Lilly's Orforglipron Outperforms Oral Semaglutide in Head-to-Head Phase 3 Trial

Eli Lilly and Company released detailed results from ACHIEVE-3, the first head-to-head Phase 3 trial comparing two oral GLP-1 receptor agonists in adults with type 2 diabetes inadequately controlled with metformin. The 52-week trial enrolled 1,698 participants across six countries. The results were published in The Lancet.

Orforglipron outperformed oral semaglutide across the primary and all key secondary endpoints, delivering significantly greater improvements in A1C (blood sugar) and weight. Orforglipron 36 mg significantly outperformed oral semaglutide 14 mg, achieving a 2.2% reduction in A1C compared to 1.4% for the latter. Additionally, participants taking orforglipron lost an average of 19.7 lbs (9.2%), which is 73.6% greater weight loss than those on semaglutide.

Improvements appeared as early as four weeks and benefits were sustained through 52 weeks. The lead investigator from University of Texas Southwestern Medical Center stated that the differences were clinically meaningful.

Beyond glucose and weight, orforglipron delivered meaningful improvements from baseline in non-HDL cholesterol, HDL cholesterol, VLDL cholesterol, total cholesterol, triglycerides, and systolic blood pressure. These findings strengthen its broader cardiometabolic profile.

Participants were randomized equally across four treatment arms: orforglipron 12 mg, orforglipron 36 mg, oral semaglutide 7 mg, and oral semaglutide 14 mg. All doses were escalated gradually using step-wise titration over four-week intervals.

The overall safety profile was consistent with prior studies. The most common adverse events for both drugs were nausea, diarrhoea, vomiting, dyspepsia, and decreased appetite. Discontinuation due to adverse events occurred in 8.7% of participants taking orforglipron 12 mg and 9.7% taking orforglipron 36 mg, compared to 4.5% for oral semaglutide 7 mg and 4.9% for oral semaglutide 14 mg.

One of orforglipron's most practical advantages is its once-daily oral dosing that can be taken any time of day with no food or water timing restrictions. For long-term diabetes management, convenience can influence adherence.

The company has submitted orforglipron for regulatory approval in over 40 countries, with a potential U.S. decision for obesity treatment expected in the second quarter of 2026. The global Phase 3 diabetes program has enrolled over 6,000 patients, with remaining registrational trial results expected later this year.

Orforglipron is a non-peptide, small-molecule oral GLP-1 receptor agonist discovered by Chugai Pharmaceutical Co., Ltd. and licensed by Lilly in 2018. Beyond diabetes, it is also being studied in obesity and overweight, obstructive sleep apnea, and hypertension in adults with obesity.