Orforglipron beats oral semaglutide on blood sugar and weight in first head-to-head trial

Eli Lilly reported on Sept. 17, 2025 that its experimental once-daily pill orforglipron outperformed oral semaglutide on blood sugar control and weight loss in ACHIEVE-3, the first Phase 3 head-to-head trial comparing two oral GLP-1 receptor agonists in adults with type 2 diabetes ^[2].

The 52-week, randomized, open-label trial enrolled 1,698 adults whose type 2 diabetes was not adequately controlled with metformin. People were assigned in equal groups to orforglipron 12 mg or 36 mg, or oral semaglutide 7 mg or 14 mg, at sites in the United States, Argentina, China, Japan, Mexico and Puerto Rico ^[1][3]. Average A1C at the start was 8.3%, and average starting weight was 97.0 kilograms, or 213.9 pounds ^[3].

On the main endpoint, orforglipron 12 mg lowered A1C by 1.9 percentage points and orforglipron 36 mg by 2.2 points at 52 weeks. Oral semaglutide lowered A1C by 1.1 points at 7 mg and 1.4 points at 14 mg ^[1][2][3]. A second analysis, which counts results regardless of whether people stayed on their assigned treatment or added other diabetes drugs, showed orforglipron lowering A1C by 1.7 and 1.9 points versus 1.2 and 1.5 points for oral semaglutide ^[1][3]. Lilly said the dose-by-dose comparisons were statistically significant ^[3].

For weight, orforglipron 12 mg produced an average 6.7% loss (14.6 pounds) and 36 mg a 9.2% loss (19.7 pounds), compared with 3.7% (7.9 pounds) for oral semaglutide 7 mg and 5.3% (11.0 pounds) for 14 mg. Lilly described that as 73.6% greater relative weight loss at the highest-dose comparison ^[1][2][3].

More participants on orforglipron reached an A1C below 7%: 80.0% at 12 mg and 85.4% at 36 mg, versus 54.6% and 66.1% for oral semaglutide ^[3]. Lilly also reported that 37.1% of people on orforglipron 36 mg reached an A1C below 5.7%, compared with 12.5% on oral semaglutide 14 mg. That measure was not controlled for family-wise type 1 error, meaning it carries a higher risk of a chance finding ^[1][2][3]. Orforglipron also improved several cardiovascular risk factors, including non-HDL cholesterol, systolic blood pressure and triglycerides, a result that likewise was not controlled for that error ^[3]. Dr. Julio Rosenstock, the trial's lead investigator, said improvements appeared as early as four weeks and were sustained ^[3].

The most common side effects for both drugs were nausea, diarrhea, vomiting, indigestion and decreased appetite ^[3]. Treatment discontinuation rates due to side effects were 8.7% (orforglipron 12 mg) and 9.7% (36 mg), compared with 4.5% (oral semaglutide 7 mg) and 4.9% (14 mg) ^[1][2][3]. Lilly said the trial was not designed to compare safety and tolerability between the two drugs, and that no liver safety signal was seen for orforglipron ^[2].

Why it matters for patients

Orforglipron is investigational and is not approved for any use as of the September 2025 announcement, so it is not an option people can ask for today ^[2]. Oral semaglutide is an approved medicine, and in this trial it was used according to its approved label instructions ^[2].

A head-to-head trial tests two drugs in the same group of people, which gives different information than comparing results from separate studies. Lilly called head-to-head trials a "gold standard for comparing potential treatments" ^[2]. In ACHIEVE-3, the primary goal was to show orforglipron was at least as good as oral semaglutide; the company reported it was better ^[2][3].

Orforglipron is a small molecule, non-peptide pill that can be taken at any time of day without restrictions on food or water intake ^[1][3]. Eating restrictions for oral semaglutide are not described in these results; the trial only states that it was given per its approved label ^[2].

Two limits are worth noting. More people stopped orforglipron than oral semaglutide because of side effects, but the study was not built to compare tolerability, so whether one drug is actually harder to take is not established ^[2]. And the results come from adults with type 2 diabetes not controlled on metformin. Whether the same differences would appear in people with obesity but without diabetes, or in people taking other diabetes medicines, has not been reported ^[1][3].

What happens next

Detailed results were published in The Lancet on Feb. 26, 2026 ^[1][3]. Lilly said it has submitted orforglipron to regulators in more than 40 countries, with a U.S. submission for type 2 diabetes planned later in 2026 and potential FDA action for obesity in the second quarter of 2026 ^[3]. Results from the three remaining ACHIEVE registrational trials are anticipated later in 2026 ^[3]. Orforglipron is also being studied for obstructive sleep apnea and hypertension in adults with obesity ^[1]. Whether the FDA will approve orforglipron for type 2 diabetes, and when, has not been disclosed ^[1][3].