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Clinical Trial
. 2024 Jan 2;331(1):38-48.
doi: 10.1001/jama.2023.24945.

Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial

Louis J Aronne  1 , Naveed Sattar  2 , Deborah B Horn  3 , Harold E Bays  4 , Sean Wharton  5 , Wen-Yuan Lin  6 , Nadia N Ahmad  7 , Shuyu Zhang  7 , Ran Liao  7 , Mathijs C Bunck  7 , Irina Jouravskaya  8 , Madhumita A Murphy  7 ; SURMOUNT-4 Investigators
Collaborators, Affiliations
Clinical Trial

Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial

Louis J Aronne et al. JAMA. .

Abstract

Importance: The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown.

Objective: To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction.

Design, setting, and participants: This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes.

Interventions: Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks.

Main outcomes and measures: The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period.

Results: Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was -5.5% with tirzepatide vs 14.0% with placebo (difference, -19.4% [95% CI, -21.2% to -17.7%]; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo.

Conclusions and relevance: In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction.

Trial registration: ClinicalTrials.gov Identifier: NCT04660643.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Aronne reported receiving grants or personal fees from Altimmune, AstraZeneca, Boehringer Ingelheim, Eli Lilly, ERX, Gelesis, Intellihealth, Jamieson Wellness, Janssen, Novo Nordisk, Optum, Pfizer, Senda Biosciences and Versanis and being a shareholder of Allurion, ERX Pharmaceuticals, Gelesis, Intellihealth, and Jamieson Wellness. Dr Sattar reported receiving personal fees or grants from Abbott Laboratories, Amgen, AstraZeneca, Boehringer, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Roche, and Sanofi outside the submitted work. Dr Horn reported research funding from Lilly and Novo Nordisk during the conduct of the study and personal fees from Eli Lilly, Novo Nordisk, and Gelesis outside the submitted work. Dr Bays reported receiving grants from Eli Lilly during the conduct of the study and grants from 89 Bio, Alon Medtech/Epitomee, Altimmune, Amgen, Boehringer Ingelheim, Kallyope, Novo Nordisk, Pfizer, Shionogi, Viking, and Vivus and personal fees from Altimmune, Amgen, Boehringer Ingelheim, and Eli Lilly outside the submitted work. Dr Wharton reported receiving nonfinancial support from Eli Lilly during the conduct of the study and personal fees from Novo Nordisk, Boehringer Ingelheim, Biohaven, Bausch Health Canada, and Eli Lilly outside the submitted work. Dr Ahmad reported being an employee and shareholder of Eli Lilly and Company during the conduct of the study. Dr Zhang reported being an employee and shareholder of Eli Lilly and Company during the conduct of the study. Dr Liao reported being an employee and shareholder of Eli Lilly and Company during the conduct of the study. Dr Bunck reported being an employee and shareholder of Eli Lilly and Company during the conduct of the study. Dr Murphy reported being an employee and shareholder of Eli Lilly and Company during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow of Participants in the SURMOUNT-4 Trial
aIncludes 10 individuals for whom the site enrollment closed and 1 who was lost to follow-up. bSee Table 3 and eTable 4 in Supplement 2 for the details of the adverse events that led to treatment discontinuation. cThe most common reasons for participant withdrawal included participant no longer wished to participate, participant unavailable to attend visits, participant moved out of state or country, and personal or family issues. dGuided by the treatment regimen estimand.
Figure 2.
Figure 2.. Effect of Tirzepatide vs Placebo on Body Weight and Waist Circumference
Observed mean values from the full analysis set are shown. Error bars represent 95% CI for the mean. The dashed vertical line at week 36 represents the randomization point. Analysis of covariance using the full analysis set with hybrid imputation least-square mean values at week 88 is also shown on the right. See eTable 3 in Supplement 2 for corresponding data for the efficacy estimand.
See this image and copyright information in PMC

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