Diabetes Dialogue: Oral GLP-1 Orforglipron in ACHIEVE-1 Trial

Video Version Only on HCPLive! In this episode of Diabetes Dialogue, hosts Diana Isaacs, PharmD, an endocrine clinical pharmacist, director of Education and Training in Diabetes Technology, and codirector of Endocrine Disorders in Pregnancy at the Cleveland Clinic, and Natalie Bellini, DNP, program director of Diabetes Technology at University Hospitals Diabetes and Metabolic Care Center, discuss the top-line results from the ACHIEVE-1 trial evaluating orforglipron—an investigational, once-daily oral glucagon-like peptide-1 receptor agonist (GLP-1 RA) developed by Eli Lilly—for adults with type 2 diabetes (T2D) inadequately controlled by diet and exercise. Isaacs and Bellini emphasized the clinical significance of orforglipron’s Phase 3 data in the ACHIEVE-1 trial, which demonstrated substantial reductions in A1c (1.3–1.6%) from a baseline of 8.0% and notable weight loss averaging 16 pounds (7.9%) at the highest dose over 40 weeks. Impressively, more than 65% of participants achieved an A1c below 6.5%, meeting the American Diabetes Association (ADA)’s target for diabetes control. The hosts highlighted the convenience advantage of orforglipron compared to oral semaglutide, which has strict dosing requirements. Oral orforglipron can be taken without food or water restrictions, potentially increasing adherence and reducing treatment burden. They also noted the drug’s favorable safety profile, with gastrointestinal side effects similar in type and incidence to existing GLP-1 RAs, and no hepatic safety signals observed in the trial. Beyond glycemic control, Isaacs and Bellini discussed the broader implications for obesity treatment, pointing to the drug’s potential utility in weight management, pending regulatory submission. They explored the possibility of using injectable GLP-1 RAs for initial weight loss followed by oral maintenance with orforglipron—potentially lowering costs and improving access. The conversation touched on the upcoming ACHIEVE trial series, which will explore orforglipron in head-to-head comparisons with other agents, its use in insulin-treated T2D, and future indications including cardiovascular risk and kidney disease. While optimistic, the hosts stressed the need for cardiovascular outcomes data to confirm orforglipron’s safety and potential benefits in this domain. If confirmed, they suggested orforglipron could become a cornerstone oral therapy for T2D and obesity. Relevant disclosures for Isaacs include Eli Lilly and Company, Novo Nordisk, Sanofi, Abbott Diabetes Care, Dexcom, Medtronic, and others. Relevant disclosures for Bellini include Abbott Diabetes Care, MannKind, Provention Bio, and others. Key Episode Timestamps 00:00:01 Discussion on OR for GLP-1 Receptor Agonist 00:02:13 Potential Impact and Patient Preferences 00:03:59 Safety and Market Potential 00:05:13 Cost and Transition Options 00:06:32 Future Trials and Side Effects 00:08:55 Cardiovascular Outcome Data and Conclusion

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