Zepbound Side Effects: Incidence Rates Across Clinical Trials
At a glance
- Most common reaction / nausea, 25% to 29% on Zepbound vs 8% on placebo [1]
- Diarrhea / 19%, 21% and 23% on 5, 10 and 15 mg vs 8% [1]
- Any GI adverse reaction / 56% at every dose vs 30% [1]
- Stopped for an adverse reaction / 4.8% (5 mg), 6.3% (10 mg), 6.7% (15 mg) vs 3.4% [1]
- Severe GI reactions / 1.7%, 2.5% and 3.1% vs 1% [1]
- Hair loss / 5%, 4% and 5% vs 1%; 7.1% of women vs 0.5% of men [1]
- Boxed warning / thyroid C-cell tumors in rats; human relevance not determined [1]
What the incidence numbers cover
Zepbound is a once-weekly subcutaneous dual GIP and GLP-1 receptor agonist. It is FDA-approved for long-term weight reduction in eligible adults and for moderate-to-severe obstructive sleep apnea in adults with obesity [1].
The percentages most often quoted for Zepbound come from one place: the adverse reactions table in the current prescribing information, which pools two randomized, double-blind, placebo-controlled trials, Study 1 (SURMOUNT-1) and Study 2 (SURMOUNT-2) [1]. In that pool, 2,519 adults received Zepbound for up to 72 weeks and 958 received placebo; mean age was 47 years, average baseline BMI was 37.4, and 25% had type 2 diabetes [1].
The label states that adverse reaction rates from clinical trials cannot be directly compared across trials because trial conditions vary [1]. The table has no column for the 2.5 mg starting dose, which the label describes as an initiation dose that is not a maintenance dose [1].
Gastrointestinal side effects by dose
| Adverse reaction | Placebo (n=958) | 5 mg (n=630) | 10 mg (n=948) | 15 mg (n=941) |
|---|---|---|---|---|
| Nausea | 8% | 25% | 29% | 28% |
| Diarrhea | 8% | 19% | 21% | 23% |
| Vomiting | 2% | 8% | 11% | 13% |
| Constipation | 5% | 17% | 14% | 11% |
| Abdominal pain | 5% | 9% | 9% | 10% |
| Dyspepsia | 4% | 9% | 9% | 10% |
| Injection site reactions | 2% | 6% | 8% | 8% |
| Fatigue | 3% | 5% | 6% | 7% |
| Hypersensitivity reactions | 3% | 5% | 5% | 5% |
| Eructation | 1% | 4% | 5% | 5% |
| Hair loss | 1% | 5% | 4% | 5% |
| GERD | 2% | 4% | 4% | 5% |
| Dizziness | 2% | 4% | 5% | 4% |
| Hypotension | 0% | 1% | 1% | 2% |
All values are from the Zepbound label's Table 1 [1].
Nausea is the most common single reaction at every dose, but the dose relationship is not a straight line: 10 mg (29%) sits slightly above 15 mg (28%) [1]. Constipation runs the other way, highest at 5 mg (17%) and lowest at 15 mg (11%), while diarrhea and vomiting climb with dose [1]. The label lists nausea, diarrhea, vomiting, constipation, abdominal pain, dyspepsia, injection site reactions, fatigue, hypersensitivity reactions, eructation, hair loss and GERD among reactions reported in at least 5% of patients [1].
How often do people stop Zepbound because of side effects?
In the same pooled trials, 4.8% of patients on 5 mg, 6.3% on 10 mg and 6.7% on 15 mg permanently discontinued treatment because of an adverse reaction, compared with 3.4% on placebo [1]. Discontinuation for gastrointestinal reactions specifically was 1.9%, 3.3% and 4.3% versus 0.5% [1]. Most of those who stopped did so in the first few months, for gastrointestinal reasons [1].
Severe gastrointestinal reactions were reported in 1.7% of patients on 5 mg, 2.5% on 10 mg and 3.1% on 15 mg, versus 1% on placebo [1]. The label does not recommend Zepbound in patients with severe gastroparesis [1].
Do the later SURMOUNT trials change the picture?
The later trials largely reproduce the same profile. SURMOUNT-3 randomized 579 adults who had already lost at least 5% of body weight during a 12-week intensive lifestyle program; the most common adverse events were gastrointestinal and most were mild to moderate [2]. Of the 287 patients treated with Zepbound for up to 72 weeks in the label's accounting of that trial, 10% discontinued for adverse reactions versus 2% on placebo [1].
