Trial design published for lowering tirzepatide dose to maintain weight loss

The design of a clinical trial that will test whether people who lose weight on tirzepatide can keep it off at a lower dose was published September 7, 2025, in the journal Obesity ^[1]. The paper describes SURMOUNT-MAINTAIN, a Phase 3b, multicenter, randomized, double-blinded, placebo-controlled study that is already underway ^[1].

Tirzepatide is a once-weekly GIP and GLP-1 receptor agonist approved to treat type 2 diabetes and obesity; it is sold as Mounjaro and Zepbound ^[1]. The trial enrolled 441 adults with obesity, defined as a BMI of at least 30 kg/m2, or at least 27 kg/m2 with at least one obesity-related condition. People with type 2 diabetes were excluded ^[1]. Participants are mostly female (65%), with a mean age of 47 years, body weight of 114 kg, BMI of 40 kg/m2 and waist circumference of 119 cm ^[1].

Everyone in the study first receives 60 weeks of open-label tirzepatide at their maximum tolerated dose, either 15 mg or 10 mg weekly ^[1]. Those who reach a plateau — defined in the trial as less than 5% body weight change between Weeks 48 and 60 — then enter a 52-week randomized phase. They are assigned to step down to 5 mg weekly, continue their maximum tolerated dose, or switch to placebo ^[1].

The main goal is the percentage of body weight reduction maintained at Week 112 among participants who reached that plateau ^[1]. The study will also track a concept the authors call "medication rescue," in which tirzepatide is restarted for participants who regain half or more of the weight they lost during the lead-in period ^[1].

The paper cites earlier trials that set up the question. In SURMOUNT-4, a 36-week tirzepatide lead-in produced a mean 21% body weight reduction, and participants switched to placebo regained 14% ^[1]. In STEP 4, after a 20-week run-in on semaglutide (sold as Ozempic, Wegovy and Rybelsus), people switched to placebo regained 7% of their body weight ^[1]. In the STEP 1 extension, one year after semaglutide and the lifestyle program stopped, participants had regained two-thirds of their prior weight loss ^[1]. The authors note that the cardiometabolic benefits seen with weight loss tend to deteriorate when weight returns after obesity medication is stopped ^[1].

The trial is funded by Eli Lilly and Company, and several authors, including corresponding author Clare J. Lee, are Lilly employees ^[1]. Other authors are affiliated with the University of Texas McGovern Medical School, Weill Cornell Medicine, the University of Toronto and the Louisville Metabolic and Atherosclerosis Research Center ^[1].

Why it matters for patients

Weight regain after stopping a GLP-1 or GIP/GLP-1 medication is well documented, and there is little randomized evidence on what a long-term maintenance strategy should look like ^[1]. The trial is built around a practical question many patients face after reaching a goal weight: stay on the highest dose that was tolerated, lower the dose, or stop. The 5 mg arm is the part specific to tirzepatide, since 5 mg is below the 10 mg and 15 mg doses used in the weight-loss phase of this study ^[1].

The paper reports only rationale, design and baseline characteristics. It includes no results on whether a 5 mg maintenance dose actually holds weight loss, whether it produces fewer side effects, or how it compares with staying on a higher dose ^[1]. Those answers are not yet available. The inclusion of a placebo arm means the trial will also document what happens to people who stop the drug entirely while continuing lifestyle intervention ^[1].

What happens next

The anticipated completion date for the trial is May 2026, according to the paper ^[1]. The trial is registered on ClinicalTrials.gov under the identifier NCT06047548 ^[1]. Results have not been reported.