Glucagon-like peptide-1 receptor agonists (GLP-1RA) provide substantial reductions in HbA1c and significant body weight loss in patients with type 2 diabetes (T2D). GL0034 is a novel long-acting, human GLP-1RA. In cellular cAMP assays GL0034 has a half-maximal effective concentration of 80 pM on GLP-1R expressing cells, but no effect on cells expressing the GIPR or the glucagon receptor. Upon SC dosing in the db/db mouse every other day for 4 weeks, GL0034 doses of 1.5, 3, and 6 nmol/kg lowered HbA1c by 1.6%, 3.2%, and 3.4%, respectively; demonstrating greater activity than that achieved with a higher dose of semaglutide (2.8%) or dulaglutide (2.0%) (Table). At 6-nmol/kg dose, GL0034 also induced a significant decrease in body weight; furthermore, plasma triglycerides and glucagon were significantly reduced by ∼74% and ∼41%, respectively. These effects of GL0034 treatment were greater than those induced by semaglutide or dulaglutide. Together, our study demonstrates that GL0034 is a potent, selective, long-acting GLP-1RA, which displays improved control of glucose homeostasis, body weight, and dyslipidemia in diabetic mice as compared with GLP-1RAs currently used for the treatment of T2D. GL0034 may serve as a promising new GLP-1RA for T2D and obese patients with T2D.
R. Thennati: None. V.S. Burade: Employee; Self; Sun Pharmaceutical Industries Ltd. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. B. Thorens: Other Relationship; Self; Servier. G.A. Rutter: Consultant; Self; Sun Pharmaceutical Industries Ltd. Research Support; Self; Servier, Sun Pharmaceutical Industries Ltd.