Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes.
OBJECTIVE
Dapagliflozin, a novel inhibitor of renal sodium-glucose cotransporter 2, allows an insulin-independent approach to improve type 2 diabetes hyperglycemia. In this multiple-dose study we evaluated the safety and efficacy of dapagliflozin in type 2 diabetic patients.


METHODS
Type 2 diabetic patients were randomly assigned to one of five dapagliflozin doses, metformin XR, or placebo for 12 weeks. The primary objective was to compare mean change from baseline in A1C. Other objectives included comparison of changes in fasting plasma glucose (FPG), weight, adverse events, and laboratory measurements.


RESULTS
After 12 weeks, dapagliflozin induced moderate glucosuria (52-85 g urinary glucose/day) and demonstrated significant glycemic improvements versus placebo (DeltaA1C -0.55 to -0.90% and DeltaFPG -16 to -31 mg/dl). Weight loss change versus placebo was -1.3 to -2.0 kg. There was no change in renal function. Serum uric acid decreased, serum magnesium increased, serum phosphate increased at higher doses, and dose-related 24-h urine volume and hematocrit increased, all of small magnitude. Treatment-emergent adverse events were similar across all groups.


CONCLUSIONS
Dapagliflozin improved hyperglycemia and facilitates weight loss in type 2 diabetic patients by inducing controlled glucosuria with urinary loss of approximately 200-300 kcal/day. Dapagliflozin treatment demonstrated no persistent, clinically significant osmolarity, volume, or renal status changes.
List
James F
JF
Global Clinical Research, Bristol-Myers Squibb, Princeton, New Jersey, USA. james.list@bms.com
Woo
Vincent
V
Morales
Enrique
E
Tang
Weihua
W
Fiedorek
Fred T
FT
D000293:Adolescent; D000328:Adult; D000368:Aged; D001559:Benzhydryl Compounds; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004232:Diuretics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D005960:Glucosides / Q000627:therapeutic use*; D006442:Glycated Hemoglobin / Q000187:drug effects / Q000378:metabolism; D006029:Glycosuria / Q000139:chemically induced; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D010919:Placebos; D051247:Sodium-Glucose Transport Proteins / Q000037:antagonists & inhibitors*; D015431:Weight Loss; D055815:Young Adult
D001559:Benzhydryl Compounds; D001786:Blood Glucose; D004232:Diuretics; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; D010919:Placebos; D051247:Sodium-Glucose Transport Proteins; C529054:dapagliflozin