Written By: Pharmacally Medical News Desk
Eli Lilly’s investigational oral GLP-1 receptor agonist orforglipron has demonstrated that it can help adults with obesity or overweight maintain clinically meaningful weight loss after switching from injectable incretin therapies in the Phase 3 ATTAIN-MAINTAIN trial.
Eli Lilly reported positive topline results from ATTAIN-MAINTAIN, a Phase 3, randomized, double-blind, placebo-controlled trial designed to evaluate orforglipron for long-term weight maintenance following prior treatment with injectable GLP-1–based therapies such as semaglutide and tirzepatide.
First Phase 3 trial focused on maintenance after injectables
ATTAIN-MAINTAIN is described as the first Phase 3 trial specifically designed to assess weight maintenance in people who transitioned from injectable incretin therapy to an oral GLP-1 agent. Participants who switched to orforglipron were able to sustain most of the weight loss achieved during prior injectable treatment, reinforcing the role of oral GLP-1 therapy as a strategy to preserve earlier weight reduction gains.
About orforglipron
Orforglipron is a once-daily, orally administered, small-molecule GLP-1 receptor agonist that does not require injection or refrigeration, providing a more convenient route of administration than peptide-based injectables. As a non-peptide GLP-1 agonist, it activates the GLP-1 receptor to enhance satiety, reduce caloric intake, and support long-term weight control, and is being developed for chronic weight management and broader cardiometabolic indications.
ATTAIN-MAINTAIN design, efficacy, and safety
The Phase 3 ATTAIN-MAINTAIN trial (NCT06584916) enrolled adults with obesity or overweight status, who had weight-related comorbidities and had previously achieved substantial weight loss on injectable incretin therapies (SURMOUNT-5) before entering the study. Participants were randomized to once-daily orforglipron (titrated up to 24–36 mg) or placebo for 52 weeks as an adjunct to lifestyle measures, and orforglipron achieved the primary and all key secondary endpoints for weight maintenance versus placebo, including sustained percent weight reduction and favorable metabolic measures.
Average body weight at the SURMOUNT‑5 baseline, at the time of switching to oral therapy, and after 52 weeks of orforglipron maintenance is shown in the Table:
Parameter | Wegovy to orforglipron | Zepbound to orforglipron |
Starting weight at SURMOUNT-5 baseline | 113.5 kg (250.2 lbs) | 115.8 kg (255.3 lbs) |
Weight at switch to oral (start of ATTAIN-MAINTAIN) | 95.0 kg (209.4 lbs) | 90.9 kg (200.4 lbs) |
Weight after 52 weeks of oral maintenance | 95.9 kg (211.4 lbs) | 95.9 kg (211.4 lbs) |
The overall safety and tolerability profile of orforglipron in ATTAIN-MAINTAIN was consistent with the GLP-1 receptor agonist class and prior orforglipron studies, with gastrointestinal adverse events such as nausea, vomiting, and diarrhea reported most frequently and generally mild to moderate in severity. No new safety signals, including no hepatic safety signal, were identified, and discontinuation rates due to adverse events were reported as low.
Kenneth Custer, Ph.D., executive vice president and president of Lilly Cardiometabolic Health, said, “Obesity is a chronic disease where sustaining weight loss is challenging.” He also noted that ATTAIN-MAINTAIN demonstrated orforglipron’s ability to maintain weight loss after direct switch from the highest tolerated injectable GLP-1 doses, positioning it as a convenient oral option for long-term obesity management if approved.
Lilly is advancing orforglipron within a broader late-stage clinical development program, including multiple Phase 3 ATTAIN trials evaluating its use in chronic weight management and metabolic disease. The company has submitted a New Drug Application to the U.S. Food and Drug Administration for use in adults with obesity or overweight, and detailed ATTAIN-MAINTAIN results are expected to be presented at an upcoming medical meeting and published in a peer-reviewed journal.
References
Lilly’s orforglipron helped people maintain weight loss after switching from injectable incretins to oral GLP-1 therapy in a first-of-its-kind Phase 3 trial, 18 December 2025, https://investor.lilly.com/news-releases/news-release-details/lillys-orforglipron-helped-people-maintain-weight-loss-after
A Study of Orforglipron for the Maintenance of Body Weight Reduction in Participants Who Have Obesity or Overweight with Weight-Related Comorbidities (ATTAIN-MAINTAIN), ClinicalTrials.gov ID NCT06584916, https://clinicaltrials.gov/study/NCT06584916