Zepbound Side Effects: Complete List of What Trials Show
In the label's main safety pool of 2,519 adults, digestive problems dominate: 56% had a GI reaction on each Zepbound dose versus 30% on placebo, and 4.8% to 6.7% stopped treatment over side effects. The boxed warning covers thyroid C-cell tumors seen in rats, not proven in humans.
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Zepbound (tirzepatide, made by Eli Lilly) most often causes digestive side effects: nausea, diarrhea, vomiting, and constipation [1]. In the label’s main safety pool of 2,519 adults across two placebo-controlled trials lasting up to 72 weeks, 56% of patients on each Zepbound dose (5, 10, or 15 mg) had a gastrointestinal adverse reaction, compared with 30% on placebo [1]. Most of these reactions happened during dose escalation and decreased over time [1].
Beyond digestion, the label lists reactions such as fatigue, hair loss, injection site reactions, and hypersensitivity, plus warnings for pancreatitis, gallbladder disease, kidney injury from dehydration, low blood sugar, and a boxed warning about thyroid C-cell tumors seen in rats [1]. Between 4.8% (5 mg) and 6.7% (15 mg) of patients permanently stopped Zepbound because of adverse reactions, versus 3.4% on placebo, and most quit within the first few months due to digestive problems [1].
Where do the side effect numbers come from?
The frequency numbers come from the prescribing label’s safety pool: Studies 1 and 2, two placebo-controlled trials in 2,519 adults treated with Zepbound for up to 72 weeks [1]. The pool’s average patient was 47 years old, 37% were male, and 25% had type 2 diabetes [1].
The label cautions that these trial rates are not directly comparable to rates in other drugs’ trials, because trials differ in design and patient populations, and the rates may differ in everyday practice [1].
How common is each Zepbound side effect by dose?
The label’s Table 1 lists adverse reactions that occurred in at least 2% of Zepbound-treated patients and more often than with placebo [1].
| Adverse reaction | Placebo | 5 mg | 10 mg | 15 mg |
|---|---|---|---|---|
| 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 (burping) | 1% | 4% | 5% | 5% |
| Hair loss | 1% | 5% | 4% | 5% |
| GERD | 2% | 4% | 4% | 5% |
| Flatulence | 2% | 3% | 3% | 4% |
| Abdominal distension | 2% | 3% | 3% | 4% |
| Dizziness | 2% | 4% | 5% | 4% |
| Hypotension | 0% | 1% | 1% | 2% |
All figures are from the label [1]. Some rows group related terms: injection site reactions include bruising, erythema, itching, pain, and rash at the injection site; fatigue includes asthenia, lethargy, and malaise [1].
How long do the digestive side effects last?
The label states that the majority of nausea, vomiting, and diarrhea events occurred during dose escalation and decreased over time [1]. The dose escalation schedule in the label is intended to reduce the risk of gastrointestinal adverse reactions [1].
Constipation followed a different pattern from the other digestive effects: it was highest at 5 mg (17%) and lowest at 15 mg (11%) [1].
In SURMOUNT-5, a 72-week trial of 751 adults comparing tirzepatide with semaglutide, gastrointestinal events were the most common adverse events in both treatment groups, were mostly mild to moderate in severity, and occurred primarily during dose escalation [3].
How many people stop Zepbound because of side effects?
Permanent discontinuation due to adverse reactions occurred in 4.8% of patients on 5 mg, 6.3% on 10 mg, and 6.7% on 15 mg, versus 3.4% on placebo [1]. Discontinuation specifically for gastrointestinal reactions occurred in 1.9% (5 mg), 3.3% (10 mg), and 4.3% (15 mg), versus 0.5% on placebo [1].
The label notes that most patients who stopped did so during the first few months of treatment, and the reason was usually a gastrointestinal reaction [1].
Two other trials showed similar patterns. In Study 3, which included a lifestyle lead-in period and treated 287 patients with Zepbound, 10% stopped due to adverse reactions versus 2% on placebo. In Study 4, 7% stopped before week 36 [1].
What less common side effects appeared in trials?
Hypotension occurred in 1.6% of Zepbound patients versus 0.1% on placebo [1]. It was more frequent in patients also taking blood pressure medication (2.2%) than in those not on it (1.2%), and it also occurred in connection with gastrointestinal events and dehydration [1].
Heart rate rose by a mean of 1 to 3 beats per minute with Zepbound, with no increase on placebo [1]. Dry mouth or dry throat was reported by 1% versus 0.1% on placebo; dysgeusia (altered taste) by 0.4% versus 0%; and dysesthesia by 0.2% to 0.4% versus 0.1% [1].
