INDIANAPOLIS, Oct. 15, 2025 — Eli Lilly and Company (NYSE: LLY) announced positive topline results from two pivotal Phase 3 trials—ACHIEVE-2 and ACHIEVE-5—evaluating orforglipron, its once-daily, oral GLP-1 receptor agonist, in adults with type 2 diabetes. Both trials met all primary and key secondary endpoints, demonstrating superior glycemic control, A1C reduction, and consistent safety, reaffirming orforglipron’s potential as a foundational therapy in diabetes management.
Science Significance
In ACHIEVE-2, orforglipron—at doses of 3 mg, 12 mg, and 36 mg—lowered A1C by up to 1.7%, significantly outperforming dapagliflozin’s 0.8% reduction, in adults whose diabetes was inadequately controlled on metformin. In ACHIEVE-5, among participants using insulin glargine, orforglipron added a further 2.1% A1C reduction compared to 0.8% with placebo. Both trials also demonstrated consistent weight loss and improvements in cardiovascular risk markers across all doses. The safety profile remained consistent with known GLP-1 therapies: gastrointestinal side effects were common but mostly mild to moderate; no hepatic safety signals were detected. discontinuations were low.
Regulatory Significance
These trial results place orforglipron on track for regulatory submissions in 2026 for treatment of type 2 diabetes. The full ACHIEVE program—including ACHIEVE-4 which is still pending—is now nearing completion, strengthening Lilly’s dossier for agencies like the FDA, EMA, and other global bodies. Lilly is also proceeding toward obesity-indication filings by end of 2025, leveraging data from its ATTAIN trials (e.g., ATTAIN-2) which showed strong weight loss in people with obesity and type 2 diabetes. The oral formulation, with its non-peptide GLP-1 receptor agonist structure and lack of food/water timing restrictions, may simplify regulatory review and patient usage.
Business Significance
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Orforglipron’s performance in these trials strengthens Lilly’s metabolic disease franchise at a moment of intense competition in GLP-1, obesity, and cardiometabolic therapies. Its ability to outperform dapagliflozin and deliver substantial A1C reductions when combined with insulin glargine gives it a strong commercial profile. Moreover, the oral, small-molecule GLP-1 class is attractive for scale, production, marketing, and patient adherence. The flexibility of dosing without food restrictions adds to its appeal versus injectable or other more constrained options. Lilly likely views orforglipron as a major revenue driver in both diabetes and obesity markets over the next several years.
Patients’ Significance
For persons with type 2 diabetes, orforglipron may offer a convenient, effective oral therapy that yields strong blood sugar control and weight reduction. The ability to lower A1C by up to 2.1%, even when on insulin therapy, could delay disease progression and reduce risks of complications. The oral formulation is likely to ease treatment burden, especially for patients reluctant to use injections or with logistical or lifestyle barriers. Weight loss and improvements in cardiovascular risk factors offer additional benefits beyond glycemic control—addressing comorbid conditions common in diabetes.
Policy Significance
Policy makers will likely view orforglipron as a tool to improve access to advanced diabetes care, especially in regions where injectable therapies are less accessible. Simpler administration (oral pill, no timing restrictions) could reduce health system costs relating to logistics, patient training, and storage. The data may influence updates to clinical guidelines in endocrinology and diabetes associations, pushing oral GLP-1 therapies higher in treatment algorithms. Payers will closely examine long-term cost-effectiveness—if orforglipron reduces hospitalizations, cardiovascular complications, and dependency on more expensive injectable therapies, that strengthens reimbursement prospects.
Transaction Highlights
Eli Lilly’s ACHIEVE-2 and ACHIEVE-5 trials enrolled adults with type 2 diabetes under different baseline treatments—metformin alone in ACHIEVE-2, and insulin glargine (with or without metformin/SGLT-2 inhibitors) in ACHIEVE-5. Across both studies, all three dose levels (3 mg, 12 mg, 36 mg) of orforglipron met the primary endpoint of statistically significant A1C reduction: in ACHIEVE-2 lowering A1C by up to 1.7% vs. 0.8% for dapagliflozin; in ACHIEVE-5 achieving up to 2.1% reduction vs. 0.8% with placebo. The efficacy held under both “efficacy” and “treatment-regimen” estimands. Safety results were aligned with prior GLP-1 trials: gastrointestinal side effects common but manageable; minimal discontinuations and no liver safety concerns. Lilly plans regulatory filings for type 2 diabetes in 2026 and is moving toward obesity indication filings by late 2025. Full trial data will be submitted to regulatory authorities and published in peer-reviewed journals.
Source: Eli Lilly and Company Press Release
