COMMENTARY

Where Do SGLT2 Inhibitors Fit in Diabetes Care?

New Class of Drugs 'Turns Glucosuria on Its Head'

Clifford J. Bailey, PhD

Disclosures

October 15, 2013

In This Article

Fitting in the SGLT2 Inhibitors

Where do the SGLT2 inhibitors fit in? First, let's look at how they work. These agents act principally on the sodium glucose transporter 2 in the proximal tubules of the kidney. Inhibiting these transporters prevents the reabsorption of filtered glucose in the kidney, and as a result glucose will pass through the nephron, ducts of Bellini, ureters, and out in the urine, thereby removing excess glucose in the urine. This type of therapy is turning glucosuria on its head, and instead of it being considered just as a marker of poor control, we are now showing how increasing glucosuria can be used as a mechanism to remove excess glucose from the blood and help control hyperglycemia.

Inhibiting SGLT2 is not entirely unknown in history; it's just that SGLT2 wasn't known. If you go back into the 1800s, apple tree bark was shown to be rich in a substance called phlorizin, and subsequently phlorizin was shown to increase the amount of glucose being excreted in the urine. In the 1980s it was shown that this could be used as a non-insulin-dependent mechanism to help control blood glucose. It was the subtle chemical manipulation of the molecule to produce stability and selectivity so that the molecule could focus predominantly on SGLT2 to inhibit this transporter, which is the main transporter for reabsorbing glucose, allowing more glucose to pass in the urine.

Most of the agents that we have at the current time to treat type 2 diabetes either enhance insulin secretion or reduce or counter insulin resistance, or they replace insulin. The key difference for the type of therapy that inhibits SGLT2 is that it is acting independently of insulin, so this gives us an opportunity to use it at many different stages during the progression of type 2 diabetes.

Several SGLT2 inhibitors are in development. Dapagliflozin is already approved in Europe and canagliflozin is approved in the United States. There are other "flozins" in advanced development, and these will be coming through in due course, so there will be several drugs in this entirely new class of agent.

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