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Reports of cardiovascular risk linked to muraglitazar (Pargluva, Bristol-Myers Squibb/Merck) dealt a setback to the drug's development and have prompted its sponsors to reconsider continuing their collaboration.
The first of a new class of diabetes drugs to gain an approval recommendation from a Food and Drug Administration (FDA) advisory panel, muraglitazar may raise the risk of cardiovascular death, according to a recent JAMA report.1
On September 9, an FDA advisory committee recommended that the agency approve muraglitazar as a treatment for type 2 diabetes (DOC News, November 2005).
However, an analysis of data presented to the agency shows that patients who took muraglitazar had more than twice the risk of heart attack or stroke, and nearly an eightfold increase in the risk of congestive heart failure, compared with those who received pioglitazone (Actos, Takeda/Lilly) or placebo.
Cleveland Clinic cardiologist Steven Nissen, MD, who co-authored the JAMA report with Eric J. Topol, MD, says muraglitazar has not been sufficiently proven to be safe.
"I was shocked" by the advisory committee's approval recommendation, Nissen says.
Glitazars are a new class of peroxisome proliferator–activated receptor (PPAR) drug. Unlike the glitazones, which target PPAR-gamma, the glitazars affect both PPAR-gamma and PPAR-alpha, the latter of which is associated with the regulation of lipids. Toxic effects such as increased cancer and cardiovascular risk have hampered development of the glitazars.
At the time the advisory committee considered the evidence for muraglitazar, the panel had no cardiologist. Nissen says this was a mistake, considering rumors the drug was linked to cardiovascular problems.
"I knew through the grapevine that there was a really big problem with this drug," he says. "I knew there was a safety signal somewhere, mainly heart failure."
When the FDA posted data from muraglitazar clinical trials at the agency's Web site, Nissen and colleagues did their own analysis. The paper was delivered to JAMA around October 10, sent out for review, and posted to the journal's Web site October 20.
On October 27, the drug companies announced that new clinical trials are required to answer questions raised by the FDA, which would take about five years to complete. Bristol-Myers Squibb (BMS) agreed to begin discussions with Merck about ending their collaborative agreement. BMS has not decided whether to continue seeking FDA approval on its own or to pull the plug on development of muraglitazar.
An FDA spokesperson declined to discuss the muraglitazar case any further
or to explain whether the agency knew about the risks of the drug prior to the
publication of the JAMA paper. 
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| DOC News | Diabetes | Diabetes Care | Clinical Diabetes | Diabetes Spectrum |
