Lilly’s Oral GLP-1 Orforglipron Demonstrates Durable Weight Maintenance In Phase 3 ATTAIN-MAINTAIN Trial; Maintains Weight Loss After Wegovy Or Zepbound

Eli Lilly and Company, announced positive topline results from the Phase 3 ATTAIN-MAINTAIN trial, evaluating orforglipron, an investigational once-daily oral small-molecule GLP-1 receptor agonist, for long-term weight maintenance following prior injectable GLP-1–based therapy.

The 52-week study assessed orforglipron as a maintenance therapy after participants completed 72 weeks of treatment with the highest tolerated doses of Wegovy® (semaglutide) or Zepbound® (tirzepatide) in the Phase 3 SURMOUNT-5 trial. Eligible participants who had reached a body-weight plateau were re-randomized to receive orforglipron or placebo, alongside lifestyle intervention.

Orforglipron met the primary endpoint and all key secondary endpoints, demonstrating superior maintenance of body-weight reduction compared with placebo using both the efficacy estimand and modified treatment-regimen estimand.

"Obesity is a chronic, progressive disease, and sustaining weight loss remains a significant challenge for many," said Kenneth Custer, Ph.D., executive vice president and president, Lilly Cardiometabolic Health. "ATTAIN‑MAINTAIN showed that orforglipron, a once-daily oral GLP-1, helped people maintain the weight they worked hard to lose. Participants in this study were able to switch directly from the highest tolerated doses of available injectable therapies onto oral doses of orforglipron. If approved for the treatment of obesity, orforglipron could provide a convenient alternative for the millions of individuals living with obesity around the globe to continue their long-term health journey."

In prespecified analyses at week 52, participants switching from Wegovy to orforglipron maintained their prior weight loss, with an average difference of 0.9 kg, while those switching from Zepbound maintained weight loss with an average difference of 5.0 kg, based on the efficacy estimand.

Post-hoc analyses at week 24, the final assessment before placebo participants were eligible for rescue therapy, showed marked divergence between treatment groups. Participants transitioning from Wegovy to orforglipron experienced a –0.1 kg change from baseline compared with a 9.4 kg weight regain in the placebo group. Similarly, participants switching from Zepbound to orforglipron showed a 2.6 kg change versus 9.1 kg with placebo.

The safety and tolerability profile of orforglipron in ATTAIN-MAINTAIN was consistent with findings from previous Phase 3 studies. The most common adverse events were gastrointestinal, generally mild to moderate in severity. Discontinuation rates due to adverse events were low across treatment arms, and no hepatic safety signal was observed.

Lilly stated that detailed results from the ATTAIN-MAINTAIN trial will be presented at an upcoming medical meeting and published in a peer-reviewed journal in 2026. The company has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval of orforglipron for the treatment of adults with obesity or overweight. Orforglipron has also been granted a Commissioner’s National Priority Voucher by the FDA.