First head-to-head pill trial finds orforglipron beats oral semaglutide
Lilly's unapproved pill outperformed Rybelsus in a first-of-its-kind trial, but the doses tested and the patient group limit what the comparison can show.
Eli Lilly said Sept. 17, 2025 that its experimental diabetes pill orforglipron produced bigger drops in blood sugar and weight than Novo Nordisk's oral semaglutide. The two companies' oral GLP-1 programs had never before been compared directly in a randomized trial [1][2].
The Phase 3 study, ACHIEVE-3, measured results at 52 weeks. Hemoglobin A1c fell by 2.2 percentage points with the top orforglipron dose, against 1.4 points with oral semaglutide, the pill Novo sells as Rybelsus for type 2 diabetes [1]. Average weight loss on that orforglipron dose was 9.2%, or 19.7 pounds, while oral semaglutide produced 5.3%, or 11 pounds [1]. When everyone who entered the study was counted, whether or not they stayed on the drug, the weight figures were 8.2% and 5.3% [1].
Just under 1,700 adults enrolled, all with type 2 diabetes that metformin had not brought under control [1]. The trial compared orforglipron doses of up to 36 milligrams with oral semaglutide doses of up to 14 milligrams, the strength approved for diabetes [1].
Side effects were mostly gastrointestinal and mild to moderate, Lilly said, matching what earlier trials of the drug had shown [1]. Among patients on the top orforglipron dose, 9.7% quit treatment because of side effects; among those on the top oral semaglutide dose, 4.9% did [1]. Lilly pointed out that ACHIEVE-3 was not set up to compare how well the two medicines are tolerated [1].
Dan Skovronsky, Lilly's chief scientific officer, said the pill "could be the main medicine" most patients need to control both diabetes and obesity [1]. Dr. Michael Weintraub of NYU Langone Diabetes & Endocrine Associates called the blood sugar control "quite impressive not only compared to other oral Type 2 diabetes medications but all Type 2 diabetes medications including injectables," yet he said a quit rate nearly twice Novo's "certainly gives me pause" [1]. Skovronsky compared orforglipron with newer injectables such as Lilly's Mounjaro and Novo's Ozempic, and placed oral semaglutide closer to the older shots Victoza and Trulicity [1].
Several doctors flagged what the trial does not settle. There is no data comparing orforglipron with higher doses of oral semaglutide, and none in people who are overweight or have obesity but not diabetes [1]. Novo expects U.S. approval of a 25-milligram obesity dose by the end of the year and has tested 50 milligrams in a Phase 3 trial [1]. Comparing 36 milligrams of orforglipron with a dose below what may soon be available "is short-changing semaglutide," Weintraub said [1]. Dr. Jaime Almandoz, who directs the Weight Wellness Program at UT Southwestern Medical Center, said it remains "a little too early to say that one is kind of a leader" in the class [1].
Why it matters for patients
Orforglipron cannot be prescribed, because it has no approval for any use [1]. Oral semaglutide already has one, as Rybelsus for type 2 diabetes [1]. The two pills also differ in kind: orforglipron is a small molecule rather than a peptide, which Lilly says the body absorbs more easily and which does not come with dietary restrictions [1].
Weight results do not carry over between patient groups. People with diabetes tend to shed fewer pounds on GLP-1 drugs than people without it, so the roughly 15% loss oral semaglutide has shown in obesity trials should not be expected in a diabetes study, Weintraub said [1]. Even so, Almandoz said head-to-head numbers help clinicians judge which pill suits a given patient [1]. Analysts put the wider GLP-1 market near $100 billion by the 2030s, with oral products possibly $50 billion of it [1].
What happens next
Lilly plans to seek approval of orforglipron for type 2 diabetes in 2026, and chief executive David Ricks told CNBC in early August that a global launch is targeted for "this time next year" [1]. The journal and medical meeting that will carry the full ACHIEVE-3 results have not been disclosed [1]. Novo's obesity application for the 25-milligram dose sits with U.S. regulators, with a decision expected by the end of the year [1].
Sources
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