Cardiometabolic Parameter Change by Weight Regain on Tirzepatide Withdrawal in Adults With Obesity: A Post Hoc Analysis of the SURMOUNT-4 Trial.

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• Tirzepatide treatment was associated with weight loss and improved cardiometabolic risk profile in the SURMOUNT-4 trial.

• Most participants (82.5%) regained at least 25% of their lost weight within a year of stopping tirzepatide treatment.

• Those with greater weight regain had greater increases in cardiometabolic risk markers, including blood pressure, fasting glucose and triglycerides, highlighting the importance of maintaining treatment for weight management.

Introduction

• Obesity increases the risk of cardiometabolic diseases.

• Tirzepatide, a dual GIP/GLP-1 receptor agonist, is currently being used to treat obesity.

• In the SURMOUNT-4 trial, participants used tirzepatide for 36-weeks, achieving weight loss and cardiometabolic improvements, before being randomised to continue treatment      or stop treatment (placebo) for a year.

• This post-hoc analysis examined whether greater weight regain after tirzepatide withdrawal influenced the cardiometabolic benefits achieved during weight loss.

Methods

• SURMOUNT-4 participants in the treatment withdrawal group who achieved ≥10% weight reduction (n=308) were grouped by % of weight regained over a year (week 36 to 88) relative to their prior weight loss (week 0 to 36): <25%, ≥25% to <50%, ≥50% to <75%, and ≥75%.

• Cardiometabolic outcomes included weight, body mass index (BMI), waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP), triglycerides, high-density lipoprotein cholesterol (HDL-C), non- HDL-C, HbA1C, fasting glucose and insulin, and indexes of insulin resistance (HOMA2-IR) and β-cell function (HOMA2-B).

•  Changes in cardiometabolic factors between weight regain groups were analysed using a mixed model for repeated measures.

Results
Participants were 47.1 (±12.2) years old, 71% were female, and demographics were similar across groups.

• By week 88, 82.5% had regained ≥25% of weight lost.

• Comparing week 88 to 36, greater weight regain was associated with larger increases in weight, BMI, WC, SBP, DBP, triglycerides, non-HDL-C, HbA1C, glucose and insulin (p≤0.002), while WC, triglycerides, non-HDL-C, insulin, and HOMA2-IR did not significantly differ when weight regain was <25% (p>0.05).

• When weight regain was <50%, BMI, WC, SBP, DBP, triglycerides, non-HDL-C, HbA1C, glucose and insulin remained significantly lower than pre-treatment (week 0) levels, (p≤0.05).

Conclusion

• Most participants regained ≥25% of the weight lost within a year of discontinuing tirzepatide.

• Higher weight regain was associated with greater reversal of the cardiometabolic improvements achieved during treatment.

• Findings highlight the need for longer-term treatment of obesity.

• This article highlighted the importance of maintaining weight reductions in the long-term to sustain cardiometabolic benefits and improve health-related quality of life.

• These findings can support discussions between patients and healthcare professionals about long-term weight management, including counselling on the wider clinical implications of stopping treatment beyond weight regain alone.

• Future research should focus on evaluating and optimising strategies to maintain weight loss after discontinuing tirzepatide or other weight‑loss medications.

• These studies should actively involve key stakeholders—such as people using weight‑loss medications and professionals across the healthcare pathway—to better understand barriers to weight‑loss maintenance and to inform the development of more effective long‑term strategies.