SGLT2 inhibitors and Euglycaemic DKA – a cautionary tale

The SGLT2 inhibitors are the newest class of hypoglycaemic agents and have been used increasingly frequently because of their efficacy, oral route of administration and added effects of weight loss and a small but significant reduction in blood pressure. Their insulin independent mode of action has meant that they can be used irrespective of β cell mass and therefore are not limited to early in the pathogenesis of T2DM. The side effect profile is well recognised with urogenital infections the most obvious (although relatively infrequent in clinical practice). However, recently, there have been reports of ketoacidosis in patients on these drugs. As of mid May 2015, the European Medicines Authority have reported a total of 101 cases of diabetic ketoacidosis in patients treated with SGLT2 inhibitors for type 2 diabetes.

Whilst there are a number of studies underway looking at their use in T1DM, SGLT2s are not licensed in T1DM but they have been used off label with reporting of euglycaemic ketoacidosis in some patients. In T1DM, the insulin independent loss of glucose from the body may result in a reduction in insulin dosing leading to a relative or absolute deficiency. SGLT2 inhibition also results in increased glucagon levels (albeit predominantly in T2DM). Glucagon is lipolytic and ketogenic which may be a contributory factor. In Type 2 diabetes, a potential mechanism is less easy to elucidate. Possibly the development of infections increasing the catabolic stress on the body or the fact that some of the patients may have had undiagnosed or slow onset Type 1 diabetes.

Since the advent of these cases being reported, the FDA and more recently the EMA have begun a review of SGLT2 inhibitors regarding their risk of DKA. There is no suggestion that patients on these gents should all be taught ketone testing. However, prudence would suggest counselling patients about their recognised side effects including urogenital infections and the potential for dehydration as well as avoiding off label prescribing without trial evidence of benefit.

Dr Mark Freeman

July 2015