Editor's note: On Jan. 19, 2012, the pharmaceutical companies AstraZeneca and Bristol-Myers Squibb announced that the FDA rejected their approval request for dapagliflozin, calling for more research data on the drug’s benefits and risks. Both companies say they remain committed to developing the drug and will work with the FDA to determine the next steps.
July 19, 2011 -- In a 9-6 vote, an advisory panel said the FDA should not yet approve dapagliflozin, a new type of diabetes drug that makes the body dump sugar and lose weight.
The split vote, as well as panelist comments, makes it uncertain whether the FDA will approve the drug, jointly made by Bristol-Myers Squibb and AstraZeneca. The FDA will certainly ask the companies to gather more data on side effects; the key question is whether the agency will ask for this data before or after approval.
Dapagliflozin is the first in a new class of diabetes drugs. Normally, the kidney recycles sugar back into the body. But dapagliflozin inhibits a transporter molecule called SGLT-2. The result: Sugar passes out of the body in the urine, lowering blood sugar without affecting insulin levels.
Another result: Patients lose weight. In clinical trials, type 2 diabetes patients who took dapagliflozin for six months lost 1 to 5 pounds. In a special study to look at weight loss in people with diabetes, 30% of those who took dapagliflozin plus metformin lost 5% of their body weight.
A downside to the drug is that diabetes often damages the kidneys. Even moderate loss of kidney function makes dapagliflozin much less effective. The drug would be given only to patients with sufficient kidney function, but some panelists questioned the value of a proposed test to determine which patients could take dapagliflozin.
And the drug has side effects. All that sugar in the urine increases patients' risk of urinary tract and genital infections. There are other worries, too -- including dehydration and heat intolerance -- but members of the advisory committee were far less worried about these side effects than about the possible risk of cancer and liver toxicity.
In clinical trials, nearly 4,300 people with type 2 diabetes received dapagliflozin for over a year; 441 patients were treated for at least two years.
In these trials, five patients showed signs of liver toxicity. Only in one case was this liver toxicity classified as "probable diagnosis of mild to moderately severe dapagliflozin-induced liver injury." But such a strong signal, even in a single patient, is worrisome.
Nine patients taking dapagliflozin developed bladder cancer; only one case was seen in those not taking dapagliflozin. Nine other patients taking dapagliflozin developed breast cancer. There were no breast cancers in those not taking dapagliflozin.
That's by no means proof that the drug causes cancer. But definitive studies might require thousands of patients. The question now before the FDA is whether the modest blood-sugar-lowering and weight-reducing benefits of dapagliflozin are worth the risk.