Weight & Metabolic
What Side Effects Were Actually Reported in the Trials?
The short answer
Gastrointestinal events — nausea, vomiting, diarrhea, constipation — were consistently the most common adverse events across every major trial, and they drove treatment discontinuation in roughly 4-7% of participants in 68-72 week obesity trials, versus under 3% on placebo. In a 3-year cardiovascular trial with older, sicker participants, discontinuation for adverse events reached 16.6%. Serious adverse events, including pancreatitis and gallstones, were consistently reported as uncommon. Meta-analyses put the odds of nausea 3-6 times higher than placebo depending on dose.
Quick answers
- What is it?
- This summarizes the adverse events actually reported in the major semaglutide and tirzepatide clinical trials, primarily gastrointestinal symptoms and the rate at which they caused people to quit treatment.
- Why are people interested in it?
- People considering these drugs want a realistic picture of the side effects reported in trials, not just anecdotes.
- What has actually been studied?
- STEP 1 (1,961 participants), SURMOUNT-1 (2,539 participants) and its 3-year extension, the SELECT cardiovascular trial (17,604 participants, older and sicker population), and meta-analyses covering thousands more participants on both drugs.
- How strong is the evidence?
- Consistent across every major trial: gastrointestinal events were the most common adverse events on both drugs, driving 4-7% discontinuation in shorter obesity trials but 16.6% in the longer, older-population SELECT trial, with serious events like pancreatitis and gallstones consistently described as uncommon.
- What don't we know yet?
- What chronic, low-grade GI symptoms cost people day to day below the discontinuation threshold, whether real-world discontinuation rates match trial rates, why SELECT's discontinuation rate was so much higher, and long-term serious-event risk beyond the few years tracked so far.
- Where can I read the original research?
- Sources at the bottom of this page: Wilding JPH, Batterham RL, Calanna S, et al., New England Journal of Medicine, 2021 (STEP 1); and Jastreboff AM, Aronne LJ, Ahmad NN, et al., New England Journal of Medicine, 2022 (SURMOUNT-1).
The short answer: Every major trial retrieved for this article reported the same pattern: gastrointestinal events — nausea, vomiting, diarrhea, constipation — were the most common adverse events on both drugs, mostly mild-to-moderate and concentrated during dose escalation. In 68-72 week obesity trials, those events drove 4-7% of participants off treatment entirely, versus under 3% on placebo. In a 3-year cardiovascular outcomes trial enrolling an older, sicker population, discontinuation for adverse events reached 16.6%. Serious adverse events — pancreatitis, gallstones — were consistently reported as uncommon across every trial and meta-analysis reviewed here.
What the research shows
The discontinuation numbers, trial by trial
In STEP 1 — semaglutide 2.4 mg versus placebo in 1,961 adults with obesity, over 68 weeks — nausea and diarrhea were the most common adverse events, described as typically transient and mild-to-moderate, subsiding over time. Adverse events led to permanent discontinuation in 4.5% of the semaglutide group (59 of 1,306 participants) versus 0.8% of the placebo group (5 of 655).
In SURMOUNT-1 — tirzepatide versus placebo in 2,539 adults with obesity, over 72 weeks — the same gastrointestinal pattern held. Discontinuation for adverse events occurred in 4.3% of participants on the 5 mg dose, 7.1% on the 10 mg dose, 6.2% on the 15 mg dose, and 2.6% on placebo. A 3-year follow-up of the same trial's prediabetes subgroup (1,032 participants followed to 176 weeks) reported no new safety signals over the extended period, with GI events remaining the most common adverse events and continuing to cluster in the first 20 weeks of dose escalation.
The largest divergence appeared in SELECT, semaglutide's cardiovascular outcomes trial — 17,604 participants, average 45 years or older, all with preexisting cardiovascular disease, followed for a mean of 39.8 months on a mean drug exposure of 34.2 months. There, 16.6% of the semaglutide group (1,461 participants) discontinued treatment for adverse events, compared with 8.2% of the placebo group (718 participants) — both figures markedly higher than the shorter obesity trials. The difference likely reflects the combination of an older, cardiovascular-disease population and roughly three times the drug exposure of a typical 68-72 week obesity trial, rather than a different side-effect profile emerging.
What the meta-analyses add
Pooling trials sharpens the picture. A 2026 systematic review of subcutaneous semaglutide in nondiabetic adults with obesity (4 randomized trials, 3,613 participants) found gastrointestinal adverse events, nausea, vomiting, diarrhea, and constipation were all significantly more frequent with semaglutide than placebo, and that discontinuation due to adverse events was more than twice as likely (relative risk 2.62, 95% CI 1.70-4.03). Serious adverse events, including acute pancreatitis and gallstone disease (cholelithiasis), were described as uncommon.
