Dapagliflozin, a Selective SGLT2 Inhibitor, Improves Glucose Homeostasis in Normal and Diabetic Rats
Songping Han 1 ,
Deborah L. Hagan 1 ,
Joseph R. Taylor 1 ,
Li Xin 1 ,
Wei Meng 2 ,
Scott A. Biller 2 3 ,
John R. Wetterau 1 4 ,
William N. Washburn 2 and
Jean M. Whaley 1
1 Metabolic Diseases Biology, Bristol-Myers Squibb Research and Development, Princeton, New Jersey
2 Metabolic Diseases Chemistry, Bristol-Myers Squibb Research and Development, Princeton, New Jersey
3 Novartis Institute for Biomedical Research, Cambridge, Massachusetts
4 Cerenis Therapeutics, Ann Arbor, Michigan
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.
EC50, half-maximal response
FPG, fasting plasma glucose
SGLT, sodium-glucose cotransporter
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.
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Dapagliflozin, a Selective SGLT2 Inhibitor, Improves Glucose Homeostasis in Normal and Diabetic Rats

10.2337/db07-1472