A new oral medication for type 2 diabetes, orforglipron, demonstrated superior blood sugar control and weight loss compared to the oral version of semaglutide, sold as Rybelsus, in a head-to-head clinical trial, according to data released Thursday by Eli Lilly.
The trial, involving nearly 1,700 adults with type 2 diabetes whose blood sugar wasn’t adequately managed with metformin, randomly assigned participants to receive either 7 or 14 milligrams of orforglipron, or 7 or 14 milligrams of oral semaglutide. Participants began the study with an average A1C level of 8.3 percent. After one year, those taking the higher dose of orforglipron experienced an average A1C reduction of 1.9 percent, while those on the higher dose of oral semaglutide saw a reduction of 1.5 percent.
The weight loss results were also notable. Individuals on the 36-milligram dose of orforglipron lost an average of almost 18 pounds, representing roughly 8 percent of their initial body weight. Those taking 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.
However, the study also revealed a higher rate of treatment discontinuation among those taking orforglipron. Approximately 10 percent of patients on the higher doses of orforglipron stopped treatment due to side effects, compared to about 5 percent of those taking semaglutide. Common side effects associated with both medications included gastrointestinal issues like nausea, diarrhea, vomiting, and indigestion.
One potential advantage of orforglipron is its flexibility regarding meal timing. Unlike Rybelsus, which must be taken on an empty stomach first thing in the morning with a small sip of water and a 30-minute waiting period before consuming anything else, orforglipron can be taken without any dietary restrictions. “This makes orforglipron easier to take,” explained 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.
Marilyn Tan, MD, a clinical professor at Stanford University School of Medicine and chief of the endocrine clinic at Stanford Health Care, highlighted the convenience for patients managing multiple medications. “Adhering to a specific schedule of spacing out various medications can be cumbersome,” she said.
Both orforglipron and oral semaglutide belong to the class of drugs known as GLP-1 receptor agonists. These medications mimic the effects of a natural gut hormone, suppressing appetite and slowing digestion, which can lead to both weight loss and improved blood sugar control. They also stimulate insulin release and reduce glucagon levels, further contributing to blood sugar regulation.
The study results indicated that both doses of orforglipron, as well as the higher dose of oral semaglutide, successfully lowered A1C levels to below 7 percent – the target goal for adults with type 2 diabetes. The lower dose of oral semaglutide nearly reached this target, missing it by just 0.1 percent.
Beverly Tchang, MD, an associate professor of clinical medicine at the Comprehensive Weight Control Center at Weill Cornell Medicine, stated that the findings “give us further reassurance that both orforglipron and semaglutide are excellent medications to treat type 2 diabetes.”
Eli Lilly has announced its intention 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 FDA approval for orforglipron as an obesity treatment, with a decision anticipated this spring.
