Breakthrough combo therapy for type 1 diabetes: SGLT2 inhibitors + GRAs boost control, cut insulin use, study reveals

The study, published in Diabetes Care, revealed that sodium-glucose cotransporter 2 (SGLT2) inhibitors plus glucagon receptor antagonists (GRAs) may reduce insulin use, improve glycemic control, and mitigate ketogenesis risk compared with SGLT2 inhibitors alone in patients with type 1 diabetes.

The researchers revealed that glucagon antagonism enhances the therapeutic effects of SGLT2 inhibition in T1D.

SGLT2 inhibitors are commonly used to treat Type 2 diabetes by blocking glucose reabsorption in the kidneys, thereby promoting excretion through urine. On the other hand, glucagon receptor antagonists work by blocking the action of glucagon, a hormone that raises blood sugar levels, thereby reducing the overall blood glucose levels.

Jeremy H. Pettus, University of California, San Diego, La Jolla, CA, and colleagues aimed to examine the effects of insulin-adjunctive therapy with an SGLT2 inhibitor and a GRA on glycemia, insulin use and ketogenesis during insulinopenia in type 1 diabetes.

For this purpose, the researchers conducted a randomized, double-blind, placebo-controlled, crossover trial to assess 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 withdrawal tests (IWT), and insulin dosing for measurement of ketogenesis and glucose during insulinopenia were completed during SGLT2 inhibitor, insulin-only (Baseline), and combination (SGLT2 inhibitor + GRA) therapy periods.

The study led to the following findings:

• Average glucose and percent time with glucose in range (70–180 mg/dL) improved with combination therapy versus Baseline and SGLT2 inhibitor (131 versus 150 and 138 mg/dL and 86% vs. 70% and 78%, respectively) without increased hypoglycemia.
• Total daily insulin use decreased with combination therapy versus Baseline and SGLT2 inhibitor (0.41 versus 0.56 and 0.52 units/kg/day).
• Peak β-hydroxybutyrate levels during IWT were lower with combination therapy than with SGLT2 inhibitor (2.0 versus 2.4 mmol/L) and similar to levels reached during the Baseline testing period (2.1 mmol/L).
• Participants reported enhanced treatment acceptability and satisfaction with combination therapy.

"These outcomes underscore the critical role of glucagon in T1D metabolism and the potential of blocking glucagon action, which could facilitate the safe use of SGLT2 inhibitors," the authors wrote.

In conclusion, combination SGLT2 inhibitor + GRA is a promising adjunctive therapy strategy for type 1 diabetes.

Reference:

Schafer C. Boeder, Robert L. Thomas, Melissa J. Le Roux, Erin R. Giovannetti, Justin M. Gregory, Jeremy H. Pettus; Combination SGLT2 Inhibitor and Glucagon Receptor Antagonist Therapy in Type 1 Diabetes: A Randomized Clinical Trial. Diabetes Care 2024; dc240212. https://doi.org/10.2337/dc24-0212