New Class of Diabetes Drugs Effective in Controlling Blood Glucose

The data were from a double-blind, placebo-controlled, randomized, parallel-group study of 47 subjects with an established diagnosis of Type 2 diabetes (ages 18-77) who were either drug-naive or on a stable dose of metformin for at least 4 weeks prior to randomization with hemoglobin A1C levels between 6 and 10 percent with a FSG of less than or equal to 240 mg/dL.  Subjects were randomized to receive either placebo (n=8) or dapagliflozin 5 mg (n=11), 25 mg (n=12), or 100 mg (n=16) once daily for 14 days in addition to their stable metformin dose and/or diet alone in an in-patient clinical research unit. 

The primary endpoint of the study was to assess both the safety and tolerability profiles of multiple doses of dapagliflozin in subjects with Type 2 diabetes.  The secondary endpoints of the study included assessing the fasting serum glucose and post challenge glucose excursion. 

On Day 13, the FSG was significantly reduced in participants receiving dapagliflozin with or without metformin as compared to their FSG levels two days prior to first dose:  -14.5 percent (p-value less than 0.05), -17.3 percent (p-value less than 0.05), -21.9 percent (p-value less than 0.001) for dapagliflozin at 5 mg, 25 mg and 100 mg, respectively.  FSG was reduced by -6.3 percent in participants receiving placebo with or without metformin.

In a second presentation this week - "Dapagliflozin, A Selective SGLT2 Inhibitor, Improves Glucose Homeostasis in Normal and Diabetic Rats" by Jean Whaley, Sc.D., Director, Diabetes Drug Discovery, Bristol-Myers Squibb, the effect of dapagliflozin on glucose homeostasis in normal and diabetic rats was reported. In diabetic rats, dapagliflozin acutely induced renal glucose excretion at doses ranging from 0.01-1.0 mg/kg of body weight without inducing hypoglycemia.  Additionally, as early as two hours after a single oral dose, there was a statistically significant reduction in plasma glucose levels in diabetic rats treated with dapagliflozin compared to untreated diabetic rats at doses of 0.1 mg/kg and 1.0 mg/kg (-101 mg/dL and -128 mg/dL), respectively (p-value less than 0.0001 at both doses).

Dapagliflozin (previously referred to as BMS-512148) is an investigational drug under development by Bristol-Myers Squibb and AstraZeneca.  It is being studied as a once-daily oral antidiabetic. The compound has a novel proposed mechanism of action, selectively inhibiting sodium glucose cotransporter 2 (SGLT2) versus SGLT1, decreasing reabsorption of glucose by the kidneys without affecting SGLT1 in the GI tract.  Dapagliflozin has a C-glucoside chemical structure, which prolongs the pharmacokinetic half-life and duration of action.  Dapagliflozin is currently in Phase IIb development.

Glucose is normally filtered by the kidney, but nearly all of it is reabsorbed in the proximal tubule by SGLT2, which is located almost exclusively in the kidney.  For patients with diabetes, retention of excess glucose by this pathway contributes to persistent high blood glucose levels, or hyperglycemia.  Inhibiting SGLT2 activity modulates reabsorption of glucose in the kidney, resulting in excretion of glucose in the urine.  Research, in animal models, indicates that modulation of renal glucose absorption with SGLT2 inhibition reduces blood glucose independent of insulin secretion or action.

Source: Diabetes In Control: American Diabetes Association 2007 Scientific Sessions; The presentation, "Dapagliflozin, a Selective Inhibitor of the Sodium-Glucose Uptake Transporter 2 (SGLT2), Reduces Fasting Serum Glucose and Glucose Excursion in Type 2 Diabetes Mellitus Patients Over 14 Days", was presented by Bernard Komoroski, PharmD, Ph.D., Senior Research Investigator, Bristol-Myers Squibb.