Combination SGLT2 Inhibitor and Glucagon Receptor Antagonist Therapy in Type 1 Diabetes: A Randomized Clinical Trial
Year: 2024
Type: article
Study designs: Randomized Controlled Trial, Clinical Trial
Abstract: OBJECTIVE: To examine the effects of insulin-adjunctive therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and a glucagon receptor antagonist (GRA) on glycemia, insulin use, and ketogenesis during insulinopenia in type 1 diabetes. RESEARCH DESIGN AND METHODS: In a randomized, double-blind, placebo-controlled, crossover trial we assessed the effects of adjunctive SGLT2 inhibitor therapy (dapagliflozin 10 mg daily) alone and in combination with the GRA volagidemab (70 mg weekly) in 12 adults with type 1 diabetes. Continuous glucose monitoring, insulin dosing, and insulin withdrawal tests (IWT) for measurement of glucose and ketogenesis during insulinopenia were completed during insulin-only (Baseline), SGLT2 inhibitor, and combination (SGLT2 inhibitor + GRA) therapy periods. RESULTS: Average glucose and percent time with glucose in range (70-180 mg/dL) improved with combination therapy versus Baseline and SGLT2 inhibitor (131 vs. 150 and 138 mg/dL [P < 0.001 and P = 0.01] and 86% vs. 70% and 78% [P < 0.001 and P = 0.03], respectively) without increased hypoglycemia. Total daily insulin use decreased with combination therapy versus Baseline and SGLT2 inhibitor (0.41 vs. 0.56 and 0.52 units/kg/day [P < 0.001 and P = 0.002]). Peak β-hydroxybutyrate levels during IWT were lower with combination therapy than with SGLT2 inhibitor (2.0 vs. 2.4 mmol/L; P = 0.048) and similar to levels reached during the Baseline testing period (2.1 mmol/L). Participants reported enhanced treatment acceptability and satisfaction with combination therapy. CONCLUSIONS: Glucagon antagonism enhances the therapeutic effects of SGLT2 inhibition in type 1 diabetes. Combination therapy improves glycemic control, reduces insulin dosing, and suggests a strategy to unlock the benefits of SGLT2 inhibitors while mitigating the risk of diabetic ketoacidosis.
Source: Diabetes Care
DOI: 10.2337/dc24-0212
Institutions: University of California San Diego, Vanderbilt University
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: American Diabetes Association, Eli Lilly and Company, Sanofi, Vanderbilt University, MannKind Corporation, UCSD-UCLA Diabetes Research Center, Diabetes Research Connection, Novo Nordisk, National Institutes of Health, University of California, San Diego, Vanderbilt Diabetes Research and Training Center, Vanderbilt University Medical Center, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences, JDRF
Awards: G117257630, Determination of Iatrogenic Hyperinsulinemia's Contribution to Insulin Resistance and Endothelial Dysfunction in Recent-Onset Type 1 Diabetes, G2923804148, G4228763881, G4558823551, G598865872, G608544753, G6228083029, G6331392353, G8021374757, UC San Diego Clinical and Translational Research Institute, G887292057, G9000052735, G9000149824, Diabetes Research Center (DRC), Experimental Endocrinology and Metabolism, Diabetes-Docs: Physician-Scientist Career Development Program (DiabDocs), Diabetes Research Center, Vanderbilt Diabetes Research Center
OpenAlex ID: W4398197254