Cardiometabolic Parameter Change by Weight Regain on Tirzepatide Withdrawal in Adults With Obesity: A Post Hoc Analysis of the SURMOUNT-4 Trial.
Level 3 - non-randomized controlled study
Post hoc cohort analysis stratified by post-randomization weight regain categories within an RCT withdrawal arm.
PubMed 41284285 · doi:10.1001/jamainternmed.2025.6112
What was done
This post hoc analysis of the SURMOUNT-4 randomized trial evaluated 308 adults with obesity who achieved at least 10% weight reduction after 36 weeks of open-label tirzepatide (10 mg or 15 mg) and were then randomized to switch to placebo for 52 weeks (weeks 36 to 88). Participants were categorized into four groups based on the proportion of lost weight regained by week 88: less than 25% (n = 54), 25% to less than 50% (n = 77), 50% to less than 75% (n = 103), and 75% or more (n = 74). Changes in cardiometabolic parameters from week 36 to week 88 were analyzed across these categories.
What was found
Most participants (254 of 308, 82.5%) regained 25% or more of their lost weight within 52 weeks of tirzepatide withdrawal. Worsening of cardiometabolic markers scaled directly with the extent of weight regain across the four groups (<25%, 25% to <50%, 50% to <75%, and ≥75% regain): - Waist circumference increased by a mean of 0.8 cm (95% CI, -1.0 to 2.6), 5.4 cm (95% CI, 4.0 to 6.8), 10.1 cm (95% CI, 8.9 to 11.3), and 14.7 cm (95% CI, 12.7 to 16.7; P < .001). - Systolic blood pressure increased by 6.8 mm Hg (95% CI, 3.9 to 9.7), 7.3 mm Hg (95% CI, 4.8 to 9.8), 9.6 mm Hg (95% CI, 7.1 to 12.1), and 10.4 mm Hg (95% CI, 8.0 to 12.8; P = .002). - Non-HDL cholesterol changed by -0.4% (95% CI, -7.3 to 6.5), 1.6% (95% CI, -2.3 to 5.5), 8.4% (95% CI, 3.9 to 12.9), and 10.8% (95% CI, 5.3 to 16.3). - Hemoglobin A1c increased by 0.14% (95% CI, 0.06 to 0.22), 0.15% (95% CI, 0.09 to 0.21), 0.27% (95% CI, 0.21 to 0.33), and 0.35% (95% CI, 0.29 to 0.41; P < .001). - Fasting insulin changed by -4.0% (95% CI, -20.7 to 12.7), 15.4% (95% CI, 2.3 to 28.5), 46.2% (95% CI, 29.5 to 62.9), and 26.3% (95% CI, 9.6 to 43.0). Participants who regained less than 25% of lost weight showed no statistically significant reversal in waist circumference, non-HDL cholesterol, or fasting insulin compared to week 36.
Why it matters
This study shows that the cardiometabolic benefits achieved during tirzepatide treatment reverse in direct proportion to weight regain upon drug withdrawal. The findings reinforce that obesity is a chronic condition requiring sustained pharmacotherapy for most patients to maintain cardiovascular and metabolic improvements.
Limits
The analysis is post hoc and observational, stratifying participants by post-randomization outcomes rather than a randomized intervention. The cohort was predominantly female (71.1%) and limited strictly to initial responders who achieved at least 10% weight loss during the first 36 weeks. Hard clinical cardiovascular outcomes were not evaluated.
Cited by
- supports In the SURMOUNT-4 trial, participants who discontinued tirzepatide experienced substantial weight regain and reversion of metabolic improvements.