Diabetes Dialogue: Retatrutide Phase 3 Data Show Major Weight Loss

Welcome back to Diabetes Dialogue: Technology, Therapeutics, & Real-World Perspectives!

Triple hormone receptor agonism is emerging as a frontier in metabolic disease treatment, and topline phase 3 results for retatrutide suggest the strategy can push weight loss and glycemic control beyond current incretin therapies, even as a separate JAMA analysis raises questions about oversight in online GLP-1 prescribing.^1,2

On the latest episode of Diabetes Dialogue, hosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, reviewed topline results from the TRIUMPH-2 and TRIUMPH-3 trials of retatrutide, a glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptor triple agonist.

TRIUMPH-2 enrolled 1000 participants with type 2 diabetes across 98 centers and tested 4 mg, 9 mg, and 12 mg doses against placebo over 80 weeks. The 12 mg dose produced weight loss up to 21% from a baseline of 106 kg, or roughly 23 kg. Hemoglobin A1C fell between 1.4 and 1.6 percentage points from a baseline of 7.7%, versus 0.2 points with placebo, a large glycemic effect given the near-normal starting A1C and discontinuation of 14% at the highest dose.

TRIUMPH-3 enrolled over 1900 participants with class II or III obesity (body mass index of 35 or higher) and established cardiovascular disease, randomized to 9 mg, 12 mg, or placebo over 80 weeks. The 12 mg dose delivered 23% weight loss versus 3% with placebo, alongside a 37% reduction in triglycerides, 17% reduction in non-high-density lipoprotein cholesterol, and 9.3 mmHg reduction in systolic blood pressure. Major adverse cardiovascular event outcomes trended favorably but did not reach significance, an expected limitation of an 80-week trial.

Gastrointestinal effects were common across both trials, including diarrhea in up to 34% of participants and nausea in up to 28%, consistent with the broader incretin class.

Isaacs and Bellini also discussed a JAMA secret-shopper study, led by Ashwin Chetty, MD, examining online GLP-1 prescribing across 49 telehealth websites. Of these, 92% prescribed the requested medication and 70% mailed it, often without required photo verification, blood work, or clinician video visits, in some cases within five minutes. Compounded formulations, including unproven sublingual drops, were frequently offered alongside add-on supplements marketed as personalization, a workaround linked to compounding rules requiring documented medical need.

Together, the findings illustrate a widening gap between the therapeutic ceiling GLP-1-based agents are reaching in controlled trials and the variable oversight surrounding real-world access to these drugs, underscoring the need for clinicians to proactively screen patients for unsupervised use.

Editors’ 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.

References

1. Eli Lilly. Lilly’s triple agonist, retatrutide, successful in two additional Phase 3 obesity trials, delivering significant improvements in weight and A1C. July 23, 2026. Accessed August 4, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-successful-two-additional

2. Chetty AK, Chen AS, Ross JS, Ramachandran R. Online prescribing of GLP-1 receptor agonists. JAMA. 2026;336(5):428. doi:10.1001/jama.2026.9131