SGLT2 inhibition and ketoacidosis – should we be concerned?

Abstract

SGLT2 inhibitors represent a novel class of oral glucose- lowering treatment that addresses some important unmet clinical needs in the treatment of type 2 diabetes, specifically weight reduction and a low propensity to cause hypoglycaemia. SGLT2 inhibition lowers the renal threshold for glucose excretion, resulting in renal glycosuria, a shift in substrate utilisation from carbohydrate to fat oxidation and hyperglucagonaemia; this poses a theoretical risk for ketoacidosis (including euglycaemic ketoacidosis) in the presence of other precipitating factors, especially reduction in insulin doses or low carbohydrate intake. There have been reports of several cases of ketoacidosis, mostly euglycaemic, and in people with type 1 or type 2 diabetes. Subsequent to this there were warnings from regulatory bodies (FDA and EMEA). In this article, we examine the reports of ketoacidosis associated with SGLT2 inhibition and try to explain the intrinsic pathophysiological mechanisms associated with this class of drugs which might contribute to ketoacidosis. The implications of these for clinical practice are summarised with key messages to health care providers.