Study finds 'substantial' weight regain after Lilly's Zepbound stopped
11 Dec 2023
Phase 3Clinical ResultDrug Approval
According to results from the Phase III SURMOUNT-4 trial published Monday in JAMA, overweight and obese patients who stopped taking Eli Lilly's Zepbound (tirzepatide) regained a "substantial" amount of weight they had lost while on the drug. However, if patients continued treatment with the weekly injectable GIP/GLP-1 agonistGIP/GLP-1 agonist, their initial weight loss was either maintained or they saw an even greater reduction.
The FDA approved Zepbound last month based on the Phase III SURMOUNT-1 and SURMOUNT-2 trials, where the drug was associated with weight reductions of up to 22.5% and 15.7%, respectively, which was significantly more than placebo in both cases at 72 weeks of treatment. The first study included patients without type 2 diabetes who are obese, or are overweight and have at least one comorbidity, while the second enrolled overweight and obese patients with type 2 diabetes.
SURMOUNT-4 sought to assess the effect of Zepbound, with diet and physical activity, on the maintenance of weight reduction. In the trial, 783 participants enrolled in an open-label lead-in period received once-weekly subcutaneous Zepbound at either the 10mg or 15mg dose for 36 weeks, at which point 670 of them were randomised to continue receiving Zepbound or switch to placebo for 52 weeks.
Nearly 10% weight loss after placebo switch
The 670 patients who completed the 36-week lead-in period experienced a 20.9% mean weight reduction. For the primary endpoint of mean percent change in weight from weeks 36 to 88, there was an additional 5.5% weight lost on average among patients who continued with Zepbound, whereas those who switched to placebo experienced a 14% weight regain.
The overall mean weight reduction from week 0 to 88 was 25.3% with Zepbound and 9.9% for placebo. On a key secondary endpoint, 89.5% receiving Zepbound at 88 weeks maintained at least 80% of the weight they had lost during the lead-in period, compared to 16.6% for the placebo group. Compared to placebo, Zepbound was also associated with significant improvements from weeks 36 to 88 in body mass index, HbA1c, fasting glucose, insulin, lipid levels, and systolic and diastolic blood pressure.
"A notable finding in the SURMOUNT-4 trial is that after switching to placebo for one year, participants ended the study with substantial body weight reduction (9.9%). However, much of their initial improvement in cardiometabolic risk factors had been reversed," the authors noted, adding that more studies would be "needed to understand the potential long-term benefits and risks of such short-term therapy."
Researchers noted that the most common side effects were mostly mild-to-moderate gastrointestinal events, which occurred more commonly with Zepbound than placebo. Treatment discontinuation due to an adverse event (AE) occurred in 7% participants during the lead-in treatment period, mainly due to gastrointestinal events. During the double-blind period, treatment discontinuation due to an AE occurred in 1.8% of participants on Zepbound versus 0.9% in the placebo group.
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