Sodium-glucose Cotransporter 2 Inhibitors and the Risk of Diabetic Ketoacidosis; from Pathophysiology to Clinical Practice

Background: SGLT-2 inhibitors are a novel class of antidiabetic drugs, recently approved for the treatment of patients with T2DM. Their cardioprotective and renoprotective action, along with their beneficial effects on metabolic parameters, makes them an attractive therapeutic option. Since 2015, when the US FDA issued warning regarding the increased risk of euDKA in the setting of SGLT-2 inhibitors administration, a vivid discussion upon the direct connection between this novel class and the major metabolic complication of diabetes mellitus is still ongoing.

Objectives: To present the underlying pathophysiology, associating SGLT-2 inhibitors and euDKA, and clinical data both in T1DM and in T2DM patients, in order to understand the clinical background which favors the development of euDKA.

Method: We conducted a comprehensive research of the relevant literature regarding the association between SGLT-2 inhibitors in clinical practice and the events of diabetic ketoacidosis, mainly euglycemic.

Results: Randomized controlled trials, meta-analyses, case series and case reports shed light on this possible connection, the background that favors euDKA, and the mediating pathophysiologic mechanisms. Many of those euDKA events developed in patients with T1DM, due to off-label use of SGLT-2 inhibitors, or in patients previously misdiagnosed as having T2DM, who in fact suffered from LADA.

Conclusion: SGLT-2 inhibitors certainly predispose to euDKA, but it is unclear if, as certain precipitating factors are usually recognized on the background, DKA would also occur in the absence of an SGLT-2 inhibitor. Further investigation is required in order to establish or not SGLT- 2 inhibitors as causative factors of euDKA.