Dr. Julian Halcox
In a fascinating session on Sunday afternoon Phillip Barter, Ulf Landmesser, John Kastelein and Christopher Cannon took attendees on a journey from the basic science of High-Density Lipoproteins (HDL) in vascular biology, through the latest clinical studies of HDL management to the future of therapy in this field. Opening the session, Barter emphasized that HDL has a much wider and more complex role in vascular biology than simply mediating reverse cholesterol transport. Anti-oxidant, anti-inflammatory, anti-proliferative, anti-apoptotic, vasodilator, vascular repair and novel metabolic functions of HDL may all have a part to play in protecting the vascular wall from atherosclerosis. Silencing DHCR24 (24-dehydrocholesterol reductase) expression attenuates the protective effect of HDL in an animal model of vascular injury independent of cholesterol efflux, identifying this pathway as a novel potential target for therapy. HDL also appears to improve glucose metabolism by stimulating insulin synthesis and secretion and increasing skeletal muscle uptake of glucose. A recent analysis of the ILLUMINATE study data published in Circulation suggested that Torcetrapib improves insulin sensitivity and abrogates the rise in glucose and Hb A1c seen in coronary patients receiving statin therapy. Ulf Landmesser continued this theme presenting data illustrating that the beneficial effects of healthy HDL on inflammation, endothelial repair and nitric oxide generation are less evident in coronary patients. Loss of HDL-associated paraoxonase activity may be relevant as may increased expression of Apoprotein C-III and decreased clusterin, although with over a 1000 different lipids and more than 70 proteins present in HDL further work is needed. John Kastelein took us into the clinical arena, challenging received wisdom by presenting data demonstrating that high levels of HDL may not be protective in some coronary patients; that increased cholesterol efflux capacity of HDL may paradoxically be associated with a worse outcome, albeit in an older study; and that genetic factors associated with increased HDL-cholesterol do not have an impact on CV-outcomes, emphasizing the complexity of the field and the challenges we face with HDL management. He did offer some hope though! A new recombinant Apo-A1 (CER-001) engineered into the form of pre-beta HDL appears to be highly effective at mediating cholesterol efflux and is just going into clinical study in an IVUS regression trial in patients with acute coronary syndromes. The session was brought to a close by Chris Cannon who presented data from the DEFINE trial of anacetrapib, one of two new CETP inhibitors in advanced clinical development. This agent has a dramatic effect on lipid metabolism more than doubling HDL-C and reducing LDL-C by over a third without having an adverse impact on blood pressure electrolyte balance, inflammation and renal function. This agent is now being studied in a large clinical trial of CAD patients (REVEAL) as is the other CETP antagonist Dalcetrapib (Dal-Outcomes) which has also had some promising early data presented at this congress (Dal-Vessel and Dal-Plaque studies). The overwhelming consensus from the faculty was that HDL, albeit complex, remains a compelling potential factor for therapy. However, LDL remains the primary lipid target for managing CVD risk and we still need definitive outcome studies from HDL modulating agents before wider routine treatment of HDL can be recommended.
Controversial issues in cardiovascular prevention - where does high-density lipoprotein stand?
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