Other companies are vying to bring a nonpeptide incretin mimetic to market as well. Novo Nordisk is pursuing late-stage trials of an oral formulation of semaglutide and has begun phase 1 trials of amycretin, a potential first-in-class combination of an amylin and GLP-1 receptor agonist. Viking Therapeutics recently completed enrollment for a phase 2 trial of its oral antiobesity candidate, VK2735, a dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist.
Lilly’s Oral GLP-1 Orforglipron Shows Significant and Competitive A1c and Weight Reductions in Phase 3 Trial
The positive topline data from the phase 3 ACHIEVE-1 trial suggest the small molecule GLP-1 mimetic could compete with blockbuster weekly injectables for reducing weight, A1c.
Eli Lilly’s investigational once-daily oral glucagon-like peptide-1 receptor agonist (GLP-1RA), orforglipron, demonstrated statistically significant reductions in both HbA1c and body weight in adults with type 2 diabetes, according to topline results from the phase 3 ACHIEVE-1 trial reported today.
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The trial met its primary endpoint, showing HbA1c reductions of 1.3% to 1.6% from a baseline of 8.0% after 40 weeks. In a key secondary endpoint, patients receiving the highest 36 mg dose experienced an average weight loss of 7.3 kg (16.0 lbs; 7.9%).1 The reductions in both measures place orforglipron efficacy on par with Novo Nordisk's injectable semaglutide (Ozempic).
More than 65% of participants in the highest-dose group achieved an HbA1c of 6.5% or less, below the diagnostic threshold for a diabetes diagnosis established by the American Diabetes Association (ADA), according to Lilly. The safety profile was consistent with that of injectable GLP-1 receptor agonists, with gastrointestinal adverse events being most commonly reported and generally mild to moderate in severity.1
“ACHIEVE-1 is the first of seven phase 3 studies examining the safety and efficacy of orforglipron across people with diabetes and obesity,” David A. Ricks, Lilly chair and CEO, said in a statement. “We are pleased to see that our latest incretin medicine meets our expectations for safety and tolerability, glucose control and weight loss, and we look forward to additional data readouts later this year.”1
News of the results triggered headlines in pharma business and consumer media citing "Ozempic-like efficacy" for the small molecule GLP-1 receptor agonist but with the benefit of oral vs subcutaneous administration. In previous phase 3 studies, semaglutide was associated with reductions in HbA1c of 1.4% to 1.6% after 30 weeks, making the orforglipron 1.3% to 1.6% at 40 weeks comparable. Participants in ACHIEVE-1 taking the highest dose of orforglipron lost an average of 7.3 kg of the mean 90.2 kg baseline weight. Participants in the phase 3 trial with semaglutide lost up to 4.7 kg from mean starting weights of up to 96.9 kg.
ACHIEVE-1
The ACHIEVE-1 trial enrolled 559 participants with type 2 diabetes across the the US, China, India, Japan, and Mexico. Participants had a baseline HbA1c between 7.0% and 9.5%, a BMI of 23 kg/m² or higher, and had not received antihyperglycemic medications for at least 90 days prior to study entry. Orforglipron doses were escalated over time to final doses of 3 mg, 12 mg, or 36 mg, with all dose groups showing statistically significant HbA1c reductions using both the efficacy and treatment-regimen estimands.1
Under the efficacy estimand, HbA1c reductions were 1.3% (3 mg), 1.6% (12 mg), and 1.5% (36 mg) vs 0.1% with placebo. Corresponding weight reductions were 4.4 kg (9.7 lbs), 5.5 kg (12.2 lbs), and 7.3 kg (16.0 lbs), compared to 1.3 kg (2.9 lbs) for placebo. Reductions in weight were statistically significant for the 12 mg and 36 mg doses.1
In the treatment-regimen estimand, HbA1c reductions were 1.2% (3 mg), 1.5% (12 mg), and 1.5% (36 mg), versus 0.4% with placebo. Weight reductions were 4.2 kg (9.3 lbs), 5.2 kg (11.5 lbs), and 7.2 kg (15.8 lbs) in the respective dose groups, compared to 1.5 kg (3.4 lbs) for placebo.1
The safety profile of orforglipron in the phase 3 trial was consistent with that known for the GLP-1 receptor agonist class. Gastrointestinal adverse events were the most common, including diarrhea (19–26%), nausea (13–18%), dyspepsia (10–20%), constipation (8–17%), and vomiting (5–14%), compared to lower incidence rates in the placebo group. Discontinuation rates due to adverse events were 6% (3 mg), 4% (12 mg), and 8% (36 mg) for orforglipron, versus 1% for placebo. Lilly reported no hepatic safety signal.1
The findings reported today follow an announcement from Pfizer earlier this week that the company would discontinue development of danuglipron, its own investigational oral GLP-1 RA candidate. The decision was based on evidence that a participant in one of the company's early-stage trials experienced a possible drug-induced liver injury. Pfizer reported that symptoms resolved upon cessation of the drug.3
The ACHIEVE phase 3 clinical program includes 5 global registrational trials involving more than 6,000 participants. Lilly plans to submit orforglipron for regulatory approval for weight management by the end of 2025, followed by submission for type 2 diabetes in 2026. The ACHIEVE-1 results will be presented at the ADA’s 85th Scientific Sessions and published in a peer-reviewed journal.1
References
1. Lilly's oral GLP-1, orforglipron, demonstrated statistically significant efficacy results and a safety profile consistent with injectable GLP-1 medicines in successful Phase 3 trial. News release. Lilly. April 17, 2025. Accessed April 17, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-demonstrated-statistically
2. Ma X, Liu R, Pratt EJ, Benson CT, Bhattachar SN, Sloop KW. Effect of food consumption on the pharmacokinetics, safety and tolerability of once-daily orally administered orforglipron (LY3502970), a non-peptide GLP-1 receptor agonist. Diabetes Ther. 2024;15(4):819-832. doi: 10.1007/s13300-024-01554-1
3. Pfizer provides update on oral GLP-1 receptor agonist danuglipron. News release. Pfizer. April 14, 2025. Accessed April 17, 2025.
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