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Isaacs and Bellini discuss recent updates on Eli Lilly's orforglipron and retatrutide and Novo Nordisk's UBT251, along with other recent GLP-1 news.
Welcome back to Diabetes Dialogue: Technology, Therapeutics, & Real-World Perspectives!
In this episode, cohosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, provide a comprehensive update on the rapidly evolving landscape of incretin-based therapies, focusing on newly published and top-line clinical trial data across oral GLP-1 receptor agonists and emerging triple agonists.
00:00:01 Intro
00:00:22 Orforglipron in the ACHIEVE-3 trial
00:03:30 Side effects from orforglipron
00:10:28 Retatrutide in the TRIUMPH-4 trial
00:18:26 Topline data on Novo Nordisk's UBT251
00:21:47 Price cuts on Ozempic, Rybelsus, and Wegovy in 2027
00:26:26 Outro
The discussion begins with the phase 3 ACHIEVE-3 trial evaluating orforglipron, a novel, nonpeptide, once-daily oral GLP-1 receptor agonist, studied head-to-head against oral semaglutide in 1,698 adults with type 2 diabetes inadequately controlled on metformin. Orforglipron demonstrated superior glycemic efficacy, achieving mean A1C reductions of 1.7% and 1.9% at the 12 mg and 36 mg doses, respectively, compared with 1.2% and 1.5% reductions seen with 7 mg and 14 mg oral semaglutide. All primary noninferiority endpoints were met, with statistical superiority observed across comparisons. Weight reduction also favored orforglipron.1
However, the enhanced efficacy was accompanied by higher rates of gastrointestinal adverse events. Nausea and other GI symptoms were reported in approximately 58–59% of patients receiving orforglipron versus 37–45% with semaglutide. Importantly, treatment discontinuation due to GI events remained relatively low (6% with orforglipron vs 3% with semaglutide), suggesting tolerability may be manageable in clinical practice. The hosts emphasize the importance of understanding how adverse events are captured in trials and highlight the role of dose titration, dietary counseling, and supportive medications in mitigating side effects. A key limitation noted is the absence of cardiovascular outcomes data for orforglipron, particularly given established cardiovascular benefit with oral semaglutide, underscoring the need for outcomes-driven decision-making in high-risk populations.1
Attention then shifts to top-line results from the phase 3 TRIUMPH-4 trial evaluating retatrutide, a first-in-class triple agonist targeting GLP-1, GIP, and glucagon receptors, in individuals with obesity and osteoarthritis. Over 68 weeks, retatrutide achieved mean weight reductions of 26.4% to 28.7% (up to 71.2 pounds), representing some of the most substantial weight loss observed in pharmacotherapy trials to date. Nearly half of participants achieved ≥25% weight loss, and up to 23.7% achieved ≥35% reduction. Clinically meaningful improvements in osteoarthritis symptoms were documented via WOMAC scoring, with one in eight participants reporting complete resolution of knee pain. Gastrointestinal adverse events were dose-dependent, and discontinuation rates ranged from 12% to 18%, reinforcing the importance of balancing efficacy with tolerability.2
The hosts also review early phase 2 data from Novo Nordisk’s investigational triple agonist (UBT251), which demonstrated 19.7% weight loss over 24 weeks in a Chinese cohort, along with improvements in waist circumference, glycemia, blood pressure, and lipids. Although preliminary, these findings highlight growing competition in the triple-agonist space and suggest continued acceleration in therapeutic innovation.3
The episode concludes with broader reflections on expanding indications for incretin-based agents, including cardiovascular disease, osteoarthritis, sleep apnea, and potentially other cardiometabolic and inflammatory conditions, alongside discussion of anticipated price reductions and increased market competition. Isaacs and Bellini characterize the current era as transformative, with incretin-based therapies poised to substantially reshape cardiometabolic risk reduction strategies in type 2 diabetes and obesity.
Editor’s Note: Isaacs reports disclosures with Dexcom, Abbott, Lilly, Novo Nordisk, Medtronic, Insulet, and others. Bellini reports disclosures with Abbott Diabetes Care, MannKind, Povention Bio, and others.
