Lilly's orforglipron pill beats dapagliflozin and adds to insulin in two Phase 3 diabetes trials

Eli Lilly reported on Oct. 15, 2025 that its experimental once-daily pill orforglipron lowered A1C more than the diabetes drug dapagliflozin in one late-stage trial, and lowered A1C more than placebo when added to insulin glargine in another. Both 40-week Phase 3 studies met their primary goals and all key secondary goals, the company said ^[1].

ACHIEVE-2 enrolled 962 adults with type 2 diabetes whose blood sugar was not controlled well enough on metformin. Their average starting A1C was 8.1%, and they took either orforglipron at 3 mg, 12 mg or 36 mg, or dapagliflozin 10 mg, once daily. At 40 weeks, A1C fell 1.3 points with the 3 mg dose and 1.7 points with the 12 mg and 36 mg doses, compared with 0.8 points for dapagliflozin, an SGLT-2 inhibitor that AstraZeneca sells as Farxiga. The differences were statistically significant, with p<0.001. A second analysis, which counted people who stopped treatment or added other diabetes medicines, showed smaller but similar results ^[1][2].

ACHIEVE-5 enrolled 546 adults taking insulin glargine, with or without metformin, an SGLT-2 inhibitor, or both. Their average starting A1C was 8.5%. Insulin doses were adjusted during the trial under a treat-to-target plan, with no restriction from week four to week 40. Over 40 weeks, A1C fell 1.5 points with orforglipron 3 mg, 2.1 points with 12 mg and 1.9 points with 36 mg, compared with 0.8 points for placebo. All doses were statistically significant versus placebo ^[1].

Side effects in both trials were mostly gastrointestinal and generally mild to moderate, Lilly said, and discontinuation rates were consistent with earlier orforglipron studies. The company reported no liver safety signal. Lilly said both trials also showed weight loss and improvements in several cardiovascular risk factors, but did not release numbers for either ^[1]. In ACHIEVE-3, a previously reported head-to-head trial, orforglipron showed greater efficacy than oral semaglutide, sold as Rybelsus ^[1][2].

"Together, these results reinforce orforglipron's potential to become a new standard of care for people living with type 2 diabetes," said Jeff Emmick, Lilly's senior vice president of product development for cardiometabolic health ^[1][2].

Why it matters for patients

Orforglipron is not approved by the FDA. It is an investigational, once-daily small molecule (non-peptide) GLP-1 receptor agonist that Lilly says can be taken at any time of day without restrictions on food or water intake ^[1]. Oral GLP-1 treatment today includes Rybelsus, Novo Nordisk's semaglutide pill ^[2]. A once-daily pill without meal or water timing rules could be simpler for some people than an injection or a pill with food restrictions, although these trials did not compare orforglipron with injectable GLP-1 drugs ^[1][2].

A1C is a measure of average blood sugar over time. The trials were not designed to show differences in heart attacks, strokes, kidney disease or deaths, and no such outcomes have been reported ^[1]. Weight loss was not a primary or key secondary endpoint for the 3 mg dose compared with dapagliflozin in ACHIEVE-2 ^[1].

Full results have not been published or presented. Lilly said detailed data will be presented at a future medical meeting and published in a peer-reviewed journal ^[1]. ACHIEVE-2 was open-label, so participants and investigators knew which treatment was given, while ACHIEVE-5 was double-blind ^[1].

What happens next

Results from ACHIEVE-4, the final global registration trial in the program, are expected in the first quarter of 2026. Lilly plans to submit orforglipron for the treatment of type 2 diabetes to regulatory agencies worldwide in 2026, and says its submission for obesity is on track for the end of this year ^[1][2]. The ACHIEVE program has enrolled more than 6,000 people with type 2 diabetes across five trials since it began in 2023. Orforglipron is also being studied for obstructive sleep apnea, hypertension and osteoarthritis pain in adults with obesity ^[1]. Whether the FDA will approve it, and when, has not been disclosed ^[1].