Better Blood Sugars, More Weight Loss With Orforglipron VS Rybelsus

Lilly has landed what could be a defining blow in the oral GLP-1 race.

In a 52-week Phase 3 trial published Wednesday in The Lancet, Lilly’s small molecule pill orforglipron beat Novo Nordisk’s oral semaglutide across the primary endpoint and all key secondary measures in adults with type 2 diabetes on background metformin.

The ACHIEVE-3 study enrolled 1,698 patients across 4 arms and marks the first head-to-head comparison between 2 oral GLP-1 receptor agonists in diabetes. While the trial was designed to test noninferiority, Lilly demonstrated superiority.

A1C: clear separation at 36 mg

At 52 weeks, patients on orforglipron 36 mg saw A1C fall by 2.2% from a baseline of 8.3% using the efficacy estimand. That compares with a 1.4% reduction for oral semaglutide 14 mg.

Even the 12 mg dose of orforglipron delivered a 1.9% A1C reduction, ahead of Novo’s 7 mg and 14 mg doses.

Using the treatment-regimen estimand, reductions were 1.9% for 36 mg orforglipron vs. 1.5% for semaglutide 14 mg.

Target achievement rates widened the gap. At 36 mg, 85.4% of participants achieved A1C <7%, compared with 66.1% on semaglutide 14 mg. For A1C ≤6.5%, rates were 76.8% vs. 50.9%. And 37.1% of patients on high-dose orforglipron reached A1C <5.7%, compared with 12.5% on semaglutide 14 mg.

Weight loss: 9.2% vs. 5.3%

Weight loss also favored Lilly.

From a baseline of 97.0 kg, patients on orforglipron 36 mg lost 9.2% of body weight, or 19.7 lbs, compared with 5.3%, or 11.0 lbs, on oral semaglutide 14 mg. Lilly characterized that as a 73.6% greater relative weight loss.

The 12 mg dose delivered 6.7% weight loss, again ahead of semaglutide.

Although the study was open label, the magnitude and consistency of separation across glycemic and weight endpoints are likely to draw attention from prescribers and payers as the oral GLP-1 market evolves.

Safety and discontinuations

The overall safety profile aligned with prior GLP-1 experience. The most common adverse events for both drugs were nausea, diarrhea, vomiting, dyspepsia and decreased appetite.

Discontinuation rates due to adverse events were higher with orforglipron: 8.7% at 12 mg and 9.7% at 36 mg, compared with 4.5% and 4.9% for semaglutide 7 mg and 14 mg, respectively.

A small molecule with fewer restrictions

Unlike oral semaglutide, which must be taken under strict fasting conditions with limited water and a waiting period before food, orforglipron can be taken without food or water timing restrictions.

Orforglipron is a non-peptide small molecule discovered by Chugai Pharmaceutical Co., Ltd. and licensed to Lilly in 2018. The broader ACHIEVE program has enrolled more than 6,000 people with type 2 diabetes across 5 global registration trials.

Regulatory timeline

Lilly says it has submitted orforglipron to regulators in over 40 countries. A potential U.S. regulatory action for obesity is expected in Q2 2026, with a U.S. diabetes submission planned later this year.

For Novo, the data intensify competitive pressure in a category it pioneered. For Lilly, ACHIEVE-3 reinforces its strategy of pushing beyond noninferiority and into clear clinical separation as the incretin race shifts from injections to pills.

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