Sodium-glucose cotransporter-2 inhibitors induced eu-glycemic diabetic ketoacidosis: The first report in a type 2 diabetic (T2D) Taiwanese and literature review of possible pathophysiology and contributing factors

Abstract

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are the newest class of oral antidiabetic drugs (OADs), approved to be a second-line OAD for type 2 diabetes in Taiwan since 2016. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) had both released statements associating the use of SGLT-2 inhibitors may increase the risk of eu-glycemic diabetic ketoacidosis (euDKA). This review reveals the possible pathophysiology with a chain of metabolic adaptions to decrease plasma glucose and increase plasma ketone bodies through pancreas, kidney, liver and adipose tissue. Moreover, euDKA is a potential and rare complication of treatment with SGLT-2 inhibitors when coexisting with triggering factors. It is an emerging challenge for clinical physicians and patients treated with SGLT-2 inhibitors. Therefore, first report of SGLT-2 inhibitor induced euDKA in a T2D Taiwanese and literature review of possible pathophysiology and contributing factors are presented in order to make more attentions in public.

Euglycemic Diabetic Ketoacidosis and Sodium-Glucose Cotransporter-2 Inhibitors: A Focused Review of Pathophysiology, Risk Factors, and Triggers

“…Sodium-glucose cotransporter (SGLT2) is a transmembrane protein and, as its name suggests, cotransports sodium and glucose across the cell membrane. Although there are six isoforms, two important forms are type 1 and 2, with the former located on the intestinal cells, and the latter mostly on the apical cells of the proximal convoluted tubules in the kidney and alpha cells of the pancreas [10,11]. These transporters are driven by the electrochemical gradient generated by the basolateral sodium/potassium-ATPase pump, and SGLT2 aids in the reabsorption of glucose from the proximal tubule segment 1 and 2 [11][12][13].…”

“…In 2013-2014, the Food and Drug Administration (FDA) approved the clinical use of SGLT2i such as canagliflozin, dapagliflozin, and empagliflozin to treat T2DM, either as monotherapy or in combination with other antidiabetic drugs. Its action mechanism leading to a decreased dose of insulin required in T1DM patients made it an off-label drug to manage T1DM [10]. Different clinical trials have well established the cardiorenal protective effect of SGLT2i [12].…”

Safety of sodium–glucose cotransporter 2 inhibitors in Asian type 2 diabetes populations

“…The risk of SGLT2i‐associated DKA remains a considerable concern among Asian type 2 diabetes mellitus patients owing to their high association with β‐cell dysfunction 124 , 125 . Nevertheless, available evidence suggests that DKA is infrequent in Asian populations.…”