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Avandia: Fishing with the wrong bait?
Posted By Peter Wehrwein On September 24, 2010 @ 4:43 pm In Diabetes | Comments Disabled
The news yesterday that FDA is putting tighter restrictions on Avandia (rosiglitazone), the diabetes drugs, was important but not surprising.
In July, an advisory panel to the agency took a rather dim view of the drug. Ten of the 32 votes were for increased warnings and tighter restrictions, and 12 were for pulling the drug off the market completely (which is what European regulators decided to do).
Avandia and a related diabetes medicine, Actos (pioglitazone), already had a “black box warning”about an increased risk of heart failure. Avandia also carries an additional warning, about heart attacks. The Health Letter‘s annual list of the top 10 health stories of the year included an item about Avandia in 2007.
And the side effects aren’t just limited to the heart. This is what our Special Health Report on diabetes has to say on the subject:
However, these medications [thiazolidinediones, or TZDs, which include rosiglitazone and pioglitazone] have been linked to to several health problems, prompting some physicians to limit prescribing them. People taking these drugs should be aware that all the TZDs can cause fluid retention and weight gain and may increase the risk of heart failure—a side effect that in 2007 prompted the FDA to ask the manufacturers of rosiglitazone (Avandia) and pioglitazone (Actos) to add a “black box” warning to these medications. These two medications have also been shown to raise the risk of bone loss and fractures, particulary among women. Rosiglitazone may also increase the risk of heart attack and is generally not recommended.
One begins to wonder who would want to take—or prescribe, if you’re a clinician—these drugs!
But here’s the catch: Avandia and other thiazolidinediones are very good at reducing insulin resistance, a central feature of diabetes and a reason blood sugar levels get out hand (insulin ushers blood sugar into cells, so when insulin is resisted, blood sugar levels climb).
Furthermore, the TZDs zero in on fat cells, and the metabolic mischief stirred up by fat cells—the chemicals and hormones they unleash—is a driving force behind diabetes.
More specifically, the TZDs work by activating a receptor in the nuclei of fat calls, called PPAR-gamma. (If you must know, PPAR stands for peroxisome proliferator-activated receptor. Occasionally acronyms can be a real blessing.)
PPAR-gamma has been called master regulator of fat cell biology. By activating PPAR-gama, the TZDs dial down the production of insulin-resistance-inducing agents (TNF-α, interleukin-1, resistin) while cranking up the production of a insulin-sensitizing hormone, adiponectin.
All good—except, not really, because of the side effects. Switching on PPAR-gama with TZDs seems to produce them, too.
But Bruce Spiegelman, a professor of cell biology at Harvard Medical School and the Dana-Farber Cancer Instiute, a Harvard affiliate, seems to have come up with an an alternate strategy for affecting PPAR-gama—one that might avoid the side effects.
In an article in July in the Nature, Spiegelman and his collaborators reported findings that showed that, in addition to its primary binding activity, rosiglitazone blocks phosphorylation of PPAR-gama. Phosphorylation is the addition of a phosphate group to an organic compound. In biochemistry, phosphorlyation often triggers an important change in how a compound behaves.
Spiegelman’s experiments—one of which included taking biopsies of fat tissue of people taking rosiglitazone—also showed that the inhibition of phosphorylation of PPAR-gama was associated with anti-diabetic effects.
Put another way, the phosphyloration of PPAR-gama in fat cells may, in fact, be a critical step in the many that wind up producing diabetes. Stop or retard phosphyloration and you might rein in the metabolic havoc caused by fat cells and their diabetes-producing ways.
An enthusiastic commentary in the same issue of Nature as Spiegelman’s article compared the research results to ” refreshing wind over the PPAR-gama field” that could revitalize the once-bustling area of research. So rather than give up on PPAR-gama as target, as has been suggested because of Avandia’s rise and fall, researchers and drug companies might focus finding ways to affect it more selectively through phosphorlyation.
Elsewhere, the commentators (who clearly have a fondness of metaphor) said the researcher community had been “fishing with the wrong bait” and that the Spiegelman results call into question all the effort that has been put into finding potent PPAR-gama activators, such as rosiglitazone.
When we spoke to Spiegelman yesterday by phone, he said he was “neutral” on the FDA move to restrict access to Avandia. But he said finding more selective compounds is a realistic goal: “It’s absolutely not pie in the sky.”
Several candidates are mentioned in the Nature article. They don’t have names and are labeled with mash-ups of letters and numbers because they’re still in the early stages of testing and development. Spiegelman told us in an email that none have been tested in humans, yet results from animal studies were promising, though they were abandoned for diabetes for one reason or another. Maybe that will change.
Rosiglitazone could be modified to be more selective, said Spiegelman, but he doubted that drug developers would try for both patent and marketing reasons.
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