Side Effects in the Big GLP-1 Trials: The Numbers Behind Nausea, Diarrhea and More
Most of the attention on GLP-1 medications goes to the weight-loss numbers. The side effects deserve the same attention. This guide goes through what participants in the two best-known trials actually reported, and what the FDA’s prescribing information warns about. It is general education, not medical advice, and it does not suggest any product, dose or provider.
The most common problem: the stomach
In the STEP 1 trial of semaglutide for weight management, published in the New England Journal of Medicine in 2021, gastrointestinal side effects were reported by 74.2% of people taking semaglutide, compared with 47.9% of people taking a placebo. Most were described as mild to moderate and temporary. They were still a real reason to stop: about 7.0% of the semaglutide group left the treatment because of side effects, versus 3.1% on placebo.
Notice the placebo number. Nearly half of the placebo group also reported a stomach complaint, which is a reminder that trial participants notice and report all kinds of symptoms.
The tirzepatide trial in numbers
The SURMOUNT-1 trial of tirzepatide showed a similar pattern. Across the three tirzepatide groups, the share of participants reporting each symptom was:
| Side effect | Tirzepatide groups | Placebo |
|---|---|---|
| Nausea | about 25% to 33% | 9.5% |
| Diarrhea | about 19% to 23% | 7.3% |
| Constipation | about 12% to 17% | 5.8% |
| Vomiting | about 8% to 12% | 1.7% |
Between 4.3% and 7.1% of people in the tirzepatide groups stopped because of side effects, compared with 2.6% on placebo. In both trials, symptoms were most common while the dose was being increased, which is one reason prescribers raise it gradually.
What the FDA label warns about
The prescribing information for semaglutide for weight management goes beyond stomach upset. Its warnings include:
- Thyroid C-cell tumors. Seen in rodent studies. People with a personal or family history of medullary thyroid carcinoma, or a condition called MEN 2, should not use the medication.
- Pancreatitis. Inflammation of the pancreas has been reported. Severe, persistent belly pain, sometimes spreading to the back, is a reason to get medical help.
- Gallbladder problems. Gallstones and gallbladder inflammation occurred more often with treatment.
- Kidney injury. Often linked to dehydration from vomiting or diarrhea.
- Allergic reactions. Serious reactions are possible.
The label lists headache, fatigue, dizziness, indigestion, gas and bloating among the other common side effects, and low blood sugar in people who also have type 2 diabetes. Rapid weight loss itself can also increase the chance of gallstones.
What this means in practice
- Tell your prescriber what you feel. Side effects can often be managed, and they are the reason many people never reach their goal dose or stop altogether.
- Do not ignore dehydration. Vomiting or diarrhea that lasts, dizziness or very little urine are reasons to call a clinician.
- Know the urgent signs. Severe belly pain, a swollen neck or trouble swallowing, an allergic reaction, or yellowing skin or eyes need prompt care.
- Eating when appetite is low is its own skill. Our guide to building a balanced plate and the article on muscle loss on GLP-1 medications cover two common concerns.
Trials also exclude many people, and real-world experience can differ. If you are comparing sources, our explainer on approved versus compounded medications covers an important safety question, and what happens when you stop covers another.
The takeaway
GLP-1 medications can work, and they also cause side effects in a large share of people, mostly digestive. A medicine’s benefits and risks belong in a conversation with a licensed clinician who knows your history.
Sources
- Wilding JPH, et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). New England Journal of Medicine, 2021.
- Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). New England Journal of Medicine, 2022. Percentages as summarized in published trial reports and Eli Lilly’s results release.
- U.S. Food and Drug Administration, prescribing information for semaglutide for chronic weight management (warnings and precautions; adverse reactions), accessdata.fda.gov.
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