Orforglipron (OFG), an oral, non-peptide GLP-1 receptor agonist, demonstrated significantly greater glycemic control and weight loss at doses ≥12 mg vs placebo (PBO) or dulaglutide (DU) 1.5 mg in a 26-week phase 2 study of adults with type 2 diabetes (T2D) (Table). These exploratory analyses investigated mechanisms by which OFG improved glycemic control in T2D by analyzing exploratory biomarkers.

Participants with T2D (mean age, 58.9 years; baseline HbA1c, 8.1%; weight, 100.3 kg) treated with diet and exercise, with/without metformin, were randomized to PBO, DU 1.5 mg, or once-daily OFG 3, 12, 24, 36, or 45 mg. Biomarkers of β-cell function and insulin sensitivity were analyzed by mixed model repeated measures, excluding data after study drug discontinuation or rescue drug initiation.

Biomarkers of β-cell function were improved by OFG at 26 weeks from baseline (Table). HOMA-B significantly increased with OFG at doses ≥12 mg vs PBO or DU. HOMA-IR (computed with insulin) significantly decreased from baseline with OFG at doses ≥24 mg but was not significantly different vs PBO and DU. Fasting glucose-adjusted glucagon significantly decreased with OFG at doses ≥12 mg vs PBO and with OFG 12, 24, and 45 mg vs DU.

These analyses suggest improved glycemic control with OFG vs DU may be partly explained by improved β-cell function and insulin sensitivity. Additional studies are ongoing to understand these mechanisms.

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Disclosure

J. Rosenstock: Research Support; Biomea Fusion, Inc. Other Relationship; Lilly Diabetes. Research Support; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Corcept Therapeutics. Other Relationship; Novo Nordisk. Research Support; Pfizer Inc. Other Relationship; Sanofi, Boehringer-Ingelheim. Research Support; Shionogi & Co., Ltd. Other Relationship; Structure Therapeutics, Inc. Advisory Panel; Terns Pharmaceuticals, Zealand Pharma A/S. Other Relationship; Applied Therapeutics, Hanmi Pharm. Co., Ltd., Oramed Pharmaceuticals. Advisory Panel; Scholar Rock. D.A. Robins: None. K.L. Duffin: Employee; Eli Lilly and Company. J.M. Wilson: Employee; Eli Lilly and Company. K.J. Mather: Employee; Eli Lilly and Company. H. Banerjee: None. Y. Lin: Stock/Shareholder; Eli Lilly and Company, Pfizer Inc., AstraZeneca. S. Eyde: None. C.M. Kazda: Employee; Eli Lilly and Company. M. Konig: None.

Funding

Eli Lilly and Company

© 2024 by the American Diabetes Association
2024
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