Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, and Preventable Safety Concern With SGLT2 Inhibitors.

Recently, the U.S. Food and Drug Administration (FDA) issued a Drug Safety Communication that warns of an increased risk of diabetic ketoacidosis (DKA) with uncharacteristically mild to moderate glucose elevations (euglycemic DKA [euDKA]) associated with the use of all the approved sodium–glucose cotransporter 2 (SGLT2) inhibitors (1). This Communication was based on 20 clinical cases requiring hospitalization captured between March 2013 and June 2014 in the FDA Adverse Event Reporting System database. The scarce clinical data provided suggested that most of the DKA cases were reported in patients with type 2 diabetes (T2D), for whom this class of agents is indicated; most likely, however, they were insulintreated patients, some with type 1 diabetes (T1D). The FDA also identified potential triggering factors such as intercurrent illness, reduced food and fluid intake, reduced insulin doses, and history of alcohol intake. The following month, at the request of the European Commission, the European Medicines Agency (EMA) announced on 12 June 2015 that the Pharmacovigilance Risk Assessment Committee has started a review of all of the three approved SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) to evaluate the risk of DKA in T2D (2). The EMA announcement claimed that as of May 2015 a total of 101 cases of DKA have been reported worldwide in EudraVigilance in T2D patients treated with SGLT2 inhibitors, with an estimated exposure over 0.5 million patient-years. No clinical details were provided except for the mention that “all cases were serious and some required hospitalisation. Although [DKA] is usually accompanied by high blood sugar levels, in a number of these reports blood sugar levels were only moderately increased” (2). With this background, it is very timely that in this issue of Diabetes Care there are two articles on this subject. Erondu et al. (3) report cases of DKA in T2D from a large clinical development program and Peters et al. (4) discuss cases from clinical practice observations of T1D and T2D patients. It is not unusual that serious safety issues related to a new drug go undetected during the relatively short clinical development programs for regulatory drug approval. This is particularly true when the safety issue is unexpected, occurring as an off-target effect, or only emerges once the drug is used widely. If serious enough, the issue may require a label warning and a mitigation plan or even consideration of drug withdrawal. DKA is an overt serious clinical condition that may be missed only if presenting with mild to moderate hyperglycemia, as it may be the case with use of SGLT2 inhibitors, which could delay diagnosis and treatment and even accelerate the progressive metabolic deterioration. Interestingly, the large clinical development programs of the three marketed SGLT2 inhibitors, comprising .40,000 T2D patients, bore no clear signal of DKA. Erondu et al. (3), representing Janssen, the manufacturer of canagliflozin, report a relatively low frequency of DKA (15 cases, 12 on canagliflozin and 3 still blinded in the CANagliflozin cardioVascular Assessment Study [CANVAS]) detected in a retrospective analysis of 17,596 participants in the development program up to May 2015. The estimated incidence ratesd0.5, 0.8, and 0.2 per 1,000 patient-years with canagliflozin 100mg, canagliflozin 300mg, and comparator, respectivelydif underwhelming, are double with the SGLT2 inhibitor. Upon our inquiry, the other two manufacturers of approved SGLT2 inhibitors, AstraZeneca and Boehringer Ingelheim, provided preliminary (unpublished)figures that are even lower than the Janssen data. In more than 18,000 patients exposed to dapagliflozin in the randomized controlled T2D study program, including DECLARE (Dapagliflozin Effect on Cardiovascular Events), the frequency of reported events suggestive of DKA (blinded and unblinded events) is less than 0.1%. Similarly in DECLARE, aiming for 17,150 patients randomized to dapagliflozin orplacebo, the total number