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Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, has been approved for the treatment of type 2 diabetes with a requirement that the manufacturer conduct postmarketing studies that address risks associated with the drug, the Food and Drug Administration announced on Jan. 8.
Approval was based on the results of 16 clinical trials in more than 9,400 patients with type 2 diabetes, which found that treatment with the drug improved hemoglobin A1C, according to the statement. Dapagliflozin is the second sodium-glucose cotransporter 2 (SGLT2) inhibitor to be approved by the FDA; the first was canagliflozin (Invokana), approved in March 2013. These agents, taken orally, work by inhibiting SGLT2 that is expressed in the kidney, reducing renal glucose reabsorption, increasing urinary excretion of glucose, and reducing plasma glucose levels.
Dapagliflozin will be marketed as Farxiga by Bristol-Myers Squibb and AstraZeneca.
In the studies, the most common adverse events associated with treatment were genital fungal infections and urinary tract infections. Other adverse events included hypotension caused by dehydration, resulting in dizziness and/or fainting and reduced renal function, according to the FDA statement, which noted that "the elderly, patients with impaired renal function, and patients on diuretics to treat other conditions appeared to be more susceptible to this risk."
Approval came less than a month after a meeting in December, when the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-1 that the benefits of dapagliflozin outweighed its risks for improving glycemic control in adults with type 2 diabetes mellitus as an adjunct to diet and exercise. The panel, however, strongly recommended that cardiovascular safety, bladder cancer, and hepatotoxicity be monitored in treated patients after approval – which is reflected in the FDA’s list of required postmarketing studies.
The same panel had recommended against approval in 2011 because of concerns over the numerical increase in bladder and breast cancers and a case of possible drug-induced liver injury. The FDA did not approve dapagliflozin, requesting more safety data, and the companies resubmitted the application for approval with more safety data and analyses last year.
The postmarketing trials required by the FDA include a cardiovascular outcomes trial that will evaluate the cardiovascular risk of dapagliflozin in patients with a high risk of cardiovascular disease at baseline and a study evaluating the risk of bladder cancer in patients enrolled in that study. Another study will evaluate bladder tumor promotion effects of the drug in rodents; two studies will evaluate the pharmacokinetics, efficacy, and safety of dapagliflozin in pediatric patients; and an enhanced pharmacovigilance program will monitor reports of liver abnormalities and pregnancy outcomes in patients treated with dapagliflozin, the FDA said.
At the December 2013 panel meeting, Bristol-Myers Squibb said that enrollment in a cardiovascular outcomes study that will eventually enroll over 17,000 patients with type 2 diabetes and established cardiovascular disease or at least two cardiovascular risk factors had already begun in Europe, where dapagliflozin was already approved. That study is the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI-58) study.
