Lilly’s oral GLP-1 orforglipron beats semaglutide in efficacy but not safety

Eli Lilly and Company announced detailed Phase III data from the ACHIEVE-3 trial evaluating its investigational oral GLP-1 receptor agonist orforglipron in adults with type 2 diabetes inadequately controlled on metformin. The results, published in The Lancet, represent the first head-to-head comparison between two oral GLP-1 therapies.

The results will be closely parsed given the implications for competition within a class currently dominated by injectable agents. Of note, orforglipron at its higher dose delivered materially greater A1C and weight reductions than oral semaglutide at 52 weeks, but with a higher adverse‑event (AE)-driven discontinuation rate.

Trial specifics

ACHIEVE-3 is a 52-week, randomized study enrolling 1,698 adults with type 2 diabetes on a metformin background. Participants were assigned to once-daily oral orforglipron at 12 mg or 36 mg, or oral semaglutide at 7 mg or 14 mg, with stepwise dose escalation in each arm.

The primary endpoint was change in A1C from a baseline of 8.3% at Week 52. Using the efficacy estimand, orforglipron 36 mg reduced A1C by 2.2%, compared with 1.4% for oral semaglutide 14 mg. In a key secondary endpoint, weight decreased by 9.2% (19.7 lbs) with orforglipron 36 mg versus 5.3% (11.0 lbs) with oral semaglutide 14 mg. Lilly reported statistically significant differences across primary and key secondary endpoints.

However, discontinuations due to adverse events were higher with orforglipron, occurring in 8.7% and 9.7% of participants in the 12 mg and 36 mg arms, respectively, compared with 4.5% and 4.9% in the oral semaglutide groups. The most common adverse events were gastrointestinal, including nausea, diarrhea, vomiting, dyspepsia, and decreased appetite.

Outlook

The findings suggest a familiar GLP-1 class tradeoff: greater glycemic and weight efficacy accompanied by increased gastrointestinal intolerance. Whether the apparent efficacy advantage reflects intrinsic potency, differences in effective exposure or titration schedules, or elements of the open-label design will be examined more closely as full peer-reviewed data are assessed. Additionally, discontinuation rates approaching twice those seen with oral semaglutide may influence real-world adherence and payer positioning if replicated outside the trial setting.

Lilly said it has submitted orforglipron to regulators in more than 40 countries and anticipates potential US FDA action for obesity in Q2 2026. A US submission for type 2 diabetes is planned later this year.