Hypersensitivity reactions split into two types: immediate reactions (within one day of dosing) in 2.1% versus 0.4% on placebo, and non-immediate reactions in 3.5% versus 2.7% [1]. Most were skin reactions such as rash and itching [1].
What should women taking Zepbound know about hair loss, birth control, and pregnancy?
Hair loss was reported much more often in women: 7.1% of women on Zepbound versus 0.5% of men, compared with 1.3% of women and 0% of men on placebo [1]. The label states that hair loss was associated with weight reduction, and no Zepbound-treated patient stopped the study because of it [1].
For women using oral contraceptives, the label advises switching to a non-oral method or adding a barrier method for 4 weeks after starting Zepbound and for 4 weeks after each dose increase, because delayed stomach emptying may reduce their efficacy [1]. In a study of a single 5 mg dose, ethinyl estradiol peak concentration fell 59% and norgestimate fell 66%, with overall exposure (AUC) reduced by about 20% [1].
The label states that Zepbound may cause fetal harm, advises stopping when pregnancy is recognized, and notes that a pregnancy exposure registry exists for monitoring outcomes [1].
What does the boxed warning about thyroid tumors say?
Zepbound’s boxed warning is based on a 2-year rat study in which tirzepatide caused thyroid C-cell adenomas and carcinomas that depended on dose and treatment duration, at exposures considered clinically relevant [1].
The label states that the human relevance of these rodent tumors has not been determined, and it is unknown whether Zepbound causes medullary thyroid carcinoma (MTC) in humans [1]. The warning names symptoms to watch for: a mass in the neck, trouble swallowing, trouble breathing, and persistent hoarseness [1]. It also states that routine monitoring of serum calcitonin or thyroid ultrasound is of uncertain value for early MTC detection [1].
In the SURMOUNT-OSA trials, no cases of medullary thyroid cancer were reported [4].
How serious can digestive reactions and kidney injury get?
Severe gastrointestinal adverse 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, with similar rates in the obstructive sleep apnea trials [1]. The label states that Zepbound is not recommended in patients with severe gastroparesis; that section was revised in February 2026 [1].
Acute kidney injury occurred in 0.5% of Zepbound patients versus 0.2% on placebo [1]. Postmarketing reports describe acute kidney injury, sometimes requiring hemodialysis, with most cases following nausea, vomiting, or diarrhea that caused dehydration [1]. The label instructs clinicians to monitor kidney function in patients reporting reactions that could lead to volume depletion, especially during treatment start and dose escalation [1].
What about gallbladder problems and pancreatitis?
Gallstones occurred in 1.1% of Zepbound patients versus 1% on placebo, cholecystitis in 0.7% versus 0.2%, and gallbladder removal in 0.2% versus 0% [1]. The label states that acute gallbladder events were associated with weight reduction [1].
Adjudicated acute pancreatitis in the weight trials occurred in 0.2% of Zepbound patients versus 0.2% on placebo (0.14 versus 0.15 patients per 100 patient-years) [1]. In the OSA trials, the rate was 0.84 per 100 patient-years with Zepbound versus 0 on placebo, with two adjudicated cases, both in the tirzepatide group of trial 2 [1][4].
The pancreatitis warning covers fatal and non-fatal hemorrhagic or necrotizing pancreatitis [1]. The label lists the signs to watch for: persistent or severe abdominal pain, sometimes radiating to the back, with or without nausea or vomiting [1].
What about allergic reactions and low blood sugar?
Severe hypersensitivity reactions occurred in 0.1% of Zepbound patients versus 0% on placebo, and postmarketing reports include anaphylaxis and angioedema [1]. The label advises caution in patients with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist, because it is unknown whether they are predisposed to these reactions with Zepbound [1].
In Study 2, which enrolled patients with type 2 diabetes, blood glucose under 54 mg/dL occurred in 4.2% of Zepbound patients versus 1.3% on placebo [1]. Among Zepbound patients also taking a sulfonylurea, the rate was 10.3%, versus 2.1% without one; the label also identifies insulin as raising hypoglycemia risk [1]. Hypoglycemia has also been reported in adults without type 2 diabetes [1].
What warnings cover the eyes, anesthesia, and the KwikPen?
The label’s diabetic retinopathy warning concerns patients with type 2 diabetes. It reports temporary worsening of diabetic retinopathy with rapid improvement in glucose control and advises monitoring patients with a history of retinopathy for progression; that section was revised in August 2026 [1][2].
On anesthesia, the label describes rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists who had residual stomach contents despite following fasting instructions before elective procedures [1]. The label instructs patients to tell their healthcare providers about any planned surgery or procedure, and states that available data are insufficient to say whether pausing the drug or changing fasting instructions reduces retained stomach contents [1].
The KwikPen warning, added in January 2026, states that a Zepbound KwikPen should never be shared between patients, even with a new needle, because of the risk of bloodborne pathogens [1][2].
