Orforglipron Outperforms Oral Semaglutide in Head-to-Head Type 2 Diabetes Trial

An investigational oral glucagon-like peptide-1 (GLP-1) receptor agonist, orforglipron (Eli Lilly), demonstrated superior glycemic control and weight loss compared with oral semaglutide in adults with type 2 diabetes, according to results from a head-to-head trial.¹

The findings position the once-daily small-molecule therapy as a potential alternative to peptide-based GLP-1 therapies that require specific administration conditions.

"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," said Julio Rosenstock, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center and lead investigator, in a statement. "Orforglipron 12 mg and 36 mg doses outperformed oral semaglutide 7 mg and 14 mg diabetes-related doses on every key end point we measured, including A_1c and weight loss, with improvements appearing as early as four weeks and sustained throughout the study."

ACHIEVE-3 (NCT06045221) is a 52-week, phase 3, randomized, open-label trial evaluating the efficacy and safety of orforglipron compared with oral semaglutide in adults with type 2 diabetes inadequately controlled on metformin. The study enrolled 1698 participants across the US, Argentina, China, Japan, Mexico, and Puerto Rico, randomized 1:1:1:1 to the 4 regimens outlined above, to receive orforglipron. The primary objective was to demonstrate noninferiority in A_1c reduction at 52 weeks for lower- and higher-dose comparisons. Both treatments were initiated at low doses with stepwise escalation every 4 weeks to maintenance dosing, with 1 patient permitted dose reduction for tolerability. Oral semaglutide requires fasting administration and water intake restrictions, whereas orforglipron does not, a distinction that may affect adherence and patient preference.

Across studied doses, orforglipron produced greater reductions in hemoglobin A_1c (HbA_1c) and body weight than oral semaglutide. In the trial, higher-dose orforglipron achieved reductions in HbA_1c exceeding those seen with the highest approved oral semaglutide dose, alongside greater weight loss. Prior reporting of the head-to-head study found that the highest dose of orforglipron reduced HbA_1c by approximately 2.2 percentage points and body weight by about 9.2% compared with reductions of roughly 1.4 percentage points and 5.3% with oral semaglutide.

Investigators also observed that a greater proportion of participants receiving orforglipron achieved near-normal glycemic levels compared with those receiving semaglutide.² Improvements were consistent across multiple dose levels, suggesting a strong treatment effect.

Overall, orforglipron demonstrated superior reductions in HbA_1c and body weight compared with oral semaglutide, with a safety profile consistent with the GLP-1 class.¹ Gastrointestinal adverse events, including nausea and diarrhea, were the most commonly reported. Overall tolerability was comparable between treatment groups, with no unexpected safety signals observed.

If approved, the oral small-molecule therapy could broaden treatment options and improve convenience for patients with type 2 diabetes requiring effective glycemic and weight management.

"The results of ACHIEVE-3 highlight the potential advantages of orforglipron over oral semaglutide for type 2 diabetes: greater A_1c 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, PhD, executive vice president and president of Lilly Cardiometabolic Health, 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."

References

1. 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. News release. Eli Lilly and Company. February 26, 2026. Accessed February 26, 2026. https://lilly.mediaroom.com/2026-02-26-Lillys-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

2. Lilly says its experimental GLP-1 pill better than Novo’s Rybelsus in diabetes study. Reuters. September 17, 2025. Accessed February 26, 2026. https://www.reuters.com/business/healthcare-pharmaceuticals/lilly-says-its-experimental-glp-1-pill-better-than-novos-rybelsus-diabetes-study-2025-09-17/