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In the United States, more than 90% of diabetes cases diagnosed are type 2 diabetes, and prevalence of this form of the disease is approximately 24 million. Poor glycemic control in the long term is linked to greater risks for cardiovascular disease, blindness, neuropathy, renal damage, and other serious complications.
The mechanism of action of dapagliflozin is as an inhibitor of sodium glucose cotransporter 2 (SGLT2). By blocking resorption of glucose in the kidney, dapagliflozin causes increased urinary glucose excretion, resulting in reduction of plasma glucose levels and body weight. The first SGLT2 inhibitor to be licensed in the United States was canagliflozin, in March 2013, and dapagliflozin is the second.
The US Food and Drug Administration (FDA) has approved 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), and insulin.
Dapagliflozin works by inhibiting 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), for marketing in March 2013. The agency is expected to announce a decision on a third SGLT-2 inhibitor, empagliflozin, 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
The safety and effectiveness of dapagliflozin were evaluated in 16 clinical trials involving more than 9400 patients with type 2 diabetes, showing improvement in hemoglobin A1c (HbA1c) levels. The most common adverse 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 underway called DECLARE-TIMI 58 (Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events) in which more than 17,000 patients will be observed 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 at a December 2013 advisory committee hearing allayed those concerns in large part.
However, data from 2 new trials designed specifically to address cardiovascular disease safety in high-risk diabetes patients raised new uncertainties about a possible increase in cardiovascular 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 the advantages of dapagliflozin.
"It lowers hemoglobin A1c, lowers blood pressure, and causes weight loss; all of these are all good things. My concern about CV [cardiovascular] safety and bladder cancer are still concerns, but we approve lots of drugs with uncertainties... DECLARE will absolutely be completed," he concluded.
More information on the approval of dapagliflozin is available on the FDA Web site.
