Another class of diabetes drugs   (March 13, 2011)

Another diabetes drug, dapagliflozin, may soon be available to treat type 2 diabetes. Dapagliflozin is the first in a new class of diabetes drugs called the "SGLT2 inhibitors" (or, if you prefer, the sodium-glucose transporter-2 inhibitors), which work by a novel mechanism of action: they cause extra loss of glucose into the urine.

Here's the background of how these drugs work: the kidneys allow glucose molecules to pass from the bloodstream into the urine, but most of the glucose molecules are subsequently actively reabsorbed 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 part of the kidney called the proximal tubule, is responsible for 90% of the reabsorption of glucose; SGLT1 accounts for only about 10%. The SGLT2 inhibitor drugs block the action of SGLT2, and hence block the reabsorption of glucose back into the bloodstream, and therefore allow extra glucose to be excreted in the urine.

Several companies have been working on the development of SGLT2 inhibitors; besides dapagliflozin, there's canagliflozin, remogliflozin, sergliflozin, AVE2268, and probably others. Many of the SGLT2 inhibitor studies have been done in comparison to a placebo (so the drug can be evaluated for use as monotherapy) or in combination with metformin or other diabetes oral medications. Dapagliflozin has been shown to improve A1c levels -- and to induce weight loss. In patients already taking metformin, it allowed additional weight loss. Or, when dapagliflozin was compared to a sulfonylurea (glipizide), patients taking the SU gained approximately three pounds while those taking dapagliflozin lost seven pounds on average.

Weight loss is an added virtue of using dapagliflozin. On the other hand, other side effects would be less desirable. There's concern that excess urinary glucose could lead to urinary tract infections (not seen) and genital infections (yes, there were more). Other possible concerns, including rate of hypoglycemia, kidney function and electrolyte abnormalities were evaluated in the clinical trials and seemed to be unaffected. Reductions in blood pressure were observed but orthostatic hypotension was not increased in patients taking dapagliflozin.

Sounds good. But wait: there's another theoretical good thing: although the clinical trials have been in patients with type 2 diabetes, there's reason to think that the SGLT2 inhibitors' mechanism of action would work just as well in people with type 1 diabetes.

This past week, Bristol-Myers Squibb and AstraZeneca, who have been jointly developing dapagliflozin, announced that an NDA (new drug application) has been accepted for review by the FDA, and that a MAA (marketing authorization application) has also been validated by the European Medicines Agency. Assuming that the data presented to the regulatory authorities is acceptable, we could see approval for dapagliflozin later this year.

One final point: nowhere on the Internet can I find the proposed brand name for dapagliflozin. Whatever they choose, I sure hope it is easier to say and spell than is dapagliflozin.