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Update with SGLT-2 Inhibitors

Mar 04, 2014

In May 2013, I wrote a blog about INVOKANA [canagliflozin] – the first sodium glucose co-transporter 2 (SGLT-2) inhibitor. It was the first Food and Drug Administration (FDA)-approved agent in this new therapeutic class for the management of type 2 diabetes. This new class was developed to target another defect for hyperglycemia (i.e., kidneys). In development, it had desired characteristics for an anti-hyperglycemic agent, such as minimal to no risk of hypoglycemia and weight loss with an effective, proven A1c reduction.

Another SGLT-2 inhibitor was approved in January 2014 for the management of type 2 diabetes – dapagliflozin or FARXIGA. In healthy individuals, approximately 90 percent of the filtered glucose is reabsorbed by SGLT2 in the proximal renal tubule.  The kidney desires to excrete excessive, filtered glucose in order to restore normal levels of glucose in the blood.  In a patient with type 2 diabetes, the kidney is dysfunctional and responds to hyperglycemia through glucose reabsorption. (Defronzo RA, Diabetes 2009) 

Dapagliflozin works similarly to canagliflozin to decrease plasma glucose due to increased glucosuria.  Theoretically, this primary action would lead to: (1) increased insulin sensitivity; (2) increased insulin secretion; and (3) decreased glucose production by the liver.  Based on the evidence, dapagliflozin has similar A1c reduction and weight reduction as canagliflozin. 

While there may be benefits to this new class, there are still some concerns.  For example, there is a risk of urinary tract or genital mycotic infections from its activity of glucosuria with canagliflozin and dapaglifozin.  On a serious note, bladder and breast cancer was found in a small number of patients who received dapagliflozin; this adverse event was the reason for its first drug application to be denied by the FDA.

In recent evidence from the Journal of Clinical Investigation, there were two studies with a small number of patients that demonstrated the effectiveness of canagliflozin and empagliflozin (not approved in the United States) on glycemic control.  In the studies, both agents increased glucose excretion in the urine.  However, both studies demonstrated an increased endogenous glucose production through elevations in glucagon levels.  This new evidence may be preliminary data showing a compensatory increase in glucagon secretion, which would contradict the class’ theoretical mechanism of action.

Providers will either prescribe or wait to write a prescription for these products as they become available on the market.  However, there may be some reluctance especially as more evidence is evolving that may counteract the proposed theories for canagliflozin and dapagliflozin.

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