On July 30, 2007, a Food and Drug Administration (FDA) panel voted 22 to 1 to keep Avandia on the market, right after agreeing by a vote of 20 to 3 that Avandia does increase heart risks. Now the FDA will decide what kind of warning should appear on the Actos and Avandia labels. It has already called for a black box warning, the sternest possible, on Avandia.
In mid-June, the New England Journal of Medicine started the ruckus by reporting that Avandia increases risk of heart attack by 43 percent. Since then, Avandia prescriptions have fallen by about forty percent. However, reports to the FDA of Avandia-related heart attacks, deaths, and hospitalizations have multiplied.
In the month before the NEJM article, only five heart attacks associated with Avandia were reported by doctors: ninety have been reported since then. Reports of heart-related hospitalizations went from eleven to 126. It appears that doctors are now acutely aware of the possibility that Avandia is implicated in their patients’ heart problems.
Another new meta-analysis, published in August’s Diabetes Care, found that both Actos and Avandia double risk of heart failure. According to the study, one of every fifty patients who takes either Actos or Avandia for 26 months will suffer heart failure. The risk, which affects men and women equally, occurs even at low doses and in patients not taking insulin.
Furthermore, it strikes people without pre-existing risk factors for heart failure, the young as well as the elderly: a quarter of the heart failures occur in people under sixty years of age.
The research, which was conducted at Wake Forest University School of Medicine in North Carolina, analyzed data from trials and studies involving over 78,000 patients.
Heart failure (the inability of the heart to pump enough blood, possibly due to fluid retention) is already listed as a potential risk of thiazolidinediones, the class of drugs that includes Actos and Avandia. (It is different from heart attack, the side effect of Avandia discussed in the NEJM article.) However, the current labels warn only against use in patients with pre-existing serious heart failure and in combination with insulin. Given the Wake Forest findings, the researchers believe that those warnings are insufficient.
The Wake Forest researchers recommend seeing your doctor if you are taking or considering use of thiazolidinediones. Others, however, believe that the drugs’ risk/benefit ratio doesn’t warrant drastic measures like switching medicines. As Dr. Larry Deeb, president for medicine and science at the ADA, told Forbes.com, “The risk for heart failure with these drugs may be one in fifty, but if you can correctly identify who that person [at risk] is, you can safely treat the other 49 and not hurt anybody.”
Yet another meta-analysis of Avandia was recently published, this time by the Cochrane Library. The study pooled data from eighteen randomized controlled trials of more than 8000 subjects, about half of whom took Avandia. Most of the trials lasted about six months; the longest covered four years.
The authors found that Avandia worked about as well to lower blood sugar as other oral anti-diabetic drugs. However, those taking Avandia gained weight, up to eleven pounds, and had twice the chance of developing edema (swelling) that can lead to heart failure. The largest reviewed trial, which involved 4000 patients, showed increased cardiovascular risk and increased risk of broken bones in women. The review authors advise a cautious approach to Avandia use, especially for people who have congestive heart failure and for thin women, who risk fracture.
Sources: International Herald Tribune; The Wall Street Journal; Forbes.com; Boston Globe; Diabetes Care, August 2007; Bloomberg.com; Cochrane Library, May 2007