What causes weight gain after stopping tirzepatide (a glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist)?

Weight Regain After Tirzepatide Discontinuation: Causes and Management

Weight regain after stopping tirzepatide occurs primarily due to the reversal of its appetite-suppressing and metabolic effects, with studies showing rapid and substantial weight regain of 50-67% within one year of discontinuation.

Mechanisms of Weight Regain

Weight regain after tirzepatide discontinuation occurs through several mechanisms:

1. Loss of appetite suppression effects:

   • Tirzepatide, as a dual GIP/GLP-1 receptor co-agonist, reduces appetite and food intake 1
   • When discontinued, these appetite-suppressing effects are lost, leading to increased food consumption

2. Reversal of metabolic improvements:

   • Tirzepatide improves insulin sensitivity and secretory responses 2
   • Discontinuation reverses these metabolic benefits, contributing to weight regain

3. Dose-dependent rebound effect:

   • Higher doses of tirzepatide lead to more significant weight regain after discontinuation 3
   • This suggests a dose-dependent physiological adaptation that rebounds when the medication is stopped

Evidence of Weight Regain

The SURMOUNT-4 trial provides the strongest evidence regarding weight regain after tirzepatide discontinuation:

• Participants who continued tirzepatide maintained and further reduced weight (additional 5.5% loss) 4
• Those switched to placebo regained 14.0% of their body weight over 52 weeks 4
• Only 16.6% of participants who discontinued tirzepatide maintained at least 80% of their initial weight loss, compared to 89.5% of those who continued treatment 4

A case series study of patients with type 2 diabetes showed:

• Dose-dependent weight regain occurred relatively early after tirzepatide discontinuation 3
• This pattern was more pronounced than with dulaglutide (a GLP-1 receptor agonist) 3

Pattern of Weight Regain

Weight regain after discontinuation of tirzepatide follows a predictable pattern:

• Begins shortly after discontinuation 3, 5
• Occurs regardless of treatment duration 5
• Can substantially mitigate the metabolic benefits achieved during treatment 5
• May continue until approaching pre-treatment weight if no intervention is implemented 4

Clinical Implications and Management

Based on the evidence, the following approach is recommended:

1. Long-term treatment consideration:

   • The American Diabetes Association strongly recommends continuing weight management medications long-term after achieving weight loss 1
   • Sudden discontinuation results in regain of 50-67% of weight loss within one year 1

2. Maintenance strategies:

   • Continue medication long-term at the lowest effective dose 1
   • Options include:
     • Maintaining full therapeutic dose (15 mg weekly) if well-tolerated
     • Reducing to lowest effective dose that maintains weight loss
     • Consider intermittent therapy with close monitoring if continuous therapy isn't feasible

3. Follow-up monitoring:

   • After establishing maintenance dose, follow-up should occur at least quarterly 1
   • Monitor for weight stability, glycemic control if applicable, side effects, and medication adherence

Caveat and Considerations

• The weight regain phenomenon is not unique to tirzepatide but appears to be common across GLP-1 receptor agonists and dual GIP/GLP-1 receptor agonists 5
• Patients should be informed about the likelihood of weight regain if treatment is discontinued
• For patients who must discontinue tirzepatide, intensive lifestyle interventions should be implemented to mitigate weight regain

The evidence clearly demonstrates that tirzepatide's effects on weight are dependent on continued treatment, with substantial weight regain occurring upon discontinuation due to the reversal of its appetite-suppressing and metabolic effects.