For tirzepatide, a systematic review spanning 10 studies and 9,873 participants with obesity or type 2 diabetes found a significantly higher body-weight reduction than placebo, GLP-1 comparators, or insulin, alongside a higher incidence of adverse-event-driven discontinuation — but notably lower rates of serious adverse events and hypoglycemia than comparators. GI adverse events (diarrhea, nausea, vomiting, decreased appetite) were higher than placebo or insulin but similar in frequency to other GLP-1 drugs.
A more granular meta-analysis of 7 tirzepatide trials in type 2 diabetes (6,609 participants) quantified the dose relationship: at the 15 mg dose, the odds ratio for nausea versus placebo was 5.60 (95% CI 3.12-10.06), for vomiting 5.50 (95% CI 2.40-12.59), and for diarrhea 3.31 (95% CI 1.40-7.85). Odds of GI events were generally similar between tirzepatide and other GLP-1 drugs, except for diarrhea at the 10 mg dose specifically (odds ratio 1.51 versus GLP-1 comparators). The 15 mg dose carried a higher discontinuation rate regardless of what it was compared against, while serious adverse events and mortality were reported as similar across all doses and comparators.
What we don't know yet
What chronic, low-grade GI symptoms cost people day to day. Trials report the rate of nausea or diarrhea as an adverse event, but none of the sources reviewed here quantified the ongoing quality-of-life burden of persistent, sub-discontinuation-threshold GI symptoms over months or years of use.
Whether discontinuation rates in routine practice match trial rates. Every figure here comes from a controlled trial with structured dose titration, monitoring, and support. Real-world discontinuation for side effects, without that infrastructure, was not measured by any source in this review.
Why SELECT's discontinuation rate was so much higher. The 16.6% figure in SELECT dwarfs the 4-7% seen in shorter obesity trials. Whether that gap is fully explained by age, cardiovascular comorbidity, and longer exposure, or whether something else about that population changed tolerability, was not isolated by the trial.
Long-term serious-event risk beyond what's been tracked. Pancreatitis and gallstone disease appear consistently as the serious events worth naming, and consistently described as rare — but the trials retrieved here mostly ran 68 weeks to 3 years. Risk over a decade or more of continuous use has not been established by this evidence base.
Whether side-effect profiles differ meaningfully by starting body weight or comorbidity. None of the meta-analyses reviewed here broke down GI adverse event rates by baseline BMI, age, or comorbidity burden in a way that would let someone anticipate their own tolerability in advance.
Sources
- Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine, 2021;384(11):989-1002. DOI
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. New England Journal of Medicine, 2022;387(3):205-216. DOI
- Jastreboff AM, le Roux CW, Stefanski A, et al. Tirzepatide for Obesity Treatment and Diabetes Prevention. New England Journal of Medicine, 2024;392(10):958-971. DOI
- Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. New England Journal of Medicine, 2023;389(24):2221-2232. DOI
- Naz F, Qaiser F, Mumtaz A, Din SU, Mustafa A, Ullah A, Perveen A, Malik J. Effectiveness & safety of semaglutide in weight reduction in obese nondiabetic patients: A systematic review and meta-analysis. Medicine (Baltimore), 2026;105(31):e49986. DOI
- Lin F, Yu B, Ling B, Lv G, Shang H, Zhao X, Jie X, Chen J, Li Y. Weight loss efficiency and safety of tirzepatide: A Systematic review. PLOS ONE, 2023;18(5):e0285197. DOI
- Karagiannis T, Avgerinos I, Liakos A, Del Prato S, Matthews DR, Tsapas A, Bekiari E. Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis. Diabetologia, 2022;65(8):1251-1261. DOI
Article records maintained via PubMed. Peptide Proof reports what studies found. It does not provide medical advice, dosing guidance, or treatment recommendations.
Topic: Weight & Metabolism | Evidence Index: semaglutide · tirzepatide
Sources
- Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1)
- New England Journal of Medicine, 2021 · n=1961 · DOI
- Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1)
- New England Journal of Medicine, 2022 · n=2539 · DOI
- Tirzepatide for Obesity Treatment and Diabetes Prevention (SURMOUNT-1, 3-year extension)
- New England Journal of Medicine, 2024 · n=1032 · DOI
- Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT)
- New England Journal of Medicine, 2023 · n=17604 · DOI
- Effectiveness & safety of semaglutide in weight reduction in obese nondiabetic patients: A systematic review and meta-analysis
- Medicine (Baltimore), 2026 · n=3613 · DOI
- Weight loss efficiency and safety of tirzepatide: A Systematic review
- PLOS ONE, 2023 · n=9873 · DOI
- Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis
- Diabetologia, 2022 · n=6609 · DOI
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