ACHIEVE-3: Orforglipron Superior to Semaglutide for Type 2 Diabetes in Phase 3 Trial

Orforglipron, an investigational once-daily small molecule oral GLP-1 receptor agonist, has proven its superior safety and efficacy versus oral semaglutide in treating type 2 diabetes (T2D) inadequately controlled with metformin.1

Announced on September 17, 2025, by parent company Eli Lilly and Company, the phase 3 ACHIEVE-3 trial compared orforglipron to oral semaglutide across 4 active treatment arms, assessing glycemic control and weight loss. By 52 weeks, orforglipron successfully met the primary and all key secondary endpoints across each dose comparison.1

“In this type 2 diabetes trial, orforglipron, even at the lower dose, outperformed both doses of oral semaglutide in reducing A1C,” Kenneth Custer, PhD, executive vice president and president of Lilly Cardiometabolic Health, said in a statement. “At the highest dose, orforglipron helped nearly 3 times as many participants reach near-normal blood sugar versus the highest dose of oral semaglutide. These results, combined with orforglipron’s once-daily oral dosing and broad scalability, reinforce its potential as a foundational treatment for type 2 diabetes.”1

Eli Lilly also recently presented detailed results from the ATTAIN-1 trial, which investigated orforglipron in adults with obesity or overweight without diabetes, at the European Association for the Study of Diabetes (EASD) Annual Meeting 2025. This investigation found 3 separate orforglipron doses – 6 mg, 12 mg, and 36 mg – showed superior body weight reduction compared to placebo, as well as reducing waist circumference.2

ACHIEVE-3 is a 52-week randomized, open-label trial including 1698 participants across the US, Argentina, China, Japan, Mexico, and Puerto Rico. Patients were randomly assigned in a 1:1:1:1 ratio to receive either 12 mg or 36 mg of orforglipron or 7 mg or 14 mg of oral semaglutide. Investigators established a primary endpoint of demonstrating the noninferiority of orforglipron versus oral semaglutide between the low and high doses.1

All participants in the orforglipron arm began the trial at a dose of 1 mg orforglipron daily, and then increased the dose in a stepwise approach at 4-week intervals until reaching their randomized maintenance dose of 12 or 36 mg. Patients in the semaglutide arm started with a dose of 3 mg daily, and increased in a stepwise manner at the same interval until reaching either 7 or 14 mg. If patients were unable to tolerate a dose of either drug, they were allowed to reduce it to the previous dose once per study.1

Orforglipron lowered A1C by an average of 1.9% (12 mg) and 2.2% (36 mg) compared to 1.1% (7 mg) and 1.4% (14 mg) with oral semaglutide at 52 weeks. A secondary endpoint saw participants on the highest orforglipron dose achieve an A1C <5.7% compared to 12.5% taking the highest dose of oral semaglutide.1

Orforglipron was also superior to oral semaglutide for weight loss, as participants taking orforglipron lost an average of 14.6 lbs (6.7%; 12 mg) and 19.7 lbs (9.2%; 36 mg) compared to 7.9 lbs (3.7%; 7 mg) and 11 lbs (5.3%; 14 mg) with oral semaglutide. This represents a 73.6% greater relative weight loss at the highest dose comparison.1

Investigators also noted the consistency of the safety and tolerability profiles between this and previous trials. The most common adverse events were gastrointestinal-related and generally mild to moderate in severity. Discontinuation rates due to adverse events were 8.7% (12 mg) and 9.7% (36 mg) for orforglipron versus 4.5% (7 mg) and 4.9% (14 mg) for oral semaglutide. Investigators also noted, however, that the study was not powered to compare the safety and tolerability of orforglipron and semaglutide.1

The ACHIEVE phase 3 global clinical development program for orforglipron is ongoing, having enrolled >6000 people with T2D across 5 global registration trials. Results are anticipated at the end of 2025 and into 2026.1

References

1. Lilly’s oral GLP-1, orforglipron, superior to oral semaglutide in head-to-head trial. Eli Lilly and Company. September 17, 2025. Accessed September 18, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-superior-oral-semaglutide-head

2. Lilly’s oral GLP-1, orforglipron, demonstrated meaningful weight loss and cardiometabolic improvements in complete ATTAIN-1 results published in The New England Journal of Medicine. Eli Lilly and Company. September 16, 2025. Accessed September 18, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-demonstrated-meaningful-weight