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

🥉 Top 5% JournalNov 25, 2025BMC medicine

Side effects of semaglutide in patients at higher risk of heart problems: a combined analysis of clinical trials

AI simplified

GLP-1 Therapies on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

A total of 54,972 participants were analyzed, revealing that semaglutide may reduce all-cause mortality and myocardial infarction risk.

Semaglutide is associated with a reduced risk of all-cause mortality (relative risk 0.85; 95% CI 0.79 to 0.91).
Participants receiving semaglutide may experience a lower risk of myocardial infarction (relative risk 0.77; 95% CI 0.69 to 0.85).
The use of semaglutide is linked to a decrease in (relative risk 0.93; 95% CI 0.88 to 0.98).
However, semaglutide is associated with an increased risk of non-serious gastrointestinal adverse events, including nausea (relative risk 3.00; 95% CI 2.63 to 3.42), vomiting (relative risk 4.12; 95% CI 3.47 to 4.90), and diarrhea (relative risk 1.88; 95% CI 1.68 to 2.11).

AI 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

We can’t show the full text here under this license. Use the link below to read it at the source.

View full text (PDF) ↗View full text (HTML) ↗View full text (PDF) ↗

Abstract

Key numbers

Full Text

Related papers