Orforglipron tops oral semaglutide on A1C and weight, with more side effects, in ACHIEVE-3

Eli Lilly's experimental once-daily pill orforglipron beat oral semaglutide on blood sugar control and weight loss in a head-to-head type 2 diabetes trial, according to full results published Feb. 26, 2026 in The Lancet ^[1][2][3]. The same data show a tolerability gap: more participants on orforglipron reported side effects and more stopped taking it ^[1][3][4].

ACHIEVE-3 enrolled 1,698 adults whose type 2 diabetes was not adequately controlled on metformin ^[1][3]. They were randomly assigned in equal groups to orforglipron 12 mg, orforglipron 36 mg, oral semaglutide 7 mg or oral semaglutide 14 mg, all taken daily, for 52 weeks. Study sites were in the United States, Argentina, China, Japan, Mexico and Puerto Rico. At the start, the group's average A1C was 8.3% and average weight was 97.0 kilograms, or 213.9 pounds ^[1][3].

On the primary endpoint, the 36 mg orforglipron dose lowered A1C by 2.2 percentage points, against 1.4 points for the 14 mg oral semaglutide dose. The 12 mg orforglipron dose lowered A1C by 1.9 points, compared with 1.1 points for oral semaglutide 7 mg ^[1][3][4]. Lilly said the improvements appeared as early as four weeks and held through the study ^[1][3].

Weight fell further on orforglipron. Average loss was 19.7 pounds, or 9.2% of body weight, at 36 mg, versus 11.0 pounds, or 5.3%, at 14 mg oral semaglutide. The company described that as 73.6% greater relative weight loss. At 12 mg, the average was 14.6 pounds, or 6.7%. A larger share of orforglipron participants also reached tighter A1C targets: 85.4% on 36 mg finished below 7%, compared with 66.1% on 14 mg oral semaglutide, and 37.1% versus 12.5% finished below 5.7% ^[1][3].

Two of the reported comparisons were not adjusted for family-wise type 1 error: the weight difference between orforglipron 12 mg and oral semaglutide 14 mg, and the share of people reaching an A1C below 5.7%. Lilly describes both as prespecified secondary endpoints showing nominal statistical significance ^[1][3].

Nausea, diarrhea, vomiting, indigestion and reduced appetite were the most frequently reported problems in both drug groups ^[1][3]. Reuters reported that roughly 58% of people taking 36 mg orforglipron had mild-to-moderate side effects, compared with 45% on 14 mg oral semaglutide, and that orforglipron users also saw an average rise in pulse rate ^[4]. Discontinuation because of side effects was 8.7% at 12 mg and 9.7% at 36 mg for orforglipron, against 4.5% at 7 mg and 4.9% at 14 mg for oral semaglutide ^[1][3][4].

"With global submissions underway and FDA action on obesity expected next quarter, we're focused on making this option available as quickly as possible," said Kenneth Custer, president of Lilly Cardiometabolic Health ^[1][3]. Asked about the side-effect gap, Custer told Reuters the overall profile is "a trade-off that patients will be very happy to make" given better blood sugar control, better weight loss and no food or water timing restrictions ^[4].

Why it matters for patients

Oral semaglutide is already sold in the United States as Rybelsus for type 2 diabetes. Orforglipron is investigational and has not been approved by any regulator ^[1][3][4]. Unlike semaglutide, orforglipron is a small-molecule pill that Lilly says can be taken at any time of day without regard to eating or drinking ^[1][3].

This study compared two oral pills in people with type 2 diabetes taking metformin. How orforglipron compares with injectable semaglutide (Ozempic, Wegovy) or with tirzepatide (Mounjaro, Zepbound) has not been reported here, and the weight results come from a diabetes trial rather than a weight-management trial ^[1][3][4]. Whether the two products differ in cost or insurance coverage has not been disclosed.

What happens next

Lilly says it has filed orforglipron with regulators in more than 40 countries. A US submission for type 2 diabetes is planned later this year, and the company expects possible FDA action on obesity in the second quarter of 2026. Lilly notes there is no guarantee the drug will be approved ^[1][3].

The broader ACHIEVE program has enrolled more than 6,000 people with type 2 diabetes across five registration trials, with detailed results from the three remaining trials expected later this year. Orforglipron is also being tested for obstructive sleep apnea and hypertension in adults with obesity. It was discovered by Chugai Pharmaceutical and licensed by Lilly in 2018 ^[1][3].