A Literature Review of the Therapeutic Perspectives of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitor-Induced Euglycemic Diabetic Ketoacidosis

Abstract

Euglycemic diabetic ketoacidosis (DKA), a side effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors, is a triad of high metabolic anion gap acidosis, raised serum and urine ketones, and serum glucose <250 mg/dl. SGLT2 inhibitors cause a carbohydrate deficit by glucosuria, which leads to an increased glucagon/insulin ratio, the metabolic shift from glucose to lipid utilization causing ketogenesis, and hence euglycemic DKA. Additional factors like the ketogenic diet, illness, surgery, and pregnancy contribute to precipitating these episodes.Keywords search included "Euglycemic DKA and SGLT2 inhibitors" in PubMed and Google Scholar, to compile data from existing articles that provide information on the withholding and restarting period of the drug after a euglycemic DKA episode. SGLT2 inhibitors, used in the treatment of type 2 DM, have an average half-life of 11-13 hours, so most articles suggested withholding the drug three days before any elective surgery but some articles suggested a longer withholding period based on other precipitating factors contributing to euglycemic DKA. Hence, we came up with patient inclusion criteria and concomitant therapies review that we need to consider in making this decision. In addition, a multidisciplinary approach is required when laying out guidelines for restarting the drug to have a unanimous approach.After reviewing the existing literature, it is clear that concrete guidelines are required to decide on drug withholding and restarting periods after a euglycemic DKA episode, as they vary among different institutions and different specialties. We believe it is crucial to consider patient inclusion criteria and concomitant therapies in forming those guidelines.

Sodium-Glucose Cotransporter 2 Inhibitor-Induced Euglycemic Diabetic Ketoacidosis: The Other Side of the Coin!

“…However, in 2015, the FDA cautioned that their use is associated with serious adverse drug events of EDKA [ 1 ]. Increased risk is observed with all SGLT-2 inhibitors suggesting class effect, with canagliflozin (hazard ratio: 3.58) having the highest risk [ 8 ].…”

“…Furthermore, they also increase renal absorption of ketone bodies. Glycosuria leads to normal or near-normal blood glucose levels [ 1 ]. This condition can be precipitated by any intercurrent illness, post-surgery, sepsis, alcoholism, and use of a ketogenic diet, where decreased intake of carbohydrates combined with lower glucose levels can further suppress insulin release and lead to EDKA.…”

“…Diaz-Ramos A et al described a case of a 44-year-old female who presented with EDKA who was started on canagliflozin four weeks earlier and had stopped insulin for two weeks [ 16 ]. Peterson C et al described EDKA in a 28-year-old type 2 diabetic, five days after he was initiated on empagliflozin 10 mg post-percutaneous coronary intervention (PCI) and required 120 hours of continuous glucose-insulin infusion for closure of the AG [ 17 ]. In a systematic review by Dutta et al, common risk factors for the development of EDKA in patients on SGLT2 inhibitors were female sex, surgery in the recent past, and concomitant use of canagliflozin with metformin [ 18 ].…”

“…SGLT2 inhibitors, also known as gliflozins, were approved by the US Food and Drug Administration (FDA) in 2013 for the treatment of type 2 diabetes mellitus (T2DM) [ 1 ]. They act through the inhibition of SGLT2 transmembrane protein (receptor) expressed on the apical cells of proximal convoluted tubules (PCT), which results in the inhibition of glucose reabsorption in PCT and facilitates its excretion in urine [ 1 ]. In addition to their blood glucose lowering effect, they have cardiovascular and reno-protective effects and cause modest reductions in blood pressure and weight loss.…”

“…However, the European Medicines Agency and US FDA have cautioned against the life-threatening complication of euglycemic diabetic ketoacidosis (EDKA), based on the incidents identified through the adverse reporting event system [ 2 , 3 ]. EDKA is defined by a triad of high anion-gap metabolic acidosis (HAGMA) with high serum and urine ketones and a blood glucose level of less than 250 mg/dL [ 1 ]. The possibility of conventional DKA is often thought of in an appropriate clinical context in a patient of T2DM, but that of EDKA is rarely considered or is missed, in view of normal or near-normal blood glucose levels.…”