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Background <p>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.</p> Methods <p>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).</p> Results <p>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.</p> <p>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>I</i><sup>2</sup> = 0.0%; <i>p</i> &lt; 0.01) and myocardial infarction (RR 0.77, 95% CI 0.69 to 0.85; <i>I</i><sup>2</sup> = 0.0%; <i>p</i> &lt; 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>I</i><sup>2</sup> = 24.1%; <i>p</i> &lt; 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).</p> Conclusions <p>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.</p> Registration <p>PROSPERO, CRD42024499511.</p>

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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

  • 期刊论文

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  • 发表日期：

    2025年11月24日

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  • Christina Dam Bjerregaard Sillassen,
  • Johanne Juul Petersen,
  • Pascal Faltermeier,
  • Delal Yucel,
  • Faiza Siddiqui,
  • Rebecca Kjær Andersen,
  • Leonardo Graever,
  • Jonas Leth Bjerg,
  • Caroline Barkholt Kamp,
  • Johannes Grand,
  • Helena Dominguez,
  • Anne Frølich,
  • Peter Gæde,
  • Christian Gluud,
  • Ole Mathiesen,
  • Janus Christian Jakobsen

摘要

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.