What are the adverse effects and black box warnings for tirzepatide (a dual GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) receptor agonist)?

Adverse Effects and Black Box Warning for Tirzepatide

Tirzepatide carries an FDA black box warning for risk of thyroid C-cell tumors, including medullary thyroid carcinoma, based on rodent studies, and is contraindicated in patients with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. 1

Black Box Warning: Thyroid C-Cell Tumors

• Tirzepatide caused dose-dependent and treatment-duration-dependent increases in thyroid C-cell tumors (adenomas and carcinomas) in rats at clinically relevant plasma exposures, though human relevance remains undetermined. 1
• The medication is absolutely contraindicated in patients with personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2). 2, 1
• Counsel patients about potential MTC risk and symptoms including neck mass, dysphagia, dyspnea, and persistent hoarseness. 1
• Routine serum calcitonin monitoring or thyroid ultrasound is of uncertain value and may increase unnecessary procedures due to low test specificity. 1
• If serum calcitonin is measured and exceeds 50 ng/L, or if thyroid nodules are detected, further evaluation is warranted. 1

Gastrointestinal Adverse Effects (Most Common)

Gastrointestinal side effects are the most frequently reported adverse events with tirzepatide, occurring in a dose-dependent manner: 39% with 5 mg, 46% with 10 mg, and 49% with 15 mg doses. 3

Specific GI Effects:

• Nausea and diarrhea are the most common GI adverse effects at any dose, followed by vomiting, constipation, abdominal pain, and dyspepsia. 2, 4, 3
• Nausea occurs in 12-18% of patients (vs 6% with placebo), with highest incidence at the 15 mg dose (OR 5.60). 4, 5
• Diarrhea affects 12-14% of patients (vs 8% with placebo). 4
• Vomiting occurs in 2-6% of patients (vs 2% with placebo), with 15 mg dose showing OR 5.50 vs placebo. 4, 5
• These GI symptoms are typically mild to moderate, transient, and most pronounced during dose initiation and escalation periods. 6, 4

Management of GI Side Effects:

• Start at the lowest dose and titrate slowly upward over several weeks. 2, 6
• Reduce meal size, avoid high-fat diets, limit alcohol and carbonated drinks. 2, 6
• Avoid use in patients with gastroparesis. 2
• Consider temporary dose reduction if symptoms are severe; anti-emetics may be used short-term for severe nausea. 6
• For diarrhea, ensure adequate hydration and consider loperamide for severe symptoms. 6

Delayed Gastric Emptying and Related Complications

• Tirzepatide delays gastric emptying through GLP-1 receptor activation, which inhibits gastric peristalsis while increasing pyloric tone. 2
• This creates risk of ileus, delayed absorption of oral medications (particularly those with narrow therapeutic index like warfarin), and increased pulmonary aspiration risk during anesthesia. 2, 6
• In the perioperative period, careful consideration of tirzepatide administration timing relative to procedures requiring general anesthesia is necessary. 2

Pancreatitis

• Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed with GLP-1 receptor agonists. 1
• In clinical trials, 14 events of acute pancreatitis occurred in 13 tirzepatide-treated patients (0.23 per 100 patient-years) versus 3 events in comparator groups (0.11 per 100 patient-years). 1
• If pancreatitis is suspected (persistent severe abdominal pain, sometimes radiating to the back, with or without vomiting), immediately discontinue tirzepatide. 6, 1
• Tirzepatide has not been studied in patients with prior pancreatitis history. 1
• Rates of acute pancreatitis across all doses remain extremely low (≤1%). 3

Hypoglycemia

• Risk of hypoglycemia increases significantly when tirzepatide is combined with insulin secretagogues (e.g., sulfonylureas) or insulin. 2, 1
• Incidence of mild hypoglycemia (blood glucose <70 mg/dL) was highest with the 10 mg dose at 22.6%. 3
• No clinically significant (<54 mg/dL) or severe hypoglycemia was reported with tirzepatide monotherapy. 4
• When used with insulin or secretagogues, reduce the dose of these concomitant medications to lower hypoglycemia risk. 1
• Hypoglycemia incidence with tirzepatide alone is similar to placebo and lower than basal insulin. 5

Cardiovascular Effects

• Increased heart rate may occur with tirzepatide. 7, 2
• If cardiac arrhythmia or tachycardia becomes symptomatic, monitoring and consideration of beta blockers may be necessary. 2
• Elevated heart rate is a recognized side effect across the GLP-1 receptor agonist class. 7

Hepatobiliary Effects

• Gallbladder disorders including cholelithiasis and cholecystitis can occur but are usually asymptomatic. 2
• May cause cholelithiasis and gallstone-related complications. 7
• Rates of cholelithiasis and cholecystitis are extremely low (≤1%) across all doses. 3

Hypersensitivity Reactions

• Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported. 1
• If hypersensitivity reactions occur, discontinue tirzepatide immediately, treat per standard of care, and monitor until symptoms resolve. 1

Drug Discontinuation

• Drug discontinuation due to adverse events is dose-dependent, with highest rates (10%) occurring at the 15 mg dose. 3
• Persistent severe nausea/vomiting despite management, signs of pancreatitis, severe constipation or bowel obstruction symptoms, and significant dehydration are indications for dose reduction or discontinuation. 6

Other Adverse Effects

• Alopecia has been reported. 2
• Injection site reactions may occur. 7
• Fatal adverse events, severe hypoglycemia, acute pancreatitis, cholelithiasis, and cholecystitis are rare (≤1%) across all tirzepatide doses. 3

Special Populations and Monitoring

• Unlike some medications in this class, specific dose adjustments for renal function are not prominently required for tirzepatide. 2
• Monitor patients at least monthly for the first 3 months, then at least quarterly thereafter, assessing for dehydration and electrolyte disturbances in those with severe GI side effects. 6
• All medications in this class are contraindicated in individuals who are or may become pregnant. 7

Cancer Risk

• Tirzepatide use in randomized controlled trials over 26 to 72 weeks did not increase overall or specific cancer risk. 8
• Despite greater increments in serum calcitonin with 10 and 15 mg doses versus placebo, no cases of papillary thyroid carcinoma were reported in included trials. 8