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

Deborah B Horn; Bruno Linetzky; Melanie J Davies; Luke J Laffin; Hui Wang; Madhumita A Murphy; Sarah Zimner-Rapuch; Eva Lau; Avigdor D Arad; Clare J Lee

doi:10.1001/jamainternmed.2025.6112

. 2025 Nov 24;186(2):157–167. doi: 10.1001/jamainternmed.2025.6112

Cardiometabolic Parameter Change by Weight Regain on Tirzepatide Withdrawal in Adults With Obesity

A Post Hoc Analysis of the SURMOUNT-4 Trial

Deborah B Horn ¹, Bruno Linetzky ², Melanie J Davies ³, Luke J Laffin ⁴, Hui Wang ⁵, Madhumita A Murphy ², Sarah Zimner-Rapuch ⁶, Eva Lau ⁷, Avigdor D Arad ², Clare J Lee ^2,^✉

¹University of Texas Center for Obesity Medicine and Metabolic Performance, Department of Surgery, McGovern Medical School, Houston

²Eli Lilly and Company, Indianapolis, Indiana

³Diabetes Research Centre, University of Leicester, NIHR Leicester Biomedical Research Centre, Leicester, United Kingdom

⁴Cleveland Clinic Foundation, Cleveland, Ohio

⁵TechData Service Company, King of Prussia, Pennsylvania

⁶Lilly France, Neuilly-sur-Seine, France

⁷Eli Lilly and Company, Lisbon, Portugal

Accepted for Publication: September 23, 2025.

Published Online: November 24, 2025. doi:10.1001/jamainternmed.2025.6112

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License, which does not permit alteration or commercial use, including those for text and data mining, AI training, and similar technologies. © 2025 Horn DB et al. JAMA Internal Medicine.

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Corresponding Author: Clare J. Lee, MD, MHS, Eli Lilly and Company, Cardiometabolic Health, Global Medical Affairs, Lilly Corporate Center, Indianapolis, IN 46285 (clare.lee@lilly.com).

Author Contributions: Dr Horn had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Horn, Linetzky, Wang, Lau, Lee.

Acquisition, analysis, or interpretation of data: Horn, Linetzky, Davies, Laffin, Murphy, Zimner-Rapuch, Lau, Arad, Lee.

Drafting of the manuscript: Linetzky, Lau, Lee.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Wang.

Administrative, technical, or material support: Linetzky.

Supervision: Murphy, Lau, Lee.

Conflict of Interest Disclosures: Dr Horn reported grants from Eli Lilly and Company during the conduct of the study; grants from Eli Lilly and Company and Novo Nordisk; personal fees from Eli Lilly and Company, Novo Nordisk, AstraZeneca, Boehringer Ingleheim, Zealand Pharmaceuticals, and Amgen; and nonfinancial support from KVK Tech Pharmaceuticals outside the submitted work. Drs Linetzky, Murphy, Zimner-Rapuch, Lau, Arad, and Lee reported employment and stock ownership from Eli Lilly and Company during the conduct of the study and outside the submitted work. Dr Davies reported grants from AstraZeneca, Novo Nordisk, and Boehringer Ingelheim; serving on the advisory board for Eli Lilly and Company, Novo Nordisk, Sanofi, AbbVie, Amgen, AstraZeneca, Biomea Fusion, Carmot/Roche, Daewoong Pharmaceutical, Zealand Pharma, Regeneron, and GlaxoSmithKline; and personal fees from Boehringer Ingelheim and Zuellig Pharma outside the submitted work. Dr Laffin reported grants from Mineralys, Arrowhead, and Eli Lilly and Company as well as personal fees from Eli Lilly and Company, AstraZeneca, Novo Nordisk, Kardigan, Novartis, Medtronic, and Recor outside the submitted work. No other disclosures were reported.

Funding/Support: This study was sponsored by Eli Lilly and Company.

Role of the Funder/Sponsor: Eli Lilly and Company was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The sponsor did not have the right to veto publication or to control the decision regarding to which journal the manuscript was submitted. Final decisions resided with the authors, which included employees of the sponsor.

Meeting Presentation: Part of the data from this analysis was presented as a poster at Obesity Week; November 3-6, 2024; San Antonio, Texas; and at the 32nd European Congress on Obesity; May 11-14, 2025; Malaga, Spain.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the participants and the study investigators and coordinators who cared for them. We thank Amelia Torcello Gomez, PhD, for her writing and editorial assistance, for which she was compensated as part of her salary as an employee of Eli Lilly and Company.

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Corresponding author.

PMCID: PMC12645400 PMID: 41284285

Key Points

Question

Does the degree of weight regain following tirzepatide withdrawal affect long-term cardiometabolic benefits in individuals with obesity or overweight?

Findings

In this post hoc analysis of the SURMOUNT-4 randomized clinical trial including 308 participants, participants experienced weight reduction and improvement in cardiometabolic parameters after a 36-week tirzepatide treatment. One year after tirzepatide withdrawal, a higher degree of weight regain was associated with a greater reversal of initial improvements in waist circumference, blood pressure, non–high-density lipoprotein cholesterol, glycemic parameters, and insulin resistance.

Meaning

In this post hoc analysis, on tirzepatide withdrawal, greater reversal of initial cardiometabolic benefits was observed in participants who regained 25% or more of their initial weight reduction vs those who did not.

This post hoc analysis of a randomized clinical trial assesses changes in cardiometabolic parameters by degree of weight regain after withdrawal of tirzepatide.

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 A_1c (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

Introduction

Obesity is a chronic disease associated with elevated risk for cardiometabolic complications. The aims of obesity treatment focus not only on reducing weight but also on mitigating weight-related complications. Current guidelines recommend obesity management medications in combination with lifestyle intervention to achieve and maintain weight reduction and improve cardiometabolic parameters in people living with obesity.^1,2,3,4 Weight regain is typically observed after withdrawal of pharmacotherapy, even with continued lifestyle intervention, as shown in withdrawal randomized clinical trials of obesity management medications.^5,6,7 Therefore, long-term treatment with obesity management medications may be required to maintain weight reduction and associated cardiometabolic benefits.

