Eli Lilly’s experimental once-daily pill orforglipron outperformed oral semaglutide in a 52-week phase 3 trial involving 1,698 adults with type 2 diabetes across six countries, posting greater reductions in both blood sugar and weight. From an average starting HbA1c of 8.3%, patients taking orforglipron saw reductions of 1.71% to 1.91%, compared with a 1.47% decline among those taking oral semaglutide. Trial participants on orforglipron also lost an average of 6.1 kg to 8.2 kg, versus 5.3 kg for semaglutide.
The findings add momentum to the growing market for oral obesity and diabetes medicines, which has expanded as drugmakers seek alternatives to injectable GLP-1 treatments such as Ozempic and Wegovy. Semaglutide-based injections have transformed treatment for type 2 diabetes and weight loss, but they require self-injection and refrigeration through the supply chain. Oral semaglutide offers a non-injectable option, though it must be taken on an empty stomach with a 30-minute wait before eating or drinking, and only about 1% of the ingested drug is absorbed. Orforglipron, a small-molecule drug, does not require refrigeration and is described as cheaper and simpler to manufacture than peptide-based drugs such as semaglutide.
Supporters of orforglipron’s prospects argue those logistical advantages could improve convenience and potentially expand access, particularly in lower-resource settings where cold-chain infrastructure is less reliable. The drug is also being watched as a significant competitor in a weight-loss market currently dominated by GLP-1 medicines including Novo Nordisk’s semaglutide and Eli Lilly’s tirzepatide. More broadly, the commercial stakes remain high: IQVIA has estimated the obesity therapeutics market could reach $200 billion by next year, while companies across the sector continue to pursue new oral and non-GLP-1 approaches.
At the same time, the trial underscored a key drawback for orforglipron: tolerability. About 59% of participants taking the drug reported gastrointestinal side effects such as nausea, vomiting, diarrhea or constipation, compared with 37% to 45% among those taking semaglutide. Around 10% of patients on orforglipron stopped treatment because of adverse effects, versus 4% to 5% on semaglutide. Researchers have not yet conducted head-to-head trials comparing orforglipron with injectable GLP-1 therapies, and the drug is still undergoing studies in patients with obesity who do not have diabetes. Those factors may temper expectations even as the late-stage results position it as one of the more prominent new challengers in the oral weight-loss drug market.
