Dapagliflozin, a Selective SGLT2 Inhibitor, Improves Glucose Homeostasis in Normal and Diabetic Rats

  1. Songping Han1,
  2. Deborah L. Hagan1,
  3. Joseph R. Taylor1,
  4. Li Xin1,
  5. Wei Meng2,
  6. Scott A. Biller23,
  7. John R. Wetterau14,
  8. William N. Washburn2 and
  9. Jean M. Whaley1
  1. 1Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, New Jersey
  2. 2Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, New Jersey
  3. 3Novartis Institute for Biomedical Research, Cambridge, Massachusetts
  4. 4Cerenis Therapeutics, Ann Arbor, Michigan
  1. Corresponding author: Jean M. Whaley, Bristol-Myers Squibb Research and Development, 311 Pennington Rocky Hill Rd., Mail Code 21-2.01, Pennington, NJ 08534. E-mail: jean.whaley{at}bms.com

Abstract

OBJECTIVE—The inhibition of gut and renal sodium-glucose cotransporters (SGLTs) has been proposed as a novel therapeutic approach to the treatment of diabetes. We have identified dapagliflozin as a potent and selective inhibitor of the renal sodium-glucose cotransporter SGLT2 in vitro and characterized its in vitro and in vivo pharmacology.

RESEARCH DESIGN AND METHODS—Cell-based assays measuring glucose analog uptake were used to assess dapagliflozin's ability to inhibit sodium-dependent and facilitative glucose transport activity. Acute and multi-dose studies in normal and diabetic rats were performed to assess the ability of dapagliflozin to improve fed and fasting plasma glucose levels. A hyperinsulinemic-euglycemic clamp study was performed to assess the ability of dapagliflozin to improve glucose utilization after multi-dose treatment.

RESULTS—Dapagliflozin potently and selectively inhibited human SGLT2 versus human SGLT1, the major cotransporter of glucose in the gut, and did not significantly inhibit facilitative glucose transport in human adipocytes. In vivo, dapagliflozin acutely induced renal glucose excretion in normal and diabetic rats, improved glucose tolerance in normal rats, and reduced hyperglycemia in Zucker diabetic fatty (ZDF) rats after single oral doses ranging from 0.1 to 1.0 mg/kg. Once-daily dapagliflozin treatment over 2 weeks significantly lowered fasting and fed glucose levels at doses ranging from 0.1 to 1.0 mg/kg and resulted in a significant increase in glucose utilization rate accompanied by a significant reduction in glucose production.

CONCLUSIONS—These data suggest that dapagliflozin has the potential to be an efficacious treatment for type 2 diabetes.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 20 March 2008. DOI: 10.2337/db07-1472.

  • Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1472.

  • All of the work described herein was conducted in its entirety at Bristol-Myers Squibb.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted March 18, 2008.
    • Received October 15, 2007.
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  1. Diabetes vol. 57 no. 6 1723-1729
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