Tirzepatide is a once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for long-term treatment of obesity, obstructive sleep apnea, and type 2 diabetes.^8,9 In the SURMOUNT-4 withdrawal trial, tirzepatide treatment for 36 weeks was associated with improvement in anthropometric parameters (eg, weight, body mass index [BMI; calculated as weight in kilograms divided by height in meters squared], and waist circumference [WC]) and in cardiometabolic parameters (eg, blood pressure [BP], lipid profile, hemoglobin A_1c [HbA_1c], fasting serum glucose [FSG], and fasting insulin) in adults with obesity or overweight with weight-related complications.⁷ Most participants randomized to the placebo arm after 36 weeks of treatment experienced weight regain.⁷ In addition, tirzepatide withdrawal was associated with reversal of most of the initial improvements in HbA_1c, FSG, fasting insulin, cholesterol, triglycerides, and BP achieved with tirzepatide treatment, despite continued lifestyle intervention.⁷

The aim of this analysis was to evaluate the degree of weight regain experienced across SURMOUNT-4 participants randomized to withdrawal of tirzepatide after 36 weeks of treatment and to assess associated changes in cardiometabolic parameters on tirzepatide withdrawal by the degree of weight regain.

Methods

Study Design and Participants

This is a post hoc analysis of the SURMOUNT-4 trial (ClinicalTrials.gov identifier: NCT04660643). The study design, participant eligibility criteria, and protocol have been published,⁷ and the trial protocol can be found in Supplement 1. Briefly, the SURMOUNT-4 trial was a phase 3 withdrawal randomized clinical trial with a 36-week, open-label tirzepatide lead-in period (week 0 to week 36), after which participants who achieved the maximum tolerated dose of tirzepatide (10 or 15 mg) were randomized 1:1 to either continue tirzepatide or switch to placebo for an additional 52-week, double-blind period (week 36 to week 88). This analysis focused on participants who were randomized to placebo and, therefore, stopped tirzepatide. Throughout the study, treatment was an adjunct to a reduced calorie diet (healthy 500 kcal per day deficit) and increased physical activity (at least 150 minutes per week). Eligible participants were adults with a BMI of 30 or greater or of 27 or greater with at least 1 weight-related complication. Key exclusion criteria included diabetes, prior or planned surgical treatment for obesity, and treatment with a medication that promotes weight reduction within 3 months prior to enrollment. Race and ethnicity were self-reported by participants using fixed selection categories (race: Asian, Black or African American, Native Hawaiian or Other Pacific Islander, or White; ethnicity: Hispanic/Latino or non-Hispanic). However, the study was not designed to represent the racial diversity of the participating countries.

The study protocol was approved by local ethical review boards. Written informed consent was obtained from all participants. This study was conducted according to local regulations and the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

Procedures

Participants were categorized by degree of weight regain from week 36 to week 88 after tirzepatide withdrawal. The degree of weight regain was assessed as a percentage of weight reduction from week 0 to week 36. The percentage of weight regain from week 36 to week 88 relative to weight reduction at week 36 was grouped into the following categories: less than 25%, 25% to less than 50%, 50% to less than 75%, and 75% or more.

Outcomes

Outcomes included changes from week 36 to week 88 in weight, BMI, and cardiometabolic parameters by categories of weight regain from week 36 to week 88 relative to weight reduction at week 36. Cardiometabolic parameters included WC, systolic BP (SBP), diastolic BP (DBP), triglycerides, non–high-density lipoprotein (HDL) cholesterol, HDL cholesterol, HbA_1c, FSG, fasting insulin, and indexes of homeostatic model assessment of insulin resistance (HOMA2-IR) and β-cell function (HOMA2-B). Changes from week 0 to week 36 and changes over week 0 to week 88 in weight, BMI, and cardiometabolic parameters were also reported by categories of weight regain from week 36 to week 88 relative to weight reduction at week 36.

Statistical Analysis

This post hoc analysis was performed on the modified intent-to-treat population, comprising all randomly assigned participants who were exposed to at least 1 dose of the study drug. The analysis only included tirzepatide-treated participants randomized to placebo who achieved 10% or more weight reduction at week 36 with the maximum tolerated dose of tirzepatide. The 10% cutoff was chosen to build an analysis population of clinically meaningful weight reduction. Most participants met this cutoff (308 of 335 participants). Only participants with a nonmissing week 36 weight measurement value and at least 1 nonmissing weight measurement value after week 36 were included in the analysis.

For the calculation of percentage of weight regain from week 36 to week 88 relative to week 36, missing weight measures at week 88 were imputed by predictions using observed data through a mixed model for repeated measures adjusted for week 0 value, week 36 value, country, sex, and maximum tolerated dose of tirzepatide at week 36. All outcomes were evaluated within each category of weight regain.

Baseline demographic and clinical characteristics (at week 0) and changes from week 0 to week 36 in clinical characteristics were assessed using descriptive summary statistics. Continuous variables were presented as means and SDs and categorical variables were presented as counts and percentages. P values for comparison among categories of weight regain from week 36 to week 88 were computed using analysis of variance in continuous data and χ² test in categorical data.

Changes from week 36 to week 88 and over the entire study (week 0 to week 88) in clinical characteristics were assessed using a mixed model for repeated measures adjusted for week 0 value, week 36 value, country, sex, and maximum tolerated dose of tirzepatide at week 36. Fasting lipids, fasting insulin, HOMA2-IR, and HOMA2-B were analyzed on log-transformed data due to their skewed distributions and then converted back on the scale of percentage change. All results were presented as least-squares means and SEs or 2-sided 95% CIs with corresponding P values. Statistical significance was defined as P < .05, and all P values were 2-tailed. All analyses presented are exploratory in nature. Statistical analyses were performed using SAS version 9.4 (SAS Institute). Data were analyzed from February 2024 to March 2025.

