Eli Lilly and Company announced positive topline results from the Phase 3 ACHIEVE-2 and ACHIEVE-5 trials evaluating orforglipron, an investigational once-daily oral GLP-1 receptor agonist, for type 2 diabetes management. In ACHIEVE-2, orforglipron (3 mg, 12 mg, 36 mg) was compared to dapagliflozin (10 mg) in adults with type 2 diabetes inadequately controlled on metformin. The trial met its primary endpoint, with orforglipron achieving A1C reductions of up to 1.7% (efficacy estimand) compared to 0.8% for dapagliflozin at 40 weeks.
In ACHIEVE-5, orforglipron was evaluated against placebo in patients with inadequate glycemic control on titrated insulin glargine, with or without metformin and/or SGLT-2 inhibitors, achieving A1C reductions of up to 2.1% versus 0.8% for placebo. Both trials also met key secondary endpoints, including significant weight loss and improvements in cardiovascular risk factors, consistent with prior studies. Orforglipron’s safety profile was consistent with previous trials, with mild-to-moderate gastrointestinal adverse events being the most common and no hepatic safety signals observed.
The ACHIEVE-2 trial randomized 962 participants, while ACHIEVE-5 included 546, both with baseline A1C between 7.0% and 10.5% and BMI ≥23 kg/m². Orforglipron’s dosing flexibility, requiring no food or water restrictions, enhances its potential as a convenient treatment option. These results build on prior findings, including superiority over oral semaglutide in ACHIEVE-3, reinforcing orforglipron’s potential as a foundational therapy for type 2 diabetes. Lilly plans to submit orforglipron for type 2 diabetes to global regulatory agencies in 2026, with obesity submissions targeted for late 2025.
The ACHIEVE program, enrolling over 6,000 participants across five trials, continues to evaluate orforglipron for additional indications, including obesity, obstructive sleep apnea, hypertension, and osteoarthritis pain. Detailed results from ACHIEVE-2 and ACHIEVE-5 will be presented at a medical meeting and published in a peer-reviewed journal in 2026, with ACHIEVE-4 results expected in early 2026.
