INDIANAPOLIS, Sept. 17, 2025 – Eli Lilly and Company (NYSE: LLY) announced today that its investigational oral GLP-1 receptor agonist orforglipron achieved superior A1C reduction and weight loss compared with Novo Nordisk’s oral semaglutide in the pivotal Phase 3 ACHIEVE-3 trial. The findings reinforce orforglipron’s potential to redefine type 2 diabetes management and expand oral options in the fast-growing GLP-1 therapeutic class.
Science Significance
The ACHIEVE-3 trial enrolled 1,698 adults with type 2 diabetes inadequately controlled with metformin. Over 52 weeks, patients received orforglipron (12 mg or 36 mg) or oral semaglutide (7 mg or 14 mg). The primary endpoint was change in A1C from baseline, while secondary endpoints included weight reduction and achievement of near-normal glycemia.
Results showed that orforglipron reduced A1C by up to 2.2%, compared to 1.4% for oral semaglutide. At the highest doses, 37.1% of participants on orforglipron achieved an A1C below 5.7% versus just 12.5% with semaglutide. Weight loss was also superior, with patients on 36 mg orforglipron losing an average of 19.7 pounds (9.2% body weight), compared to 11.0 pounds (5.3%) with semaglutide.
Beyond glycemic and weight benefits, orforglipron also improved cardiovascular risk markers, including non-HDL cholesterol, triglycerides, and systolic blood pressure. These findings underscore the scientific potential of non-peptide oral GLP-1 therapies to deliver efficacy comparable to injectables, while broadening accessibility through once-daily oral dosing.
Regulatory Significance
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Lilly confirmed plans to submit global regulatory applications for orforglipron in type 2 diabetes in 2026, supported by the ACHIEVE-3 data and additional ongoing Phase 3 studies enrolling more than 6,000 participants worldwide.
Regulators are likely to view orforglipron’s head-to-head superiority as compelling clinical evidence, particularly given the widespread use of oral semaglutide and the unmet need for scalable oral treatments. If approved, orforglipron could become the first broadly available non-peptide oral GLP-1 therapy with demonstrated superiority over an existing standard of care.
Business Significance
The GLP-1 market is one of the fastest-growing sectors in biopharma, valued at more than $40 billion globally in 2024. Oral formulations are expected to significantly expand access and adoption, particularly in primary care.
By outperforming oral semaglutide, orforglipron positions Lilly to capture substantial market share in the oral GLP-1 segment, complementing its injectable franchise, which includes tirzepatide. Analysts expect orforglipron could strengthen Lilly’s cardiometabolic portfolio and drive long-term revenue growth across diabetes, obesity, and related comorbidities.
Kenneth Custer, Ph.D., president of Lilly Cardiometabolic Health, emphasized: “Head-to-head trials are a gold standard. Orforglipron outperformed semaglutide in both glycemic control and weight reduction, reinforcing its potential as a foundational treatment for type 2 diabetes.”
Patients’ Significance
For patients, orforglipron offers a once-daily oral option that can be taken without restrictions on food or water intake. This contrasts with oral semaglutide, which requires fasting before administration.
Superior A1C reduction, greater weight loss, and ease of use may translate into improved adherence and better long-term outcomes for millions of people with type 2 diabetes worldwide. Given the global burden of diabetes, with more than 500 million affected adults, an effective oral GLP-1 could significantly expand access to advanced therapy beyond injectable-only regimens.
Policy Significance
The results also carry implications for healthcare systems and payers. Diabetes accounts for billions in annual healthcare costs due to complications such as kidney failure, heart disease, and amputations.
Broader adoption of cost-effective oral GLP-1 therapies could reduce long-term complications, lower hospitalization rates, and help curb the rising economic burden of diabetes. Policymakers and insurers may prioritize access to oral formulations, particularly if they improve outcomes in underserved populations or reduce disparities in diabetes care.
Transaction Highlights
In the pivotal Phase 3 ACHIEVE-3 trial, orforglipron demonstrated clear superiority over oral semaglutide in both glycemic control and weight reduction. At 52 weeks, orforglipron lowered A1C by up to 2.2% compared to 1.4% with oral semaglutide, achieving the primary endpoint. Importantly, 37.1% of patients on the highest dose of orforglipron achieved near-normal blood sugar levels (A1C <5.7%) compared to just 12.5% with semaglutide. Weight reduction results further reinforced orforglipron’s clinical benefit, with patients losing an average of 19.7 pounds (9.2% of body weight) on the 36 mg dose versus 11 pounds (5.3%) with semaglutide, representing a 73.6% relative improvement. In addition, orforglipron improved cardiovascular risk markers such as non-HDL cholesterol, systolic blood pressure, and triglycerides. The safety profile remained consistent with prior studies, with gastrointestinal side effects being the most commonly reported and discontinuation rates modest across both treatment groups. These results strengthen Lilly’s case for regulatory submissions in 2026, supported by data from more than 6,000 participants enrolled across the global ACHIEVE program.
Source: Eli Lilly and Company Press Release
