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# Lilly’s Oral GLP-1 Orforglipron Beats Oral Semaglutide in Trial
- URL: https://www.fdaweb.com/lillys-oral-glp-1-orforglipron-beats-oral-semaglutide-in-trial/
- Published: 2026-02-26T12:00:00.000Z
- Updated: 2026-09-14T13:34:30.000Z
- Author: David McFarland
- Tags: Drugs, #legacy-id-D5160726

Eli Lilly says its investigational oral GLP-1 receptor agonist orforglipron delivered significantly greater reductions in blood sugar and body weight than oral semaglutide (Novo Nordisk’s Rybelsus)in a 52-week head-to-head Phase 3 trial of adults with Type 2 diabetes. Results from the ACHIEVE-3 study, [published 2/26](https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2826%2900202-3/abstract?ref=fdaweb.com) in *The Lancet*, showed that the highest dose of orforglipron (36 mg) reduced A1C levels by 2.2% from a baseline of 8.3%, compared with a 1.4% reduction for oral semaglutide 14 mg, meeting the primary endpoint and demonstrating statistical superiority, according to the company.

In a key secondary endpoint, Lilly says patients receiving orforglipron 36 mg lost 19.7 pounds (9.2% of body weight) from a baseline of 97 kg (213.9 lbs), compared with 11.0 pounds (5.3%) for those taking oral semaglutide 14 mg — a 73.6% greater relative weight loss. The 12 mg dose of orforglipron also outperformed both 7 mg and 14 mg doses of oral semaglutide across glycemic and weight endpoints.

“This is the first head-to-head comparison between two oral GLP-1 receptor agonists in adults with type 2 diabetes, and the differences were clinically meaningful,” says Julio Rosenstock, clinical professor at the University of Texas Southwestern Medical Center and the study’s lead investigator. Improvements in A1C and weight loss emerged as early as four weeks and were sustained through week 52, he adds.

Lilly says the data show that a substantially higher proportion of patients on orforglipron achieved guideline-recommended glycemic targets. At week 52, 85.4% of patients on orforglipron 36 mg reached A1C of less than 7%, compared with 66.1% on oral semaglutide 14 mg. More than one-third (37.1%) of patients on the highest orforglipron dose achieved near-normoglycemia (A1C less than 5.7%), versus 12.5% with semaglutide 14 mg.

Orforglipron also produced improvements in cardiovascular risk markers, including non-HDL cholesterol, HDL cholesterol, VLDL cholesterol, total cholesterol, systolic blood pressure and triglycerides, it says.

Regarding safety, Lilly says the overall safety and tolerability profile was consistent with the GLP-1 class. The most common adverse events in both treatment groups were gastrointestinal, including nausea, diarrhea, vomiting, dyspepsia and decreased appetite. However, discontinuations due to adverse events were higher with orforglipron — 8.7% for the 12 mg dose and 9.7% for 36 mg — compared with 4.5% and 4.9% for oral semaglutide 7 mg and 14 mg, respectively, it says.

Orforglipron is a once-daily, small-molecule (non-peptide) oral GLP-1 receptor agonist that can be taken without food or water restrictions — a potential convenience advantage over oral semaglutide, which must be taken under specific fasting conditions. An NDA for a weight-loss indication is currently under review, with a U.S. regulatory decision expected in the second quarter of 2026\. A submission for Type 2 diabetes is planned later this year.