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

• For the primary endpoint, orforglipron 36 mg lowered A1C by 2.2% vs. 1.4% with oral semaglutide 14 mg in ACHIEVE-3
• In a key secondary endpoint, participants on orforglipron 36 mg lost 19.7 lbs (9.2%) compared to 11.0 lbs (5.3%) with oral semaglutide 14 mg, representing a 73.6% greater relative weight loss
• Lilly has submitted orforglipron to regulators in over 40 countries, with potential U.S. action for obesity in Q2 2026

Eli Lilly and Company (NYSE: LLY) today announced detailed results from ACHIEVE-3, the first head-to-head Phase 3 trial evaluating the safety and efficacy of orforglipron, a small molecule oral GLP-1 without food or water restrictions, compared with oral semaglutide in adults with type 2 diabetes inadequately controlled with metformin.

The 52-week trial enrolled 1,698 participants across four treatment arms: orforglipron 12 mg and 36 mg, and oral semaglutide 7 mg and 14 mg. In ACHIEVE-3, orforglipron outperformed oral semaglutide across the primary and all key secondary endpoints, delivering significantly greater improvements in A1C and weight.1,2 The results were published today in The Lancet.

“ACHIEVE-3 gives us the first head-to-head comparison between two oral GLP-1 receptor agonist therapies in adults with type 2 diabetes, and the differences were clinically meaningful,” said Dr. Julio Rosenstock, clinical professor of medicine at the University of Texas Southwestern Medical Center and lead investigator.

“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 four weeks and sustained throughout the study.”

ACHIEVE-3 Full Results

Orforglipron also showed clinically meaningful improvements from baseline across key cardiovascular risk factors, including non-HDL cholesterol, HDL cholesterol, VLDL cholesterol, total cholesterol, systolic blood pressure and triglycerides.4

“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,” said Kenneth Custer, Ph.D., executive vice president and president of Lilly Cardiometabolic Health. “With global submissions underway and FDA action on obesity expected next quarter, we’re focused on making this option available as quickly as possible.”

The overall safety and tolerability profile of orforglipron in ACHIEVE-3 was consistent with previous trials. For orforglipron and oral semaglutide, the most common adverse events were nausea, diarrhea, vomiting, dyspepsia and decreased appetite. Treatment discontinuation rates due to adverse events were 8.7% (12 mg) and 9.7% (36 mg) for orforglipron vs. 4.5% (7 mg) and 4.9% (14 mg) for oral semaglutide.

Lilly has submitted orforglipron to regulators in over 40 countries, with submission for type 2 diabetes in the U.S. planned later this year.