Results

Participants

Among the 335 participants from the modified intent-to-treat population who were randomized to the placebo arm in the SURMOUNT-4 study, 308 participants (with any weight measurement after week 36) achieved at least 10% reduction in imputed weight by the end of the 36-week open-label lead-in period with tirzepatide treatment and were included in this analysis (eFigure 1 in Supplement 2). Among the 308 participants assigned to placebo, 266 (86.4%) completed the study visit at week 88 with an observed weight measurement (eTable 1 in Supplement 2). 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. Baseline (week 0) demographic and clinical characteristics were similar across categories of weight regain from week 36 to week 88 (Table 1; eTable 2 in Supplement 2). There were no statistically significant differences among weight regain categories for any of the variables at week 0.

Table 1. Baseline (Week 0) Demographic and Clinical Characteristics by Categories of Weight Regain in Participants Randomized to Tirzepatide Withdrawal^a.

Characteristic	Participants, No. (%)					P value
	Weight regain at week 88				Overall (N = 308)
	<25% (n = 54)	≥25 to <50% (n = 77)	≥50 to <75% (n = 103)	≥75% (n = 74)	Overall (N = 308)
Age, mean (SD), y	46.3 (12.6)	46.4 (14.3)	48.0 (10.8)	47.1 (11.5)	47.1 (12.2)	.80
Sex
Female	36 (66.7)	60 (77.9)	74 (71.8)	49 (66.2)	219 (71.1)	.37
Male	18 (33.3)	17 (22.1)	29 (28.2)	25 (33.8)	89 (28.9)	.37
Self-reported race
Asian	5 (9.3)	3 (3.9)	10 (9.7)	3 (4.1)	21 (6.8)	.45
Black or African American	4 (7.4)	9 (11.7)	11 (10.7)	6 (8.1)	30 (9.7)
Native Hawaiian or Other Pacific Islander	1 (1.9)	0	0	0	1 (0.3)
White	44 (81.5)	65 (84.4)	80 (77.7)	64 (86.5)	253 (82.1)
Self-reported ethnicity
Hispanic or Latino	27 (50.0)	38 (49.4)	48 (46.6)	29 (39.2)	142 (46.1)	.55
Non-Hispanic	27 (50.0)	39 (50.6)	55 (53.4)	45 (60.8)	166 (53.9)	.55
Maximum tolerated dose of tirzepatide at week 36 before withdrawal, mg
10	2 (3.7)	6 (7.8)	5 (4.9)	3 (4.1)	16 (5.2)	.68
15	52 (96.3)	71 (92.2)	98 (95.1)	71 (95.9)	292 (94.8)	.68
Duration of obesity, mean (SD), y	15.9 (10.0)	14.4 (12.5)	14.7 (11.4)	14.4 (9.5)	14.8 (11.0)	.86
Weight-related complications
0	18 (33.3)	27 (35.1)	29 (28.2)	26 (35.1)	100 (32.5)	.42
1-2	23 (42.6)	33 (42.9)	49 (47.6)	31 (41.9)	136 (44.2)
>2	13 (24.1)	17 (22.1)	25 (24.3)	17 (23.0)	72 (23.4)
Weight, mean (SD), kg	111.2 (22.5)	107.5 (26.9)	103.1 (22.0)	107.7 (20.2)	106.7 (23.1)	.19
BMI, mean (SD)^b	39.2 (6.6)	38.8 (8.7)	37.4 (6.1)	38.7 (6.1)	38.4 (7.0)	.35
BMI category
≥25 to <30	0	2 (2.6)	3 (2.9)	1 (1.4)	6 (1.9)	.58
≥30 to <35	17 (31.5)	25 (32.5)	40 (38.8)	23 (31.1)	105 (34.1)
≥35 to <40	13 (24.1)	25 (32.5)	33 (32.0)	24 (32.4)	95 (30.8)
≥40	24 (44.4)	25 (32.5)	27 (26.2)	26 (35.1)	102 (33.1)
Waist circumference, mean (SD), cm	116.6 (14.3)	114.2 (14.5)	113.0 (15.5)	117.0 (13.9)	114.9 (14.7)	.27
Blood pressure, mean (SD), mm Hg
Systolic	124.3 (12.1)	126.1 (13.6)	125.3 (12.4)	124.3 (12.8)	125.1 (12.7)	.78
Diastolic	79.2 (7.9)	81.6 (7.6)	82.0 (8.5)	80.9 (7.7)	81.1 (8.0)	.21
Pulse rate, mean (SD), beats/min	72.4 (9.6)	74.7 (9.1)	73.0 (9.2)	71.6 (8.4)	73.0 (9.1)	.20
Triglycerides, mean (SD), mg/dL	125.5 (60.6)	126.8 (66.4)	142.0 (123.1)	127.2 (77.2)	131.8 (90.7)	.58
Non–HDL-C, mean (SD), mg/dL	139.6 (38.4)	139.2 (32.0)	147.4 (40.2)	135.8 (34.2)	141.2 (36.7)	.18
HDL-C, mean (SD), mg/dL	51.1 (11.1)	52.4 (12.9)	50.1 (13.6)	53.6 (14.4)	51.7 (13.2)	.34
Hemoglobin A_1c, mean (SD), %	5.6 (0.4)	5.5 (0.4)	5.5 (0.4)	5.5 (0.4)	5.5 (0.4)	.23
Hemoglobin A_1c category
<5.7%	28 (51.9)	51 (66.2)	69 (67.0)	50 (67.6)	198 (64.3)	.22
≥5.7%	26 (48.1)	26 (33.8)	34 (33.0)	24 (32.4)	110 (35.7)	.22
Fasting glucose, mean (SD), mg/dL	93.1 (11.5)	94.6 (11.7)	93.9 (10.0)	94.4 (10.2)	94.0 (10.7)	.87
Fasting insulin, mean (SD), μIU/mL	13.6 (11.1)	13.5 (10.7)	13.8 (9.8)	13.0 (11.6)	13.5 (10.6)	.96

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Abbreviations: BMI, body mass index; HDL-C, high-density lipoprotein cholesterol.

