SGLT2 inhibitors & euDKA risks…why?

AusDoc reports a bunch of people saying watch out for DKA in patients on SGLT2 inhibitors who may be having surgery or are unwell. You know those tongue twisters dapagliflozin, empagliflozin, ertugliflozin, etc. These drugs block sodium-glucose cotransporter 2 in the kidney to inhibit renal glucose reabsorption through an insulin-independent mechanism, which in turn lowers glucose levels through increased urinary glucose excretion. More details on the pharmacology can be found here. Thus SGLT2 inhibitors helps control diabetes type 2.

Now if you believe the pharmaceutical industry hype these drugs will prevent diabetic patient from having heart attacks and keep them off dialysis. For more useful information on this have a read of this post on BroomeDocs by Casey Parker.

These drugs have had their problems. After overcoming my fears of bladder cancer and concerns about increasing toe amputations and Fourniers gangrene, this new hazard may reduce my enthusiasm for these drugs.

So how does a drug which works to make you pee out sugar cause DKA? It would seems that this is a different type of DKA, and as none of the warning letters satisfied my curiosity for Why, I’d thought I’d hunt for a theory or two.

I am used to managing DKA in DMT1. You know, the teen who thinks that 24 beers on a Saturday night is cool and forgets to take his insulin for the next 2 days. Gets dumped in ED by his concerned mates, looking very sick (abdominal pain, shortness of breath, fatigue, nausea, and vomiting) with a glucose of 30 and pH of 6.9. Or, a young 5 year old whose parents have missed the gradual weight loss, drinking lots, peeing lots and then turns up with belly pain. This kind of DKA happens because there is no insulin to help metabolise sugar so the body switches over to fatty acid metabolism with ketoacids (eg., acetoacetate and β-hydroxybutyrate) being produced. The result is metabolic acidosis.

DKA caused by SGLT2 inhibitors is a little bit different. Glucose levels decrease with SGLT2 inhibition because you pee it out. Because glucose triggers the release of insulin, the drop in glucose levels results in less insulin production. This is good, and helps explain the drugs beneficial effect on weight unlike diabetes drugs which just make the pancreas work harder, like sulphonylureas. SGLT2 inhibitors also act independently on pancreatic alpha cells, further increase plasma glucagon levels and stimulate hepatic ketogenesis. It has also been speculated that they may decrease renal clearance of ketone bodies (making a urine dipstick for ketones less reliable), further increasing the concentration of ketones in the body. Thus a new acronym arises to describe euglycaemic or euDKA. This paper explains more of the science of this problem.

There is a also a case report of empagliflozin unmasking type 1 diabetes in someone who was originally thought to have type 2 diabetes. In such a person, positive GAD antibodies would change the diagnosis to LADA.

So, now I need to tell my patient who are on these drugs to come in for a checkup when they are sick and not eating or drinking well and to make sure their surgeon and anesthetist know what they are taking.

Finally for all you herbal fans, the first non selective SGLT inhibitor was extracted from unripe apples and the bark of apple trees way back in 1835. Unfortunately, it is broken down in the stomach and one if its metabolites causes severe diarrhoea making it not very useful to treat diabetes.

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