ACHIEVE-3: Orforglipron Achieves Superiority to Oral Semaglutide in Poorly Controlled T2D

On February 26, 2026, Eli Lilly announced detailed results from the phase 3 ACHIEVE-3 trial, the first head-to-head comparison of orforglipron and oral semaglutide in patients with type 2 diabetes (T2D) inadequately controlled with metformin.1

Orforglipron is an investigational, once-daily small molecule non-peptide oral GLP-1 receptor agonist, which can be taken at any time of day without restrictions on food and water intake. Lilly is currently running phase 3 trials of orforglipron for both T2D and weight management in patients with obesity or overweight and ≥1 weight-related medical problem. Additionally, it is under investigation as a potential treatment for obstructive sleep apnea and hypertension in adults with obesity.1

“ACHIEVE-3 gives us the first head-to-head comparison between 2 oral GLP-1 receptor agonist therapies in adults with type 2 diabetes, and the differences were clinically meaningful,” Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City, professor of medicine at the University of Texas Southwestern Medical Center and lead investigator, said in a statement. “Orforglipron 12 mg and 36 mg doses outperformed oral semaglutide 7 mg and 14 mg diabetes-related doses on every key endpoint we measured, including A1C and weight loss, with improvements appearing as early as 4 weeks and sustained throughout the study.”1

ACHIEVE-3 was a phase 3, randomized, open-label study conducted across 131 locations worldwide. Patients were eligible for inclusion if they had T2D with HbA1c ≥7% to ≤10.5%, as well as having been on stable diabetes treatment with metformin ≥1500 mg/day during the 90 days before screening. Patients were excluded if they had type 1 diabetes (T1D), were currently receiving or planning to receive treatment for diabetic retinopathy or macular edema, had a history of ketoacidosis or hyperosmolar state or coma within 6 months prior to screening, or had a New York Heart Association (NYHA) functional classification IV congestive heart failure, among other criteria.2

A total of 1698 patients were enrolled in the trial and were randomly assigned to 4 treatment arms: orforglipron 12 mg and 36 mg, and oral semaglutide 7 mg and 14 mg. The primary endpoint was the change in A1C from baseline to week 52, with secondary endpoints including the change in weight from baseline and the percentage of achieving A1C <7%, ≤6.5%, and <5.7% at week 52.1

Ultimately, orforglipron lowered A1C by 2.2% in the 36 mg arm and by 1.9% in the 12 mg arm, compared to reductions of 1.1% and 1.4% in semaglutide 7 mg and 14 mg, respectively. Additionally, participants receiving orforglipron saw a body weight reduction of 9.2% in the 36 mg arm and 6.7% in the 12 mg arm, compared to 3.7% and 5.3% in semaglutide 7 mg and 14 mg, respectively. Orforglipron also displayed clinically meaningful improvements from baseline across non-HDL and HDL cholesterol, VLDL cholesterol, total cholesterol, systolic blood pressure, and triglycerides.1

“The results of ACHIEVE-3 highlight the potential advantages of orforglipron over oral semaglutide for type 2 diabetes: greater A1C reduction, more weight loss, and the ability to take it without food or water timing restrictions – that’s a combination that could matter significantly to people managing their disease day in and day out,” Kenneth Custer, PhD, executive vice president and president of Lilly Cardiometabolic Health, said in a statement. “With global submissions underway and FDA action on obesity expected next quarter, we’re focused on making this option available as quickly as possible.”1

References

1. Eli Lilly and Company. Lilly’s oral GLP-1, orforglipron, delivered superior blood sugar control and weight loss compared to oral semaglutide in head-to-head type 2 diabetes trial published in The Lancet. February 26, 2026. Accessed February 26, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-delivered-superior-blood-sugar

2. Eli Lilly and Company. A Study of Orforglipron (LY3502970) Compared With Semaglutide in Participants With Type 2 Diabetes Inadequately Controlled With Metformin (ACHIEVE-3). ClinicalTrials.gov Identifier: NCT06045221. Updated September 22, 2025. Accessed February 26, 2026. https://clinicaltrials.gov/study/NCT06045221