SGLT2 Inhibitors, Ketogenesis, and Ketoacidosis

PROJECT SUMMARY/ABSTRACT Sodium-glucose cotransport inhibitors (SGLT2i) lower the plasma glucose concentration by promoting glucosuria and have been shown to be effective in preventing cardiovascular events, including heart failure, and in slowing the progression of chronic kidney disease in diabetic and nondiabetic individuals. However, the uptake of the SGLT2i, especially in the general medical community but also by cardiologists and nephrologists, has been retarded by the development of diabetic ketoacidosis. Although uncommon in T2DM, DKA occurs in 3-5% of T1DM individuals treated with SGLT2i and primarily for this reason the SGLT2i have not been approved by FDA for use in T1DM individuals. Consequently, T1DM subjects have been excluded from all large-scale CV and renal outcome studies. Further, the glucose lowering efficacy of the SGLT2i is blunted by their stimulation of hepatic glucose production (HGP), which offsets by ~50% the amount of glucose excreted in the urine. Therefore, a clearer understanding of the mechanisms involved in the stimulation of ketosis and EGP are needed. In the present grant proposal, we will employ innovative study designs with radioisotopes and stable isotopes to elucidate the mechanisms via which empagliflozin augments hepatic glucose production and stimulates ketogenesis (Protocols I, II, and III), while in Protocols IV and V we will examine whether pioglitazone can block the SGLT2i-induced stimulation of ketosis and HGP. If this can be demonstrated, this would allow T1DM, as well as T2DM, subjects to be safely treated with SGLT2i and to receive the cardiovascular and renal benefits of this antidiabetic class of drugs.