The Role of HDL in Healthy Lipid Function: Research Updates

OCTOBER 23, 2010
There is a strong association between HDL cholesterol and coronary syndrome, but whether HDL is causally related to atherosclerosis and cardiovascular disease is not clearly understood, according to Daniel Rader, MD.

In his presentation, “Advances in the Management of HDL,” Rader, who is the director of Preventative Cardiology & Lipid Clinic, at the Hospital of the University of Pennsylvania, focused on presenting information that would provide further insight into the processes that regulate HDL production and the relation to cardiovascular health.

While much attention has been focused on elevating HDL levels in an effort to improve overall heart function, Rader said what investigators must research is just how HDL functions before taking steps to create effective therapeutic drugs.

What is known is that low HDL is usually accompanied by other risk factors, including: insulin resistance, inflammation, and hypertension. Presently, there is data that suggest apo-A1 (apolipoprotien A1) relates to atherosclerosis, which may be a starting point in better understanding how HDL functions. The mechanism by which they are related still needs further definition, he said. One theory is that  apo-A1 affects reverse cholesterol transport, which mediates the protective effect of HDL and apo-A1, he said.

So then the question remains, whether or not physicians should begin treating people at risk for coronary disease by targeting low HDL levels to reduce that risk. Currently, the options for treating HDL are limited, however, he said.

One of the approaches in treating HDL is advocating exercise, by Rader said the goal in exercise must be weight loss to see any substantial effect on raising these levels. A high fat diet may raise HDL cholesterol, but also LDL cholesterol, which is undesirable. Likewise, estrogen hormone replacement in postmenopausal women, may  raise HDL cholesterols, but other complications make it an undesirable treatment as well.

So, then the approach of using pharmacotherapy to raise HDL is the next approach, he said. Current therapies involve statins, fibrates, and niacin. Rader said for the majority of patients whose triglycerides whose triglycerides is not an issue, he turns to niacin, a treatment that has been used for more than 50 years. “We’ve known for decades that niacin suppresses free fatty acid release from adipose tissue,” he said.

Niacin suppresses lipolysis in adipocytes and activates receptor GPR109A, which may explain why niacin effectively reduces LDL and raised HDL.

Rader next highlighted niacin-mediated cutaneous flushing. The two types of skin cells that react to niacin by expressing the receptors are langerhans cell and Keratinocytes. The cells release prostaglandins. In Europe, research indicates that laropiprant antagonists act on DP1 receptors to reduce flushing of niacin and make  niacin more tolerable.

On the question of whether niacin should be added to a statin, Rader discussed a number of current studies that are evaluating the efficacy of this combination therapy. The two trials currently evaluating the therapy are: HPS2-Thrive, which uses niacin and laropiprant; the second study is AIM-HIGH, which includes patients with CVD and low HDL levels, that are given either simvastatin and niacin, or simvastatin alone.

For further insight into HDL’s role, Rader also discussed CETP inhibition. CETP plays a key role on the interplay of lipid proteins. Research from Japan shows that genetically low CETP levels increase HDL levels and lower LDL. However, the ILLUMINATE trial, which tested the role of CETP by providing patients with Torcetrapib to lower  levels of CETP resulted in high mortality rates. Rader suggested one reason for the complication may be that inhibiting CETP constipates the natural lipid producing process and prevents full reverse cholesterol transport. Another theory is that inhibiting CETP promotes the ABCG1 pathway, he said.

Currently, two CETP inhibitors being tested in clinical trials are dalcetrapib and anacetrapib.

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