Orforglipron Shows Greater A1C, Weight Reduction Than Oral Semaglutide

Orforglipron (Foundayo) 17.2 mg was associated with significantly greater weight loss and hemoglobin A_1C (A_1C) reduction than oral semaglutide 25 mg at 52 weeks in adults with type 2 diabetes (T2D). Lilly announced the results from an indirect treatment comparison presented at the 62nd Annual Meeting of the European Association for the Study of Diabetes in Milan, Italy.¹

Results Favor Orforglipron on Weight and A1C

On average, participants taking orforglipron 17.2 mg lost 1.5% more of their body weight than those taking oral semaglutide 25 mg (95% CI, –2.7% to –0.2%), and orforglipron lowered A1C by 0.3% more (95% CI, –0.6% to –0.1%). The analysis was covariate-adjusted for gender, age, baseline A_1C, and baseline weight. Analyses using different statistical methods produced consistent results, with orforglipron showing 1.5% to 2.4% greater weight loss and 0.3% to 0.6% greater A1C reduction.¹

All figures reflect the efficacy estimand, which represents treatment efficacy had every randomized participant stayed on study intervention for 52 weeks without starting additional antihyperglycemic medication for more than 14 days. The abstract describing the analysis focuses on adults with T2D and a body mass index of 25 kg/m² or higher.¹

Rachel Batterham, OBE, MBBS, PhD, FRCP, senior vice president of medical innovation and external engagement at Lilly Cardiometabolic Health, said head-to-head trials remain the best way to compare 2 medicines, but other approaches can supply useful data when those trials do not exist. The indirect results suggest orforglipron may deliver A_1C and weight lowering "similar to the 25 mg dose of oral semaglutide," she said in the news release.¹

What The Trials Showed

ACHIEVE-3 (NCT06045221) was a phase 3, 52-week, randomized, open-label trial of orforglipron versus oral semaglutide (Rybelsus) in 1698 adults with T2D inadequately controlled with metformin. Participants were enrolled in the United States, Argentina, China, Japan, Mexico, and Puerto Rico and randomized 1:1:1:1 to orforglipron 9 mg or 17.2 mg or oral semaglutide 7 mg or 14 mg.¹

The primary objective was to show that orforglipron was noninferior for A_1C reduction from baseline at 52 weeks when comparing the lower and higher doses.²

At 52 weeks, orforglipron lowered A_1C by an average of 1.9% (9 mg) and 2.2% (17.2 mg), compared with 1.1% (7 mg) and 1.4% (14 mg) for oral semaglutide. Participants taking orforglipron lost an average of 14.6 lb (6.7%) at 9 mg and 19.7 lb (9.2%) at 17.2 mg, versus 7.9 lb (3.7%) at 7 mg and 11.0 lb (5.3%) at 14 mg with oral semaglutide.¹

PIONEER PLUS (NCT04707469), which tested oral semaglutide 25 mg and 50 mg against 14 mg, was the other data source for the indirect comparison.³ In Novo Nordisk's 2023 announcement of that trial, the mean A_1C fell 1.9 percentage points with the 25 mg dose and 1.5 percentage points with 14 mg from a baseline of 9.0%. Body weight fell 7.0 kg with 25 mg and 4.5 kg with 14 mg from a mean baseline of 96.4 kg.³

Administration and Regulatory Context for Pharmacists

Orforglipron is a once-daily, small molecule (nonpeptide), oral glucagon-like peptide-1 receptor agonist that can be taken any time of day without restrictions on food and water intake. Batterham said that simple administration, together with the comparison data, is what makes orforglipron a potentially foundational therapy for adults with T2D.¹

Foundayo is FDA-approved for adults with obesity, or some adults with overweight who also have weight-related medical problems, and orforglipron is being studied as a potential T2D treatment. A 25 mg once-daily dose of oral semaglutide is not approved in the US for T2D, and Novo Nordisk has submitted an application to the FDA seeking approval of that dose.¹

The release did not include safety or tolerability data for the indirect comparison. In ACHIEVE-3, gastrointestinal events were the most frequently reported adverse events, and discontinuations due to adverse events ranged from 8.7% to 9.7% with orforglipron versus approximately 4.5% to 4.9% with oral semaglutide.²

REFERENCES

1. Lilly's Foundayo (orforglipron) 17.2 mg showed greater weight loss and A1C reduction than oral semaglutide 25 mg among adults with type 2 diabetes in a new indirect treatment comparison. News release. Eli Lilly and Company. September 29, 2026. Accessed September 29, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-foundayo-orforglipron-172-mg-showed-greater-weight-loss

2. Gallagher A. Orforglipron demonstrates superior blood sugar control compared with oral semaglutide. Drug Topics. February 26, 2026. Accessed September 29, 2026. https://www.drugtopics.com/view/orforglipron-demonstrates-superior-blood-sugar-control-compared-with-oral-semaglutide

3. Everts Q. Higher dose of oral semaglutide more effective for patients with T2D. Drug Topics. March 28, 2023. Accessed September 29, 2026. https://www.drugtopics.com/view/higher-dose-of-oral-semaglutide-more-effective-for-patients-with-t2d

4. Gallagher A. Orforglipron demonstrates superior glycemic control for type 2 diabetes. Drug Topics. October 16, 2025. Accessed September 29, 2026. https://www.drugtopics.com/view/orforglipron-demonstrates-superior-glycemic-control-for-type-2-diabetes