What do endoscopy studies show about holding the drug?
The OCULUS randomized trial studied GLP-1 and GIP agonist medications as a class, not Zepbound alone. In its interim analysis of 60 patients (32 holding one dose, 28 continuing), clinically significant residual gastric volume occurred in 3.1% of the hold group versus 25.0% of the continue group, and the trial was stopped early [6]. In the subgroup of 25 patients on a clear-liquid diet the day before, no one had clinically significant residual volume [6]. As an overall conclusion, the trial found that continuing the medication in the preprocedural period did not increase the risk of other adverse events [6].
A BMJ cohort study of 43,365 adults with type 2 diabetes compared GLP-1 receptor agonist users with SGLT-2 inhibitor users before upper endoscopy. Aspiration risk was similar between the groups (risk ratio 0.98), but procedure discontinuation was higher with GLP-1 receptor agonists (risk ratio 1.99) [7].
These are class-level studies; decisions about holding Zepbound before a procedure belong with the prescriber and the procedure team.
What happened to the suicidal ideation warning?
The label’s Recent Major Changes section shows the Suicidal Behavior and Ideation warning was removed in February 2026 [1][2].
In January 2026, the FDA requested removal of that labeling language from Saxenda, Wegovy, and Zepbound after a review found no increased risk of suicidal ideation or behavior with GLP-1 receptor agonist medications [5]. The review included a meta-analysis of 91 placebo-controlled trials with 107,910 patients and a Sentinel cohort study of 2,243,138 users [5].
The FDA advises patients to tell a health professional about new or worsening depression, suicidal thoughts, or unusual changes in mood or behavior, and to call or text 988, which provides free support 24 hours a day, 7 days a week [5].
Who should not take Zepbound?
The label lists two contraindications: a personal or family history of medullary thyroid carcinoma, or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2); and known serious hypersensitivity to tirzepatide or any of the drug’s excipients [1].
The label also states that coadministration with other tirzepatide-containing products or with any GLP-1 receptor agonist is not recommended, and that safety and effectiveness have not been established in pediatric patients [1].
What lab changes and antibodies were seen?
Zepbound produced mean increases in pancreatic amylase of 20% to 25% and lipase of 28% to 35%, versus increases of 2.1% and 5.8% respectively on placebo [1]. The label states the clinical significance of these elevations is unknown in the absence of other signs and symptoms of pancreatitis [1].
Anti-tirzepatide antibodies developed in 64.5% of Zepbound-treated patients (1,591 of 2,467) in the weight trials and 60.6% in the OSA trials [1]. The label reports no clinically significant effect of these antibodies on the drug’s pharmacokinetics or effectiveness [1]. However, patients with the antibodies had more hypersensitivity reactions (6.2% versus 3%) and more injection site reactions (11.3% versus 1%) than those without them [1].
Does Zepbound cause muscle loss?
The label states that tirzepatide lowers body weight with greater fat mass loss than lean mass loss [1]. A DXA substudy of SURMOUNT-1 measured this directly in 160 participants (124 on tirzepatide, 36 on placebo; 73% female) at week 72 [9].
With tirzepatide, body weight fell 21.3%, fat mass fell 33.9%, and lean mass fell 10.9%; with placebo, the changes were 5.3%, 8.2%, and 2.6% [9]. About 75% of the weight lost was fat and 25% was lean mass in both the tirzepatide and placebo groups, a split the study notes is similar to what dietary restriction studies report [9].
What has been reported after approval?
Postmarketing reports for tirzepatide include ileus, intestinal obstruction, and severe constipation including fecal impaction; and acute renal failure or worsening chronic renal failure, sometimes requiring hemodialysis [1]. The label cautions that because these reports are voluntary, their frequency cannot be reliably estimated and causation cannot be established [1].
Separately, the FDA’s list of potential signals from October through December 2024 includes non-arteritic anterior ischemic optic neuropathy (NAION) for the GLP-1 receptor agonist class, with Zepbound and Mounjaro among the named products [8]. The FDA states it is evaluating the need for regulatory action; this is a potential signal under review, not a confirmed side effect [8].
What do longer-term studies show?
In Study 4, 335 patients were treated with Zepbound for up to 88 weeks, and the adverse reactions were similar to those in Studies 1 and 2 [1]. The OSA trials (467 adults) also showed adverse reactions similar to the weight trials [1].
In SURMOUNT-OSA, serious adverse events occurred in 7.5% of participants overall, with similar percentages in the tirzepatide and placebo groups, and no deaths were reported [4].
SURPASS-CVOT, a trial of 13,299 adults with type 2 diabetes and cardiovascular disease comparing tirzepatide with dulaglutide, found a similar incidence of adverse events in both groups, though gastrointestinal events were more common with tirzepatide [10].
