Tirzepatide Demonstrates Sustained Weight Loss but Discontinuation Results in Weight Regain: SURMOUNT-4 Trial

Detailed results from the phase 3 SURMOUNT-4 clinical trial of tirzepatide (Zepbound™; Eli Lilly and Company) showed that withdrawal of the antiobesity medication following open-label treatment for 36 weeks in adults with obesity or overweight was followed by a mean weight regain of 14% over the next 52 weeks while continuation of tirzepatide resulted in additional weight loss of 6.7%.

^{Courtesy of Eli Lilly}

SURMOUNT-4 participants who continued tirzepatide treatment from week 36 to 88 achieved a total mean weight loss of 26% from study entry. Study findings were published online December 11, 2023, in JAMA.

“The SURMOUNT-4 trial results emphasize the need to continue pharmacotherapy to prevent weight regain and ensure the maintenance of weight reduction and its associated cardiometabolic benefits,” wrote first author Louis J Aronne, MD, of the Comprehensive Weight Control Center and Division of Endocrinology, Diabetes and Metabolism at Weill Cornell Medicine, and colleagues.

Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) hormone mimetic that is administered subcutaneously once weekly. In November 2023, the US Food and Drug Administration approved tirzepatide as an adjunct to a reduced calorie diet and increased physical exercise for adults with obesity or overweight and at least 1 weight-related condition requiring chronic weight management.

Aronne and colleagues conducted the phase 3, randomized withdrawal clinical trial to examine the effect of 36-week open-label, once-weekly treatment with tirzepatide followed by a 52-week, double-blind, placebo-controlled assessment on adults with body mass index (BMI) ≥30 kg/m2 or ≥27 kg/m2 plus a weight complication, excluding diabetes.

The primary end point was mean percent change in weight from the week 36 randomization to week 88, with secondary end points including proportion of patients who maintained ≥80% of the lead-in period weight loss across either treatment arm.

Among the 670 participants who completed the 36-week lead-in period, the mean age was 48 years old; 71% were women, 80.1% were White, and mean weight was 107.3 kg, according to the study.

FINDINGS

From the lead-in randomization (week 36) to week 88, researchers observed a mean -5.5% reduction in weight loss among patients in the tirzepatide group compared to a mean 14.0% weight gain among those in the placebo group (95% CI -21.2% to -17.7%; P<.001).

Also, investigators noted at week 88 that 300 participants (89.5%) in the tirzepatide-treated group had maintained ≥80% of their lead-in weight loss, compared to 16.6% of patients in the placebo group (P<.001).

“The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo,” stated Aronne and colleagues.

Researchers added that the safety profile of tirzepatide among SURMOUNT-4 participants was consistent with profiles observed previously in SURMOUNT and SURPASS trials. The most frequently reported adverse events included gastrointestinal effects such as nausea, diarrhea, constipation, and vomiting, according to the study.

“Patients, providers and the public do not always understand obesity is a chronic disease that often requires ongoing treatment, which can mean that treatment is stopped once weight goals are met," Jeff Emmick, MD, PhD, senior vice president, product development, Lilly, said in a statement.² "However, studies like SURMOUNT-4 show that continued therapy can help people living with obesity maintain their weight loss."

Aronne and colleagues emphasize similarly that, “At least 5 trials (including the present study) across various classes of medications, including potent antiobesity medications such as semaglutide, have demonstrated that weight is substantially regained after cessation of pharmacotherapy. 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.”

References

1. Aronne LJ, Sattar N, Horn DB, et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA. Published online December 11, 2023. doi:10.1001/jama.2023.24945 2. Lilly's Zepbound™ (tirzepatide) achieved additional 6.7% weight loss following a 36-week open-label lead-in period, for a total mean weight loss of 26.0% from study entry over 88 weeks. Press release. Eli Lilly and Company. Published December 11, 2023. Accessed December 12, 2023. https://investor.lilly.com/news-releases/news-release-details/lillys-zepboundtm-tirzepatide-achieved-additional-67-weight-loss