Antidiabetic agent - dapagliflozin

Another potential therapy for Type 2 diabetes is the inhibition of sodium-dependent glucose transporters, or SGLTs. Almost all of the glucose in the plasma that is filtered by the kidney is reabsorbed, and this is mediated by SGLT1 and SGLT2. This action prevents the glucose being excreted in the urine, but in diabetics who have too much glucose in their plasma, this is not ideal.

The majority of this action is a result of the action of SGLT2, and so if this could be inhibited, the theory is that it would normalise plasma glucose levels by increasing urinary excretion of glucose and stopping the renal reabsorption process. In addition, it is thought this inhibition would be unlikely to cause hypoglycaemia as it does not alter any of the normal glucose counter-regulatory mechanisms.

Numerous compounds that act in this way are being developed, and the furthest advanced of these is Bristol-Myers Squibb's dapagliflozin, which is being co-developed with AstraZeneca.¹ Several trials have been carried out, including one in which 47 patients who either had not had their diabetes treated with drugs or who were stable on metformin were given 5, 25 or 100mg once a day for 14 days, and the mean amount of glucose excreted in the urine over the 24 hours following the first dose increased with dose. Over the two weeks of the study, the levels of glucose excretion were stable, and the inhibition of glucose re-absorption was greater at the end of the 14 days.²

A longer randomised trial was carried out in 389 patients, all of whom were treatment naïve. They were given 2.5, 5, 10, 20 or 50mg of dapagliflozin once a day for 12 weeks, or extended release metformin, or placebo. Each dose of the new agent gave better glycaemic control than placebo, and the fasting plasma glucose levels reduced more with increasing doses. It had no effect on insulin concentrations. Various other trials are under way, looking at dapagliflozin both alone and in combination with other agents.³