Head-to-head trial shows Eli Lilly’s oral GLP-1 orforglipron outperforms oral semaglutide

## Head-to-head trial shows Eli Lilly’s oral GLP-1 orforglipron outperforms oral semaglutide A clinical trial for diabetes that pitted orforglipron, a diabetes and weight-loss pill developed by Eli Lilly, against oral semaglutide, made by Novo Nordisk, suggests the former pill may have the edge in reducing blood sugar and weight. The results, published in *The Lancet*, are “very encouraging” for the safety and efficacy of orforglipron in people with type 2 diabetes, according to Daniel Drucker, an endocrinologist at the University of Toronto. He notes that more options for managing type 2 diabetes will be beneficial, especially if these new oral medications are priced reasonably. Orforglipron is a once-a-day pill that acts on glucagonlike peptide 1 (GLP-1) receptors. Oral semaglutide has been on the market since 2019, sold as the once-daily pill Rybelsus by Novo Nordisk. In December 2025, Novo Nordisk’s Wegovy pill became the first oral GLP-1 medication approved by the U.S. Food and Drug Administration for obesity. The trial, involving 1,698 participants, compared 12-milligram and 36-milligram doses of orforglipron with 7 mg and 14 mg of oral semaglutide. After 52 weeks, participants taking the 36 mg dose of orforglipron experienced a nearly 2% reduction in a key blood sugar marker, while those on 14 mg of oral semaglutide saw a reduction of about 1.5%. Rozalina McCoy, an endocrinologist at the University of Maryland, expressed hope that orforglipron could help patients with type 2 diabetes become less reliant on insulin, which can contribute to weight gain and has higher treatment burdens. GLP-1 drugs have also shown cardiovascular benefits, although further trials are needed to evaluate orforglipron’s heart health effects. In terms of weight loss, the 36-milligram doses of orforglipron resulted in an average body weight reduction of 8% (nearly 20 pounds), compared to a 5% (11 pounds) reduction with 14 mg of oral semaglutide. However, it is noted that the trial compared orforglipron with doses currently approved for diabetes treatment, while higher doses of oral semaglutide for obesity could yield different results. Eli Lilly stated that the trial utilized the lower doses of semaglutide because they were the only approved doses for type 2 diabetes at the time of the trial. If approved, orforglipron will be available in six doses ranging from 1 mg to 36 mg. The trial also reported higher rates of adverse side effects such as nausea and vomiting for orforglipron compared to semaglutide, with more participants discontinuing orforglipron during the study. McCoy emphasized that it’s important to match treatment to the right patient and counsel them on potential side effects. Both drugs increase insulin secretion and satiety levels by targeting GLP-1 receptors. Oral versions require higher doses to withstand digestion. Orforglipron, being a nonpeptide small molecule, absorbs more readily in the gut without degrading in the stomach, making it easier to produce and potentially more affordable. Eli Lilly expects a decision from U.S. federal regulators on the approval of orforglipron for obesity as soon as this spring, with plans to submit it for review for type 2 diabetes later this year.