By: Dr. Geoffrey Modest
So, I don’t mean to overdo this HDL thing, but there was a study finding that a synthetic oral HDL mimic significantly reduced atherosclerotic plaques in mice (see DOI 10.1194/jlr.M049262). Details (in very brief):
–They created HDL-like nanoparticles (based on multiple apo-A-1 mimetic peptides on a scaffold) and administered them to LDL receptor-null mice (a commonly used animal model for atherosclerosis, with a human-like lipoprotein profile) for 10 weeks orally.
–The oral med was undetectable in the blood, but caused significant reductions in VLDL and LDL but increases in HDL (perhaps by intestinal effects), and reduced the development of whole aorta atherosclerotic lesions by 55% and aortic sinus lesions by 71%. They note that the plasma changes in lipids was these apo A-1 mimetic peptides were much more than other apo A-1 mimetics, which typically do not change cholesterol levels but do decrease atherosclerosis in several animal studies.
There have been concerns about the efficacy of raising HDL levels in humans, primarily based on studies of 2 CETP inhibitors, where there have been dramatic increases of HDL without clinical benefit. a leading cardiologist editorialized that if another CETP inhibitor does not improve clinical outcomes, we should pretty much abandon HDL as a target of therapy and accept it as only a marker of cardioprotection. But, as I’ve mentioned several times in prior blogs, the issue may be targeting CETP inhibition as a means to increase HDL. Even though there are epidemiologic studies showing that those with genetically lower CETP levels have higher HDL and decreased cardiac mortality, perhaps the drugs we are making to inhibit CETP pharmacologically are creating dysfunctional and perhaps even pro-inflammatory HDL. For me, HDL is conceptually still an appealing target for anti-atherosclerotic therapy, given our understanding of the physiology (reverse cholesterol transport and inducing cholesterol efflux from macrophages, as well as their anti-inflammatory and anti-oxidant effects). There have been a few human studies in the past 2 decades with some intriguing results. in one, they used an IV infusion of apolipoprotein A-1 Milano and phospholipids, where apo A-1 Milano is a natural variant found in a small village in Italy where is very little atherosclerosis and coupled this with phospholipid to create an HDL mimic (see Nissen SE et al. JAMA 2003; 290:2292-300). They found that infusing this into 47 patients with coronary atherosclerosis led to a 14.3 mm3 reduction in atheroma volume by intravascular ultrasound, a 4.2% decrease from baseline, in only 5 weekly treatments… I also remember a small study done many years ago (not sure of reference) which found that a parenteral infusion of HDL itself led to significant decrease in atheroma volume within 5-6 weeks. the point is: I think the proclaimed death of HDL as a target, even if there is another negative CETP inhibitor study, is premature…. and these poor little mice have reinvigorated this discussion.
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