ACHIEVE-3: Lilly's pill beats Novo's pill head-to-head in type 2 diabetes

Eli Lilly said on September 17, 2025 that its experimental daily pill, orforglipron, beat Novo Nordisk's oral semaglutide on blood sugar control in the first head-to-head trial of the two oral GLP-1 drugs in people with type 2 diabetes ^[1][2]. The topline results came from the Phase 3 ACHIEVE-3 study, which followed nearly 1,700 adults whose type 2 diabetes was not well managed on metformin alone ^[1].

At 52 weeks, the highest orforglipron dose lowered hemoglobin A1C — a measure of average blood sugar — by 2.2%, compared with 1.4% for oral semaglutide ^[1]. That was the trial's main goal, and Lilly said its drug was superior ^[1].

Weight loss also favored the Lilly pill. Patients on the highest orforglipron dose lost an average of 9.2% of their body weight, or 19.7 pounds, versus 5.3%, or 11 pounds, on oral semaglutide ^[1]. When all patients were counted regardless of whether they stopped treatment, orforglipron's average weight loss was 8.2% and oral semaglutide's was 5.3% ^[1].

The dose comparison matters

The study tested orforglipron at up to 36 milligrams against oral semaglutide at up to 14 milligrams — the dose already approved for type 2 diabetes under the brand name Rybelsus ^[1]. Novo Nordisk has been working on higher strengths: the company expected U.S. regulators to approve a 25-milligram oral semaglutide pill for obesity by the end of 2025, and has also run a Phase 3 trial of a 50-milligram dose ^[1].

That gap drew criticism from outside experts. Dr. Michael Weintraub, an endocrinologist at NYU Langone Diabetes & Endocrine Associates, said comparing 36 mg of orforglipron to a dose of semaglutide lower than what may eventually be approved "is short-changing semaglutide" ^[1]. Dr. Jaime Almandoz of UT Southwestern Medical Center said it is "a little too early to say that one is kind of a leader in the class," though he added that head-to-head data helps doctors match patients to pills ^[1]. Lilly Chief Scientific Officer Dan Skovronsky noted the company cannot run trials against medicines that are not yet approved, but said he is confident orforglipron can beat higher oral semaglutide doses ^[1].

Weintraub separately called orforglipron's blood sugar control "quite impressive not only compared to other oral Type 2 diabetes medications but all Type 2 diabetes medications including injectables" ^[1].

Side effects and dropouts

Safety and tolerability were consistent with earlier orforglipron trials, Lilly said, with the most common side effects being gastrointestinal and mild to moderate in severity ^[1]. But 9.7% of patients on the highest orforglipron dose stopped treatment because of side effects, compared with 4.9% on the highest dose of oral semaglutide ^[1]. Lilly said the study was not designed to compare safety and tolerability between the two drugs ^[1].

Almandoz said the findings were "nothing outside the realm of what one would expect" from GLP-1s and that he saw no concerning signals ^[1]. Weintraub said a discontinuation rate "almost double" that of the Novo pill "certainly gives me pause," and that the gastrointestinal effects are "likely something we will need to be mindful of" ^[1].

Why it matters for patients

Both drugs are pills, which matters for people who do not want weekly injections or who have run into supply and access problems with them ^[1]. But they work differently: oral semaglutide is a peptide, while orforglipron is a small molecule that Lilly says is absorbed more easily and does not carry the dietary restrictions that come with the Novo pill ^[1].

For now, the trial answers one narrow question — 36 mg orforglipron versus 14 mg oral semaglutide in adults with type 2 diabetes on metformin ^[1]. It does not tell patients how orforglipron compares with the 25 mg or 50 mg semaglutide pills, or how the two perform in people with obesity but not diabetes ^[1]. People with diabetes typically lose less weight on GLP-1s than people without it, so these numbers should not be read as obesity results ^[1].

What happens next

Lilly said it expects to file for U.S. approval of orforglipron in type 2 diabetes in 2026, and CEO David Ricks told CNBC in early August 2025 that the company hoped to launch the pill globally "this time next year" ^[1]. Detailed ACHIEVE-3 results were slated for presentation at a medical meeting and publication in a peer-reviewed journal ^[1]; the specific venue and date are not stated in these sources.