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EASD: New First in Class Drug Effective in Phase III Trial

Posted: Wednesday, October 07, 2009

An investigational drug targeting an insulin-independent pathway in Type 2 diabetes produced early and substantial reductions in blood glucose and body weight in a phase III study.

After 24 weeks of treatment, glycated hemoglobin levels declined from 0.7% to 0.8% with dapagliflozin, an inhibitor of renal sodium-glucose co-transporter 2 (SGLT2). That compared to a decline of 0.3% among patients in a placebo group (P<0.05), according to Cliff Bailey, PhD, of Aston University in Birmingham, U.K..

Patients receiving the drug also lost 3 to 4 kg of body weight, as opposed to less than 2 kg with placebo (P<0.05).

SGLT2 is a key molecule in the reabsorption of glucose in the kidneys, where it is put back into circulation, Bailey explained. Inhibiting it forces the kidneys instead to put glucose into urine where it is excreted, thereby lowering blood glucose.

Dapagliflozin was the first SGLT2 inhibitor to reach clinical testing, and is now the first for which phase III data have been reported.

In the current trial, 546 patients with Type 2 diabetes poorly controlled with metformin were randomized to three doses of dapagliflozin (2.5, 5 or 10 mg once daily) or placebo in addition to their previous doses of metformin.

Mean HbA1c levels at baseline were 8.1% and mean metformin doses ranged from about 1,800 to 1,900 mg/day in the four groups.

About one-quarter of each dapagliflozin group had at least a 5% decrease in body weight, compared with 6% of the placebo group who lost that much, Bailey said. However, corresponding data on the proportion of patients meeting HbA1c targets were not available.

Bailey did report on a variety of other outcomes, all expressed as mean change from baseline:

    * Diastolic blood pressure: -2.1 to -5.1 mm Hg for dapagliflozin, -0.1 mm Hg for placebo (P not reported)
    * Fasting plasma glucose: -17.8 to -23.5 mg/dL for dapagliflozin, -6.0 mg/dL for placebo (P<0.05)
    * Hematocrit: 0.98% to 1.65% increase for dapagliflozin, -1.14% for placebo (P not reported)
    * Uric acid: -0.53 to -0.82 mg/dL for dapagliflozin, -0.04 mg/dL for placebo (P not reported)

Bailey said orthostatic hypotension was not increased with the drug, despite the decreases in blood pressure. Nor were there any differences between the dapagliflozin groups and placebo in the incidence of hypoglycemic episodes.

Serious adverse events were rare, and only 17 patients in the study, distributed evenly across treatment groups, discontinued because of adverse events.

Some increase was seen in female genital infections, with up to 13% of patients taking dapagliflozin affected, compared with 5% of the placebo group. Bailey said this potential side effect was not a focus of the study, but said it was a concern that would be followed in future trials.

Session co-chair Hannele Yki-Järvinen, MD, of the University of Helsinki in Finland, said dapagliflozin appeared promising on the basis of these data, but some questions remain.

"It looks wonderful, glucose goes down, blood pressure goes down," she said. But, she added, "I wonder if this degree of decrease in glucose levels actually improves insulin action and insulin secretion. Those are the type of things we would like to influence with the drug."

John Buse, MD, of the University of North Carolina in Chapel Hill, commented that the HbA1c reduction was relatively modest -- about the same as drugs such as sitagliptin (Januvia) and less than some other drug classes, he said.

Nevertheless, he said the weight loss and lack of other major adverse effects were in dapagliflozin's favor. If it's "a drug you can give to everybody" with even modest efficacy, it would find a place, he suggested.

Other phase III trials of the drug are underway, according to its manufacturers, Bristol-Myers Squibb and AstraZeneca.

Source: Diabetes In Control: Bailey C, et al "Dapagliflozin as an add-on to metformin lowers hyperglycaemia in Type 2 diabetes patients inadequately controlled with metformin alone" Diabetologia 2009; 52: S76.

 
 
 
 
 
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