What are the potential side effects of trizepitide in an adult patient with type 2 diabetes or obesity?

Side Effects of Tirzepatide

Tirzepatide causes predominantly gastrointestinal side effects that are typically mild-to-moderate and transient, occurring most frequently during dose escalation, with nausea (10-31%), diarrhea (7-23%), vomiting (2-12%), and constipation (3-5%) being the most common adverse events. 1, 2

Common Gastrointestinal Side Effects

The most frequent adverse effects are gastrointestinal in nature and occur in a dose-dependent manner:

• Nausea occurs in approximately 10-31% of patients, representing the most common adverse event 1, 2
• Diarrhea affects 7-23% of patients 1, 2
• Vomiting occurs in 2-12% of patients 1, 2
• Constipation develops in approximately 3-5% of patients 1, 2
• Abdominal pain occurs in 3-5% of patients 1

These gastrointestinal effects are primarily experienced during the dose-escalation period in the first 20 weeks of treatment and typically improve with continued use 3, 2. Slow titration, starting at 2.5 mg weekly and increasing gradually every 4 weeks, can minimize these symptoms 1.

Other Common Side Effects

Beyond gastrointestinal effects, patients may experience:

• Alopecia (hair loss) in 1-6% of patients 1
• Injection site reactions occur frequently 2
• Esophageal reflux is commonly reported 2
• Elevated heart rate requiring monitoring, with consideration of beta blockers if symptomatic cardiac arrhythmias or tachycardia develop 2

Serious Adverse Events

While less common, several serious adverse events require vigilant monitoring:

Pancreatitis

• Pancreatitis has been reported in clinical trials, though causality has not been definitively established 1, 2
• Discontinue tirzepatide immediately if pancreatitis is suspected, particularly with persistent severe abdominal pain 2
• Use with caution in patients with a history of pancreatitis 2

Gallbladder Disease

• May cause cholelithiasis (gallstones) and gallstone-related complications including cholecystitis 1, 2
• Monitor for signs and symptoms of gallbladder disorders 1

Kidney-Related Concerns

• Use caution in patients with kidney disease when initiating or increasing doses due to potential risk of acute kidney injury 2
• Hydration monitoring is important, especially if taking insulin or sulfonylurea 1

Severe Gastrointestinal Disorders

• Severe gastrointestinal disorders including severe constipation, small bowel obstruction, and ileus progression have been reported 2

Thyroid Concerns

• Risk of thyroid C-cell tumors observed in rodents; human relevance has not been determined 2
• Absolute contraindication in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 (MEN2) 1, 2

Hypoglycemia Risk

• Hypoglycemia can occur, particularly when tirzepatide is combined with insulin or insulin secretagogues (such as sulfonylureas), though the risk is low when used as monotherapy 2
• The glucose-dependent mechanism of action minimizes hypoglycemia risk when used alone 1

Drug Interactions and Special Considerations

• Delayed gastric emptying may affect absorption of oral medications, particularly those with narrow therapeutic index (such as warfarin) or whose efficacy depends on threshold concentration 2
• Oral contraceptives: Advise patients using oral hormonal contraception to use or add a non-oral contraception method for 4 weeks after initiation and after each dose escalation due to delayed gastric emptying affecting absorption 2

Treatment Discontinuation Rates

• Serious adverse events occurred in 38% higher rate with semaglutide (a related GLP-1 receptor agonist) versus placebo, though tirzepatide has a similar safety profile 4
• Treatment discontinuation due to adverse events occurs in fewer than 5% of patients 5
• Most adverse effects are less frequent with lower doses, emphasizing the importance of gradual dose titration 1

Mitigation Strategies

To minimize gastrointestinal side effects:

• Start with the lowest dose (2.5 mg weekly) and titrate gradually every 4 weeks 1
• Reduce portion sizes and increase fiber intake 1
• Take with meals to mitigate adverse effects 1
• Limit alcohol and carbonated beverages 4

Long-Term Safety Profile

• No new safety signals were identified in 3-year studies 3
• Other than COVID-19, the most common adverse events were gastrointestinal, most of which were mild to moderate in severity 3
• The gastrointestinal side effects typically improve with continued use 2