Orforglipron Maintains Weight Loss After Discontinuation of Injectable GLP-1

Orforglipron, an investigational, once-daily oral glucagon-like peptide-1 (GLP-1) receptor agonist, maintained weight loss as an adjunct to a healthy diet and physical activity for those who discontinued semaglutide (Wegovy) or tirzepatide (Zepbound). In the ATTAIN-MAINTAIN (NCT06584916) trial, patients from the SURMOUNT-5 (NCT05822830) trial could receive randomized treatment with orforglipron or the placebo.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 at Lilly Cardiometabolic Health, said in a news release.¹ "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.”

In the SURMOUNT-5 trial, investigators compared tirzepatide to semaglutide, finding that tirzepatide demonstrated superiority across the primary end point and 5 key secondary end points. Reductions included body weight and waist circumference at 72 weeks. The primary outcome included percent change from baseline body weight to week 72. Secondary end points included the percentage of participants who achieved 10% or greater, 15% or greater, 20% or greater, and 25% or greater body weight reductions; change from baseline in waist circumference; change from baseline in body mass index; and percent change from baseline in body weight with tirzepatide 15 mg and semaglutide 2.4 mg.²

In the current study, orforglipron met the primary end point of superior percent maintenance of body weight reduction. The oral drug helped maintain weight at 95 kg with semaglutide, from 95.9 kg to 95.9 kg, and from 90.9 kg to 95.9 kg with tirzepatide. As for safety, the profile of orforglipron was consistent with phase 3 studies. The most common adverse events (AEs) were mild to moderate in severity and were generally gastrointestinal. Approximately 4.8% and 7.2% of those who received semaglutide and tirzepatide, respectively, discontinued oral treatment, compared with the placebo at 7.6% and 6.3%, respectively.¹

“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.” Custer said in the press release.¹

Previously, in another phase 3 trial, orforglipron also demonstrated significant weight loss, reductions in hemoglobin A_1c, and improvements in cardiometabolic risk factors at week 72. For 3 doses of the drug, the mean percent change from baseline in body weight was approximately –5.5%, –7.8%, and –10.5%, respectively, compared with –2.2% for the placebo. For body weight reductions of 10% or more, approximately 23.9%, 35.5%, and 50.1% of patients, respectively, achieved this outcome compared with 7% for the placebo.³

Furthermore, in 2 other trials, investigators found that all 3 doses demonstrated improvements in hemoglobin A_1c. The treatment-regimen estimand in change in hemoglobin A_1c from the baseline of 8.1% was 1.2%, 1.5%, and 1.6% for the 3 mg, 12 mg, and 36 mg doses, compared with 0.8% for dapagliflozin. In the other trial, changes from a baseline of 8.5% decreased by 1.6%, 1.9%, and 1.8%, respectively, compared with 0.8% for the placebo.⁴

READ MORE: Obesity Management Resource Center

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REFERENCES

1. 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. News release. Eli Lilly. December 18, 2025. Accessed January 2, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-orforglipron-helped-people-maintain-weight-loss-after

2. Gallagher A. Tirzepatide shows superior weight loss over semaglutide in phase 3 trial. Drug Topics. May 12, 2025. Accessed January 2, 2026. https://www.drugtopics.com/view/tirzepatide-shows-superior-weight-loss-over-semaglutide-in-phase-3-trial

3. Gallagher A. Orforglipron shows significant weight loss in new phase 3 study. Drug Topics. September 4, 2025. Accessed January 2, 2026. https://www.drugtopics.com/view/orforglipron-shows-significant-weight-loss-in-new-phase-3-study

4. Gallagher A. Orforglipron demonstrates superior glycemic control for type 2 diabetes. Drug Topics. October 16, 2025. Accessed January 2, 2026. https://www.drugtopics.com/view/orforglipron-demonstrates-superior-glycemic-control-for-type-2-diabetes