FDA Approves Dapagliflozin (Farxiga) for Type 2 Diabetes

The US Food and Drug Administration (FDA) has approved AstraZeneca and Bristol-Myers Squibb's dapagliflozin (Farxiga) for the treatment of type 2 diabetes.

It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus as monotherapy, as initial therapy with metformin, or as an add-on to other oral glucose-lowering agents, including metformin, pioglitazone, glimepiride, sitagliptin (Januvia, Merck), and insulin.

Dapagliflozin works by inhibiting sodium glucose cotransporter 2 (SGLT2) and blocking resorption of glucose in the kidney, leading to an increase in urinary glucose excretion and lowering of both plasma glucose levels and body weight.

Dapagliflozin is the second SGLT2 inhibitor to be licensed in the United States. The FDA cleared the first, canagliflozin (Invokana, Janssen Pharmaceuticals), for marketing in March 2013. FDA is expected to announce a decision on a third SGLT-2 inhibitor, empagliflozin (Boehringer Ingelheim/Lilly), by the end of March 2014.

Dapagliflozin is already approved in the 28 member states of the European Union, where it is known by the brand name Forxiga, and in Argentina, Australia, Brazil, Iceland, Mexico, Norway, and New Zealand.

FDA Requiring Several Postmarketing Studies

Dapagliflozin's safety and effectiveness were evaluated in 16 clinical trials involving more than 9400 patients with type 2 diabetes, showing improvement in HbA_1c. The most common side effects among those treated with dapagliflozin were genital fungal infections and urinary-tract infections.

Because a numeric increase in bladder cancer was seen with dapagliflozin in one of these trials, dapagliflozin is not recommended for patients with active bladder cancer or moderate to severe renal impairment.

The FDA is requiring the companies to perform several postmarketing studies, including one already under way called DECLARE-TIMI 58 in which more than 17,000 patients will be followed for 4 to 5 years to ascertain whether dapagliflozin is associated with increased risks for cardiovascular events, liver problems, or malignancies.

Other required postmarketing trials will further assess bladder cancer and the drug's effect in a pediatric population. The FDA is also requiring an enhanced pharmacovigilance program to monitor reports of liver problems and pregnancy outcomes.

The FDA had previously rejected dapagliflozin in January 2012, in part because of the breast- and bladder-cancer concerns. New data provided by Bristol-Myers Squibb at a December 2013 advisory committee hearing allayed those concerns in large part.

However, data from 2 new trials designed specifically to address CVD safety in high-risk diabetes patients raised new uncertainties about a possible increase in CV events.

Although the FDA's Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) voted 10 to 1 in favor of its licensure at the December hearing, panel members emphasized the importance of completion of DECLARE-TIMI.

Erica H. Brittain, PhD, a biostatistician at the National Institute for Allergy and Infectious Diseases, had voted against approval of dapagliflozin at an earlier EMDAC hearing held in 2011 but voted for it in December.

"Even though my official vote has changed, my feeling hasn't changed very much, because not much has changed since then… It's really critical that DECLARE get done. I'm voting contingent on the notion that it will be finished," she said at the time.

While also voicing caution about the safety data at the December hearing, Milton Packer, MD, the Gayle and Paul Stoffel Distinguished Chair in Cardiology and professor and chair of the department of clinical sciences at the University of Texas Southwestern Medical Center, Dallas, reminded the panel of dapagliflozin's advantages.

"It lowers hemoglobin A_1c, lowers blood pressure, and causes weight loss; all of these are all good things. My concern about CV safety and bladder cancer are still concerns, but we approve lots of drugs with uncertainties… DECLARE will absolutely be completed," he concluded.

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FDA Approves Dapagliflozin (Farxiga) for Type 2 Diabetes Treatment

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Miriam E. Tucker

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