Video brief · 2026-09-09
What Side Effects Were Actually Reported in the Trials?
Semaglutide and tirzepatide are prescription medications, FDA-approved for type 2 diabetes and for chronic weight management. Because they have been tested in some of the largest drug trials of the past decade, we actually have a clear picture of what side effects showed up, how often, and how many people stopped treatment because of them.
The pattern is the same in every major trial: gastrointestinal events. Nausea, vomiting, diarrhea and constipation were the most common adverse events, usually described as mild to moderate, and concentrated during the weeks when the dose was being stepped up.
The discontinuation numbers put that in perspective. In STEP 1, a 68-week trial of semaglutide in 1,961 adults with obesity, 4.5% of the semaglutide group stopped permanently because of adverse events versus 0.8% on placebo. In SURMOUNT-1, a 72-week trial of tirzepatide in 2,539 adults, discontinuation for adverse events ran from 4.3% to 7.1% depending on dose, against 2.6% on placebo. In SELECT, a three-year cardiovascular trial in 17,604 older adults with existing heart disease, 16.6% of the semaglutide group discontinued for adverse events versus 8.2% on placebo. That higher figure likely reflects an older, sicker group and roughly three times the drug exposure, not a new side-effect profile.
Meta-analyses sharpen the picture. A 2022 pooled analysis of seven tirzepatide trials in Diabetologia found the odds of nausea at the highest dose were about five and a half times those on placebo. Serious events, including pancreatitis and gallstones, were consistently reported as uncommon across every trial and review.
The limits: none of these sources measured the day-to-day burden of persistent low-grade symptoms, and real-world discontinuation outside a monitored trial has not been captured here. Risk over a decade of use is also beyond what these trials ran. Decisions about these medications belong with a physician.
Sources
- Wilding JPH et al., STEP 1: Once-Weekly Semaglutide in Adults with Overweight or Obesity
- New England Journal of Medicine 2021
- Jastreboff AM et al., SURMOUNT-1: Tirzepatide Once Weekly for the Treatment of Obesity
- New England Journal of Medicine 2022
- Lincoff AM et al., SELECT: Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes
- New England Journal of Medicine 2023
- Karagiannis T et al., tirzepatide systematic review and meta-analysis in type 2 diabetes
- Diabetologia 2022
Peptide Proof reports what studies found. We do not give medical advice, dosing guidance, or treatment recommendations.