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    Saturday, October 22, 2005

    More Pargluva: The idea behind this Pargluva (easier to remember than muraglitazar, don't you think?) is an interesting one. The drug is a peroxisome proliferator–activated receptor agonist. That's a meaningless mouthful, I know. But peroxisome proliferator-activated receptors (PPARs), are a type of nuclear transcription factor, a protein which acts as an on-off switch for genes. The PPARs influence genes responsible for cholesterol and blood sugar regulation. Pargluva is an "agonist" or contender for binding them. It influences the PPAR by binding to it. There are different types of PPARs, but for this discussion, only two matter - an alpha type which influences triglyceride levels and a gamma type, which influences blood sugar levels. We already have drugs that limit themselves to the alpha type. They are the cholesterol -lowering medications Lopid (gemfibrizol) and Tricor. We already have drugs that work only on the gamma type PPAR. They are Avandia and Actos. (We used to have a third, Rezulin, but it was withdrawn from the market because it caused liver problems.)

    Pargluva is unique because it acts on both the alpha and the gamma type PPARs. In theory, it should then give a double benefit - lowered triglycerides and lower blood sugar levels.

    Both Actos and Avandia have been associated with congestive heart failure, which has signaled the lawyers to start circling. (Here's a more nuanced look at the problem.) It's no surprise, then, that Pargluva would be, too. There have been no studies comparing Pargluva directly to Actos and Avandia.

    As hard as it may be to believe, there's much we don't understand about lipids and glucose and our bodies' cellular processes. We know that when blood sugar is high, triglycerides go up, too. (Although the reverse is not true. You can have high triglycerides and have a normal blood sugar.) When a diabetic's blood sugar improves, so do his triglycerides. Might there not be a reason for that which we haven't yet elucidated? Perhaps somehow, the triglycerides play a role in protecting cells from damage done by the elevated glucose. (Triglycerides are the major components of cell membranes.) Of the two types of PPARs it influences, Pargluva has more of an impact on the triglyceride-controlling PPAR than on the glucose-controlling PPAR. It could be that in combinging the two, it disturbs some delicate balance between triglycerides and glucose that results in more cardiovascular disease, especially when combined with other glucose-lowering medications. Who knows? It's just idle speculation, but worth investigating further before it gets FDA approval.

    UPDATE: Derek Lowe has more thoughts.

    posted by Sydney on 10/22/2005 12:34:00 PM 0 comments


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