How Close Are We to an Oral Weight Loss Drug?

Prevalence of Obesity in the US

According to data from the National Health and Nutrition Examination Survey, between August 2021 and August 2023, the prevalence of obesity in adults was 40.3%. Obesity is considered a chronic condition that increases the risk of hypertension, type 2 diabetes, coronary heart disease, stroke, and certain cancers. Furthermore, prevalence of obesity has continued to increase among both men and women between 1999 and 2018.

GLP-1 Receptor Agonist as a Drug for Weight Loss

If you haven't heard already, there are several FDA-approved weight loss drugs on the market, and there are two drugs that are GLP-1 receptor agonist; 1) Zepbound (Tirzepatide), developed by Eli Lilly, and 2) Wegovy (Semaglutide) developed by Novo Nordisk.

What is GLP-1?

GLP-1 is glucagon-like peptide-1, a peptide hormone produced and released by intestinal L-cells of our gut in response to food intake. GLP-1 peptide plays a key role as an incretin, which means it stimulates insulin secretion and helps regulate blood sugar. GLP-1 can also reduce appetite, therefore decreasing food intake and slow gastric emptying to induce weight loss. A GLP-1 drug such as Zepbound or Wegovy is an incretin mimetic that binds to the GLP-1 receptors to elicit its function described previously.

Brief Description of Zepbound and Wegovy

Companies like Eli Lilly and Novo Nordisk already have their respective injectable GLP-1 receptor agonist drug in the market. Eli Lilly’s drug prescribed for weight loss is called tirzepatide, or Zepbound, whereas Novo Nordisk’s drug is called semaglutide or Wegovy. These are both given by subcutaneous injections once per week. The difference between the two drugs is that tirzepatide is a dual-agonist, which means it targets receptors for also glucose-dependent insulinotropic polypetide (GIP), not just GLP-1 receptor. Both drugs are effective in inducing weight loss; Zepbound results in weight loss about about 15-21% of starting weight at 72 weeks, while Wegovy results in weight loss about 13-15% of starting weight at similar time frame. The common side effects of these two drugs are similar. The side effects include nausea, diarrhea, constipation, and site reactions.

Both of these drugs have been effective in inducing weight loss, but so far, the route of administration of both drugs is a subcutaneous injection via prefilled pen. A drug administration that requires a needle to be injected under the skin in the abdomen, upper arm, or thigh area may not be the preferred option by everyone.

So here comes Eli Lilly’s oral GLP-1 drug, orforglipron, which is a pill given once daily for weight loss and lowering blood sugar levels.   

Orforglipron Clinical Trial Results.

Pharmaceutical company Eli Lilly recently made a splash in the scientific news cycle for announcing the progress of their Phase 3 clinical trial called ATTAIN-2 study, and the results are in!

According to Eli Lilly, the subjects of this study included over 1,600 adults with obesity or overweight and Type 2 diabetes. The data shows that compared to placebo group. The group who received the highest dose of orforglipron (36 mg) lost an average of 22.9 lbs (10.5%), and their A1C levels were reduced by an average of 1.8%. A1C percentage level is percentage of hemoglobin that is coated with glucose (sugar), which has been used as an indicator of blood sugar levels in patients with diabetes. The drug can be taken at any time of day, without food restrictions, and its safety profile is like that of other injectable GLP-1 agonist drugs, which include diarrhea, constipation and nausea. Compared to the other injectable GLP-1 receptor agonist drug, the weight loss induced by orforglipron is less robust. However, this oral GLP-1 agonist pill provides an alternative way to administer the drug for weight loss and lowering blood sugar levels for people with obesity and type 2 diabetes.

What’s next?

According to Eli Lilly, the company believes they are ready to package their clinical data to initiate global regulatory submissions for orforglipron, which is a crucial step toward market entry.

Analysts with Citi believes that “orforglipron is poised to be the first commercially successful oral GLP-1." Despite its suboptimal efficacy (relative to the injectable version such as Zepbound), 10.5% weight loss is still an impressive rate of weight loss. Furthermore, an oral medication for weight loss will provide another option, for some it may be the preferred option over the injectables when pursuing weight loss and/or blood sugar control to improve their health. Nonetheless, this is an exciting scientific advancement for the world of medicine focusing on obesity and type 2 diabetes.

References

Drucker, Daniel J. “GLP-1 Physiology Informs the Pharmacotherapy of Obesity.” Molecular Metabolism, vol. 57, Mar. 2022, article no. 101351. ScienceDirect, https://www.sciencedirect.com/science/article/pii/S2212877821001988

Emmerich, S. D. et al. (2024). Obesity and Severe Obesity Prevalence in Adults: United States, August 2021–August 2023. CDC National Center for Health Statistics. https://www.cdc.gov/nchs/products/databriefs/db508.htm

Fryar CD, Carroll MD, Afful J. Prevalence of overweight, obesity, and severe obesity among adults aged 20 and over: United States, 1960–1962 through 2017–2018. NCHS Health E-Stats, Centers for Disease Control and Prevention. 2020. Updated February 8, 2021. Accessed January 29, 2021. www.cdc.gov/nchs/data/hestat/obesity-adult-17-18/obesity-adult.htm External link

“Hemoglobin A1C Test.” Yale Medicine, Yale School of Medicine, accessed 4 Sept. 2025. Yale Medicine, https://www.yalemedicine.org/conditions/hemoglobin-a1c-test-hba1c-test-blood-sugar

Kansteiner, Fraiser. “Lilly Rounds Out Oral GLP-1 Approval Bid with Phase 3 Obesity Win for Patients with Diabetes.” Fierce Biotech, 26 Aug. 2025, accessed 4 Sept. 2025. Fierce Biotech, https://www.fiercebiotech.com/biotech/lilly-rounds-out-oral-glp-1-approval-bid-ph-3-win-patients-obesity-and-diabetes.

“Lilly’s Oral GLP-1, Orforglipron, Is Successful in Third Phase 3 Trial.” Eli Lilly and Company Investor Relations, 26 Aug. 2025, accessed 4 Sept. 2025. Eli Lilly and Company, https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-successful-third-phase-3-trial

Overweight & Obesity Statistics. NIH National Institute of Diabetes and Digestive and Kidney Diseases. (n.d.). https://www.niddk.nih.gov/health-information/health-statistics/overweight-obesity#trends

Rodriguez, Patricia J., Brianna M. Goodwin Cartwright, Samuel Gratzl, R. Brar, C. Baker, T. J. Gluckman, and N. L. Stucky. “Semaglutide vs Tirzepatide for Weight Loss in Adults With Overweight or Obesity.” JAMA Internal Medicine, vol. 184, no. 9, 2024, pp. 1056–1064, DOI:10.1001/jamainternmed.2024.2525.

“Weight Loss Medication | Wegovy® (semaglutide) Injection 2.4 mg.” Wegovy®, Novo Nordisk, accessed 4 Sept. 2025. https://www.wegovy.com/.

Zepbound® (tirzepatide) Injection for Adults with Obesity or OSA. Zepbound®, Eli Lilly and Company, accessed 4 Sept. 2025. https://zepbound.lilly.com/.

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