The adverse effects associated with semaglutide use in patients at increased risk of cardiovascular events: a systematic review with meta-analysis and Trial Sequential Analysis

Abstract

Background: Semaglutide's disease-specific weight-reducing effects are well established, but its adverse effects, which may not be disease-specific, have not been systematically assessed. The aim of this review was to assess the adverse effects associated with semaglutide use compared with placebo in patients at increased risk of cardiovascular events.

Methods: We searched six electronic databases and other sources from inception to 31/03/2025. Randomized trials comparing semaglutide (oral or subcutaneous) with placebo in patients at increased risk of cardiovascular events were eligible. The search identified 8370 records. Two review authors independently screened all studies for eligibility. Data were synthesized using meta-analysis and Trial Sequential Analysis (TSA). Risk of bias was assessed with the Cochrane Risk of Bias tool - version 2; our eight-step procedure was used to assess if the thresholds for statistical significance were crossed, and the certainty of the evidence was assessed by the Grading of Recommendations, Assessment, Development and Evaluations. Primary outcomes were all-cause mortality and serious adverse events (SAEs). Secondary outcomes included myocardial infarction and non-serious adverse events (AEs).

Results: The analysis included 50 trials, with a total of 54,972 participants randomized. Nineteen (38%) enrolled participants with type 2 diabetes (T2DM), 17 (34%) with overweight, 5 (10%) with T2DM and chronic kidney disease, 5 (10%) with T2DM and overweight, and 4 (8%) involved other patient populations. Meta-analysis and TSA showed evidence of beneficial effects of semaglutide on all-cause mortality (relative risk (RR) 0.85; 95% CI 0.79 to 0.91; I² = 0.0%; p < 0.01) and myocardial infarction (RR 0.77, 95% CI 0.69 to 0.85; I² = 0.0%; p < 0.01). None of these analyses showed signs of heterogeneity, and the evidence was of high certainty. Meta-analysis showed that semaglutide decreased the risk of SAEs (RR 0.93, 95% CI 0.88 to 0.98; I² = 24.1%; p < 0.01), but increased the risk of several non-serious gastrointestinal AEs including nausea (RR 3.00, 95% CI 2.63 to 3.42), vomiting (RR 4.12, 95% CI 3.47 to 4.90), and diarrhea (RR 1.88, 95% CI 1.68 to 2.11).

Conclusions: In patients at increased risk of cardiovascular events, semaglutide reduced the risk of mortality, SAEs, and myocardial infarction but increased the risk of several non-serious gastrointestinal AEs.

Registration: PROSPERO, CRD42024499511.

Keywords: Meta-analysis; Placebo; Safety; Semaglutide; Systematic review; Trial sequential analysis.

Fig. 1

Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flow diagram of the study selection process. A total of 50 trials were included in this review. In addition, 96 ongoing studies, five cross-over trials without results before cross-over, and one withdrawal trial were identified, but not included

Fig. 2

Fixed-effect meta-analysis of the relative risk of all-cause mortality with semaglutide versus placebo. I² is a statistical value for assessing heterogeneity. A value of I² = 0% indicates no heterogeneity

Fig. 3

Random-effects meta-analysis of the relative risk of serious adverse events with semaglutide versus placebo. I² is a statistical value for assessing heterogeneity. A value of I² = 24.1% indicates moderate heterogeneity. T2DM, type 2 diabetes mellitus