Lilly’s oral GLP-1 orforglipron tops Phase 3 trials in type 2 diabetes

New Delhi: Eli Lilly and Company has announced positive topline results from the Phase 3 ACHIEVE-2 and ACHIEVE-5 trials. ACHIEVE-2, the second head-to-head trial in the program, evaluated orforglipron versus dapagliflozin, an SGLT-2 inhibitor, in adults with type 2 diabetes inadequately controlled on metformin.

Separately, ACHIEVE-5 assessed orforglipron versus placebo in adults with type 2 diabetes and inadequate glycemic control with titrated insulin glargine, with or without metformin and/or SGLT-2 inhibitors. In both trials, orforglipron (3 mg, 12 mg, 36 mg) met the primary and all key secondary endpoints at 40 weeks for both the efficacy and treatment-regimen estimands, delivering significant A1C reduction and weight loss as well as improvements in multiple cardiovascular risk factors, all consistent with previously disclosed studies in type 2 diabetes.^1,2,3

“Orforglipron has now demonstrated superiority over two active comparators in clinical trials for type 2 diabetes,” said Jeff Emmick, M.D., Ph.D., senior vice president of product development, Lilly Cardiometabolic Health. “In ACHIEVE-2, orforglipron outperformed dapagliflozin, a commonly used SGLT-2 therapy, and in ACHIEVE-3, showed greater efficacy than oral semaglutide. The findings from ACHIEVE-5 add to this momentum, showing significant A1C reduction and weight loss when used in combination with titrated basal insulin. Together, these results reinforce orforglipron’s potential to become a new standard of care for people living with type 2 diabetes.”

In the ACHIEVE-2 trial, orforglipron demonstrated significant reductions in A1C from a baseline of 8.1% at week 40. At doses of 3 mg, 12 mg, and 36 mg, the efficacy estimand showed decreases of –1.3%, –1.7%, and –1.7% respectively, compared with –0.8% for dapagliflozin 10 mg. The treatment-regimen estimand results were consistent, with reductions of –1.2%, –1.5%, and –1.6% versus –0.8% for dapagliflozin.

In the ACHIEVE-5 trial, starting from a baseline A1C of 8.5% at week 40 with titrated insulin glargine, orforglipron again showed strong efficacy. Reductions for the efficacy estimand were –1.5%, –2.1%, and –1.9% for the 3 mg, 12 mg, and 36 mg doses, compared with –0.8% for placebo. The treatment-regimen estimand findings were similar, with reductions of –1.6%, –1.9%, and –1.8% compared to –0.8% for placebo.

The company clarified thataAll doses of orforglipron achieved statistical significance vs. the comparator, with p<0.001 under both the efficacy and treatment-regimen estimand. Also, the Insulin glargine doses were adjusted per a treat-to-target algorithm with no restriction from week four to week 40.

In both trials, the overall safety and tolerability profile of orforglipron, as well as treatment discontinuation rates, were consistent with previous studies. The most common adverse events were gastrointestinal-related and generally mild-to-moderate in severity. No hepatic safety signal was observed.

The detailed results of these trials will be presented at a future medical meeting and published in a peer-reviewed journal. Results are expected in the first quarter of 2026 for ACHIEVE-4, the final global registration trial in the ACHIEVE program. Lilly plans to submit orforglipron for the treatment of type 2 diabetes to global regulatory agencies in 2026, while submission for the treatment of obesity is on track to occur by the end of this year.