How does Zepbound affect other oral medicines?
Zepbound delays stomach emptying, and the label states this delay is largest after the first dose and diminishes over time [1]. A first 5 mg dose reduced acetaminophen peak concentration by 55%, but by week 6 on 15 mg there was no meaningful effect [1].
The label advises monitoring patients taking oral drugs with a narrow therapeutic index, such as warfarin, when given together with Zepbound [1]. Suspected side effects can be reported to Eli Lilly at 1-800-545-5979 or to the FDA’s MedWatch program at 1-800-FDA-1088 [1].
Any question about a dose, a side effect, or whether to continue or pause treatment should go to the prescriber.
Sources
- National Library of Medicine DailyMed. ZEPBOUND (tirzepatide) injection, solution.
- US Food and Drug Administration. ZEPBOUND (tirzepatide) injection prescribing information.
- New England Journal of Medicine. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity.
- PubMed Central. Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity.
- US Food and Drug Administration. FDA Requests Removal of Suicidal Behavior and Ideation Warning from GLP-1 RA Medications. January 13, 2026.
- JAMA Internal Medicine. Holding vs Continuing GLP-1/GIP Agonists Before Upper Endoscopy: The OCULUS Randomized Clinical Trial.
- BMJ. Glucagon-like peptide-1 receptor agonists before upper gastrointestinal endoscopy and risk of pulmonary aspiration or discontinuation of procedure: cohort study. October 22, 2024.
- US Food and Drug Administration. October - December 2024: New Safety Information or Potential Signals of Serious Risks Identified from the FDA Adverse Event Monitoring System.
- PubMed Central. Body composition changes during weight reduction with tirzepatide in the SURMOUNT-1 study of adults with obesity or overweight.
- New England Journal of Medicine. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes.
- US Food and Drug Administration. FDA Approves First Medication for Obstructive Sleep Apnea.
Frequently asked questions
What is the most common Zepbound side effect?
Nausea is the most common, reported by 25% of patients on 5 mg, 29% on 10 mg, and 28% on 15 mg, versus 8% on placebo. Diarrhea (19% to 23%) and constipation (17% at 5 mg, 14% at 10 mg, 11% at 15 mg) were also common, with vomiting at 8% to 13%.
How long does Zepbound nausea last?
The label states that the majority of nausea, vomiting, and diarrhea events occurred during dose escalation and decreased over time. In SURMOUNT-5, gastrointestinal events were mostly mild to moderate and occurred primarily during escalation.
Does Zepbound cause hair loss, and why more in women?
Hair loss occurred in 7.1% of women on Zepbound versus 0.5% of men, compared with 1.3% of women and 0% of men on placebo. The label associates it with weight reduction, and no Zepbound patient stopped treatment because of it.
Does Zepbound affect birth control pills?
Yes. The label advises switching to a non-oral contraceptive or adding a barrier method for 4 weeks after starting and after each dose increase, because delayed stomach emptying may reduce pill efficacy. A single 5 mg dose cut ethinyl estradiol peak levels 59% and norgestimate 66%.
Can Zepbound cause pancreatitis?
The warning covers fatal and non-fatal hemorrhagic or necrotizing pancreatitis. In the pooled weight trials, adjudicated pancreatitis occurred in 0.2% of Zepbound patients versus 0.2% on placebo. Signs include persistent or severe abdominal pain, sometimes radiating to the back.
Is the thyroid cancer warning proven in humans?
No. The boxed warning is based on rat studies showing dose- and duration-dependent thyroid C-cell tumors, and the label states that human relevance has not been determined. In the SURMOUNT-OSA trials, no medullary thyroid cancer cases were reported.
Does Zepbound cause muscle loss?
In a DXA substudy of 160 participants, lean mass fell 10.9% with tirzepatide versus 2.6% with placebo at week 72, but about 75% of the weight lost was fat in both groups. The label states tirzepatide produces greater fat mass loss than lean mass loss.
Should Zepbound be stopped before surgery or endoscopy?
The label says data are insufficient to know whether pausing the drug or changing fasting reduces retained stomach contents, and instructs patients to tell providers about planned procedures. In the OCULUS trial, holding one dose of a GLP-1 or GIP agonist lowered clinically significant residual gastric volume (3.1% vs 25.0%). A BMJ cohort of adults with type 2 diabetes found similar aspiration risk for GLP-1 users versus SGLT-2 inhibitor users (risk ratio 0.98) but more procedure discontinuations (1.99). This decision belongs with the prescriber and procedure team.
This article summarizes FDA labeling, published research and company information current as of September 14, 2026. It is not medical advice and does not replace a conversation with your own healthcare provider. How we research and verify.