Side Effects of Zepbound (Tirzepatide)
Zepbound causes predominantly gastrointestinal side effects—including nausea (28-44%), diarrhea (21-30%), and constipation (11-24%)—that are typically dose-dependent and most pronounced during dose initiation and escalation. 1, 2
Common Gastrointestinal Side Effects
The most frequent adverse effects are gastrointestinal in nature and generally mild to moderate in severity:
- Nausea occurs in 17-22% of patients and is the most common side effect 3
- Diarrhea affects 13-16% of patients 3
- Vomiting occurs in 6-10% of patients 3
- Constipation affects 11-24% of patients 2
- Abdominal pain, dyspepsia, and gastroesophageal reflux can also occur 1, 4
These gastrointestinal symptoms are primarily related to delayed gastric emptying caused by GLP-1 receptor activation, which inhibits gastric peristalsis while increasing pyloric tone. 1 The symptoms typically occur during dose escalation and often improve with continued use. 4
Serious Gastrointestinal Complications
Severe gastrointestinal complications require immediate attention:
- Pancreatitis has been reported in clinical trials, though causality has not been established; discontinue Zepbound if pancreatitis is suspected 5, 4
- Gallbladder disorders (cholelithiasis and cholecystitis) can occur but are usually asymptomatic, with rates ≤1% across all doses 1
- Small bowel obstruction/ileus has been reported, even in patients without prior abdominal surgery or conventional risk factors 6, 4
Endocrine and Metabolic Side Effects
Thyroid and hypoglycemia risks require specific monitoring:
- Risk of thyroid C-cell tumors has been observed in rodents; Zepbound is contraindicated in patients with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 5, 1
- Hypoglycemia risk increases when used with insulin or insulin secretagogues (sulfonylureas), occurring in 0.2-1.7% of patients on tirzepatide monotherapy 3, 1
Cardiovascular Side Effects
- Increased heart rate may occur and requires monitoring; if cardiac arrhythmia or tachycardia becomes symptomatic, consider beta blockers 1
Other Notable Side Effects
- Alopecia (hair loss) has been reported 1
- Injection site reactions may occur but are typically mild 1
- Acute kidney injury risk exists due to dehydration from gastrointestinal side effects; use caution when initiating or increasing doses in patients with kidney disease 5
Medication Interactions and Special Considerations
Delayed gastric emptying creates important clinical implications:
- Delayed absorption of oral medications may occur, particularly affecting medications with narrow therapeutic index 4
- Increased risk of pulmonary aspiration during anesthesia requires consideration of timing relative to surgical procedures 1
- Oral contraceptive efficacy may be reduced; patients should switch to non-oral contraceptive methods or add barrier methods for 4 weeks after initiation and after each dose escalation 5
Risk Mitigation Strategies
To minimize side effects, implement gradual dose titration:
- Start at the lowest dose and slowly increase over several weeks 4
- Reduce meal size and avoid high-fat foods 4
- Limit alcohol and carbonated drinks 4
- Ensure adequate hydration to prevent constipation 4
- Avoid use in patients with gastroparesis 1
When to Discontinue or Reduce Dose
Consider dose reduction or discontinuation for: