Sodium-glucose transporter 2 (SGLT-2) inhibitors

There are currently seven classes of antidiabetic agents for the treatment of type 2 diabetes (indeed, eight if you include bromocriptine, which has FDA approval for this use) but this is about to change with the launch of dapagliflozin which is expected later this year. ‘Dapa’ was given its European licence in April 2012 and is the first of a class of drugs which inhibit the action of the sodium-glucose transporter 2 (SGLT-2); three more are in development.

SGLT-2 is predominantly found in the proximal tubules of the kidney where it is responsible for the majority of glucose reabsorption from the glomerular filtrate. Blocking its action promotes glycosuria and is an entirely novel way of reducing blood glucose levels. In trials, once daily, oral administration of dapa (10mg OD) achieves an HbA1c reduction of ~0.8% (typical of add-on therapies) but with the added benefits of weight loss (around 3Kg) and a reduction in systolic blood pressure.

The drug is generally well tolerated but there is (as might be anticipated) an increase in genital (thrush) and urinary tract infection. The FDA has delayed licensing in the US on the basis of a ‘signal’ of increased bladder and breast cancer risk, but the numbers are small and I suspect these concerns will turn out to be unfounded.

One exciting aspect of the SGLT-2 mechanism of action is the potential for use with insulin, and so for use in both type 1 and type 2 diabetes, especially where weight is an issue. Whether this will be sanctioned by NICE remains to be seen, and the drug will have to navigate its way through a Single Technology Appraisal, planned for 2013….

Professor Steve Bain