Long-Term Semaglutide Safety in the SELECT Heart Trial: Fewer Serious Events, More GI Side Effects
In the landmark SELECT trial, semaglutide 2.4 mg reduced serious adverse events compared to placebo (33.4% vs 36.4%), though more patients stopped due to GI side effects, and no suicide risk was found.
Quick Facts
What This Study Found
In the massive SELECT cardiovascular outcomes trial, semaglutide 2.4 mg weekly was actually safer overall than placebo for serious adverse events: 33.4% of semaglutide patients had SAEs versus 36.4% on placebo (p<0.001), driven largely by fewer cardiac events (11.5% vs 13.5%).
However, more patients stopped semaglutide due to side effects (16.6% vs 8.2%), with gastrointestinal problems being the main reason (10.0% vs 2.0%). Gallbladder disorders were slightly more common with semaglutide (2.8% vs 2.3%, p=0.04), mainly gallstones rather than inflammation. Crucially, suicide and self-injury rates were identical and very low in both groups (0.11%). No new safety concerns were identified.
Key Numbers
SAEs: 33.4% semaglutide vs 36.4% placebo (p<0.001) · cardiac SAEs: 11.5% vs 13.5% · discontinuation: 16.6% vs 8.2% · GI discontinuation: 10.0% vs 2.0% · gallbladder: 2.8% vs 2.3% · suicide/self-injury: 0.11% both groups
How They Did This
Pre-specified safety analysis from the SELECT randomized controlled trial. Patients with established cardiovascular disease and overweight/obesity received semaglutide 2.4 mg or placebo once weekly. Researchers analyzed serious adverse events, all adverse events leading to treatment discontinuation, and prespecified adverse events of special interest. Two-sided p-values were used for treatment comparisons.
Why This Research Matters
SELECT is the largest and longest cardiovascular outcomes trial of semaglutide in people with obesity. This safety analysis provides the most definitive long-term safety data available — critically important given that tens of millions of people are now taking this drug. The finding that semaglutide actually reduced serious adverse events compared to placebo is reassuring, and the suicide/self-injury data directly addresses a widely publicized safety concern.
The Bigger Picture
This SELECT safety analysis essentially provides a clean bill of health for long-term semaglutide use at the obesity dose. The finding that serious events were lower — not higher — with semaglutide challenges the narrative that GLP-1 drugs are dangerous. The suicide data is particularly important: European and FDA regulators had investigated this signal, and these large-scale data show no signal whatsoever. This shifts the risk-benefit conversation firmly in semaglutide's favor for cardiovascular patients with obesity.
What This Study Doesn't Tell Us
The study population had established cardiovascular disease — results may not generalize to healthier obesity patients. The mean treatment duration is not specified in the abstract. Patients who discontinued due to GI side effects may have self-selected out early, potentially underestimating long-term GI burden. Industry-sponsored (Novo Nordisk).
Questions This Raises
- ?Can the GI discontinuation rate be reduced with slower dose titration or combination antiemetic strategies?
- ?Does the gallstone risk increase with longer treatment duration or greater weight loss?
- ?Will similarly reassuring safety profiles emerge from ongoing trials of tirzepatide and other GLP-1 drugs?
Trust & Context
- Key Stat:
- 33.4% vs 36.4% serious adverse events Semaglutide patients had significantly fewer serious adverse events than placebo patients (p<0.001), driven by fewer cardiac events — 11.5% vs 13.5%
- Evidence Grade:
- This is a pre-specified safety analysis from a large, multicenter, double-blind, placebo-controlled randomized trial — the gold standard for drug safety evaluation. The SELECT trial is one of the most important obesity drug trials ever conducted. Evidence strength is rated strong.
- Study Age:
- Published in 2025. This is the most current comprehensive safety analysis from the SELECT trial. The findings represent the definitive long-term safety data for semaglutide 2.4 mg in cardiovascular patients with obesity.
- Original Title:
- Safety profile of semaglutide versus placebo in the SELECT study: a randomized controlled trial.
- Published In:
- Obesity (Silver Spring, Md.), 33(3), 452-462 (2025)
- Authors:
- Kushner, Robert F(4), Ryan, Donna H(2), Deanfield, John(5), Kokkinos, Alexander, Cercato, Cintia, Wilding, John, Burguera, Bartolome, Wu, Chau-Chung, Craciun, Anca-Elena, Pall, Denes, Hramiak, Irene, Hjelmesæth, Jøran, Harder-Lauridsen, Nina M, Weimers, Petra, Jeppesen, Ole Kleist, Kallenbach, Klaus, Lincoff, A Michael, Lingvay, Ildiko
- Database ID:
- RPEP-11973
Evidence Hierarchy
Frequently Asked Questions
Does semaglutide cause suicidal thoughts?
No. In this large trial, suicide and self-injury rates were identical in semaglutide and placebo groups — just 0.11% in both. Despite media reports raising this concern, the largest controlled study to date found no signal whatsoever.
Why do so many people stop taking semaglutide?
About 16.6% of patients stopped semaglutide (vs 8.2% on placebo), and the main reason was gastrointestinal side effects like nausea and vomiting — affecting 10% of the semaglutide group vs 2% on placebo. However, most of these were not serious enough to be classified as serious adverse events.
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Cite This Study
https://rethinkpeptides.com/research/RPEP-11973APA
Kushner, Robert F; Ryan, Donna H; Deanfield, John; Kokkinos, Alexander; Cercato, Cintia; Wilding, John; Burguera, Bartolome; Wu, Chau-Chung; Craciun, Anca-Elena; Pall, Denes; Hramiak, Irene; Hjelmesæth, Jøran; Harder-Lauridsen, Nina M; Weimers, Petra; Jeppesen, Ole Kleist; Kallenbach, Klaus; Lincoff, A Michael; Lingvay, Ildiko. (2025). Safety profile of semaglutide versus placebo in the SELECT study: a randomized controlled trial.. Obesity (Silver Spring, Md.), 33(3), 452-462. https://doi.org/10.1002/oby.24222
MLA
Kushner, Robert F, et al. "Safety profile of semaglutide versus placebo in the SELECT study: a randomized controlled trial.." Obesity (Silver Spring, 2025. https://doi.org/10.1002/oby.24222
RethinkPeptides
RethinkPeptides Research Database. "Safety profile of semaglutide versus placebo in the SELECT s..." RPEP-11973. Retrieved from https://rethinkpeptides.com/research/kushner-2025-safety-profile-of-semaglutide
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Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.