Automated Insulin Delivery With SGLT2i Combination Therapy in Type 1 Diabetes

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a new class of blood sugar (glucose)–lowering drugs that have been approved by the FDA within the past decade for the treatment of type 2 diabetes (T2DM) in conjunction with diet and exercise. SGLT2i lower blood glucose levels by preventing the kidneys from reabsorbing glucose, thereby lowering blood glucose concentrations by spilling more glucose into the urine. Auspiciously, recent studies have also demonstrated that SGLT2i not only improve blood sugar control but also improve heart and kidney function.

Given the favorable efficacy and safety of SGLT2i in the treatment of T2DM, there has been a heightened interest in using SGLT2i as an adjunct to insulin therapy in patients with type 1 diabetes (T1DM), in whom many risks of worse heart and kidney health are similar to those of patients with T2DM. However, to date, the safety and efficacy of SGLT2i in the treatment of T1DM have not been established; therefore, this class of drug has not been approved by the FDA.

A major concern with SGLT2i is the risk of euglycemic diabetic ketoacidosis (euDKA), a condition in which the body can be “tricked” into an inappropriate and potentially life-threatening starvation-like response. To assess the efficacy and safety of the SGLT2i empagliflozin (EMPA) in T1DM, Garcia-Tirado et al performed a randomized controlled crossover trial in which adults with T1DM received 5 mg/day of EMPA or no drug (NOEMPA) added to their usual insulin pump therapy. Continuous glucose monitoring systems were used to assess volunteers’ time-in-range (TIR) and demonstrated that participants treated with EMPA versus NOEMPA had higher daytime TIR. No improvement in daytime TIR was accompanied by more frequent hypoglycemia. During the study, none of the participants developed genital infections or pain during urination. However, many developed mild ketosis, and one volunteer developed DKA warranting hospitalization despite frequent blood ketone level checks.

Therefore, in sum, while SGLT2i are a promising adjunct drug for glucose control in T1DM, the improvement in glucose control comes with a substantial risk of ketosis and potentially life-threatening euDKA, requiring frequent monitoring of blood ketone levels. This frequent ketone testing may impose an additional burden on patients with T1DM  who often are already “diabetes fatigued.” Long-term outcome studies will be necessary to fully evaluate the efficacy and safety of SGLT2i in the treatment of T1DM and to determine if the benefit of daytime improvement of glycemic control outweighs the increased risk of developing DKA, especially in patients on insulin pumps in whom a risk of disruption of insulin delivery and thus DKA can occur unnoticed at night. Taken together, Garcia-Tirado et al’s study supports the idea that SGLT2i deserve consideration in a select fraction of patients with T1DM under careful monitoring. Larger studies will be required to provide conclusive evidence for or against this concept.