Orforglipron Maintains Weight Loss in Patients Switching from Semaglutide or Tirzepatide

Orforglipron has met the primary and all key secondary endpoints in the phase 3 ATTAIN-MAINTAIN trial by providing superior weight maintenance compared to placebo in patients enrolled from the phase 3 SURMOUNT-5 trial, as announced by parent company Eli Lilly on December 18, 2025.1

Orforglipron is an investigational, once-daily small molecule oral glucagon-like peptide-1 (GLP-1) receptor agonist, made to be taken at any time of the day without restrictions on food or water intake. Lilly is currently running phase 3 studies to investigate orforglipron in type 2 diabetes, for weight management in adults with obesity and overweight with ≥1 weight-related medical issue, for sleep apnea, for hypertension, and for knee osteoarthritis in adults with obesity, as well as stress urinary incontinence and cardiovascular and renal outcomes.1

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

SURMOUNT-5 was a phase 3b, open-label, controlled trial, including adult participants with obesity but without type 2 diabetes. Patients were randomly assigned in a 1:1 ratio to either the maximum tolerated dose of tirzepatide – 10mg or 15 mg - or the maximum tolerated dose of semaglutide – 1.7 mg or 2.4 mg – subcutaneously once weekly for 72 weeks.2

A total of 751 participants were included in SURMOUNT-5 – least-squares mean percent change in weight at week 72 was -20.2% (95% CI, -21.4 to -19.1) with tirzepatide and -13.7% (95% CI, -14.9 to -12.6) with semaglutide (P <.001). The least-squares mean change in waist circumference was -18.4 cm (95% CI, -19.6 to -17.2) with tirzepatide and -13 cm (95% CI, -14.3 to -11.7) with semaglutide (P <.001). Additionally, participants in the tirzepatide group were more likely than those in the semaglutide group to have weight reductions of ≥10%, 15%, 20%, and 25%.2

The ATTAIN-MAINTAIN trial was a 52-week, randomized, double-blind, placebo-controlled trial. Adult patients with obesity or overweight and weight-related comorbidities who previously completed SURMOUNT-5 were enrolled in the trial – a total of 376 participants were enrolled and randomly assigned in a 3:2 ratio to either orforglipron maximum tolerated dose (24 mg or 36 mg) or placebo, as an adjunct to healthy diet and physical activity. ATTAIN-MAINTAIN’s primary endpoint was to demonstrate superiority in body weight maintenance in patients who had achieved plateau with either semaglutide or tirzepatide.1

A total of 376 participants were randomized into the trial. Patients were initially given a 12 mg dose of once-daily oral orforglipron or matching placebo, which was then increased every 4 weeks until the randomized maintenance dose of 36 mg or maximum tolerated dose was reached. All participants who regained ≥50% of their body weight from SURMOUNT-5 were treated with rescue orforglipron therapy.1

Ultimately, patients who switched to orforglipron from semaglutide maintained previously achieved weight loss, with an average difference of 0.9 kg. Those who switched from tirzepatide also maintained their achieved weight loss, with an average difference of 5 kg, using the efficacy estimand. In post-hoc analyses at 24 weeks, the change in body weight from ATTAIN-MAINTAIN baseline for patients switching from semaglutide was -0.1 kg vs 9.4 kg for placebo. Similarly, patients switching from tirzepatide saw a change from baseline of 2.6 kg vs 9.1 kg for placebo.1

The safety and tolerability profile of orforglipron was also consistent with previous orforglipron phase 3 studies. The most common adverse events were gastrointestinal and generally mild to moderate in severity. Discontinuation rates due to adverse events were 4.8% (orforglipron from semaglutide), 7.6% (placebo from semaglutide), 7.2% (orforglipron from tirzepatide), and 6.3% (placebo from tirzepatide).1

“Participants in this study were able to switch directly from the highest tolerated doses of available injectable therapies onto oral doses of orforglipron,” Custer said. “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.”1

Lilly has submitted a New Drug Application to the US Food and Drug Administration (FDA) for orforglipron for the treatment of obesity or overweight in adults. Orforglipron has been granted a Commissioner’s National Priority Voucher from the FDA.1

References

1. Biro N. 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. December 18, 2025. Accessed December 18, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-orforglipron-helped-people-maintain-weight-loss-after

2. Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as compared with semaglutide for the treatment of obesity. New England Journal of Medicine. 2025;393(1):26-36. doi:10.1056/nejmoa2416394