American multinational pharmaceutical company Eli Lilly and Company has been testing its daily oral glucagon-like peptide-1 or GLP-1 pill called Orforglipron. More recent results, including one published in the New England Journal of Medicine on 16 September 2025, show high potential to become an alternative to more common semaglutide medications like Ozempic and Wegovy in managing type 2 diabetes and inducing weight loss.
From Injections to Pills: Orforglipron from Eli Lilly and Company Marks a Turning Point in GLP-1 Treatments
How the Pill Works and Differs from Other GLP-1 Drugs
The science behind orforglipron is based on mirroring the natural GLP-1 pathway of the body. It specifically activates GLP-1 receptors to boost insulin release, reduce liver glucose output, slow digestion, and curb appetite through brain signaling. These mechanisms work together to support meaningful weight loss and better blood sugar balance.
What sets it apart is that it is an oral drug. Traditional GLP-1 drugs like semaglutide, which are sold as Ozempic and Wegovy, are protein-based peptide injectables that cannot survive digestion. Orforglipron is a small-molecule compound stable in the digestive system. This design permits administration via the oral route with degradation.
Convenience is another important distinction. Lilly reports that orforglipron can be taken daily without restrictions related to meals or water. This contrasts with Rybelsus, the oral version of semaglutide, which must be consumed on an empty stomach under strict timing. Simpler rules may improve patient comfort and long-term adherence.
Clinical Trials of Orforglipron and Notable Results
Two international clinical trials demonstrated the potential of orforglipron. ACHIEVE-1 tested it among adults with type 2 diabetes, while ATTAIN-1 focused on individuals with obesity or overweight conditions without diabetes. These trials spanned between 40 and 72 weeks, measuring changes in body weight, blood sugar, and other health markers.
Findings from ATTAIN-1, which were detailed and discussed in a paper published in August 2025, highlighted impressive outcomes. Participants on the highest dose of 36 milligrams lost an average of 12.4 percent of body weight over 72 weeks. That translated to approximately 27 pounds, compared with just 2 pounds among those given placebo treatment.
Other results added weight to the evidence. Nearly 60 percent of participants lost at least 10 percent of their starting weight. Nearly 40 percent achieved reductions greater than 15 percent. There were also measurable improvements in blood pressure, cholesterol level, waist size, and inflammation. These underscore wide-ranging impacts beyond weight loss.
Promise and the Caveats and What These Mean for Patients
The introduction of an effective oral GLP-1 could reshape obesity and diabetes treatment. Lilly has announced plans to file for regulatory review before the end of 2025. The pharmaceutical company is targeting to secure approval in 2026 for type 2 diabetes and weight management indications not only in the U.S. but also across critical global markets.
Implications reach beyond medicine. It can lower barriers to treatment because it is a simple pill that is easier to administer or take. The fact that it is a small molecule may also prove less costly to manufacture than peptide-based drugs. Greater accessibility, combined with convenience, could make adherence more likely for a wide range of patients.
The drug still has some limitations. Gastrointestinal issues remain the most common side effects, particularly at higher doses, leading to some treatment discontinuations. Average weight loss also trails injectable competitors. Wegovy reports about 15 percent reductions. Long-term safety, especially cardiovascular outcomes, still requires further study.
FURTHER READINGS AND REFERENCES
- Eli Lilly and Company. 16 September 2025. Lilly’s Oral GLP-1, Orforglipron, Demonstrated Meaningful Weight Loss and Cardiometabolic Improvements in Complete ATTAIN-1 Results Published in The New England Journal of Medicine. Eli Lilly and Company. Available via PDF
- Kawai, T., Sun, B., Yoshino, H., Feng, D., Suzuki, Y., Fukazawa, M., Nagao, S., Wainscott, D. B., Showalter, A. D., Droz, B. A., Kobilka, T. S., Coghlan, M. P., Willard, F. S., Kawabe, Y., Kobilka, B. K., and Sloop, K. W. 2020. “Structural Basis for GLP-1 Receptor Activation by LY3502970, An Orally Active Nonpeptide Agonist.” Proceedings of the National Academy of Sciences. 117(47): 29959-29967. DOI: 1073/pnas.2014879117
- Ma, X., Liu, R., Pratt, E. J., Benson, C. T., Bhattachar, S. N., and Sloop, K. W. 2024. “Effect of Food Consumption on the Pharmacokinetics, Safety, and Tolerability of Once-Daily Orally Administered Orforglipron (LY3502970), A Non-peptide GLP-1 Receptor Agonist.” Diabetes Therapy. 15(4): 819-832. DOI: 1007/s13300-024-01554-1
- Wharton, S., Aronne, L. J., Stefanski, A., Alfaris, N. F., Ciudin, A., Yokote, K., Halpern, B., Shukla, A. P., Zhou, C., Macpherson, L., Allen, S. E., Ahmad, N. N., and Klise, S. R. 2025. “Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment.” New England Journal of Medicine. DOI: 1056/nejmoa2511774