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January 27, 2014
The Nasty Side of HDL
A recurring theme here when I talk about cardiovascular drug discovery is how poorly we understand human lipidology. Surprise after surprise has followed on efforts to lower LDL and/or raise HDL, to the point that a person really has to wonder if the success of the statin drugs was a fluke. (And they could be a fluke in more than one way - perhaps the LDL-lowering effects are, for some reason, more beneficial through that mechanism than they might otherwise be, or as many have speculated, there might be off-target effects that are also helpful).
Everyone seems to agree, though, that raising HDL is (or would be) a good thing. Attempts to do that pharmacologically, though, have come to grief, so the evidence we have is through longitudinal studies and the occasional mutant line with unusually high HDL. Both of those have their pitfalls when it comes to drug targeting - there are, for example, people with HDL-raising mutations that don't see to show any good effect for it.
Now comes this paper in Nature Medicine that identifies an oxidized form of HDL (specifically, ApoA1 protein) in arterial plaques. This modified protein is useless for cholesterol scavenging, exacerbates inflammation, and impairs biogenesis of normal HDL. This makes it a good candidate as a diagnostic marker (which is where the paper is aimed, rightly), and also a good candidate for anyone working on HDL-raising ideas to keep an eye on.
Merck, for example, is pushing ahead with their CETP inhibitor compound anacetrapib Last report I saw on that one was on some rather alarming pharmacokinetics - the drug appears to take a long time to wash out. Long, as in "still detectable several years after the last dose". Given that it looks like something that could be used to line a nonstick frying pan (like most of the other CETP compounds), that's quite believable. As late as Merck is in the clinic, they're not going to be able to jump in and start looking for this new oxidized HDL form so easily. But it would be something to think about
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