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CME/CE

FDA Approval: Dapagliflozin for Type 2 Diabetes

  • Authors: News Author: Miriam E. Tucker
    CME Author: Laurie Barclay, MD
  • CME/CE Released: 1/27/2014
  • THIS ACTIVITY HAS EXPIRED
  • Valid for credit through: 1/27/2015
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Target Audience and Goal Statement

This article is intended for primary care clinicians, endocrinologists, diabetologists, and other specialists who care for patients with type 2 diabetes.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  1. Describe a new FDA approval of dapagliflozin for the treatment of type 2 diabetes.
  2. Identify data underlying a new FDA approval of dapagliflozin for the treatment of type 2 diabetes.
  3. List adverse effects associated with use of dapagliflozin for the treatment of type 2 diabetes.


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Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.


Author(s)

  • Miriam E. Tucker

    Miriam E. Tucker is a freelance writer for Medscape.

    Disclosures

    Disclosure: Miriam E. Tucker has disclosed no relevant financial relationships.

Editor(s)

  • Amy Nadel

    Disclosures

    Disclosure: Amy Nadel has disclosed no relevant financial relationships.

CME Author(s)

  • Laurie Barclay, MD

    Freelance writer and reviewer, Medscape, LLC

    Disclosures

    Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

  • Yullee C. Chui

    Program Manager, Medscape, LLC

    Disclosures

    Disclosure: Yullee C. Chui has disclosed no relevant financial relationships.

Nurse Planner

  • Amy Bernard, MS, BSN, RN-BC

    Lead Nurse Planner, Medscape, LLC

    Disclosures

    Disclosure: Amy Bernard, MS, BSN, RN-BC, has disclosed no relevant financial relationships.


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CME/CE

FDA Approval: Dapagliflozin for Type 2 Diabetes

Authors: News Author: Miriam E. Tucker CME Author: Laurie Barclay, MDFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

CME/CE Released: 1/27/2014

Valid for credit through: 1/27/2015

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Clinical Context

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.

Study Synopsis and Perspective

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.

Clinical Implications

  • The FDA has approved dapagliflozin for the treatment of adults with type 2 diabetes, as an adjunct to diet and exercise, to improve glycemic control. It may be used as monotherapy; as initial treatment in combination with metformin; or in combination with pioglitazone, glimepiride, sitagliptin, insulin, or other drugs that lower glucose levels.
  • A total of 16 safety and efficacy trials enrolling more than 9400 patients with type 2 diabetes showed improvement in HbA1c levels associated with dapagliflozin. The FDA is requiring the drug manufacturers to conduct several postmarketing studies, to carry out an enhanced pharmacovigilance program, and to complete DECLARE-TIMI to assess safety concerns.
  • The most common adverse effects associated with dapagliflozin were genital fungal infections and urinary tract infections. A numeric increase in bladder cancer rates occurred with dapagliflozin in one of the clinical trials. Patients with active bladder cancer or moderate to severe renal impairment should not take dapagliflozin. Required postmarketing trials will evaluate whether dapagliflozin is associated with increased risks for cardiovascular events, liver problems, and bladder or other malignancies.

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