SGLT2 Inhibitors May Predispose to Ketoacidosis

Abstract

Context: Sodium glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic drugs that increase urinary excretion of glucose, thereby improving glycemic control and promoting weight loss. Since approval of the first-in-class drug in 2013, data have emerged suggesting that these drugs increase the risk of diabetic ketoacidosis. In May 2015, the Food and Drug Administration issued a warning that SGLT2 inhibitors may lead to ketoacidosis.

Evidence acquisition: Using PubMed and Google, we conducted Boolean searches including terms related to ketone bodies or ketoacidosis with terms for SGLT2 inhibitors or phlorizin. Priority was assigned to publications that shed light on molecular mechanisms whereby SGLT2 inhibitors could affect ketone body metabolism.

Evidence synthesis: SGLT2 inhibitors trigger multiple mechanisms that could predispose to diabetic ketoacidosis. When SGLT2 inhibitors are combined with insulin, it is often necessary to decrease the insulin dose to avoid hypoglycemia. The lower dose of insulin may be insufficient to suppress lipolysis and ketogenesis. Furthermore, SGLT2 is expressed in pancreatic α-cells, and SGLT2 inhibitors promote glucagon secretion. Finally, phlorizin, a nonselective inhibitor of SGLT family transporters decreases urinary excretion of ketone bodies. A decrease in the renal clearance of ketone bodies could also increase the plasma ketone body levels.

Conclusions: Based on the physiology of SGLT2 and the pharmacology of SGLT2 inhibitors, there are several biologically plausible mechanisms whereby this class of drugs has the potential to increase the risk of developing diabetic ketoacidosis. Future research should be directed toward identifying which patients are at greatest risk for this side effect and also to optimizing pharmacotherapy to minimize the risk to patients.

Figure 1.

Potential mechanisms whereby adjunctive therapy with SGLT2 inhibitors may promote ketosis and increase the risk of ketoacidosis in T1D patients. SGLT2 inhibitors (SGLT2i) decrease glucose by an insulin-independent mechanism. To minimize the risk of hypoglycemia, T1D patients may need to decrease their insulin dose, which is predicted to increase the rate of adipose tissue lipolysis and hepatic ketogenesis. In addition, SGLT2 inhibitors have been demonstrated to increase plasma glucagon levels in T2D patients (12, 13), possibly to compensate for increased urinary excretion of glucose. In addition, it has recently been reported that SGLT2 inhibitors increase preproglucagon gene expression by acting directly upon pancreatic α-cells (14). Furthermore, phlorizin (a nonselective inhibitor of SGLT1 and SGLT2) has been demonstrated to increase renal tubular reabsorption of acetoacetate (9). If selective SGLT2 inhibitors mimic this action of phlorizin, it is possible that they could also decrease renal clearance of ketone bodies.