In patients at increased cardiovascular risk, semaglutide was associated with lower mortality, , and myocardial infarction but more gastrointestinal side effects.
Evidence
A systematic review and meta-analysis with trial sequential analysis of 50 randomized placebo-controlled trials including 54,972 participants found reduced all-cause mortality (RR 0.85), myocardial infarction (RR 0.77), and serious adverse events (RR 0.93), alongside higher nausea (RR 3.00), vomiting (RR 4.12), and diarrhea (RR 1.88).
Caveat
Because this was a review across mixed high-cardiovascular-risk populations and placebo-controlled trials, the results describe pooled semaglutide effects rather than adverse-effect rates for any single disease group or head-to-head comparator.
Simplified
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 (SAEs). Secondary outcomes included myocardial infarction and (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; I = 0.0%; p < 0.01) and myocardial infarction (RR 0.77, 95% CI 0.69 to 0.85; I = 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; I = 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). 2 2 2
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.
Key numbers
0.85
Reduction in All-Cause Mortality
of all-cause mortality with semaglutide vs. placebo.
3.00
Increased Risk of Nausea
of nausea with semaglutide vs. placebo.
4.12
Increased Risk of Vomiting
of vomiting with semaglutide vs. placebo.
Full Text
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Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: CDBS’s husband has previously been employed at Novo Nordisk, Kalundborg, as ‘facility manager’ and ‘sprinkler technician’ (employed from September 1, 2024, to August 31, 2025). PG has received lecture fees for Novo Nordisk, AstraZeneca, Eli Lilly, Bayer, and MSD and has served in Advisory Boards for Novo Nordisk, AstraZeneca, and Bayer. The remaining authors declare no known competing interests.
