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

Tirzepatide Side Effects

Tirzepatide commonly causes gastrointestinal side effects including nausea (10-31%), diarrhea (7-23%), vomiting (2-12%), constipation (3-5%), abdominal pain (3-5%), and alopecia (1-6%), with symptoms typically being dose-dependent. 1

Gastrointestinal Side Effects

• Gastrointestinal adverse events are the most common side effects of tirzepatide, occurring in 39-49% of patients depending on dose (5mg: 39%, 10mg: 46%, 15mg: 49%) 2
• Nausea and diarrhea are the most frequently reported GI symptoms across all doses 2
• Dyspepsia and gastroesophageal reflux can also occur 1
• GI side effects are typically dose-dependent and more common at higher doses 2
• Management strategies 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 (for constipation) 1
  • Avoiding use in patients with gastroparesis 1

Delayed Gastric Emptying and Related Complications

• Tirzepatide delays gastric emptying through GLP-1 receptor activation, which inhibits gastric peristalsis while increasing pyloric tone 3
• This effect is mediated through the vagus nerve, as GLP-1 receptors on the myenteric plexus activate pathways that inhibit vagal activity on the gut 3
• Potential complications include:
  • Risk of ileus, especially in patients with pre-existing gastrointestinal motility disorders 3
  • Delayed absorption of oral medications 3
  • Increased risk of pulmonary aspiration during anesthesia 3
  • Rare cases of appendicitis have been reported, possibly related to changes in gastrointestinal motility 4

Metabolic and Endocrine Side Effects

• Mild hypoglycemia (blood glucose <70 mg/dL) occurs in up to 22.6% of patients, most commonly with the 10mg dose 2
• Risk of hypoglycemia increases when used with insulin or insulin secretagogues 1
• FDA Black Box Warning: Tirzepatide can increase the risk of thyroid C-cell tumors and is contraindicated in patients with:
  • Personal or family history of medullary thyroid carcinoma 1
  • Multiple endocrine neoplasia syndrome type 2 1

Cardiovascular Effects

• Increased heart rate (typically around 5 bpm) may occur 1
• If cardiac arrhythmia/tachycardia becomes symptomatic, monitoring and consideration of beta blockers may be necessary 1
• Cardiovascular outcomes trials have shown no increased risk of major adverse cardiovascular events (MACE) 5
• In fact, tirzepatide may offer cardiovascular benefits, with hazard ratios <1.0 versus pooled comparators in meta-analyses 6

Hepatobiliary Effects

• Gallbladder disorders can occur but are usually not symptomatic 1
• Rates of cholelithiasis and cholecystitis are extremely low (≤1%) 2

Rare but Serious Side Effects

• Acute pancreatitis occurs in ≤1% of patients 2
• Fatal adverse events are extremely rare (≤1%) 2
• Severe hypoglycemia is rare (≤1%) 2

Discontinuation Rates

• Drug discontinuation due to adverse events is highest with the 15mg dose (10% of patients) 2
• Treatment discontinuation rates in clinical trials: 10% with 5mg tirzepatide, 12% with 10mg, 18% with 15mg, compared to 3% with placebo 7

Special Considerations

• Perioperative period: Consider timing of tirzepatide administration in relation to surgical procedures requiring general anesthesia due to delayed gastric emptying 3
• Renal impairment: Unlike some other medications in this class, specific dose adjustments for renal function are not prominently mentioned in guidelines for tirzepatide 1
• Monitoring: Healthcare providers should monitor for potential consequences of delayed absorption of oral medications 3

Tirzepatide's side effect profile is generally consistent with that of GLP-1 receptor agonists, with most adverse events being mild to moderate in severity 5. The dual action on both GLP-1 and GIP receptors may contribute to its pronounced effects on gastrointestinal motility 3.