267-OR: ADA Presidents' Select Abstract: Combining an SGLT Inhibitor with a Glucagon Receptor Agonist (GRA) in Subjects with Type 1 Diabetes—A Randomized Clinical Trial

Abstract

SGLTi treatment improves glycemic control and reduces insulin dosing but increases the risk of diabetic ketoacidosis (DKA). Combination therapy (SGLTi + GRA) could augment glycemic and insulin dosing benefits while mitigating DKA risk. Subjects with T1D (n=12) received 4-week insulin-adjunctive treatments with (a) SGLTi (dapagliflozin 10 mg) + placebo and (b) SGLTi + GRA (volagidemab 70 mg) in a cross-over, double-blind design. At baseline and end of each treatment, CGM and insulin dosing were recorded, and subjects completed an 8-hr insulin withdrawal test (IWT). Average glucose improved with both SGLTi (138 mg/dL; P < 0.01) and SGLTi + GRA (131 mg/dL; P < 0.01) compared to Baseline (150 mg/dL). Total daily insulin dose was reduced with SGLTi (0.52 U/kg/day) compared to Baseline (0.56 U/kg/day; P = 0.06) and was reduced further with SGLTi + GRA treatment (0.41 U/kg/day; P < 0.01 vs SGLTi). Peak beta-hydroxybutyrate (BHB) concentrations during IWT were lower with SGLTi + GRA treatment (2.03 mmol/L) than with SGLTi alone (2.44 mmol/L; P = 0.04); there was no significant difference in peak BHB with either treatment vs Baseline (2.14 mmol/L). Treatment with SGLTi + GRA improved glycemic control, reduced insulin use, and mitigated ketosis during hypoinsulinemia. These data suggest that combination adjunctive therapy may be effective to address multiple metabolic abnormalities in T1D. Disclosure S.C.Boeder: Consultant; Cecelia Health, Research Support; Dexcom, Inc., REMD Biotherapeutics, Eli Lilly and Company. M.J.Le roux: None. E.R.Giovannetti: None. A.Armstrong: None. L.Carter: None. R.L.Thomas: None. J.M.Gregory: Advisory Panel; Eli Lilly and Company, vTv Therapeutics, Other Relationship; Medtronic. J.Pettus: Advisory Panel; Sanofi, Novo Nordisk, Lilly, MannKind Corporation, Consultant; Carmot Therapeutics, Inc., Diasome. Funding National Institutes of Health (P30DK063491, UL1TR001442); Diabetes Research Connection