SI conversions: To convert triglycerides to mmol/L, multiply by 0.0113; HDL-C to mmol/L, multiply by 0.0259; hemoglobin A_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.

^{^a}

Data in participants with ≥10% weight reduction at week 36 (randomization).

^{^b}

Calculated as weight in kilograms divided by height in meters squared.

Summary of Weight Regain at Week 88 Relative to Weight Reduction at Week 36

A waterfall plot of the percentage weight regain from week 36 to week 88 on tirzepatide withdrawal is shown in eFigure 2 in Supplement 2. Of the 308 participants included in this analysis, 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. Therefore, at week 88, 254 participants (82.5%) who stopped tirzepatide regained 25% or more of the initial weight reduction achieved at week 36 and 54 (17.5%) regained less than 25%.

Changes in Cardiometabolic Parameters During the Lead-In Period (Week 0 to Week 36)

The summary of changes in cardiometabolic parameters from week 0 to week 36 during the tirzepatide lead-in treatment period by categories of weight regain at week 88 is presented in Table 2 and eTable 2 in Supplement 2. There was a decrease in weight, BMI, WC, SBP, DBP, triglycerides, non-HDL cholesterol, HDL cholesterol, HbA_1c, FSG, fasting insulin, HOMA2-IR, and HOMA2-B.

Table 2. Clinical Characteristics at Week 36 (Randomization) and Week 88 by Categories of Weight Regain in Participants Randomized to Tirzepatide Withdrawal^a.

