Does tirzepatide (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist) cause more rebound weight gain than semaglutide (GLP-1 receptor agonist) in patients with type 2 diabetes?

Rebound Weight Gain: Tirzepatide vs Semaglutide

Both tirzepatide and semaglutide cause substantial weight regain after discontinuation, with no evidence that one causes more rebound weight gain than the other—both require lifelong treatment to maintain weight loss benefits. 1

Evidence on Weight Regain After Discontinuation

Semaglutide Weight Regain Data

• After cessation of semaglutide, significant weight regain occurs, with 11.6% of lost weight regained after 52 weeks of discontinuation 1
• Sudden discontinuation results in regain of one-half to two-thirds of the weight loss within 1 year, making lifelong treatment necessary for sustained benefits 1
• Weight regain begins rapidly upon discontinuation regardless of tapering strategy, with a mean weight regain of 6.9% of lost weight over 48 weeks in the STEP 4 trial 2

Tirzepatide Weight Regain Data

• Sudden discontinuation of tirzepatide results in regain of one-half to two-thirds of the weight loss within 1 year, identical to semaglutide 2
• Weight regain occurs rapidly upon discontinuation regardless of how the medication is stopped 2
• Weight maintenance trials of anti-obesity medications demonstrate that discontinuation leads to rapid weight regain, emphasizing the importance of continuous treatment 2

Comparative Weight Loss Efficacy (Context for Understanding Regain)

While not directly addressing rebound, understanding the magnitude of initial weight loss provides context:

• Tirzepatide 15mg achieves 20.9% weight loss at 72 weeks, significantly superior to semaglutide 1
• Semaglutide 2.4mg achieves 14.9% weight loss at 68 weeks 1
• In real-world data, after 1 year of treatment, semaglutide 2.4mg resulted in -14.1% weight loss while tirzepatide resulted in -16.5% weight loss 3

Critical Clinical Implications

Lifelong Treatment Requirement

• Both medications must be used lifelong to maintain weight loss, as discontinuation leads to substantial regain regardless of which agent is used 1, 2
• Patients should be counseled that antiobesity medications, such as semaglutide and tirzepatide, must be used in conjunction with lifestyle changes and may need to be used lifelong 1

No Tapering Benefit

• Weight regain occurs regardless of tapering strategy—both medications can simply be stopped when clinically indicated without gradual dose reduction 2
• The elimination half-life of tirzepatide is 5 days, allowing for gradual clearance even with abrupt cessation 2

Metabolic Consequences of Discontinuation

• Stopping either medication leads to loss of cardiometabolic improvements, including beneficial effects on blood pressure, lipid profiles, and glucose metabolism 1
• Improvements in inflammatory markers will be lost after stopping either agent 1

Strategies to Minimize Weight Regain

If discontinuation is necessary for either medication:

• Intensify lifestyle interventions immediately, including a 500-kcal reduction below daily requirements and minimum 150 minutes/week of physical activity 1
• Establish monthly weight monitoring for the first 6 months after discontinuation 1
• Consider alternative weight management approaches, including metabolic surgery if BMI criteria are met 1
• Combine medication with sustained lifestyle modifications during treatment to optimize long-term outcomes 1

Common Pitfall to Avoid

Do not assume tirzepatide causes more rebound weight gain simply because it produces greater initial weight loss—the proportional regain (one-half to two-thirds of lost weight) is identical for both medications, making the absolute amount of regain proportional to the initial weight loss achieved. 1, 2