SURMOUNT-4 enrolled 783 adults in a 36-week open-label tirzepatide lead-in, and 335 of them continued treatment for up to 88 weeks; 7% discontinued before the week-36 randomization because of adverse reactions [1]. The label notes that adverse reactions in both trials were similar to those in the pooled weight-management trials [1].
Gallbladder and pancreatic events
The pooled weight trials also reported gallbladder events: cholelithiasis in 1.1% of Zepbound-treated patients versus 1% on placebo, cholecystitis in 0.7% versus 0.2%, and cholecystectomy in 0.2% versus none [1]. The label states that acute gallbladder events were associated with weight reduction [1].
Adjudication-confirmed acute pancreatitis occurred in 0.2% of Zepbound-treated patients and 0.2% of placebo patients in the weight trials, or 0.14 versus 0.15 patients per 100 years of exposure [1]. In the two obstructive sleep apnea trials, the exposure-adjusted rate was 0.84 patients per 100 years on Zepbound and 0 on placebo [1]. The label says to discontinue Zepbound if pancreatitis is suspected [1].
Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported after marketing; 0.1% of Zepbound-treated patients in the weight trials had a severe hypersensitivity reaction compared with none on placebo [1].
Hair loss
Hair loss was reported in 5% of patients on 5 mg, 4% on 10 mg and 5% on 15 mg versus 1% on placebo [1]. The label describes it as associated with weight reduction and more frequent in women: 7.1% of women versus 0.5% of men on Zepbound, and 1.3% of women versus 0% of men on placebo [1]. No Zepbound-treated patient discontinued for hair loss; one placebo-treated patient did [1].
Heart rate, blood pressure and laboratory changes
Heart rate rose by a mean of 1 to 3 beats per minute [1]. Hypotension was reported in 1.6% of Zepbound-treated patients versus 0.1% on placebo, and was more frequent in patients taking antihypertensive medication (2.2% versus 1.2%) [1]. Mean amylase rose 20% to 25% and lipase 28% to 35%, with the label stating that the clinical significance is unknown in the absence of signs of pancreatitis [1]. Anti-tirzepatide antibodies were detected in 64.5% of Zepbound-treated patients in the weight trials, with no clinically significant effect on pharmacokinetics or effectiveness found [1].
The boxed warning
Zepbound carries a boxed warning for thyroid C-cell tumors. In rats, tirzepatide caused dose- and duration-dependent thyroid C-cell tumors at clinically relevant exposures, and the label states that it is unknown whether Zepbound causes these tumors, including medullary thyroid carcinoma, in humans [1]. Zepbound is contraindicated in patients with a personal or family history of MTC or Multiple Endocrine Neoplasia syndrome type 2 [1]. The label also states that routine serum calcitonin monitoring or thyroid ultrasound is of uncertain value for early detection [1].
What post-market reports can and cannot tell you
FDA's adverse event reporting system holds reports for tirzepatide, but the agency states that the data cannot be used to estimate how often an event occurs and that the existence of a report does not establish that the drug caused it [4]. The percentages above come from controlled trials of the FDA-approved product. FDA states that compounded tirzepatide is not FDA approved and is not reviewed for safety, effectiveness or quality before marketing [5].
Frequently asked questions
How common is nausea with Zepbound?
What percentage of people stop Zepbound because of side effects?
Does Zepbound cause pancreatitis?
Does Zepbound cause gallstones?
Is low blood sugar a risk with Zepbound?
Does Zepbound cause hair loss?
References
- U.S. National Library of Medicine, DailyMed. Zepbound injection (tirzepatide) prescribing information. Zepbound injection (tirzepatide) label
- Wadden TA, Chao AM, Machineni S, Kushner R, Ard J, Srivastava G, et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial. Nat Med. 2023;29(11):2909-2918. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial
- Look M, Dunn JP, Kushner RF, Cao D, Harris C, Gibble TH, et al. Body composition changes during weight reduction with tirzepatide in the SURMOUNT-1 study of adults with obesity or overweight. Diabetes Obes Metab. 2025;27(5):2720-2729. Body composition changes during weight reduction with tirzepatide in the SURMOUNT-1 study of adults with obesity or overweight
- FDA Adverse Event Monitoring System (AEMS) Public Dashboard | FDA. FDA Adverse Event Monitoring System (AEMS) Public Dashboard | FDA
- FDA’s Concerns with Unapproved GLP-1 Drugs Used for Weight Loss | FDA. FDA’s Concerns with Unapproved GLP-1 Drugs Used for Weight Loss | FDA