Outcome	Weight regain at week 88				Overall (N = 308)	P value
Outcome	<25% (n = 54)	≥25 to <50% (n = 77)	≥50 to <75% (n = 103)	≥75% (n = 74)	Overall (N = 308)	P value
Weight, kg
Week 36, mean (SD)	85.1 (19.8)	82.7 (22.8)	80.2 (19.5)	88.1 (18.8)	83.6 (20.4)	.07
Percentage change from week 0 to week 36, mean (SD)	−23.6 (7.2)	−23.4 (6.3)	−22.6 (6.1)	−18.3 (5.7)	−21.9 (6.6)	<.001
Week 88, LSM (95% CI)	87.2 (86.0 to 88.4)	91.5 (90.7 to 92.3)	94.5 (93.5 to 95.5)	107.0 (105.6 to 108.4)	95.5 (94.5 to 96.5)	NA
Percentage change from week 36 to week 88, LSM (95% CI)	3.2 (1.8 to 4.6)^b	11.7 (10.5 to 12.9)^b	18.5 (17.1 to 19.9)^b	22.9 (20.9 to 24.9)^b	15.1 (13.9 to 16.3)^b	<.001
BMI ^c
Week 36, mean (SD)	29.9 (5.9)	29.8 (7.3)	29.0 (5.8)	31.6 (5.9)	30.0 (6.3)	.05
Change from week 0 to week 36, mean (SD)	−9.2 (3.1)	−9.0 (3.1)	−8.3 (2.3)	−7.0 (2.3)	−8.3 (2.8)	<.001
Week 88, LSM (95% CI)	30.6 (30.2 to 31.0)	33.1 (32.7 to 33.5)	34.1 (33.7 to 34.5)	38.6 (38.0 to 39.2)	34.3 (33.9 to 34.7)	NA
Change from week 36 to week 88, LSM (95% CI)	0.9 (0.5 to 1.3)^b	3.3 (2.9 to 3.7)^b	5.1 (4.7 to 5.5)^b	6.9 (6.3 to 7.5)^b	4.4 (4.0 to 4.8)^b	<.001
Waist circumference, cm
Week 36, mean (SD)	97.0 (14.6)	94.2 (15.4)	95.2 (14.8)	100.8 (14.3)	96.6 (15.0)	.03
Change from week 0 to week 36, mean (SD)	−19.6 (9.1)	−20.0 (7.4)	−17.9 (7.9)	−16.2 (8.5)	−18.3 (8.2)	.02
Week 88, LSM (95% CI)	97.6 (95.8 to 99.4)	99.4 (98.0 to 100.8)	105.3 (104.1 to 106.5)	115.0 (113.0 to 117.0)	104.8 (103.8 to 105.8)	NA
Change from week 36 to week 88, LSM (95% CI)	0.8 (−1.0 to 2.6)	5.4 (4.0 to 6.8)^b	10.1 (8.9 to 11.3)^b	14.7 (12.7 to 16.7)^b	8.4 (7.4 to 9.4)^b	<.001
Systolic blood pressure, mm Hg
Week 36, mean (SD)	113.7 (12.8)	113.8 (11.8)	114.9 (12.6)	114.4 (10.7)	114.3 (12.0)	.92
Change from week 0 to week 36, mean (SD)	−10.6 (12.4)	−12.3 (13.0)	−10.5 (12.7)	−9.9 (12.5)	−10.8 (12.6)	.67
Week 88, LSM (95% CI)	120.4 (117.5 to 123.3)	121.3 (118.8 to 123.8)	124.6 (122.1 to 127.1)	124.5 (122.1 to 126.9)	123.0 (121.6 to 124.4)	NA
Change from week 36 to week 88, LSM (95% CI)	6.8 (3.9 to 9.7)^b	7.3 (4.8 to 9.8)^b	9.6 (7.1 to 12.1)^b	10.4 (8.0 to 12.8)^b	8.7 (7.3 to 10.1)^b	.002
Diastolic blood pressure, mm Hg
Week 36, mean (SD)	73.9 (8.8)	76.0 (8.7)	77.3 (8.2)	76.5 (8.9)	76.2 (8.6)	.13
Change from week 0 to week 36, mean (SD)	−5.3 (7.5)	−5.6 (8.5)	−4.7 (10.1)	−4.3 (9.0)	−5.0 (9.0)	.83
Week 88, LSM (95% CI)	76.8 (74.6 to 79.0)	77.7 (75.9 to 79.5)	81.2 (79.4 to 83.0)	80.4 (78.6 to 82.2)	79.3 (78.3 to 80.3)	NA
Change from week 36 to week 88, LSM (95% CI)	2.8 (0.6 to 5.0)^d	1.6 (−0.2 to 3.4)	3.9 (2.1 to 5.7)^b	4.3 (2.5 to 6.1)^b	3.2 (2.2 to 4.2)^b	<.001
Pulse rate, beats/min
Week 36, mean (SD)	77.7 (9.0)	78.0 (7.6)	77.9 (9.7)	78.1 (9.2)	77.9 (9.0)	1.00
Change from week 0 to week 36, mean (SD)	5.4 (9.7)	3.3 (8.3)	4.9 (9.1)	6.5 (8.4)	5.0 (8.9)	.18
Week 88, LSM (95% CI)	72.5 (70.2 to 74.8)	71.2 (69.5 to 72.9)	71.9 (70.2 to 73.6)	73.7 (71.9 to 75.5)	72.3 (71.3 to 73.2)	NA
Change from week 36 to week 88, LSM (95% CI)	−5.4 (−7.7 to −3.1)^b	−6.7 (−8.4 to −5.0)^b	−5.7 (−7.4 to −4.0)^b	−4.2 (−6.0 to −2.4)^b	−5.5 (−6.5 to −4.6)^b	.50
Triglycerides, mg/dL^e
Week 36, mean (SD)	85.7 (31.0)	89.7 (38.9)	88.6 (40.7)	102.0 (58.2)	91.6 (43.9)	.12
Change from week 0 to week 36, mean (SD)	−39.8 (45.0)	−37.2 (51.6)	−53.4 (93.4)	−25.2 (58.2)	−40.2 (69.5)	.06
Week 88, LSM (95% CI)	84.7 (74.9 to 94.5)	87.6 (80.9 to 94.3)	104.6 (97.0 to 112.2)	109.2 (99.8 to 118.6)	97.4 (93.1 to 101.7)	NA
Percentage change from week 36 to week 88, LSM (95% CI)	5.5 (−6.7 to 17.7)	5.3 (−2.7 to 13.3)	29.6 (20.2 to 39.0)^b	18.9 (8.7 to 29.1)^b	16.1 (11.0 to 21.2)^b	NA
Non–HDL-C, mg/dL^e
Week 36, mean (SD)	129.4 (41.7)	129.4 (31.4)	133.9 (37.9)	130.5 (31.4)	131.2 (35.5)	.81
Change from week 0 to week 36, mean (SD)	−10.2 (32.6)	−9.8 (29.0)	−13.4 (30.0)	−5.3 (23.7)	−10.0 (28.9)	.33
Week 88, LSM (95% CI)	124.9 (116.3 to 133.5)	128.3 (123.2 to 133.4)	138.4 (132.5 to 144.3)	139.2 (132.3 to 146.1)	133.6 (130.3 to 136.9)	NA
Percentage change from week 36 to week 88, LSM (95% CI)	−0.4 (−7.3 to 6.5)	1.6 (−2.3 to 5.5)	8.4 (3.9 to 12.9)^b	10.8 (5.3 to 16.3)^b	5.6 (3.1 to 8.1)^b	NA
HDL-C, mg/dL^e
Week 36, mean (SD)	47.2 (11.8)	50.3 (11.5)	48.0 (11.6)	49.5 (11.7)	48.8 (11.7)	.39
Change from week 0 to week 36, mean (SD)	−3.9 (8.9)	−2.1 (8.0)	−2.1 (8.0)	−4.1 (7.9)	−2.9 (8.1)	.24
Week 88, LSM (95% CI)	55.9 (53.2 to 58.6)	57.7 (55.5 to 59.9)	53.8 (52.0 to 55.6)	54.0 (52.0 to 56.0)	55.2 (54.2 to 56.2)	NA
Percentage change from week 36 to week 88, LSM (95% CI)	19.7 (13.8 to 25.6)^b	16.7 (12.6 to 20.8)^b	13.6 (9.7 to 17.5)^b	13.4 (9.3 to 17.5)^b	15.4 (13.2 to 17.6)^b	NA
Hemoglobin A_1c, %
Week 36, mean (SD)	5.1 (0.3)	5.0 (0.3)	5.0 (0.3)	5.0 (0.4)	5.0 (0.3)	.54
Change from week 0 to week 36, mean (SD)	−0.51 (0.25)	−0.41 (0.28)	−0.51 (0.27)	−0.46 (0.23)	−0.47 (0.26)	.07
Week 88, LSM (95% CI)	5.2 (5.1 to 5.3)	5.2 (5.1 to 5.3)	5.3 (5.2 to 5.4)	5.4 (5.3 to 5.5)	5.3 (5.26 to 5.34)	NA
Change from week 36 to week 88, LSM (95% CI)	0.14 (0.06 to 0.22)^b	0.15 (0.09 to 0.21)^b	0.27 (0.21 to 0.33)^b	0.35 (0.29 to 0.41)^b	0.24 (0.20 to 0.28)^b	<.001
Fasting glucose, mg/dL
Week 36, mean (SD)	85.6 (7.7)	84.6 (7.8)	83.6 (7.3)	85.5 (7.1)	84.7 (7.5)	.29
Change from week 0 to week 36, mean (SD)	−7.5 (9.8)	−10.0 (10.5)	−10.3 (9.1)	−9.0 (9.6)	−9.4 (9.7)	.36
Week 88, LSM (95% CI)	89.2 (87.0 to 91.4)	92.1 (90.3 to 93.9)	92.8 (90.6 to 95.0)	94.3 (92.3 to 96.3)	92.3 (91.3 to 93.3)	NA
Change from week 36 to week 88, LSM (95% CI)	3.8 (1.6 to 6.0)^b	6.9 (5.1 to 8.7)^b	9.2 (7.0 to 11.4)^b	9.0 (7.0 to 11.0)^b	7.6 (6.6 to 8.6)^b	<.001
Fasting insulin, μIU/mL^e
Week 36, mean (SD)	7.5 (6.3)	7.1 (5.6)	6.9 (5.3)	8.8 (4.9)	7.5 (5.5)	.13
Change from week 0 to week 36, mean (SD)	−6.5 (7.6)	−6.4 (8.3)	−6.8 (9.0)	−4.2 (9.6)	−6.0 (8.8)	.24
Week 88, LSM (95% CI)	5.6 (4.6 to 6.6)	6.2 (5.4 to 7.0)	8.0 (7.0 to 9.0)	9.6 (8.4 to 10.8)	7.4 (6.8 to 8.0)	NA
Percentage change from week 36 to week 88, LSM (95% CI)	−4.0 (−20.7 to 12.7)	15.4 (2.3 to 28.5)^d	46.2 (29.5 to 62.9)^b	26.3 (9.6 to 43.0)^b	23.3 (15.1 to 31.5)^b	NA

