First Phase II Short-Term Study On Dapagliflozin Shows Promising Results

Armen Hareyan's picture


In a 14-day, Phase IIa study of the safety profile of multiple doses of the investigational compound dapagliflozin.

Dapagliflozin i a selective inhibitor of the Sodium-Glucose Transporter 2 administered alone or concomitantly with metformin in subjects with Type 2 diabetes.

No discontinuations due to adverse events and no serious adverse events were reported. The study, presented this week at the annual meeting of the American Diabetes Association, also reported that dapagliflozin, in development by Bristol-Myers Squibb Company and AstraZeneca (NYSE: AZN), statistically significantly reduced fasting serum glucose (FSG) and post challenge glucose excursion in subjects with Type 2 diabetes.

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. 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.


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.

There were no discontinuations due to adverse events and no serious adverse events were reported. Adverse events included two events of hypoglycemia in subjects receiving dapagliflozin co-administered with metformin. There were two events of vulvovaginal infection in the study (one subject receiving dapagliflozin alone and one subject receiving dapagliflozin+metformin). Adverse events occurred with similar frequency in subjects receiving dapagliflozin or placebo. The most frequently reported adverse events were: constipation (n=7; 1/19 on dapagliflozin+metformin, 3/20 on dapagliflozin alone, 2/6 on placebo+metformin, 1/2 on placebo alone), nausea (n=5; 4/19 on dapagliflozin+metformin, 1/6 on placebo+metformin), and diarrhea (n=4; 3/19 on dapagliflozin+metformin, 1/6 on placebo+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).

Type 2 diabetes is the most common form of diabetes, accounting for approximately 90-95 percent of diabetes cases. Having Type 2 diabetes increases the risk of many serious complications, including heart disease or stroke, high blood pressure, amputation (particularly legs), blindness, nerve damage, and kidney failure. The risk of stroke and the rate of deaths due to heart disease are two to four times higher among people with diabetes, and about 65 percent of deaths among people with diabetes are due to heart disease and stroke.

The A1C test (also known as hemoglobin A1C) is used primarily to monitor the glucose control of diabetics over time. The goal of those with diabetes is to keep their blood glucose levels as close to normal as possible. This helps to minimize the complications caused by chronically elevated glucose levels, such as progressive damage to body organs like the kidneys, eyes, cardiovascular system, and nerves. The A1C test gives apicture of the average amount of glucose in the blood over the last few months. It can help a patient and his doctor know if the measures they are taking to control the patient's diabetes are successful or need to be adjusted.

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. Thecompound 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.