain effects on serious adverse events (RR 1.01, 95% CI 0.78 to 1.29; 15 studies, 9054 participants; very low-certainty evidence). Semaglutide likely results in little to no difference in quality of life (SF-36 physical functioning score: MD 2.12, 95% CI 0.95 to 3.28; 9 studies, 6083 participants; moderate-certainty evidence). Semaglutide may result in little to no absolute difference in MACE (RR 0.63, 95% CI 0.44 to 0.90; 9 studies, 7647 participants; low-certainty evidence) and mortality (RR 0.69, 95% CI 0.48 to 0.98; 14 studies, 8953 participants; low-certainty evidence). For most outcomes, the main reasons for downgrading certainty of evidence were related to imprecision and inconsistency. Semaglutide versus placebo (long term: 26 months) At long-term follow-up, semaglutide likely reduces percentage body weight (MD -11.11, 95% CI -16.47 to -5.75; I² = 94%; 2 studies, 15,124 participants; moderate-certainty evidence), and likely increases the proportion of people achieving 5% weight loss (RR 2.74, 95% CI 1.95 to 3.84; 2 studies, 17,876 participants; moderate-certainty evidence). Its effects on non-serious adverse events are very uncertain (RR 1.21, 95% CI 1.10 to 1.34; 1 study, 305 participants; very low-certainty evidence), with likely little to no difference in serious adverse events (RR 0.92, 95% CI 0.88 to 0.95; 2 studies, 17,908 participants; moderate-certainty evidence), and a likely increase in adverse events leading to withdrawal (RR 2.03, 95% CI 1.86 to 2.20; 2 studies, 17,908 participants; moderate-certainty evidence). Semaglutide likely results in little to no clinically significant differences in quality of life (EQ-5D-5L: MD 0.02, 95% CI 0.02 to 0.02; moderate-certainty evidence), MACE (RR 0.81, 95% CI 0.73 to 0.90; moderate-certainty evidence), and mortality (RR 0.82, 95% CI 0.72 to 0.94; moderate-certainty evidence). For most outcomes, the main reasons for downgrading certainty of evidence were related to risk of bias and imprecision. AUTHORS' CONCLUSIONS: Semaglutide results in a clinically relevant weight loss at medium-term follow-up compared to placebo, which is likely to be sustained in the long term, while taking the drug. While semaglutide increases the risk of adverse events leading to withdrawal, it appears to be of limited clinical relevance in absolute terms at medium-term, and clinically relevant at long-term follow-up. The effects of semaglutide on quality of life, MACE, and mortality are likely limited or uncertain. Most studies were funded by the drug's manufacturer, raising important concerns about conflicts of interest. We identified 46 ongoing studies that may strengthen future evidence syntheses. Further independent studies are needed, particularly in underrepresented populations, to better understand the broader effects of semaglutide in the management of obesity. FUNDING: This Cochrane review was funded by the World Health Organization (WHO). REGISTRATION: Original protocol (10.1002/14651858.CD015092) published in September 2022. The modifications to the original protocol were prospectively registered in PROSPERO (CRD420250654193) in February 2025.