By: Sariah Grant, PharmD Candidate c/o 2027

            The rise of glucagon-like peptide -1 receptor agonist medications have transformed the course of type 2 diabetes and weight loss therapy. Subcutaneous injectable medications such as  Ozempic, Wegovy, Mounjaro, and Zepbound have become the new standard due to demonstrated efficacy. United States obesity rates have declined from 39.9% in 2022 to 37% in 2025, accounting for 7.6 million U.S citizens alone.¹ Despite, their rapid growth, GLP-1 utilization trends do not appear to be near plateau, supported by expanding insurance coverage initiatives such as the Centers for Medicare and Medicaid Services’ BALANCE model (Better Approaches to Lifestyle and Nutrition for Comprehensive hEalth.) ²

In parallel, pharmaceutical companies are investing more into the research and development of GLP-1s more now than ever before.  Newer agents aim to address limitations such as injectable administration and long-term adherence.³  Most recently on April 01, 2026, Foundayo, a novel oral GLP-1 agonist was released into the market to reduce excess body weight and maintain long-term weight loss in obese adults or overweight adults with at least one weight related comorbid condition. It is indicated for use in combination with a reduced-calorie diet and increased physical exercise. Foundayo represents the advancements of pharmaceutical GLP-1 research, becoming the second oral formulation GLP-, improving patient accessibility and convenience. Foundayo  is also notably the first new molecular entity approved under the U.S. Food and Drug Administration’s Commissioner’s National Priority Voucher (CNPV) pilot program for critical national health.⁴

Mechanism of Action

            Glucagon-like peptide-1 is an incretin hormone that is released from the small intestine, which helps regulate blood glucose levels. It triggers insulin secretion, inhibits glucagon, slows gastric emptying, and promotes satiety. ⁵ The enzyme dipeptidyl peptidase-4 (DPP-4) degrades endogenous GLP-1, causing the hormone to have short-lasting effects and the need for GLP-1 agonists drugs that can bypass the enzymatic degradation for therapeutic weight loss effects. Initial development of GLP-1 products focused on injectable subcutaneous to improve pharmacokinetics and delivery to prevent rapid degradation and poor stability. ⁶

            Foundayo (orforglipron) is a novel, once daily oral small molecule GLP-1 receptor partial agonist developed to provide similar metabolic benefits as traditional GLP-1 therapies, while improving convenience and adherence. Clinical trials and meta-analyses show that orforglipron produces significant reductions in body weight, HbA1c, and cardiometabolic risk factors, with effects that are dose dependent.⁷

            Conventional peptide GLP-1 therapies are structurally similar to the native hormone and are typically administered by injection due to degradation in the gastrointestinal tract and poor oral bioavailability. In contrast, orforglipron is designed to be orally active without peptide stabilization technologies. As orforglipron is a small molecule, it is chemically stable in the acidic gastric environment and is not a substrate for degradation by enzymes such as DPP-4. This eliminates the need for complex formulating strategies or absorption enhancers to combat degradation, which are typical for traditional GLP-1 formulations. ⁷

Clinical Trial Evaluation

The efficacy of orforglipron has been evaluated across  ATTAIN, for obesity, and ACHIEVE, for type 2 diabetes, clinical trial programs. These include both Phase 2 dose-finding studies and Phase 3 confirmatory randomized controlled trials.⁸

The ATTAIN program consists of randomized, double-blind, placebo-controlled Phase 2 and Phase 3 trials evaluating orforglipron for chronic weight management in adults with obesity or who are overweight with at least one weight-related comorbidity. Across these studies, several hundred to over one thousand participants were enrolled at multinational clinical sites, representing a diverse adult population with cardiometabolic risk factors.⁸

Eligible participants included adults over 18 years with a body mass index (BMI) ≥30 kg/m² or ≥27 kg/m² with at least one weight-related comorbidity such as hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease, excluding individuals with diabetes. Key exclusion criteria included prior GLP-1 receptor agonist use, history of pancreatitis, significant gastrointestinal disease, or severe renal impairment.⁸

The primary endpoint in Phase 2 ATTAIN studies was percent change in body weight from baseline. Orforglipron demonstrated statistically significant, dose-dependent weight reduction compared with placebo, with p-values <0.001 across multiple dose cohorts.⁸ Secondary endpoints included waist circumference, blood pressure, and lipid panel changes, all showing favorable trends compared with placebo.⁸

Gastrointestinal adverse effects were the most commonly reported safety outcomes, including nausea, diarrhea, vomiting, constipation, and decreased appetite. These effects were generally mild to moderate in severity, most commonly occurring during dose escalation. Discontinuation rates due to adverse events were low but higher in treatment groups compared with placebo. Importantly, no increased signal for pancreatitis or severe hypoglycemia was observed in non-diabetic populations.⁸

The ACHIEVE program includes Phase 2 and Phase 3 randomized controlled trials evaluating orforglipron in adults with type 2 diabetes inadequately controlled on other therapy, most commonly metformin.⁹ Participants included adults with baseline HbA1c levels approximately between 7.0% and 10.0%, reflecting persistent hyperglycemia despite standard care. Key exclusion criteria included prior GLP-1 receptor agonist use, insulin therapy in selected populations, and significant gastrointestinal or pancreatic disease.⁹

In Phase 2 ACHIEVE trials, the primary endpoint was change in HbA1c from baseline. Orforglipron demonstrated significant HbA1c reductions of up to approximately −2.1% compared with placebo (p < 0.001).⁹ Secondary outcomes included body weight reduction of approximately 10–12% and improvements in fasting plasma glucose and cardiometabolic parameters.⁹

