SGLT2 Inhibitors in Type 1 Diabetes: The Metabolic Perspective.

The introduction of the sodium-glucose cotransporter-2 inhibitors (SGLT2i) was a landmark moment in the treatment of diabetes. Their unique insulin independent mechanism of action, results in decreased reabsorption of glucose at the renal tubular level and increased glucosuria, which lowers blood glucose along with modest weight reduction due to caloric loss in the urine. Today, the SGLT2i are approved not only for their glycemic benefits, but also to reduce the risk of heart failure (HF) hospitalization and progression to chronic kidney disease (CKD) in patients with type 2 diabetes (T2DM) and CKD/HF. Notably, the SGLT2i are also approved for cardiorenal benefits in those without diabetes. However, SGLT2i are not approved for use in those with type 1 diabetes (T1DM) due to the increased risk for diabetic ketoacidosis (DKA) and euglycemic ketoacidosis. This review provides an overview of the various metabolic effects seen with the use of SGLT2i and dual SGLT1/2 inhibitors in patients with T1DM, including beneficial effects on glycemia despite a paradoxical increase in endogenous glucose production (EGP), changes in insulin sensitivity, hyperglucagonemia and changes in substrate oxidation. We also discuss mechanisms leading to increased ketogenesis and a higher risk of DKA in those with T1DM and potential measures to mitigate this risk, so that patients with T1DM can safely avail the robust glycemic and cardiorenal benefits of these agents.