This issue of Hot Topics in Cardiology focuses on high-density lipoprotein cholesterol (HDL-C), the so-called good cholesterol. It is indeed recognized as a protective factor for atherosclerotic plaque formation. High levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides are associated with a high risk of cardiovascular disease, and it has been observed that low HDL-C may worsen such a risk. Although numerous studies have been conducted to clarify the magnitude of the relationship between high HDL-C and its cardiovascular protective action, this connection has not yet been completely elucidated. Nevertheless, HDL-C was considered a good provider for atheroprotection; thus, research in recent years focused on the development of pharmacological agents that could ameliorate the HDL-C profile.
Kausik K. Ray, in this issue, describes the beneficial roles of HDL-C (from the direct action to remove excess cholesterol from the blood to its numerous pleiotropic effects) and in light of the explained mechanisms presents available and experimental treatments. Lifestyle modification should be the first action physicians recommend to patients. When necessary, pharmacological agents can be introduced.
To date, the agents approved for enhancing HDL-C level are fibrates and niacin. The main clinical trials and evidences of the efficacy of these drugs are described and reviewed. The oldest agent, niacin, is being studied in several trials, but preliminary data from the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) study found niacin had little clinical benefit when added to statin therapy.
Particular attention is given to new approaches for HDL-C raising agents. New molecules have been developed from exploitation of the pathway in which HDL-C is involved: cholesteryl ester transfer protein (CETP) inhibitors, HDL mimetics, infusion of apolipoprotein AI_Milano (apo AI_Milano), apo AI mimetics, and apo AI upregulators. Up to now, inhibitors of CETP have been the most studied agents; these molecules should favor the removal of cholesterol from the vessel wall and the raising of HDL-C. Several agents that act on CETP (ie, torcetrapib, dalcetrapib, and anacetrapib) have been tested. “Off-target” adverse effects of the first agent, torcetrapib, led to an increase in cardiovascular events—an effect considered unrelated to CETP inhibition. Anacetrapib was studied in a safety trial (DEFINE) and found to cause a significant increase in HDL, as well as a fall in LDL, and was not associated with an increase in cardiovascular events. A large outcomes trial is now starting.
Dalcetrapib has been evaluated in phase II trials showing a good lipid efficacy and tolerability. A large phase III trial (dal-OUTCOMES) has completed enrollment and is in the treatment/follow-up phase. Results from the dal-VESSEL and dal-PLAQUE studies are anticipated at the European Society of Cardiology 2011 Congress. As part of the larger dal-HEART program, these trials should assess efficacy and safety of dalcetrapib on endothelial function and atherosclerotic plaque in patients with hypercholesterolemia. Additional new approaches are evaluating the infusion of HDL or its mimetics, and the effect of apo AI mimetics, but testing is in an earlier phase with these agents.
All told—HDL-C is a very “hot” topic, and this monograph is up to the minute on the latest developments.