SURMOUNT-4: Tirzepatide Withdrawal Linked to 20 Percentage-Point Weight Regain

Louis J. Aronne, MD

Tirzepatide injection (Zepbound) was associated with a nearly 20 percentage-point difference in mean weight reduction versus placebo from week 36 to week 88 among treated patients with obesity, according to new data from SURMOUNT-4.¹

In findings from Lilly’s phase 3 trial, approximately 9 in 10 patients receiving combination GIP/GLP-1 receptor agonist tirzepatide at 88 weeks maintained ≥80% of their weight loss during the SURMOUN-4 lead-in period, versus just 16.6% of patients receiving placebo (P <.001). Overall, patients with body mass index (BMI) ≥30 kg/m² reported a mean percent body weight change of -19.4% with tirzepatide from weeks 36 to 88 versus placebo (95% CI, -21.2 to -17.7; P <.001).

The SURMOUNT-4 investigators noted the findings—combined with other late-stage research into clinical weight-loss agents—emphasize the importance of continued pharmacotherapy for the prevention of weight regain and maintained cardiometabolic benefits with treatments including tirzepatide.

“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,” they wrote. “A notable finding in the SURMOUNT-4 trial is that after switching to placebo for 1 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.”

Led by Louis J. Aronne, MD, of the Comprehensive Weight Control Center and Division of Endocrinology, Diabetes and Metabolism at Weill Cornell Medicine, investigators conducted the phase 3, randomized withdrawal trial to assess 36-week open-label, once-weekly, 10 or 15 mg tirzepatide followed by a 52-week, double-blind, placebo-controlled assessment of adults with BMI ≥30 kg/m² or ≥27 kg/m² plus a nondiabetic weight complication.

The team sought a primary end point of 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 SURMOUNT-4 participants who completed the 36-week lead-in period, mean age was 48 years old; 71% were women, 80.1% were White, and mean weight was 107.3 kg. Mean weight reduction during the lead-in period was 20.9%.

From the lead-in randomization to week 88, Aronne and colleagues observed a mean -5.5% reduction in weight loss among patients who maintained tirzepatide, versus a mean 14.0% gain among patients randomized to placebo. They additionally observed that 300 patients (89.5%) on tirzepatide at week 88 had maintained ≥80% of their lead-in weight loss, versus just 16.6% of patients receiving placebo.

“Time-to-event analysis showed that continued tirzepatide treatment during the double-blind period reduced the risk of returning to greater than 95% baseline body weight for those who had already lost at least 5% since week 0 by approximately 98% compared with placebo,” investigators additionally noted.

Investigators added that the SURMOUNT-4 patient population reported safety profiles consistent with those observed in previous SURMOUNT and SURPASS trials assessing tirzepatide in patients with obesity and overweight status. The most frequently reported adverse events included gastrointestinal effects such as nausea, diarrhea, constipation and vomiting.

In a statement accompanying the new data, Lilly executives contextualized the SURMOUNT-4 findings as implicative for the evolving field of long-term clinical weight reduction intervention.²

“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. "However, studies like SURMOUNT-4 show that continued therapy can help people living with obesity maintain their weight loss."

Aronne and colleagues concurred, concluding that, “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.¹

“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,” they wrote.

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. 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. Published December 11, 2023. https://investor.lilly.com/news-releases/news-release-details/lillys-zepboundtm-tirzepatide-achieved-additional-67-weight-loss}