SGLT2 inhibitors -- an upcoming class of medications for diabetes

Dr. Bill Quick Health Pro March 15, 2009
  • Sodium-glucose transporter-2 (SGLT2) is the name of a "transporter protein" in the kidneys that has become a hot topic in diabetes research. In people with normal blood glucose (BG) levels, glucose is not excreted into the urine, but thanks to SGLT2, remains in the body. Which is a good thing: glucose represents a major fuel to keep the body's machinery going, and losing glucose into the urine would be wasteful.

     

    Actually, the kidneys allow glucose molecules to pass from the bloodstream into the renal plumbing (in an area of the kidney called the glomerulus), but the glucose is subsequently reabsorbed via active transport mechanisms (in an area called the proximal convoluted tubule) rather than being lost with the urine. Two sodium-glucose co-transporters have been identified that cause the glucose to be reabsorbed: SGLT1 and SGLT2. One of these, SGLT2, which is found only in the proximal tubule of the kidney, accounts for most of the reabsorption of glucose. The other, SGLT1, which is also found in the gut and other tissues, accounts for only about 10% of glucose reabsorption.


    In people with diabetes and elevated blood glucose levels, the SGLT transporters function just the same as in folks with normal BG levels: they encourage glucose that was going to be flushed out in the urine to reabsorbed into the bloodstream. That's a bad thing, as the BG is too high already, so returning the filtered glucose to the bloodstream is counterproductive.


    It was exciting to find that some chemicals can actually block the activity of the SGLT transporters. Since they block the action of the SGLT transporters, they are called SGLT inhibitors. And it is more exciting to find selective SGLT2 inhibitors, that worked only in the kidney. And even more exciting to find that the loss of glucose into the urine that would result from the activity of these SGLT2 inhibitor drugs does cause both the BG levels and the A1C to decrease. And, despite the increase in urinary glucose excretion and increased urinary volume, few patients in clinical trials complained of excessive urination.


    Several companies are evaluating different SGLT2 inhibitors in clinical trials: there's dapagliflozin, remogliflozin, sergliflozin, AVE2268, and probably others. What's especially intriguing about the SGLT2 inhibitors is that they do not intervene with glucose metabolism, so these drugs would be complementary to present approaches to glucose regulation.


    To date, trials have shown some decrease in A1C, and minimal side effects concerning the excessive urinary volumes. A review of one study is available at SGLT2 Inhibitors for the Treatment of Diabetes. Other reported side effects include both constipation and diarrhea, nausea, and reports of hypoglycemia, and some women developed vaginal infections (presumably because of the high glucose concentration in the urine allowing yeast organisms to flourish). In another study, some important blood constituents were affected: serum magnesium increased, serum phosphate increased, hematocrit increased. Renal function apparently is not disturbed. And one side effect that's been routinely seen is a good thing: weight loss.


  • When might these drugs become available? Not for several years: they still need to go through large (Phase III) trials, and problems could be found in these larger trials that would kill the development of one or more of the SGLT2 inhibitors. But assuming that the Phase III trials succeed, we can expect that sometime in the future, the next class of diabetes drugs will be the SGLT2 inhibitors.