The most common adverse effects were gastrointestinal, including nausea, diarrhea, constipation, and abdominal discomfort. These events were dose-dependent and typically temporary. Hypoglycemia was uncommon in patients not receiving insulin or insulin secretagogues.⁹

Phase 3 Comparative Efficacy (ACHIEVE-3):

In the Phase 3 ACHIEVE-3 head-to-head trial, orforglipron was compared with oral semaglutide in adults with type 2 diabetes inadequately controlled on metformin. The primary endpoint was change in HbA1c at 52 weeks. Orforglipron demonstrated superior glycemic reduction (−2.2% vs −1.4%, between-group difference −0.8%, p < 0.001).¹⁰ Weight loss was also greater with orforglipron (−9.2% vs −5.3%, p < 0.001).¹⁰

Expanded Clinical Comparison and Implications

Orforglipron enters a GLP-1 receptor agonist landscape currently dominated by injectable therapies such as semaglutide and tirzepatide, which have demonstrated substantial weight reduction, HbA1c control, and cardiovascular benefit in select populations. However, these therapies require subcutaneous administration, which may limit long-term adherence in certain patients.

In contrast, orforglipron is a once-daily oral small-molecule GLP-1 receptor agonist that does not require peptide stabilization technologies or injectable delivery systems. Unlike oral semaglutide, which relies on absorption-enhancing formulation strategies to overcome gastrointestinal degradation, orforglipron is chemically stable and orally bioavailable without such requirements.⁷

In ACHIEVE-3, orforglipron demonstrated superior HbA1c reduction and greater weight loss compared with oral semaglutide, suggesting competitive efficacy within the oral GLP-1 category.¹⁰ While injectable GLP-1 receptor agonists may still achieve greater absolute weight loss and have more established cardiovascular outcome data, orforglipron may improve accessibility and adherence due to its oral formulation.

From a clinical perspective, orforglipron may be most useful in patients requiring GLP-1 therapy who prefer to avoid injections or have barriers to injectable adherence. However, the absence of long-term cardiovascular outcome data remains an important limitation when compared with established injectable agents.³,⁶

Conclusion

Orforglipron represents a significant advancement in GLP-1 receptor agonist therapy by delivering clinically meaningful weight loss and glycemic improvement with a once-daily oral small-molecule formulation. Across the ATTAIN and ACHIEVE clinical trial programs, it demonstrated statistically significant improvements in metabolic outcomes compared with placebo and comparators, with a safety profile consistent with class-related gastrointestinal effects.⁸,⁹

Although injectable GLP-1 receptor agonists remain the standard of care due to extensive long-term outcome data, orforglipron addresses a potential adherence issue by eliminating the requirement for subcutaneous administration while maintaining comparable efficacy. The ACHIEVE-3 trial further supports its potential role as a competitive oral alternative within the GLP-1 class.¹⁰

However, its ultimate clinical positioning will depend on long-term safety data, cardiovascular outcomes trials, and real-world adherence outcomes. As the GLP-1 landscape continues to evolve, orforglipron represents a shift toward more accessible, patient-centered metabolic therapies that may broaden treatment adoption for obesity and type 2 diabetes.⁶,⁷

References:

1. Witters D, James MP. Obesity Rate Declining in U.S. Gallup.com. Published https://news.gallup.com/poll/696599/obesity-rate-declining.aspx. Published 10/28/2025.
2. Centers for Medicare & Medicaid Services. BALANCE model: Better Approaches to Lifestyle and Nutrition for Comprehensive Health. CMS.gov. https://www.cms.gov/priorities/innovation/innovation-models/balance. Last Updated 04/10/2026.
3. Karedath J, Nall S, Kaur M, et al. Comparative Effectiveness and Safety of Oral versus Subcutaneous Semaglutide in Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis. Cureus. 2025;17(4):e82497. doi:10.7759/cureus.82497. Published 04/18/2025.
4. U.S. Food and Drug Administration. FDA approves first new molecular entity under National Priority Voucher Program. FDA.gov.  https://www.fda.gov/news-events/press-announcements/fda-approves-first-new-molecular-entity-under-national-priority-voucher-program. Published 04/01/2026.
5. Collins L, Costello RA. Glucagon-Like Peptide-1. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/books/NBK551568/. Published on 01/2026. Last updated 02/29/2024.
6. Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27(4):740-756. doi:10.1016/j.cmet.2018.03.001
7. Kansakar U, Jankauskas SS, Pande S, Mone P, Varzideh F, Santulli G. Orforglipron: a comprehensive review of an oral small-molecule GLP-1 receptor agonist for obesity and type 2 diabetes. Int J Mol Sci. 2026;27(3):1409. doi:10.3390/ijms27031409
8. Eli Lilly and Company. Lilly’s Phase 2 results published in New England Journal of Medicine. https://investor.lilly.com/news-releases/news-release-details/lillys-phase-2-results-published-new-england-journal-medicine.  Published on 06/23/2023.
9. Eli Lilly and Company. Lilly’s oral GLP-1 orforglipron delivered superior blood sugar control and weight loss in clinical trials. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-delivered-superior-blood-sugar. Published on 02/26/2026.
10. Eli Lilly and Company. Phase 3 ACHIEVE-3 trial results comparing orforglipron with oral semaglutide in type 2 diabetes. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-delivered-superior-blood-sugar. Published on 02/26/2026.

Published by Rho Chi Post