What are the potential side effects of tirzepatide (dual GIP and GLP-1 receptor agonist) in a patient with type 2 diabetes or obesity, particularly those with a history of pancreatitis or thyroid cancer?

Tirzepatide Side Effects

Tirzepatide commonly causes dose-dependent gastrointestinal side effects, with nausea and diarrhea being most frequent, and carries important warnings regarding thyroid C-cell tumors (contraindicated in patients with personal or family history of medullary thyroid carcinoma or MEN 2) and increased heart rate. 1

Gastrointestinal Side Effects (Most Common)

The gastrointestinal effects are the predominant side effects and occur in a dose-dependent manner:

• Nausea, diarrhea, vomiting, constipation, and abdominal pain are the most frequently reported adverse events 1, 2
• Overall GI adverse event rates increase with dose: 39% at 5 mg, 46% at 10 mg, and 49% at 15 mg weekly 3
• Dyspepsia and gastroesophageal reflux can also occur 1
• These symptoms are typically mild to moderate in severity and are dose-dependent 1, 2

Management strategies to minimize GI side effects include:

• Starting at a low dose and titrating slowly upward 1
• Reducing meal size 1
• Limiting alcohol and carbonated drinks 1
• Avoiding high-fat diets 1
• Avoiding use in patients with gastroparesis 1

Serious Endocrine Warnings

Thyroid C-cell tumor risk is a critical contraindication:

• Tirzepatide increases the risk of thyroid C-cell tumors and is absolutely contraindicated in patients with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 1, 4

Hypoglycemia risk:

• Risk of hypoglycemia increases significantly when tirzepatide is used with insulin or insulin secretagogues 1
• Mild hypoglycemia (blood glucose <70 mg/dL) was highest with the 10 mg dose at 22.6% 3
• Severe hypoglycemia remains rare (≤1%) across all doses 3

Delayed Gastric Emptying and Complications

Tirzepatide delays gastric emptying through GLP-1 receptor activation, which has important clinical implications:

• The mechanism involves inhibition of gastric peristalsis while increasing pyloric tone 1
• This creates risk of ileus, delayed absorption of oral medications, and increased risk of pulmonary aspiration during anesthesia 1
• Consideration of timing relative to surgical procedures requiring general anesthesia is necessary 1
• Emerging evidence suggests potential association with appendicitis, possibly related to altered GI motility 5

Cardiovascular Effects

• Increased heart rate may occur with tirzepatide 1
• If cardiac arrhythmia or tachycardia becomes symptomatic, monitoring and consideration of beta blockers may be necessary 1
• Importantly, tirzepatide showed no increased risk of major adverse cardiovascular events, with hazard ratios <1.0 for all cardiovascular events analyzed 6

Hepatobiliary Effects

• Gallbladder disorders including cholelithiasis and cholecystitis can occur but are usually asymptomatic 1
• Rates remain extremely low (≤1%) across all doses 1, 3
• Fatal adverse events and acute pancreatitis are also rare (≤1%) 3

Other Side Effects

• Injection site reactions may occur 1
• Alopecia has been reported 1
• Drug discontinuation due to adverse events was highest with the 15 mg dose at 10% 3

Special Populations and Monitoring

For patients with history of pancreatitis:

• Acute pancreatitis rates remain extremely low (≤1%) across all doses, but this history warrants careful monitoring 3

Renal considerations:

• Unlike some other medications in this class, specific dose adjustments for renal function are not prominently required for tirzepatide 1

Medication interactions:

• Healthcare providers should monitor for potential consequences of delayed absorption of oral medications due to delayed gastric emptying 1