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Abstract

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Objective:

To review the literature and describe the pharmacologic, pharmacokinetic, and pharmacodynamic properties; clinical safety; and efficacy of dapagliflozin, a new drug currently under review by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes.

Data Sources:

A MEDLINE (1995-November 2011) and ClinicalTrials.gov search was conducted using the terms dapagliflozin, sodium-glucose cotransporter 2 inhibitor, and SGLT2 inhibitor. Reference citations from publications identified were also reviewed.

Study Selection and Data Extraction:

All English-language studies, including abstracts, evaluating dapagliflozin use in humans were included in this review.

Data Synthesis:

Dapagliflozin is the first-in-class oral sodium-glucose cotransporter 2 (SGLT2) inhibitor that represents a new potential therapeutic option for the treatment of type 2 diabetes mellitus. Its mechanism of action is insulin- and insulin-sensitivity independent. Preliminary data suggest that dapagliflozin decreases hemoglobin A_1c, fasting plasma glucose, and postprandial plasma glucose, while also promoting weight loss. In Phase 1, 2, and 3 clinical trials, dapagliflozin has exhibited a safety and tolerability profile similar to that of placebo.

Conclusions:

Dapagliflozin is a novel oral antihyperglycemic agent that has demonstrated promise as monotherapy and as synergistic combination therapy with currently available agents in Phase 3 clinical trials. On January 19, 2012, the FDA issued a complete response letter to AstraZeneca and Bristol-Myers Squibb regarding the new drug application for dapagliflozin. The FDA is requesting additional clinical data—from ongoing studies and potentially new clinical trials—to better describe the risk-benefit profile of the drug. Both manufacturers remain committed to the development of dapagliflozin, and there are currently 8 Phase 3 trials ongoing. Dapagliflozin has the potential to be the next new oral agent in the diabetes drug armamentarium.

Keywords

dapagliflozin SGLT2 inhibitor sodium-glucose cotransporter 2 inhibitor type 2 diabetes mellitus

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References

WebMD Diabetes Health Center. World diabetes: 366 million cases and counting. http://diabetes.webmd.com/news/20110914/world-diabetes-366-million-cases-and-counting (accessed 2011 Nov 14).

National diabetes fact sheet, 2011. Centers for Disease Control and Prevention. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf (accessed 2011 Nov 14).

Centers for Disease Control and Prevention. Number of Americans with diabetes expected to double or triple by 2050. http://www.cdc.gov/media/pressrel/2010/r101022.html (accessed 2011 Nov 14).

United Kingdom Prospective Diabetes Study (UKPDS). Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ 1995; 310:83–8.

UK Prospective Diabetes Study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. UK Prospective Diabetes Study (UKPDS) Group. Diabetes 1995; 44:1249–58.

Ganong

. Formation and excretion of urine. In: Review of medical physiology. 22nd ed. New York: Lange Medical Publishing, 2005: 699–734.

Deetjen

, von Baeyer

, Drexel

. Renal glucose transport. In: Seldin

, Giebisch

eds. The kidney: physiology and pathophysiology. 2nd ed. New York: Raven Press, Ltd., 1992: 2873–88.

Wright

. Renal Na+-glucose cotransporters. Am J Physiol Renal Physiol 2001; 280:F10–8.

Wright

, Turk

. The sodium/glucose cotransport family SLC5. Eur J Physiol 2004; 447:510–8.

10.

van den Heuvel

, Assink

, Willemsen

, Monnens

. Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2). Hum Genet 2002; 111:544–7.

11.

Bristol-Myers Squibb Company, AstraZeneca. NDA 202293 Dapagliflozin: Endocrinologic & Metabolic Advisory Committee background document. Bristol-Myers Squibb, AstraZeneca July 13, 2011. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM262996.pdf (accessed 2011 Nov 14).

12.

Kasichayanula

, Liu

, Zhang

, Pfister

, LaCreta

, Boulton

. Influence of hepatic impairment on the pharmacokinetics and safety profile of dapagliflozin: an open-label, parallel-group, single-dose study. Clin Ther 2011; 33:1798–808.

13.

Kasichayanula

, Chang

, Hasegawa

. Pharmacokinetics and pharmacodynamics of dapagliflozin, a novel selective inhibitor of sodium-glucose co-transporter type 2, in Japanese subjects without and with type 2 diabetes mellitus. Diabetes Obes Metab 2011; 13:357–65.

14.

Komoroski

, Vachharajani

, Boulton

. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Ther 2009; 85:520–6.

15.

Kasichayanula

, Liu

, Shyu

. Lack of pharmacokinetic interaction between dapagliflozin, a novel sodium-glucose transporter 2 inhibitor, and metformin, pioglitazone, glimepiride or sitagliptin in healthy subjects. Diabetes Obes Metab 2011; 13:47–54.

16.

Komoroski

, Vachharajani

, Feng

, Li

, Kornhauser

, Pfister

. Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes. Clin Pharmacol Ther 2009; 85:513–9.

17.

List

, Woo

, Morales

, Tang

, Fiedorek

. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 2009; 32:650–7.

18.

Wilding

JPH

, Norwood

, T'joen

, Bastien

, List

, Fiedorek

. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus sensitizers: applicability of a novel insulin-dependent treatment. Diabetes Care 2009; 32:1656–62.

19.

Ferrannini

, Ramos

, Salsali

, Tang

, List

. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise. Diabetes Care 2010; 33:2217–24.

20.

National Institutes of Health. ClinicalTrials.gov. http://clinicaltrials.gov/ct2/results?term=dapagliflozin+monotherapy (accessed 2011 Nov 14).

21.

Nauck

, Del Prato

, Meier

. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011 Aug 4. (Epub ahead of print).

22.

Bailey

, Gross

, Pieters

, Bastien

, List

. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010; 375:2223–33.

23.

Strojek

, Yoon

, Hruba

, Elze

, Langkide

, Parikh

. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomised, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab 2011; 13:928–38.

24.

Obermeier

, Yao

, Khanna

. In vitro characterization and pharmacokinetics of dapagliflozin (BMS-512148), a potent sodium-glucose cotransporter type II inhibitor, in animals and humans. Drug Metab Dispos 2010; 38:405–14.

Dapagliflozin for the Treatment of Type 2 Diabetes

Abstract

Objective:

Data Sources:

Study Selection and Data Extraction:

Data Synthesis:

Conclusions:

Keywords

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References