Dapaglifozin, a novel investigational antidiabetic agent that increases excretion of glucose in urine, independent of insulin secretion or insulin action, appeared safe and effective in early clinical trials.
In a randomized double-blind study, dapagliflozin in each of three doses significantly increased the excretion of excess glucose in urine compared with placebo, reported Bernard Komoroski, PharmD., Ph.D., an investigator for drug-maker Bristol-Myers Squibb, at the American Diabetes Association meeting.
The drug seemed to be well tolerated. Although there were two case of hypoglycemia, both occurred in patients also taking metformin (Glucophage) after a long fast, Dr. Komoroski said.
Dapagliflozin (BMS-512148), developed jointly by Bristol-Myers Squibb and AstraZeneca, is the first drug to reach clinical trials in a new category of agents, called selective inhibitors of the sodium-glucose uptake transporter 2 (SGLT2).
The novel action in this class involves inhibition of glucose reabsorption in the proximal renal tubule, although glucose reabsorption still occurs farther downstream in the kidney, Dr. Komoroski said.
In animal studies, SGLT2 inhibition activity modulated reabsorption of glucose by the kidney, causing the excess glucose to be excreted in urine. The end result is a decrease in serum glucose independent of either insulin secretion or insulin action.
The investigators conducted a phase II study in 47 adults with type 2 diabetes. The patients, ages 18 to 77, were all either naïve to antidiabetic agents, or on a stable dose of metformin for at least four weeks before randomization.
Baseline glycosylated hemoglobin (HbA1c) levels ranged from 6% to 10%, and the patients had fasting serum glucose levels of 240 mg/dL or less.
The participants were randomized to receive either placebo (eight patients) or dapagliflozin at doses of 5 mg (11 patients), 25 mg (12 patients), or 100 mg (16 patients) once daily for two weeks. The drugs were taken in addition to the patients’ stable metformin dose or diet. The study was conducted with patients staying in an inpatient clinical research unit.
The primary outcomes were safety and tolerability of multiple doses of dapagliflozin. Secondary endpoints included fasting serum glucose, and post-challenge glucose excursions.
The authors found that on day 13, the fasting serum glucose was significantly reduced in participants receiving dapagliflozin with or without metformin, compared with levels measured two days before they received their first doses.
Among patients on the 5 mg dose there was a 14.5% reduction in fasting serum glucose (P<0.05). The reduction was 17.3% in the 25 mg group (P<0.05) and 21.9% in the 100-mg group (P<0.001). In contrast, patients on placebo with or without metformin had a 6.3% decrease in fasting serum glucose. The mean amount of glucose eliminated in the urine within 24 hours of the first dose was 45.2 g in the 5-mg group, 75.3 g in the 25-mg dose group, and 81.3 g in the 100-mg dose group.
Dapagliflozin also significantly reduced the response to a 75 g oral glucose tolerance test (P<0.001). There were no apparent changes in body weight, urine volume, or urinary sodium excretion, Dr. Komoroski said.
Adverse events included hypoglycemia in two patients, both on metformin and dapagliflozin, and two vulvovaginal infections, one occurring in a patient on dapagliflozin alone, and the other in a patient on the SGLT2 inhibitor plus metformin.
American Diabetes Association 2007 Scientific Sessions: oroski B et al. “Dapagliflozin (BMS-512148), 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.” Abstract 0188, presented June 24