Combination SGLT2 Inhibitor and Glucagon Receptor Antagonist Therapy in Type 1 Diabetes: A Randomized 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.

Graphical abstract

Figure 1

CGM average glucose (A), glucose SD (B), and percent time with glucose in target range (70–180 mg/dL) (C), above range (>180 mg/dL) (D), and below range (<70 mg/dL) (E) are shown for Baseline, SGLT2 inhibitor + placebo, and SGLT2 inhibitor + GRA testing periods. Data are summarized as means and 95% CIs. Mean values, represented with columns, are also annotated at the bottom of each column. Dots depict individual values for each participant. Significant P values, determined with multiple comparisons tests, are indicated above brackets. TAR, time above range; TBR, time below range; TIR, time in range.

Figure 2

Average total daily insulin dose (A), average total daily basal dose (B), average total daily bolus dose (C), and scores from the DMSAT (D) are shown for Baseline, SGLT2 inhibitor + placebo, and SGLT2 inhibitor + GRA testing periods. Data are summarized as means and 95% CIs. Mean values, represented with columns, are also annotated at the bottom of each column. Dots depict individual values for each participant. Significant P values, determined with multiple comparisons tests, are indicated above brackets.

Figure 3

IWT. A–F: Serum insulin concentrations during the IWT (limit of detection of serum insulin [LOD]) (A), termination time (duration) of IWT (B), plasma glucose concentrations during IWT (C), peak plasma glucose achieved during IWT (D), BHB concentrations during IWT and number of participants remaining in IWT at each time point (E), and peak BHB achieved during IWT (F) are shown for Baseline, SGLT2 inhibitor + placebo, and SGLT2 inhibitor + GRA testing periods. Data are summarized as means and 95% CIs. For bar graphs (B, D, and F), mean values, represented with columns, are also annotated at the bottom of each column; dots depict individual values for each participant; and significant P values, determined with multiple comparisons tests, are indicated above brackets. G and H: Kaplan-Meier curve demonstrating IWT termination due to elevated BHB (≥3.0 mmol/L) (G) and reason for IWT termination during each testing period (H). A, C, E, and G: x-axis represents time elapsed (minutes) during IWT.