Do patients experience sustained weight loss after stopping tirzepatide (a dual GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) receptor agonist)?

Weight Regain After Discontinuing Tirzepatide

Patients experience substantial weight regain after discontinuing tirzepatide, with evidence showing that withdrawing the medication leads to significant loss of the weight reduction benefits achieved during treatment. 1

Evidence on Weight Regain After Discontinuation

• The SURMOUNT-4 randomized clinical trial demonstrated that when tirzepatide was discontinued after 36 weeks of treatment, patients regained an average of 14.0% of their body weight over the next 52 weeks, compared to continued weight loss of 5.5% in those who remained on the medication 1
• Only 16.6% of patients who discontinued tirzepatide maintained at least 80% of their initial weight loss, compared to 89.5% of those who continued treatment 1
• A 2025 narrative review of randomized studies found that weight regain occurs rapidly after cessation of therapy with GLP-1 receptor agonists or dual GIP/GLP-1 receptor agonists like tirzepatide, regardless of treatment duration 2
• This rebound weight gain substantially mitigates the metabolic benefits achieved through the initial weight loss 2

Mechanism of Action and Weight Loss Efficacy

• Tirzepatide is a dual GIP/GLP-1 receptor co-agonist that activates key mediators of insulin secretion also expressed in brain regions regulating food intake 3
• During treatment, tirzepatide produces significant weight loss, with studies showing:
  • Mean weight reduction of 8.47 kg compared to usual care (CI, −9.49 to −7.45 kg) 4
  • Between 3% to 67% of participants achieving at least 10% weight reduction from baseline 4
  • Overall mean weight reduction of 20.9% during the 36-week lead-in period of the SURMOUNT-4 trial 1

Clinical Implications for Practice

• Long-term use of tirzepatide is necessary to maintain weight loss benefits, as discontinuation leads to substantial weight regain 5, 1
• For patients with weight recurrence after bariatric surgery, tirzepatide has shown effectiveness with 15.5% mean weight loss at 6 months, but studies note that "weight regain after discontinuation of the medication is highly likely" 6
• The American Medical Association recommends tirzepatide for chronic weight management in adults with obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) with at least one weight-related comorbidity 5

Safety Considerations

• The most common adverse events with tirzepatide are gastrointestinal, including nausea, vomiting, diarrhea, and constipation 5, 7
• A meta-analysis showed that while the overall risk of serious adverse events is not higher compared to placebo, tirzepatide carries an elevated risk of GI side effects, serious GI events, and discontinuation due to adverse effects 7

Clinical Pearls and Caveats

• Weight maintenance strategies should be discussed with patients before considering discontinuation of tirzepatide 2, 1
• Future research needs to focus on optimal treatment duration or identifying techniques that involve dosage reduction to prevent weight regain 2
• The high cost of tirzepatide (average wholesale price of $1,272 for a 30-day supply) may limit long-term use for some patients 5, 6
• Tirzepatide must be used in conjunction with lifestyle modifications for optimal results 5