Eli Lilly and Company has reported detailed Phase 3 results showing its investigational oral GLP-1 receptor agonist, orforglipron, delivered greater reductions in blood sugar and body weight than oral semaglutide at 52 weeks in adults with type 2 diabetes inadequately controlled on metformin.
The findings come from ACHIEVE-3, a 52-week, randomized, open-label global trial that enrolled 1,698 participants across the United States, Argentina, China, Japan, Mexico and Puerto Rico. The study compared once-daily orforglipron at maintenance doses of 12 mg and 36 mg against oral semaglutide at 7 mg and 14 mg. Participants had a baseline A1C of 8.3% and an average body weight of 97 kg.
Under the efficacy estimand, which reflects outcomes assuming participants remained on treatment, A1C reductions at week 52 were 1.1% and 1.4% with oral semaglutide 7 mg and 14 mg, respectively. In comparison, A1C fell by 1.9% with orforglipron 12 mg and 2.2% with orforglipron 36 mg, with the higher-dose comparisons achieving statistical significance versus both semaglutide doses. Using the treatment-regimen estimand, which includes treatment discontinuations and rescue therapy, A1C reductions were 1.2% and 1.5% for semaglutide 7 mg and 14 mg, compared with 1.7% and 1.9% for orforglipron 12 mg and 36 mg.
Weight loss followed a similar pattern. Based on the efficacy estimand, body weight declined by 3.7% (3.6 kg) and 5.3% (5.0 kg) with semaglutide 7 mg and 14 mg, respectively. Orforglipron achieved reductions of 6.7% (6.6 kg) at 12 mg and 9.2% (8.9 kg) at 36 mg. Under the treatment-regimen estimand, weight loss ranged from 3.9% to 5.3% with semaglutide and from 6.1% to 8.2% with orforglipron.
A higher proportion of participants receiving orforglipron achieved key glycaemic targets. Under the efficacy estimand, 80.0% and 85.4% of participants on 12 mg and 36 mg orforglipron reached an A1C below 7%, compared with 54.6% and 66.1% on semaglutide 7 mg and 14 mg. For the more stringent A1C threshold of 6.5% or lower, rates were 71.8% and 76.8% with orforglipron versus 40.9% and 50.9% with semaglutide. Achievement of near-normoglycaemia, defined as A1C below 5.7%, occurred in 25.4% and 37.1% of patients on orforglipron 12 mg and 36 mg, compared with 7.8% and 12.5% on semaglutide 7 mg and 14 mg. Some secondary comparisons were not controlled for family-wise type 1 error.
Beyond glucose control and weight, orforglipron demonstrated clinically meaningful improvements in cardiovascular risk markers, including non-HDL cholesterol, HDL cholesterol, VLDL cholesterol, total cholesterol, systolic blood pressure and triglycerides.
The overall safety and tolerability profile of orforglipron was consistent with earlier studies of GLP-1 receptor agonists. The most common adverse events in both treatment groups were gastrointestinal, including nausea, diarrhoea, vomiting, dyspepsia and decreased appetite. Discontinuation rates due to adverse events were higher with orforglipron, at 8.7% for the 12 mg dose and 9.7% for the 36 mg dose, compared with 4.5% and 4.9% for semaglutide 7 mg and 14 mg.
All participants receiving orforglipron began at 1 mg once daily and escalated in stepwise fashion at four-week intervals to their assigned maintenance dose. Those assigned to semaglutide began at 3 mg once daily and titrated upward similarly. Participants unable to tolerate higher doses were permitted a one-time dose reduction during the study, with minimum doses set at 3 mg for orforglipron and 7 mg for semaglutide.
Orforglipron is an investigational, once-daily, small-molecule, non-peptide oral GLP-1 receptor agonist that can be taken without restrictions related to food or water intake. The molecule was discovered by Chugai Pharmaceutical Co., Ltd. and licensed to Lilly in 2018. In addition to type 2 diabetes, the drug is being studied for chronic weight management in adults with obesity or overweight and at least one weight-related condition, as well as for obstructive sleep apnoea and hypertension in adults with obesity.
The broader ACHIEVE Phase 3 global development programme has enrolled more than 6,000 people with type 2 diabetes across five registrational trials since its initiation in 2023. Lilly has submitted orforglipron to regulatory authorities in more than 40 countries and plans to file for type 2 diabetes approval in the United States later this year, with additional Phase 3 data expected in the coming months.
