SGLT2 inhibitor has durable antihyperglycemic effect, genital infections more common

June 28, 2011

Dapagliflozin, an investigational selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, has durable efficacy in controlling blood glucose as add-on therapy to metformin with a low risk of hypoglycemia, said Clifford J. Bailey, MD, Professor of Clinical Science at Aston University in Birmingham, UK.

Dapagliflozin, an investigational selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, has durable efficacy in controlling blood glucose as add-on therapy to metformin with a low risk of hypoglycemia, said Clifford J. Bailey, MD, Professor of Clinical Science at Aston University in Birmingham, UK.
     “This is an entirely new approach to the treatment of diabetes; to remove the excess blood glucose by increasing the elimination of glucose in the urine,” said Bailey. “The key advantage here is that the mechanism is not dependent on either the amount of insulin secreted or the action of insulin, whereas most other treatments are dependent on one or the other of those 2 issues, which are major pathogenic issues in type 2 diabetes.”
     He presented data from an extension study in which 546 patients with type 2 diabetes inadequately controlled on metformin alone were randomized to placebo or 1 of 3 dosages of dapagliflozin (2.5, 5.0, or 10.0 mg/day). Those who completed the 24-week study were eligible to continue on their originally assigned blinded treatment for an additional 78 weeks (total of 102 weeks).
     Fewer patients assigned to placebo completed the extension phase than those assigned to dapagliflozin (63.5% vs. 68.3% to 79.8%, depending on the dose), due mainly to more patients taking placebo discontinuing for lack of efficacy.
     The 10-mg dose of dapagliflozin achieved a 0.78% lowering of glycosylated hemoglobin (HbA1c) after 102 weeks, with the 2.5- and 5-mg doses achieving HbA1c reductions of 0.48% and 0.58%, respectively. “There was a concomitant reduction of fasting plasma glucose, and at the same time there was also a reduction of body weight,” said Bailey. No serious hypoglycemic events were reported in any group.
     “There was a small but what I consider manageable increase in genital and urinary tract infections…but only 1 individual in this trial of 546 discontinued because of a recurrent urinary tract issue, and 1 discontinued because of genital infection,” he said. Events suggestive of genital infection occurred in 11.7% to 14.6% of patients in the dapagliflozin groups compared with 5.1% in the placebo group.
     One patient receiving dapagliflozin developed transitional cell bladder cancer, and 1 other experienced breast cancer. The total body of evidence with dapagliflozin shows no evidence of carcinogenicity, mutagenicity, or teratogenicity, said Bailey, and the total number of cancers emerging has not been different between placebo and dapagliflozin. He added that trials of other agents that caused weight loss have also found excess cancers, but weight loss itself may make certain tumors (eg, breast) easier to detect, he said.
     “In principle, this treatment approach [SGLT2 inhibition] should be a very flexible add-on to other treatments, more or less, at any stage in the natural history of the disease, and…with any of the other treatments that are available providing that the patients have adequate renal function and don’t have any reactions in the form of infections in the urinary tract or genitalia,” said Bailey.