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May 15, 2015 – The American Food and Drug Administration (FDA) is warning that the type 2 diabetes medicines Canagliflozin (Invokana), Dapagliflozin (Farxiga), and Empagliflozin (Jardiance) may lead to ketoacidosis, a serious condition where the body produces high levels of blood acids called ketones that may require hospitalization. FDA is continuing to investigate this safety issue and will determine whether changes are needed in the prescribing information for this class of drugs, called sodium-glucose cotransporter-2 (SGLT2) inhibitors.
SGLT2 inhibitors are a class of prescription medicines that are FDA-approved for use with diet and exercise to lower blood sugar in adults with type 2 diabetes. When untreated, type 2 diabetes can lead to serious problems, including blindness, nerve and kidney damage, and heart disease. SGLT2 inhibitors lower blood sugar by causing the kidneys to remove sugar from the body through the urine. These medicines are available as single-ingredient products and also in combination with other diabetes medicines such as metformin. Based on the warning issued, patients should pay close attention for any signs of ketoacidosis and seek medical attention immediately if they experience symptoms such as difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue or sleepiness. Do not stop or change your diabetes medicines without first talking to your prescriber.
Health care professionals should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing these signs or symptoms; discontinue SGLT2 inhibitors if acidosis (ketoacidosis in particular) is confirmed, and take appropriate measures to correct the acidosis and monitor sugar levels.
This safety announcement by the FDA comes just on the heels of a very interesting publication in Nature Medicine from April 2015, which indicates that inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Increased glucagon secretion itself has been known for a very long time to increase the formation of ketones in patients with diabetes and this may be how treatments with gliflocin drugs and ketoacidosis in patient meet each other.
The researchers around the first author C. Bonner briefly summarize the rather complex mechanism that may lead to increased glucagon production under dapagliflozin treatment as follows: Type 2 diabetes (T2D) is characterized by chronic hyperglycemia resulting from a deficiency in insulin signaling, because of insulin resistance and/or defects in insulin secretion; it is also associated with increases in glucagon and endogenous glucose production (EGP). Gliflozins, including dapagliflozin, are a new class of approved oral antidiabetic agents that specifically inhibit sodium-glucose co-transporter 2 (SGLT2) function in the kidney thus preventing renal glucose reabsorption and increasing glycosuria in diabetic individuals while reducing hyperglycemia. However, gliflozin treatment in subjects with T2D increases both plasma glucagon and EGP by so far unknown mechanisms. In spite of the rise in EGP, T2D patients treated with gliflozin have lower blood glucose levels than those receiving placebo, possibly because of increased glycosuria; however, the resulting increase in plasma glucagon levels represents a possible concerning side effect, especially in a patient population already affected by hyperglucagonemia. They demonstrate that SGLT2 is expressed in glucagon-secreting alpha cells of the pancreatic islets. They further found that expression of SLC5A2 (which encodes SGLT2) was lower and glucagon (GCG) gene expression was higher in islets from T2D individuals and in normal islets exposed to chronic hyperglycemia than in islets from non-diabetics. Moreover, hepatocyte nuclear factor 4-A(HNF4A) is specifically expressed in human alpha cells, in which it controls SLC5A2 expression, and its expression is downregulated by hyperglycemia. In addition, inhibition of either SLC5A2 via siRNA-induced gene silencing or SGLT2 via dapagliflozin treatment in human islets triggered glucagon secretion through K-ATP channel activation. Finally, the researchers found that dapagliflozin treatment further promotes glucagon secretion and hepatic gluconeogenesis in healthy mice, thereby limiting the decrease of plasma glucose induced by fasting. Collectively, these results identify a heretofore unknown role of SGLT2 and designate dapagliflozin an alpha cell secretagogue, whichmay lead to glucogen liberation and eventually increases in ketone production. In some patients, such mechanisms may lay grounds for clinically overt ketoacidosis.