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Abbreviations: BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; LSM, least-squares mean; NA, not applicable.

^{^a}

Data in participants with 10% or more weight reduction at week 36.

^{^b}

P ≤ .001 vs week 36.

^{^c}

Calculated as weight in kilograms divided by height in meters squared.

^{^d}

P < .05 vs week 36.

^{^e}

Fasting lipids and insulin at week 88 and percentage change from week 36 to week 88 were analyzed on log-transformed data and then converted back on the scale of percentage change. No statistical comparison among weight regain categories available for fasting lipids and insulin at week 88 and percentage change from week 36 to week 88.

There were statistically significant differences among categories of weight regain at week 88 for the changes from week 0 to week 36 in weight, BMI, and WC. Namely, greater weight regain at week 88, after 52 weeks of tirzepatide withdrawal, was associated with smaller initial reductions in weight, BMI, and WC at week 36 after completing the tirzepatide treatment period. There were no statistically significant differences among weight regain categories for the decreases from week 0 to week 36 in BP, fasting lipids, HbA_1c, FSG, fasting insulin, and HOMA2-IR.

Changes in Cardiometabolic Parameters During the Randomized Period (Week 36 to Week 88)

The summary of changes in cardiometabolic parameters from week 36 to week 88 after tirzepatide withdrawal by categories of weight regain at week 88 is presented in Table 2 and eTable 2 in Supplement 2. Changes over time are displayed in Figure 1, Figure 2, and Figure 3. On tirzepatide withdrawal, greater weight regain at week 88 was associated with greater reversal of improvements in weight, BMI, WC, BP, triglycerides, non-HDL cholesterol, HbA_1c, FSG, fasting insulin, and HOMA2-IR. After withdrawal of tirzepatide, from week 36 to week 88, the mean change in weight increased by weight regain category (<25% weight regain, 3.2% [95% CI, 1.8-4.6]; 25% to <50%, 11.7% [95% CI, 10.5-12.9]; 50% to <75%, 18.5% [95% CI, 17.1-19.9]; ≥75%, 22.9% [95% CI, 20.9-24.9]; P < .001), as did BMI (0.9 [95% CI, 0.5-1.3], 3.3 [95% CI, 2.9-3.7], 5.1 [95% CI, 4.7-5.5], and 6.9 [95% CI, 6.3-7.5], respectively; P < .001), WC (0.8 cm [95% CI, −1.0 to 2.6], 5.4 cm [95% CI, 4.0-6.8], 10.1 cm [95% CI, 8.9-11.3], and 14.7 cm [95% CI, 12.7-16.7], respectively; P < .001), SBP (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), DBP (2.8 mm Hg [95% CI, 0.6-5.0], 1.6 mm Hg [95% CI, −0.2 to 3.4], 3.9 mm Hg [95% CI, 2.1-5.7], and 4.3 mm Hg [95% CI, 2.5-6.1], respectively; P < .001), triglycerides (5.5% [95% CI, −6.7 to 17.7], 5.3% [95% CI, −2.7 to 13.3], 29.6% [95% CI, 20.2 to 39.0], and 18.9% [95% CI, 8.7 to 29.1], respectively), non-HDL 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), HbA_1c (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), FSG (3.8 mg/dL [95% CI, 1.6-6.0], 6.9 mg/dL [95% CI, 5.1-8.7], 9.2 mg/dL [95% CI, 7.0-11.4], and 9.0 mg/dL [95% CI, 7.0-11.0], respectively; P < .001), 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), and HOMA2-IR (0.6% [SE, 5.07], 12.6% [SE, 4.39], 39.5% [SE, 5.44], and 27.0% [SE, 5.49], respectively). Changes at week 88 in WC, triglycerides, non-HDL cholesterol, fasting insulin, and HOMA2-IR in participants with less than 25% weight regain were not significantly different compared with week 36.

Figure 1. — 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. — 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. — 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.

Of note, a statistically significant mean increase from week 36 to week 88 in HDL cholesterol was observed across all categories of weight regain (<25% weight regain, 19.7% [95% CI, 13.8-25.6]; 25% to <50%, 16.7% [95% CI, 12.6-20.8]; 50% to <75%, 13.6% [95% CI, 9.7-17.5]; ≥75%, 13.4% [95% CI, 9.3-17.5]; P ≤ .001) (Table 2). On the other hand, a statistically significant decrease from week 36 to week 88 in HOMA2-B was observed for the less than 25% and the 25% to less than 50% weight regain categories (eTable 2 in Supplement 2).

Changes in Cardiometabolic Parameters Over the Entire Study (Week 0 to Week 88)

Changes in cardiometabolic parameters over the entire study (week 0 to week 88) by categories of weight regain at week 88 are shown in eFigures 3 to 6 in Supplement 2. Overall, at week 88, participants with 75% or more weight regain after tirzepatide withdrawal reversed cardiometabolic parameters to baseline (week 0) values. Participants with less than 25% and 25% to less than 50% weight regain had significantly lower values than baseline at week 88 in WC, SBP, DBP, triglycerides, non-HDL cholesterol, HbA_1c, FSG, and fasting insulin.

