Do Mounjaro (tirzepatide) side effects differ from those of traditional Glucagon-Like Peptide-1 (GLP-1) agonists?

Mounjaro (Tirzepatide) Side Effects Compared to Traditional GLP-1 Agonists

Yes, Mounjaro (tirzepatide) has different side effects compared to traditional GLP-1 agonists due to its dual mechanism of action as both a GIP and GLP-1 receptor agonist, resulting in potentially greater gastrointestinal effects but also more significant weight loss and glycemic benefits. 1

Pharmacological Differences

• Tirzepatide is the first dual GIP/GLP-1 receptor co-agonist (known as a "twincretin"), while traditional agents like semaglutide, dulaglutide, and liraglutide are selective GLP-1 receptor agonists only 1, 2
• Tirzepatide binds to the GIP receptor with high affinity but has approximately five times less affinity for the GLP-1 receptor compared to endogenous GLP-1 1
• Tirzepatide has a long half-life of approximately 5 days, allowing for once-weekly dosing similar to other long-acting GLP-1 agonists 1

Efficacy Differences

• Tirzepatide produces greater reductions in HbA1c (1.24-2.58%) and body weight (5.4-11.7 kg) compared to selective GLP-1 receptor agonists like semaglutide and dulaglutide 1, 2
• In clinical trials, a higher percentage of patients achieved normoglycemia (HbA1c <5.7%) with tirzepatide (23.0-62.4%) compared to traditional GLP-1 agonists 2, 3
• Weight loss effects are more pronounced with tirzepatide, with 20.7-68.4% of patients losing more than 10% of their baseline body weight 2, 4

Common Side Effects

• The most common adverse effects for both tirzepatide and traditional GLP-1 agonists are gastrointestinal in nature 1:

  • Nausea and vomiting
  • Dyspepsia
  • Diarrhea
  • Gastrointestinal reflux
  • Constipation

• These gastrointestinal side effects appear to be dose-dependent and more frequent with short-acting than long-acting GLP-1 receptor agonists 1

Gastrointestinal Effects

• Both tirzepatide and traditional GLP-1 agonists delay gastric emptying, which contributes to their glucose-lowering effects but also to their gastrointestinal side effect profile 1
• The delay in gastric emptying occurs through inhibition of gastric peristalsis and increased pyloric tone, mediated by vagal nerve activity 1
• Tachyphylaxis (diminishing response) to the gastric emptying effect occurs with continuous exposure to both tirzepatide and traditional GLP-1 agonists, though delayed gastric emptying still persists to some degree 1

Management of Side Effects

• For both tirzepatide and traditional GLP-1 agonists, the following strategies can help manage gastrointestinal side effects 1:
  • Start at a low dose and titrate upward slowly
  • Reduce meal size
  • Limit alcohol and carbonated drinks
  • Avoid high-fat diets
  • Avoid use in patients with gastroparesis

Cardiovascular Effects

• Both tirzepatide and traditional GLP-1 agonists have shown cardiovascular benefits 1, 2
• Traditional GLP-1 agonists like liraglutide and semaglutide have demonstrated reduced rates of cardiovascular death, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes at high cardiovascular risk 1
• Early data suggest tirzepatide may also provide cardiovascular benefits, though long-term cardiovascular outcomes trials are still ongoing 2

Perioperative Considerations

• Both tirzepatide and traditional GLP-1 agonists may increase the risk of pulmonary aspiration during anesthesia due to delayed gastric emptying 1
• The American Society of Anesthesiologists recommends stopping these medications either the day before (for daily doses) or the week before (for weekly injections) elective procedures 1

Unique Aspects of Tirzepatide

• The dual action of tirzepatide on both GIP and GLP-1 receptors creates some unique effects 1, 2:
  • GIP receptor activation augments glucagon secretion during euglycemia or hypoglycemia but inhibits it during hyperglycemia, potentially providing better protection against hypoglycemia 1
  • Tirzepatide improves insulin sensitivity and insulin secretory responses to a greater extent than selective GLP-1 agonists like semaglutide 2
  • Tirzepatide causes greater weight loss despite similar reductions in appetite compared to selective GLP-1 agonists 2

Clinical Implications

• When choosing between tirzepatide and traditional GLP-1 agonists, consider 1, 2, 4:
  • Tirzepatide may be preferred when greater weight loss and glycemic control are priorities
  • Traditional GLP-1 agonists may be preferred if gastrointestinal tolerability is a concern
  • Start with lower doses of tirzepatide and titrate slowly to minimize gastrointestinal side effects
  • Monitor for cardiac arrhythmias/tachycardia with both medication classes, especially in patients with pre-existing cardiac conditions 1