How does Mounjaro (tirzepatide) cause diarrhea?

How Mounjaro (Tirzepatide) Causes Diarrhea

Mounjaro (tirzepatide) primarily causes diarrhea through its action as a dual GIP and GLP-1 receptor agonist, which delays gastric emptying and increases intestinal secretions, leading to altered gastrointestinal motility and fluid balance. 1

Mechanism of Action and Diarrhea

• Tirzepatide acts as a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, which affects multiple gastrointestinal processes 2
• GLP-1 receptor activation slows gastric emptying and alters intestinal transit time, which can disrupt normal bowel function 1
• The medication increases intestinal secretions through activation of specific receptors, similar to how other GLP-1 receptor agonists and secretagogues work 3
• Diarrhea is one of the most common adverse events reported with tirzepatide, occurring in approximately 12-14% of patients taking the medication 4

Dose-Dependent Relationship

• Gastrointestinal side effects, including diarrhea, show a dose-dependent relationship with tirzepatide 4
• Higher doses of tirzepatide (15 mg) are associated with increased rates of diarrhea compared to lower doses (5 mg) 4
• In clinical trials, the incidence of gastrointestinal adverse events was 39% with 5 mg, 46% with 10 mg, and 49% with 15 mg of tirzepatide 4

Clinical Significance and Management

• Diarrhea with tirzepatide is typically mild to moderate in severity and often transient, improving over time as the body adapts to the medication 5
• In clinical trials, diarrhea rarely led to serious adverse events, though it was one of the reasons some patients discontinued the medication 1
• The FDA label notes that severe gastrointestinal adverse reactions occurred in 0.4-1.3% of patients receiving tirzepatide, compared to 0.9% with placebo 1
• Gradual dose escalation (starting at 2.5 mg and increasing by 2.5 mg increments after at least 4 weeks) helps minimize gastrointestinal side effects including diarrhea 1

Comparison to Other Medications

• The mechanism of diarrhea with tirzepatide is similar to that seen with other GLP-1 receptor agonists, though the dual action on GIP receptors may contribute to its specific side effect profile 2
• Like other secretagogues such as linaclotide, tirzepatide can increase intestinal fluid secretion, though through different receptor pathways 3
• In studies of linaclotide (another medication that increases intestinal secretions), diarrhea occurred in 16.3% of patients compared to 2.3% with placebo, which is comparable to the rates seen with tirzepatide 3

Special Considerations

• Patients with pre-existing gastrointestinal conditions may be at higher risk for diarrhea when taking tirzepatide 1
• The FDA label specifically notes that tirzepatide "has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients" 1
• When diarrhea occurs, it's important to rule out infectious causes before attributing it solely to the medication, especially in immunocompromised patients 6
• Adequate hydration is essential when experiencing diarrhea to prevent dehydration and potential acute kidney injury, which has been reported with GLP-1 receptor agonists 1

Monitoring and Precautions

• Patients should be monitored for signs of dehydration when experiencing diarrhea, especially those with renal impairment 1
• The FDA label warns that severe gastrointestinal adverse reactions may occur and recommends monitoring renal function in patients with renal impairment who report severe gastrointestinal adverse reactions 1
• If diarrhea persists or becomes severe, dose reduction or temporary discontinuation may be necessary 1