A predisposition to diabetic ketoacidosis (DKA) used to be regarded as one of the hallmarks of type 1 diabetes mellitus. There was a presumption that patients with type 2 diabetes (T2DM), although deficient in insulin action, had sufficient background levels of insulin to prevent the formation of ketone bodies. Thus, during periods of extreme hyperglycaemia, they would not develop acidaemia and would manifest as ‘hyperosmolar non-ketotic acidosis’ (abbreviated to ‘HONK’, although this is now referred to as ‘hyperosmolar hyperglycaemic state’).
Subsequently, there were several reports of DKA in T2DM patients of African-Caribbean background. These rare cases were thought to represent severe underlying insulin resistance aggravated by reduced insulin secretion due to glucose toxicity (induced by the extreme hyperglycaemia). Following treatment for the acute decompensation, long-term insulin was rarely required.
Over the past couple of years, DKA in T2DM has become a major talking point and this follows on from the introduction of the sodium-glucose transporter-2 (SGLT-2) inhibitor class of anti-diabetic agents. In 2015, the US Food and Drugs Administration issued a Drug Safety Communication warning ‘that the type 2 diabetes medicines canagliflozin, dapagliflozin, and empagliflozin may lead to ketoacidosis’ and this was followed by a similar statement by the European Medicines Agency in February 2016. This possible adverse effect of the SGLT-2 inhibitors was entirely unexpected and has led to a flurry of activities:
First, there has been a recognition that DKA is a relatively common event in patients designated as having T2DM (predating the SGLT-2 class).
Second, there is no doubt that some of the cases have been in patients misclassified as having T2DM, when they were type 1 (or LADA) cases.
Third, there are plausible reasons why SGLT-2 inhibitors may increase ketone body levels
Forth, when SGLT-2 inhibitors are used appropriately, levels of DKA are very low (for example in the EMPA-REG OUTCOME study of over 7,000 patients there was no difference in DKA rates between patients receiving empagliflozin versus placebo).
This is clearly a developing field which we will periodically review…
Professor Steve Bain