Investigational diabetes drug associated with improved glycemic control

45th Annual Meeting of the European Association for the Study of Diabetes

Two studies presented today suggest that dapagliflozin, an investigational oral antidiabetic agent, appears safe and efficacious for patients with inadequately controlled type 2 diabetes.

The once-daily oral agent (Bristol-Myers Squibb, AstraZeneca) is designed to decrease hyperglycemia by selectively inhibiting glucose reabsorption by renal sodium-glucose transporter-2.

Late-stage clinical study results demonstrated a beneficial effect of dapagliflozin as an add-on to metformin. Cliff Bailey, PhD, FRCP, FRCPath, professor of clinical science at Aston University in Birmingham, United Kingdom, presented data from Study 014ST, a phase-3, randomized, double-blind, placebo controlled, multicenter trial. Patients with type 2 diabetes (n=546) and inadequate glycemic control were randomly assigned to once-daily dapagliflozin (2.5 mg, 5 mg, 10 mg) or placebo plus metformin.

Bailey said, at all doses studied, the drug was associated with significant reductions in HbA1c levels — the primary endpoint — after 24 weeks of treatment. More patients assigned to dapagliflozin achieved a target HA1c <7% and greater reductions in fasting plasma glucose compared with patients assigned to placebo.

Weight loss was “continuous and progressive with dapagliflozin,” according to the researchers.

Changes in blood pressure ranged from –3.1 mm Hg to –5.9 mm Hg for systolic BP and –2.1 mm Hg to –2.7 mm Hg for diastolic BP with dapagliflozin, compared with –0.3 mm Hg for systolic BP and –0.4 mm Hg for diastolic BP with placebo.

Adverse events were generally balanced across all groups, Bailey said. Rates of urinary tract infections were similar or lower with dapagliflozin (2.5 mg, 4.4%; 5 mg, 7.3%; 10 mg, 8.1%) compared with placebo (8%). However, rates of genital infections were higher with dapagliflozin vs. placebo (2.5 mg, 8%; 5 mg, 13.1%; 10 mg, 8.9%; placebo, 5.1%). Researchers noted “no meaningful changes” in markers for renal impairment or increased serum creatinine.

Finally, rates of hypoglycemia were similar in both groups, and ranged from 2.2% to 3.7% with dapagliflozin to 2.9% with placebo.

Dapagliflozin for insulin-resistant diabetes

In a second study, researchers presented 12-week data on dapagliflozin in patients who were poorly controlled with insulin plus oral antidiabetes agents (metformin and/or thiazolidinediones).

The multicenter study included a small preliminary cohort (n=4) who received 20 mg dapagliflozin, baseline oral antidiabetes agents and 50% of baseline insulin dose to monitor glycemic parameters with reduced insulin dosing. A larger primary cohort (n=71) was randomly assigned once-daily dapagliflozin (10 mg or 20 mg) or double-blind placebo, plus baseline oral antidiabetes agents and 50% of baseline insulin.

Twelve weeks of treatment revealed lower HbA1c levels, postprandial glucose and weight with dapagliflozin compared with placebo. More than 65% of patients assigned to either dose of dapagliflozin experienced a decrease in HbA1c of 0.5% or more vs. 15.8% of patients assigned placebo.

Blood pressure also decreased in both dapagliflozin groups compared with an increase in the placebo group.

Adverse events were similar to those reported in the aforementioned study, and included pollakiuria, back pain, nasopharyngitis, nausea, headache and upper respiratory tract infection. Hypoglycemia was reported in seven patients assigned to the 10-mg dose, six patients assigned the 20-mg dose and three patients assigned placebo; the only episode of major hypoglycemia was in the placebo group.

“In insulin-resistant patients who had insulin reduced by 50%, dapagliflozin was well tolerated and improved glycemic control and lowered weight more than placebo,” the researchers concluded.

Both studies were sponsored by Bristol-Myers Squibb and AstraZeneca. – by Katie Kalvaitis

It is fascinating that glycosuria, long considered a sign of hyperglycemia of modest adverse consequence by virtue of its osmotic diuretic effect, might offer benefit as a mechanism of reducing glycemia in a non-insulin-dependent fashion, with the additional advantage of causing calorie loss with consequent weight benefit. The potential negatives of urogenital tract infection need full evaluation, but this may prove an important new therapeutic approach for diabetes.

– Zachary T. Bloomgarden, MD

Endocrine Today Editorial Board member

For more information:

Bailey CJ. OP 29 #169.

Wilding JPH. OP 29 #170. Both presented at: the 45th Annual Meeting of the European Association for the Study of Diabetes; Sept. 29-Oct. 2, 2009; Vienna.