A new oral medication for type 2 diabetes, orforglipron, has demonstrated superior effectiveness compared to Rybelsus, the first oral GLP-1 drug, in a recent head-to-head clinical trial. The findings, released February 26, 2026, suggest a potential new option for the millions of Americans managing this chronic condition, and could soon expand to include a treatment for obesity. While orforglipron showed promise in lowering blood sugar and promoting weight loss, researchers likewise noted a higher incidence of side effects leading some participants to discontinue treatment.
The study, involving nearly 1,700 adults with type 2 diabetes whose blood sugar wasn’t adequately controlled with metformin, randomly assigned participants to receive either two doses of orforglipron (12mg or 36mg) or two doses of semaglutide, the active ingredient in Rybelsus (7mg or 14mg). After one year, those taking the higher dose of orforglipron experienced an average reduction of 1.9 percent in their A1C levels, a measure of long-term blood sugar control. This compared to a 1.5 percent reduction in A1C levels for those on the higher dose of oral semaglutide. The goal for adults with type 2 diabetes is to get A1C levels below 7 percent, and both doses of orforglipron and the higher dose of semaglutide achieved this target.
Beyond blood sugar control, orforglipron also showed a more significant impact on weight loss. Participants on the higher orforglipron dose lost nearly 18 pounds, representing about 8 percent of their initial body weight. In contrast, those on the higher dose of oral semaglutide lost an average of 11.5 pounds, or just over 5 percent of their starting weight. “So on efficacy alone, orforglipron looks better,” said Osama Hamdy, MD, PhD, an associate professor at Harvard Medical School and medical director of the Obesity Clinical Program at the Joslin Diabetes Center in Boston.
Side Effects and Treatment Discontinuation
Despite the promising results, orforglipron was associated with a higher rate of side effects. Like other GLP-1 receptor agonists, both drugs caused gastrointestinal issues such as nausea, diarrhea, vomiting, and indigestion. However, a greater proportion of patients taking orforglipron—almost 10 percent on the higher doses—discontinued treatment compared to those taking semaglutide, where approximately 5 percent stopped treatment.
Convenience and Timing with Meals
One potential advantage of orforglipron is its flexibility regarding meal timing. According to Eli Lilly, Notice no restrictions on eating or drinking when taking the medication. This contrasts with Rybelsus, which requires patients to take it first thing in the morning on an empty stomach, with a compact sip of water, and avoid eating or drinking for 30 minutes afterward. This can be a significant benefit for individuals taking multiple medications, according to Melanie Jay, MD, a professor at the New York University Grossman School of Medicine and director of the NYU Langone Comprehensive Program on Obesity Research in New York City. “This makes orforglipron easier to take,” she said.
Marilyn Tan, MD, a clinical professor at Stanford University School of Medicine and chief of the endocrine clinic at Stanford Health Care in California, echoed this sentiment, noting that adhering to a strict medication schedule can be challenging. “Adhering to a specific schedule of spacing out various medications can be cumbersome,” Dr. Tan explained.
How GLP-1 Drugs Work
Both orforglipron and oral semaglutide belong to a class of drugs called GLP-1 (glucagon-like peptide-1) receptor agonists. These medications mimic a natural hormone in the gut, which helps to regulate appetite and slow digestion, often leading to weight loss and improved blood sugar control. They also stimulate insulin release in response to meals and reduce glucagon levels, further contributing to better glycemic control.
Eli Lilly plans to submit an application to the U.S. Food and Drug Administration (FDA) for approval of orforglipron as a treatment for diabetes “as soon as possible.” The company is also seeking approval for its use in obesity, with an FDA decision anticipated this spring. This potential approval would add to the growing number of options for managing both conditions, offering patients more tailored treatment approaches.
The study results “supply us further reassurance that both orforglipron and semaglutide are excellent medications to treat type 2 diabetes,” said Beverly Tchang, MD, an associate professor of clinical medicine at the Comprehensive Weight Control Center at Weill Cornell Medicine in New York City.
Disclaimer: This article provides information for general knowledge and informational purposes only, and does not constitute medical advice. It is essential to consult with a qualified healthcare professional for any health concerns or before making any decisions related to your health or treatment.
The FDA is expected to develop a decision regarding orforglipron’s approval for obesity treatment this spring. Further research will continue to evaluate the long-term effects and optimal use of this new medication.
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