Diabetes Dialogue: SURMOUNT-3 and -4 Inform Use of Tirzepatide in Obesity

Management of obesity is a more prominent topic of discussion among healthcare providers now than ever before in history. Due in part to rising prevalence of obesity and its impact on health systems, but also as a result of advances in therapies, with these advances centered around the GLP-1 receptor agonists and combination agents.

During early October, the community was offered further insight into the potential of one of these agents, tirzepatide (Mounjaro) in the form of trial results from SURMOUNT-3 and SURMOUNT-4, which were presented at ObesityWeek and the European Association for the Study of Diabetes Annual Meeting, respectively.

SURMOUNT-3

SURMOUNT-3 was designed to assess the effects of tirzepatide relative to placebo therapy following a lead-in period where patients were exposed to an intensive lifestyle intervention. A double-blind, placebo-controlled trial, participants were randomized in a 1:1 ratio to tirzepatide or placebo therapy for 72 weeks following the 12-week lead-in period.¹

In the treatment efficacy estimand, results indicated use of tirzepatide was associated with an additional 21.1% mean weight loss following the lead-in period compared to a 3.3% increase in body weight among the placebo group 3.3% with placebo (estimated treatment difference [ETD], −24.5 percentage points; 95% Confidence Interval [CI], −26.1 to −22.8; P < .001). Analysis of the treatment regimen estimated suggested the mean change in body weight at week 72 was −18.4% with tirzepatide and 2.5% with placebo (ETD, −20.8 percentage points; 95% CI, −23.2 to −18.5; P < .001).¹

Additional analysis suggested the percentage of participants achieving additional weight reduction of 5% or greater was met in 87.5% of the tirzepatide group compared to 16.5% of the placebo group achieving this threshold (odds ratio, 34.6; 95% CI 19.2 to 62.6; P < .001).¹

SURMOUNT-4

SURMOUNT-4 was designed to assess the effect of tirzepatide discontinuation on body weight reduction in people with overweight or obesity relative to continued therapy. With this in mind, patients were randomized to tirzepatide or placebo therapy for 52 weeks after a 36-week open-label tirzepatide lead-in period. The primary endpoint of the trial was the mean percent change in body weight from week 36 to week 88.

At the end of the 36-week lead-in period, study participants achieved a mean weight loss of 21.1%. Upon analysis of the primary endpoint, results suggested use of tirzepatide was associated with a superior mean percent change in body weight relative to placebo. In contrast, those randomized to placebo experienced a mean weight regain of 14.8% at 88 weeks (Placebo-adjusted net change: -21.4%). The tirzepatide group achieved a mean body weight reduction of 26.0% during the trial.

In this special edition episode of Diabetes Dialogue: Technology, Therapeutics, & Real-World Perspectives, hosts Diana Isaacs, PharmD, an endocrine clinical pharmacist, director of Education and Training in Diabetes Technology, and codirector of Endocrine Disorders in Pregnancy at the Cleveland Clinic, and Natalie Bellini, DNP, program director of Diabetes Technology at University Hospitals Diabetes and Metabolic Care Center, discuss the results of these studies and how it might help inform use of tirzepatide if approved by the US Food and Drug Administration for chronic weight management.

Relevant disclosures for Dr. Isaacs include Eli Lilly and Company, Novo Nordisk, Sanofi, Abbott Diabetes Care, Dexcom, Medtronic, and others. Relevant disclosures for Dr. Bellini include Abbott Diabetes Care, MannKind, Provention Bio, and others.

References:

1. Wadden TA, Chao AM, Machineni S, et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial [published online ahead of print, 2023 Oct 15]. Nat Med. 2023;10.1038/s41591-023-02597-w. doi:10.1038/s41591-023-02597-w
2. Tirzepatide demonstrated significant and superior weight loss compared to placebo in two pivotal studies. Eli Lilly and Company. July 27, 2023. Accessed October 26, 2023. https://investor.lilly.com/news-releases/news-release-details/tirzepatide-demonstrated-significant-and-superior-weight-loss