Endocrinology: SGLT2 Inhibitors: adverse/beneficial effects
Euglycaemic DKA is an important to recognise side effect of SGLT2 inhibitors and should be thought of in any patient with an unexplained raised anion gap acidosis and normal blood sugar level who is on one of these drugs.
Exactly how these agents cause EuDKA has yet to be determined.
However, it is hypothesised that as these agents lower blood sugar levels by increasing the excretion of glucose, the resulting reduction in plasma glucose results in reduced insulin secretion from pancreatic beta-cells and these patients enter a state of relative insulin deficiency.
This leads to a lowering of the antilipolytic activity of insulin, and the consequent stimulation of the production of free fatty acids, which are then converted to ketone bodies by beta-oxidation in the liver.
Moreover, insulin stimulates the activity of acetyl-CoA carboxylase, which produces malonyl-CoA, a potent inhibitor of carnitine palmitoyltransferase (CPT-I).
Given that CPT-I promotes the transport of fatty acids into mitochondria and hence increases the rate of beta-oxidation, the decrease in the circulating level of insulin promotes the production of ketone bodies through activation of CPT-I.
SGLT-2 inhibitors like dapagliflozin promote increased glucose excretion because they inhibit glucose reabsorption in the kidney. This corresponds to a calorie load of 200-400 kcal per day. In some patients, this results in dramatic weight loss, although on average this equates to 1-2% reduction in weight over 6 months.
SGLT-2 inhibitors are recognised to increased total cholesterol, (both HDL and LDL), although cardiovascular outcome studies as yet do not suggest this translates into increased risk of MACE events. In fact, the EMPA-reg study with empagliflozin demonstrated a reduction in overall mortality.
SGLT-2 inhibitors are associated with increased urate excretion.