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

Abstract

Importance: In the SURMOUNT-4 trial, most adults with obesity who had tirzepatide withdrawn following a 36-week treatment regained weight. The association between the degree of weight regain and cardiometabolic parameters after tirzepatide withdrawal is unknown.

Objective: To assess changes in cardiometabolic parameters by degree of weight regain after withdrawal of tirzepatide.

Design, setting, and participants: This post hoc analysis of the SURMOUNT-4 trial included tirzepatide-treated participants with 10% or greater weight reduction at week 36 initially randomized to placebo. Data were collected from March 2021 to May 2023, and data were analyzed from February 2024 to March 2025.

Interventions: After 36 weeks of tirzepatide treatment (maximum tolerated dose of 10 mg or 15 mg), participants were randomized 1:1 to continue tirzepatide or to switch to placebo for 52 weeks (week 36 to 88).

Main outcomes and measures: Changes from week 36 to week 88 in cardiometabolic parameters on tirzepatide withdrawal were assessed by the degree of weight regain at week 88 as a percentage of weight lost while receiving tirzepatide from week 0 to 36: less than 25%, 25% to less than 50%, 50% to less than 75%, and 75% or more.

Results: Of 308 included participants, 219 (71.1%) were female, 89 (28.9%) were male, and the mean (SD) age was 47.1 (12.2) years. There were 54 participants in the less than 25% weight regain group, 77 in the 25% to less than 50% group, 103 in the 50% to less than 75% group, and 74 in the 75% or more group. Baseline demographic and clinical characteristics were similar across categories. During the initial 36 weeks of tirzepatide treatment, participants' weight decreased and cardiometabolic parameters improved. After withdrawal of tirzepatide, from week 36 to week 88, the mean change in waist circumference increased by weight regain category (<25% weight regain, 0.8 cm; 95% CI, -1.0 to 2.6; 25% to <50%, 5.4 cm; 95% CI, 4.0-6.8; 50% to <75%, 10.1 cm; 95% CI, 8.9-11.3; ≥75%, 14.7 cm; 95% CI, 12.7-16.7; P < .001), as did systolic blood pressure (6.8 mm Hg [95% CI, 3.9-9.7], 7.3 mm Hg [95% CI, 4.8-9.8], 9.6 mm Hg [95% CI, 7.1-12.1], and 10.4 mm Hg [95% CI, 8.0-12.8], respectively; P = .002), non-high-density lipoprotein cholesterol (-0.4% [95% CI, -7.3 to 6.5], 1.6% [95% CI, -2.3 to 5.5], 8.4% [95% CI, 3.9-12.9], and 10.8% [95% CI, 5.3-16.3], respectively), hemoglobin A1c (0.14% [95% CI, 0.06-0.22], 0.15% [95% CI, 0.09-0.21], 0.27% [95% CI, 0.21-0.33], and 0.35% [95% CI, 0.29-0.41], respectively; P < .001), and fasting insulin (-4.0% [95% CI, -20.7 to 12.7], 15.4% [95% CI, 2.3-28.5], 46.2% [95% CI, 29.5-62.9], and 26.3% [95% CI, 9.6-43.0], respectively). Changes at week 88 in waist circumference, non-high-density lipoprotein cholesterol, and fasting insulin in those with less than 25% weight regain were not significantly different compared with week 36.

Conclusions and relevance: In this post hoc analysis of the SURMOUNT-4 trial, among participants with obesity who achieved weight reduction with 36-week tirzepatide treatment, withdrawing tirzepatide led to 25% or greater weight regain in most participants within 1 year and was associated with a greater reversal of their initial cardiometabolic parameter improvements compared with those who maintained weight reduction. These findings underscore the importance of continued obesity treatment.

Trial registration: ClinicalTrials.gov Identifier: NCT04660643.

Figure 1.. Change in Weight, Body Mass Index (BMI), and Waist Circumference by Categories of Weight Regain on Tirzepatide Withdrawal

Data in participants randomized to tirzepatide withdrawal with 10% or more weight reduction at week 36. Week 0 to week 36 was the tirzepatide lead-in period. Week 36 to week 88 was the tirzepatide withdrawal period. Data are least-squares means; error bars indicate SEs. Statistical significance was observed among weight regain categories for weight, BMI (calculated as weight in kilograms divided by height in meters squared), and waist circumference. ^aP ≤ .001 vs week 36.

Figure 2.. Change in Blood Pressure by Categories of Weight Regain on Tirzepatide Withdrawal

Data in participants randomized to tirzepatide withdrawal with 10% or more weight reduction at week 36. Week 0 to week 36 was the tirzepatide lead-in period. Week 36 to week 88 was the tirzepatide withdrawal period. Data are least-squares means; error bars indicate SEs. Statistical significance was observed among weight regain categories for systolic blood pressure and diastolic blood pressure. ^aP ≤ .001 vs week 36. ^bP < .05 vs week 36.

Figure 3.. Change in Glycemic Parameters by Categories of Weight Regain on Tirzepatide Withdrawal

Data in participants randomized to tirzepatide withdrawal with 10% or more weight reduction at week 36. Week 0 to week 36 was the tirzepatide lead-in period. Week 36 to week 88 was the tirzepatide withdrawal period. Data are least-squares means for hemoglobin A_1c (HbA_1c) and fasting serum glucose (FSG) and estimates for fasting insulin; error bars indicate SEs. Fasting insulin was analyzed on log-transformed data and then converted back on the scale of percentage change. Statistical significance was observed among weight regain categories for HbA_1c and FSG. No statistical comparison among weight regain categories was available for fasting insulin. To convert HbA_1c to proportion of total hemoglobin, multiply by 0.01; glucose to mmol/L, multiply by 0.055; insulin to pmol/L, multiply by 6.945. ^aP ≤ .001 vs week 36. ^bP < .05 vs week 36.