What are the side effects of tirzepatide (GLP-1 and GIP receptor agonist)?

Side Effects of Tirzepatide

Gastrointestinal side effects are the most common adverse events with tirzepatide, occurring in a dose-dependent manner (39% at 5mg, 46% at 10mg, and 49% at 15mg), with nausea and diarrhea being the most frequent, typically mild to moderate and transient during dose escalation. 1, 2

Common Gastrointestinal Side Effects

• Nausea is the most frequently reported adverse effect, occurring in 17-22% of patients across all doses 3
• Diarrhea affects 13-16% of patients and is dose-dependent 3
• Vomiting occurs in 6-10% of patients, increasing with higher doses 3
• Esophageal reflux can occur and should be managed by limiting alcohol and carbonated drinks 1
• These GI symptoms are primarily mild to moderate in severity, occur mainly during initial treatment and dose escalation, and gradually diminish over time 4, 2

Metabolic and Endocrine Side Effects

• Hypoglycemia (blood glucose <54 mg/dL) is rare when tirzepatide is used alone (0.2-1.7%), but risk increases significantly when combined with insulin or sulfonylureas 3, 1
• Elevated heart rate (tachycardia) may occur and requires monitoring, especially in patients with pre-existing cardiovascular conditions 1
• Beta-blockers should be considered if tachycardia becomes symptomatic 1

Serious Adverse Events (Rare but Important)

• Cholelithiasis and gallstone-related complications can occur with tirzepatide use 1
• Acute pancreatitis occurs in ≤1% of patients across all doses 2
• Cholecystitis is extremely rare (≤1%) 2
• Diabetic retinopathy worsening has been reported, particularly in patients with pre-existing retinopathy 1
• Severe electrolyte disturbances from prolonged GI symptoms can lead to life-threatening arrhythmias, including ventricular fibrillation, particularly at the 15mg dose 5

Black Box Warning

• Thyroid C-cell tumor risk: Tirzepatide carries a black box warning regarding the risk of thyroid C-cell tumors observed in rodent studies 1
• Contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 1

Drug Discontinuation

• 10% of patients on the 15mg dose discontinue therapy due to adverse events, the highest rate among all doses 2
• Drug discontinuation due to adverse events increases in a dose-dependent manner 2

Injection Site and Other Effects

• Injection site reactions can occur with tirzepatide 1
• Delayed gastric emptying may affect absorption of other oral medications, particularly those with narrow therapeutic indices such as warfarin 1

Renal Considerations

• Use caution when initiating or increasing doses in patients with kidney disease 1
• Establish baseline renal function before starting therapy 1
• Use with caution in patients with severe renal impairment or end-stage renal disease 1

Mitigation Strategies

• Start at a low dose (5mg) and titrate upward slowly to improve tolerability and minimize GI side effects 1
• Reduce meal size to help manage symptoms 1
• Avoid high-fat diet to help with constipation 1
• Monitor electrolytes vigilantly, particularly in patients on high doses (15mg) or those with additional risk factors for electrolyte disturbances 5
• Monitor heart rate regularly, especially in patients with cardiovascular conditions 1
• Close monitoring is required for patients with history of pancreatitis 1

Comparative Safety Profile

• Tirzepatide's adverse event profile is consistent with the GLP-1 receptor agonist class, with GI side effects being the primary concern 6
• When compared to semaglutide 1mg weekly, tirzepatide showed similar rates of nausea (17-22% vs 18%), diarrhea (13-16% vs 12%), and vomiting (6-10% vs 8%) 3
• Serious adverse events occurred in 5-7% of tirzepatide patients versus 3% with semaglutide 3