New Study of Clinical Trials Links Diabetes Drug
Avandia with Heart Attack Risk
JAMA publications release two reports on dangers of
Avandia (rosiglitazone) prior to FDA review
June
28, 2010 - Eleven years after the introduction of the diabetes
drug Avandia (rosiglitazone), data from available clinical trials show
an increased risk for heart attack associated with its use and suggest
an unfavorable benefit-to-risk ratio, according to a report posted
online today that will appear in the July 26 print issue of Archives
of Internal Medicine, one of the JAMA/Archives journals.
Participants with a greater than 4 inch increase in
waist size from baseline to the third follow-up visit had a 70 percent
higher risk of type 2 diabetes - June 22, 2010
The study is one of two by JAMA publications
reporting on the dangers of Avandia that have been released in advance
of an upcoming Food and Drug Administration meeting that will review the
safety of the drug.
Rosiglitazone was approved in 1999 to treat
hyperglycemia (high blood glucose levels) among patients with type 2
diabetes, according to background information in the article. Concerns
about the cardiovascular safety of rosiglitazone first arose in 2007,
when a meta-analysis demonstrated a significantly increased risk for
myocardial infarction (heart attack) and a borderline significant
increase for cardiovascular death.
The debate over the medication's
safety has continued during the past three years, and the U.S. Senate
Committee on Finance recently released a report providing additional
details about internal analyses conducted by the U.S. Food and Drug
Administration and by GlaxoSmithKline (GSK), the drug's manufacturer.
No large, definitive cardiovascular outcomes trials
have been conducted with rosiglitazone. However, as a consequence of a
2004 court settlement in New York, GSK was required to post clinical
trial results on a public web site. Steven E. Nissen, M.D., and Kathy
Wolski, M.P.H., of The Cleveland Clinic Foundation, searched this GSK
data and MEDLINE through February 2010 and identified 56 trials
involving 35,531 patients, 19,509 of whom received rosiglitazone and
16,022 who received control medications.
Why is
this medication prescribed?
Rosiglitazone,
trade name "Avandia," is used along with
a diet and exercise program and
sometimes with one or more other
medications to treat type 2 diabetes
(condition in which the body does not
use insulin normally and, therefore,
cannot control the amount of sugar in
the blood).
Rosiglitazone is in
a class of medications called
thiazolidinediones. It works by
increasing the body's sensitivity to
insulin, a natural substance that helps
control blood sugar levels.
Rosiglitazone is not used to treat type
1 diabetes (condition in which the body
does not produce insulin and, therefore,
cannot control the amount of sugar in
the blood) or diabetic ketoacidosis (a
serious condition that may occur if high
blood sugar is not treated).
In the combined studies, rosiglitazone therapy was
associated with a significantly increased risk of myocardial infarction
by an estimated 28 percent to 39 percent, although the risk of
cardiovascular death was not increased.
"An alternative analysis that
included trials with no cardiovascular events found a similar hazard,"
the authors write. "Subgroups classified by study duration and
comparator drug also showed elevated odds ratio estimates."
"These findings are consistent with prior
meta-analyses conducted by GSK, the FDA and most independent
investigators demonstrating an increased risk of myocardial infarction
in patients treated with rosiglitazone," they continue. "The FDA has
announced that it will conduct an advisory committee meeting in July
2010 to consider whether to remove rosiglitazone from the market."
The mechanisms by which rosiglitazone may cause
cardiovascular harm are not clear, the authors note, but could involve
increases in low-density lipoprotein (LDL, or "bad" cholesterol) levels
or genetic effects associated with the production of an enzyme linked to
plaque rupture.
"The public health implications of these results
are considerable. There are more than 23 million persons with diabetes
in the United States alone and nearly 300 million worldwide.
Cardiovascular disease is the leading cause of death in patients with
type 2 diabetes, representing approximately 68 percent of all causes of
mortality," the authors conclude.
"Although hyperglycemia has been
associated with an increased risk of microvascular adverse events, there
are now 12 classes of drugs that are approved to lower blood glucose
levels, including insulin. Because no unique benefits of rosiglitazone
use have been identified, administration of this agent solely to lower
blood glucose levels is difficult to justify."
Editor's Note: Dr. Nissen has received research
support from AstraZeneca, Atherogenics, Eli Lilly, Novartis, Pfizer,
Resverlogix, Takeda, Daiichi-Sankyo and Sanofi-Aventis through The
Cleveland Clinic Center for Clinical Research in within the last five
years. He has consulted for a number of pharmaceutical companies without
financial compensation. All honoraria, consulting fees or any other
payments from any for-profit entity are paid directly to charity, so he
receives neither income nor tax deduction.
June
28, 2010 - Eleven years after the introduction of the diabetes
drug Avandia (rosiglitazone), data from available clinical trials show
an increased risk for heart attack associated with its use and suggest
an unfavorable benefit-to-risk ratio, according to a report posted
online today that will appear in the July 26 print issue of Archives
of Internal Medicine, one of the JAMA/Archives journals. 