Of note, a significant increase from baseline to week 88 in HDL cholesterol was observed across all categories of weight regain (eFigure 5C in Supplement 2).

Discussion

This post hoc analysis evaluated the association between the degree of weight regain and cardiometabolic parameters on withdrawal of tirzepatide in participants who achieved clinically meaningful (≥10%) weight reduction during the 36-week tirzepatide lead-in treatment in the SURMOUNT-4 trial. As expected and in line with similar research with obesity management medications,^5,6,7 withdrawal of tirzepatide led to most participants regaining weight despite continued lifestyle intervention. Interestingly, the magnitude of weight regain following 1 year of tirzepatide withdrawal varied widely. For example, we found that most participants (254 [82.5%]) had regained 25% or more of the initial weight reduction achieved during the 36-week tirzepatide lead-in treatment. Weight regain of 25% or more of initial weight reduction has clinical relevance given the evidence to date suggesting the loss of cardiometabolic benefit at or beyond this level of weight regain.^10,11 Furthermore, approximately 1 in 2 participants have regained 50% or more of the weight reduction and 1 in 4 regained most (≥75%) of the weight reduction, with almost 9% of participants experiencing more than 100% weight regain. On the other hand, a small fraction of the participants (54 [17.5%]) experienced limited weight regain (<25%) on withdrawal of tirzepatide and with continued lifestyle modification. Approximately 4% of participants continued to lose weight on withdrawal of tirzepatide and continued lifestyle intervention. There were no apparent differences in baseline demographic and clinical characteristics of participants across the different categories of weight regain. Combined, most participants regained weight on withdrawal of tirzepatide, and there was a heterogeneity in the different magnitudes of weight regain observed across the participants, likely related to different factors underlying the pathophysiology of obesity and treatment response.

Overall, greater weight regain on tirzepatide withdrawal was associated with a greater reversal of improvements in cardiometabolic parameters, including WC, BP, lipids, and HbA_1c with tirzepatide treatment. This observation is consistent with the findings observed with lifestyle intervention in the Look AHEAD trial¹⁰ and with the withdrawal of glucagon-like peptide-1 receptor agonist semaglutide, 2.4 mg, in the STEP 1 trial extension.¹¹ In the SURMOUNT-4 trial, participants who maintained the weight reduction (<25% weight regain) at week 88 also maintained on average the benefits gained in central adiposity, triglycerides, non-HDL cholesterol, fasting insulin, and insulin resistance. In another study, repeated cycles of weight reduction and weight regain may be detrimental to health, as the regained weight after intentional weight reduction may be proportionally higher in fat mass, thus potentially impacting the body composition in an unhealthy way.¹² Combined, these observations support the health benefits of sustained, long-term treatment of obesity.

The impact on lipid parameters, including triglycerides and non-HDL, with tirzepatide withdrawal was as expected. For example, the reversal of improvement in triglycerides and non-HDL on tirzepatide withdrawal was significantly greater in participants who regained a substantial amount (≥50%) of their initial weight reduction. On the other hand, a mean reduction in HDL cholesterol was observed with tirzepatide treatment followed by a statistically significant increase in HDL cholesterol on tirzepatide withdrawal. The transitory decrease in HDL cholesterol with weight reduction and subsequent increase reverting the initial effect has previously been observed in people reducing weight through diet.¹³ Further insights on the effect of tirzepatide-induced weight changes on HDL cholesterol changes are currently being investigated.

Additionally, SBP significantly increased on withdrawal of tirzepatide across all categories of weight regain, with higher increase observed with greater magnitudes of weight regain. Previous analyses of the SURPASS clinical trials and the SURMOUNT-1 ambulatory BP monitoring substudy reported a decrease in SBP with tirzepatide treatment in participants with type 2 diabetes and/or obesity.^14,15 The improvement in BP with tirzepatide treatment and subsequent deterioration on withdrawal of tirzepatide is likely related to both weight-dependent and weight-independent mechanisms.¹⁴ The proposed weight-independent mechanisms for the effect of incretins on BP include reduction in sympathetic activity, a natriuretic effect through the inhibition of renin angiotensin aldosterone system and subsequent inhibition of the sodium reabsorption at the level of the kidneys, and a beneficial effect on vascular remodeling and on endothelial function.¹⁶ However, further studies are needed to understand these mechanisms.

Notably, the reversal in glycemic benefits in HbA_1c and FSG were observed early on within 16 weeks of withdrawing tirzepatide likely due to the known direct glucose-lowering effect of tirzepatide, and as expected, the magnitude of reversal in HbA_1c improvement was greater with higher degrees of weight regain.^17,18 Similarly, there was a trend for greater reversal in the improvement in markers of insulin resistance, such as fasting insulin and HOMA2-IR, with higher magnitudes of weight regain on tirzepatide withdrawal. On the other hand, a marker of β-cell function, HOMA2-B, decreased with tirzepatide treatment and decreased further with withdrawal of tirzepatide. This observation is in contrast to previously reported post hoc studies of tirzepatide in adults with type 2 diabetes and obesity, where a significant increase in HOMA2-B with tirzepatide treatment was observed.^19,20 Therefore, further studies are warranted to confirm the observations with regard to insulin resistance and pancreatic β-cell function in adults with obesity.

Finally, although some improvement from baseline was still observed in all assessed cardiometabolic parameters despite partial weight regain of up to 50% after 1 year of tirzepatide withdrawal, these findings support the importance of long-term maintenance of weight reduction through lifestyle intervention and obesity management medications to sustain cardiometabolic benefits and improved health-related quality of life.^6,11,21,22 Together, these results may inform patient-clinician conversations and shared decision-making on long-term weight management focused on sustained health benefits and help counsel patients on the implications of treatment discontinuation. Future studies are warranted to evaluate and optimize strategies for maintenance of weight reduction.

