Phase 3 Data Support Oral Orforglipron for Weight Maintenance After GLP-1–Based Weight Loss

Eli Lilly and Company reported positive topline results from the Phase 3 ATTAIN-MAINTAIN trial showing that once-daily oral orforglipron met the primary and all key secondary endpoints for maintenance of body weight reduction compared with placebo at 52 weeks in adults with obesity or overweight.

According to the company, ATTAIN-MAINTAIN evaluated weight maintenance in participants who had previously completed 72 weeks of treatment with the highest tolerated doses of injectable incretin therapies—specifically the GLP-1 receptor agonist semaglutide or the dual GIP/GLP-1 receptor agonist tirzepatide—and had reached a body weight plateau. Participants were re-randomized to receive oral orforglipron or placebo as an adjunct to a healthy diet and physical activity.

At 52 weeks, orforglipron demonstrated superior percent maintenance of body weight reduction compared with placebo using both the efficacy estimand and the modified treatment-regimen estimand. In pre-specified analyses, participants who switched from semaglutide to orforglipron maintained their previously achieved weight loss with an average difference of 0.9 kg, while those who switched from tirzepatide maintained their previously achieved weight loss with an average difference of 5.0 kg, based on the efficacy estimand.

Post-hoc analyses at 24 weeks—the final time point before placebo participants were eligible for rescue therapy—showed that patients switching from semaglutide to orforglipron had a mean change in body weight of −0.1 kg compared with 9.4 kg for placebo. Among patients switching from tirzepatide, the mean change was 2.6 kg with orforglipron compared with 9.1 kg for placebo.

Observed mean body weight at the start of the preceding SURMOUNT-5 trial was 113.5 kg among participants initially treated with semaglutide and 115.8 kg among those treated with tirzepatide. At the start of ATTAIN-MAINTAIN, mean body weight was 95.0 kg and 90.9 kg, respectively. After 52 weeks of oral maintenance therapy, mean body weight was 95.9 kg in both groups.

The overall safety and tolerability profile of orforglipron in ATTAIN-MAINTAIN was consistent with prior Phase 3 studies, according to Lilly. The most common adverse events were gastrointestinal-related and were generally mild to moderate in severity. Discontinuation due to adverse events ranged from 4.8% to 7.2% among participants receiving orforglipron and from 6.3% to 7.6% among those receiving placebo. No hepatic safety signal was observed.

“Obesity is a chronic, progressive disease, and sustaining weight loss remains a significant challenge for many,” said Kenneth Custer, PhD, executive vice president and president of Lilly Cardiometabolic Health. “ATTAIN-MAINTAIN showed that orforglipron, a once-daily oral GLP-1, helped people maintain the weight they worked hard to lose.”

Lilly reported that detailed results from ATTAIN-MAINTAIN will be presented at a future medical meeting and published in a peer-reviewed journal. The company has submitted a new drug application to the US Food and Drug Administration for orforglipron for the treatment of adults with obesity or overweight. Orforglipron has also received a Commissioner’s National Priority Voucher from the FDA.

Orforglipron is an investigational, non-peptide, once-daily oral GLP-1 receptor agonist that can be taken without restrictions on food or water intake. The ATTAIN Phase 3 global clinical development program has enrolled more than 4 500 participants with obesity or overweight across 2 registrational trials. In addition to weight management, orforglipron is being studied for type 2 diabetes and several obesity-related comorbid conditions.

ATTAIN-MAINTAIN (NCT06584916) was a 52-week, randomized, double-blind, placebo-controlled Phase 3 trial conducted in the United States that enrolled 376 participants in a 3:2 ratio to receive orforglipron at a maximum tolerated dose or placebo. Eligibility required completion of the SURMOUNT-5 trial and demonstration of a weight plateau, defined as less than 5% body weight change between weeks 60 and 72 of SURMOUNT-5.

Reference: Lilly's orforglipron helped people maintain weight loss after switching from injectable incretins to oral GLP-1 therapy in first-of-its-kind Phase 3 trial. Eli Lilly. News release. December 18, 2025. Accessed December 19, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-orforglipron-helped-people-maintain-weight-loss-after