Continued treatment with tirzepatide not only maintained but also increased weight loss among individuals with overweight and obesity whereas discontinuing tirzepatide saw a rebound of the weight lost, according to findings from the phase 3 SURMOUNT-4 trial published in the Journal of the American Medical Association.¹

In this study, the researchers sought to examine the role of continuing or withdrawing tirzepatide along with diet and exercise in maintaining the reduction in body weight in participants with overweight or obesity. The trial was conducted at 70 centers in Brazil, Argentina, Taiwan and the US, and included a 36-week open-label tirzepatide lead-in period followed by a 52-week double-blind, placebo-controlled period. The eligible participants were adults with BMI ≥30 along with a comorbid condition on account of the body weight other than diabetes, most commonly hypertension and dyslipidemia. At baseline, the mean BMI was 38.4 and waist circumference was 115.2 cm.

Tirzepatide was administered subcutaneously once a week for 36 weeks at the maximum tolerable dose (10 or 15 mg) to 783 participants who were enrolled in an open-label lead-in period. At week 36, 670 study subjects were randomized (1:1) to either stay on tirzepatide (n = 355) or switch to a placebo (n = 355) for a 52-week period. The mean percent change in weight from week 36 (at the time of randomization) to week 88 was the main outcome. The percentage of participants who maintained at least 80% of the weight loss during the lead-in period at week 88 was an important secondary end goal.

The 670 participants, including 71% women, who had completed the 36-week lead-in period recorded a mean weight loss of 20.9%. Between weeks 36 and 88, the average percentage additional change in weight was -5.5% with continuous use of tirzepatide, while those randomized to placebo (withdrawal of tirzepatide) gained 14.0% of the weight (difference -19.4%). When compared to 16.6% of participants who received a placebo at 88 weeks after the beginning of the lead-in phase, 89.5% (n=300) of those who received tirzepatide maintained at least 80% of the weight loss during the lead-in period (P <.001). The mean weight reduction with tirzepatide, between week 0 and week 88, was 25.3%, while for placebo it was 9.9% at the end of the study. Throughout the study, an improvement was noted in body weight, BMI, waist circumference, glycemic profile, lipid levels and blood pressure with tirzepatide.

Compared to placebo, tirzepatide caused more frequent gastrointestinal problems (such as nausea, vomiting, diarrhea and constipation) that were mostly mild to moderate in nature.

Based on their findings, the authors drew a conclusion that discontinuing tirzepatide caused a rebound in weight gain in obese or overweight subjects, but continuing treatment preserved and increased the initial weight loss. The authors note that “the consistency of these data across therapeutic classes spanning more than 2 decades suggests that obesity is a chronic metabolic condition similar to type 2 diabetes and hypertension requiring long-term therapy in most patients”. This trial therefore highlights the need for continuous treatment to maintain the weight loss and prevent rebound weight gain.

Reference

1. Louis J Aronne, et al; SURMOUNT-4 Investigators. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA. 2024 Jan 2;331(1):38-48. doi: 10.1001/jama.2023.24945.