Strengths and Limitations

Strengths of this analysis included the randomized withdrawal design of the SURMOUNT-4 trial with continued lifestyle intervention in the placebo arm, high study completion rate, a wide range of weight regain observed after tirzepatide withdrawal (which allowed for categorical evaluation of weight regain), and long-term follow-up data over 52 weeks to observe changes in anthropometrics and cardiometabolic parameters. Limitations included the post hoc nature of the analysis, lack of data on the impact on body composition, and objective measures on physical activity and diet to correlate with this analysis. In addition, longer time is needed to determine if the preserved benefits seen with lower weight regain would eventually be lost, and the categorical evaluation of weight regain may not have allowed for a more detailed look at the weight regain cutoff associated with reversal of cardiometabolic benefits from weight reduction.

Conclusions

In this post hoc analysis of the SURMOUNT-4 trial, most participants (82%) among those who achieved clinically meaningful weight reduction with tirzepatide treatment regained 25% or more of their initial weight reduction within 1 year of withdrawing tirzepatide. Higher weight regain on withdrawal of tirzepatide was associated with a greater reversal of improvements in cardiometabolic parameters achieved with tirzepatide treatment. These findings support the need for continued obesity treatment in adults living with obesity.

Supplement 1.

Trial Protocol

jamainternmed-e256112-s001.pdf^{(9.9MB, pdf)}

Supplement 2.

eTable 1. Summary of Weight Regain at Week 88 Relative to Weight Reduction at Week 36: Observed vs Imputed Data

eTable 2. HOMA2-IR and HOMA2-B at Week 0 (Baseline), Week 36 (Randomization), and Week 88 by Categories of Weight Regain in Participants Randomized to Tirzepatide Withdrawal

eFigure 1. Flow of Participants

eFigure 2. Waterfall Plot of the Percentage Weight Regain From Week 36 to Week 88 on Tirzepatide Withdrawal

eFigure 3. Change in Weight, BMI, and Waist Circumference From Baseline by Categories of Weight Regain

eFigure 4. Change in Blood Pressure From Baseline by Categories of Weight Regain

eFigure 5. Percentage Change in Fasting Lipids From Baseline by Categories of Weight Regain

eFigure 6. Change in Glycemic Parameters From Baseline by Categories of Weight Regain

jamainternmed-e256112-s002.pdf^{(383.3KB, pdf)}

Supplement 3.

Data Sharing Statement

jamainternmed-e256112-s003.pdf^{(18.6KB, pdf)}

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21.Wing RR, Espeland MA, Clark JM, et al. ; Action for Health in Diabetes (Look AHEAD) Study Group . Association of weight loss maintenance and weight regain on 4-year changes in CVD risk factors: the Action for Health in Diabetes (Look AHEAD) clinical trial. Diabetes Care. 2016;39(8):1345-1355. doi: 10.2337/dc16-0509 [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Kolotkin RL, Andersen JR. A systematic review of reviews: exploring the relationship between obesity, weight loss and health-related quality of life. Clin Obes. 2017;7(5):273-289. doi: 10.1111/cob.12203 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocol

jamainternmed-e256112-s001.pdf^{(9.9MB, pdf)}

Supplement 2.

eTable 1. Summary of Weight Regain at Week 88 Relative to Weight Reduction at Week 36: Observed vs Imputed Data

eTable 2. HOMA2-IR and HOMA2-B at Week 0 (Baseline), Week 36 (Randomization), and Week 88 by Categories of Weight Regain in Participants Randomized to Tirzepatide Withdrawal

eFigure 1. Flow of Participants

eFigure 2. Waterfall Plot of the Percentage Weight Regain From Week 36 to Week 88 on Tirzepatide Withdrawal

eFigure 3. Change in Weight, BMI, and Waist Circumference From Baseline by Categories of Weight Regain

eFigure 4. Change in Blood Pressure From Baseline by Categories of Weight Regain

eFigure 5. Percentage Change in Fasting Lipids From Baseline by Categories of Weight Regain

eFigure 6. Change in Glycemic Parameters From Baseline by Categories of Weight Regain

jamainternmed-e256112-s002.pdf^{(383.3KB, pdf)}

Supplement 3.

Data Sharing Statement

jamainternmed-e256112-s003.pdf^{(18.6KB, pdf)}

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PERMALINK

Cardiometabolic Parameter Change by Weight Regain on Tirzepatide Withdrawal in Adults With Obesity

Deborah B Horn, DO, MPH

Bruno Linetzky, MD

Melanie J Davies, MD

Luke J Laffin, MD

Hui Wang, PhD

Madhumita A Murphy, MD

Sarah Zimner-Rapuch, PharmD

Eva Lau, MD, PhD

Avigdor D Arad, PhD

Clare J Lee, MD, MHS

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Study Design and Participants

Procedures

Outcomes

Statistical Analysis

Results

Participants

Table 1. Baseline (Week 0) Demographic and Clinical Characteristics by Categories of Weight Regain in Participants Randomized to Tirzepatide Withdrawala.

Summary of Weight Regain at Week 88 Relative to Weight Reduction at Week 36

Changes in Cardiometabolic Parameters During the Lead-In Period (Week 0 to Week 36)

Table 2. Clinical Characteristics at Week 36 (Randomization) and Week 88 by Categories of Weight Regain in Participants Randomized to Tirzepatide Withdrawala.

Changes in Cardiometabolic Parameters During the Randomized Period (Week 36 to Week 88)

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

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

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

Changes in Cardiometabolic Parameters Over the Entire Study (Week 0 to Week 88)

Discussion

Strengths and Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases

Table 1. Baseline (Week 0) Demographic and Clinical Characteristics by Categories of Weight Regain in Participants Randomized to Tirzepatide Withdrawal^a.

Table 2. Clinical Characteristics at Week 36 (Randomization) and Week 88 by Categories of Weight Regain in Participants Randomized to Tirzepatide Withdrawal^a.