Stopping Tirzepatide may lead to Weight Regain and Backslide Heart-Metabolic Gains: JAMA
USA: Researchers have found in a new study that stopping tirzepatide (Zepbound) often leads to weight regain, along with the loss of earlier health improvements.
A post-hoc analysis of the SURMOUNT-4 trial found significant worsening in waist circumference, systolic blood pressure, and HbA1c between weeks 36 and 88. Therefore, long-term, continuous use of anti-obesity medications may be needed to maintain weight loss and its cardiometabolic benefits.
The analysis published in JAMA Internal Medicine sheds light on how weight regain after discontinuing tirzepatide affects long-term metabolic health in adults with obesity. The study, led by Deborah B. Horn from the University of Texas Center for Obesity Medicine and colleagues, evaluated whether the extent of weight regain after tirzepatide withdrawal determines how much of the initial health improvements are lost.
The findings stem from the SURMOUNT-4 randomized clinical trial, which initially enrolled adults with obesity or overweight who received tirzepatide for 36 weeks. All participants had achieved at least a 10% weight reduction during this initial phase. They were then randomized either to continue tirzepatide or switch to placebo for the following 52 weeks.
This post-hoc analysis focused on 308 participants who were switched to a placebo after week 36. Researchers assessed how cardiometabolic parameters changed based on the percentage of weight regained by week 88. Participants were grouped into four categories: those who regained less than 25% of lost weight, 25% to <50%, 50% to <75%, and 75% or more.
Key findings of the analysis were as follows:
- Greater weight regain after stopping tirzepatide was linked to a stronger reversal of the health improvements achieved during treatment.
- All participants experienced reductions in weight, waist circumference, blood pressure, lipid levels, and glycemic markers during the initial 36 weeks of tirzepatide therapy.
- These health gains began to decline once tirzepatide was discontinued.
- By week 88, waist circumference increased across all categories, ranging from 0.8 cm in the lowest regain group to 14.7 cm in those who regained 75% or more of the lost weight.
- Systolic blood pressure also increased, with rises ranging from 6.8 mmHg to 10.4 mmHg, depending on the degree of weight regain.
- Deterioration was similarly noted in non–HDL cholesterol, HbA1c, fasting insulin, and other glycemic parameters.
- Participants who regained less than 25% of their lost weight maintained most of their improvements in waist circumference, insulin resistance, and non–HDL cholesterol.
- A majority of participants—approximately 82%—regained at least 25% of the weight they had lost within one year after stopping tirzepatide.
The authors emphasized that these findings reinforce the chronic nature of obesity, indicating that long-term pharmacological therapy may be necessary to sustain both weight loss and associated metabolic improvements. They also acknowledged limitations, including the post-hoc design and the absence of data on body composition, physical activity, and dietary patterns.
"Overall, the study reveals that withdrawing tirzepatide commonly results in significant weight regain and deterioration of cardiometabolic health, highlighting the importance of continued treatment for adults living with obesity," the authors concluded.
Reference:
Horn DB, Linetzky B, Davies MJ, et al. Cardiometabolic Parameter Change by Weight Regain on Tirzepatide Withdrawal in Adults With Obesity: A Post Hoc Analysis of the SURMOUNT-4 Trial. JAMA Intern Med. Published online November 24, 2025. doi:10.1001/jamainternmed.2025.6112
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