Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, Georgia, USA; Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are currently in clinical use for the treatment of adults with type 2 diabetes. The SGLT2 inhibitor class of drugs approved by the U.S. Food and Drug Administration include canagliflozin, dapagliflozin, and empagliflozin. To improve glycemic control in diabetic patients, these oral antidiabetic drugs promote glycosuria by inhibiting renal tubular reabsorption of glucose via SGLT2 expressed in the proximal tubule. Recently, several case reports have revealed the development of ketoacidosis in type 1 and type 2 diabetic patients treated with SGLT2 inhibitors. The characteristic features of diabetic ketoacidosis (DKA), in the absence of SGLT2 inhibitor therapy, include insulin deficiency and an increase in the circulating levels of counter-regulatory hormones (e.g., glucagon), which would stimulate lipolysis in adipose tissue and ketogenesis in liver to enhance the circulating levels of ketone bodies. Of importance, in diabetic patients treated with an SGLT2 inhibitor, a decrease in the administered insulin dose, an increase in glucagon secretion, and/or a decrease in insulin-to-glucagon ratio have been shown to promote ketoacidosis. Strategies aimed at treating DKA should follow the key procedures including: i) insulin infusion at a specified dosage without interruption to prevent worsening of ketoacidosis; and ii) avoidance of excessive insulin to prevent severe hypoglycemia. With regard to the diagnosis and monitoring of DKA, it is critically important to determine the circulating levels of β-hydroxybutyrate (one of the three ketone bodies), which would improve treatment strategies to resolve ketoacidosis and reduce the risk of severe hypoglycemia.