Research now going beyond reaching low LDL cholesterol

Studies are under way to test drugs that use different mechanisms to raise levels of HDL cholesterol.

By Susan J. Landers — Posted Aug. 1, 2005

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Washington -- As the quest continues for earlier identification of people at risk for heart disease, taking a closer look for possible triggers in the bloodstream is emerging as a key element.

Studies have consistently shown that lower numbers are better for low-density lipoprotein cholesterol, and researchers suspect that higher numbers are better for high-density lipoprotein cholesterol.

Thus, three large studies are under way to test different mechanisms for raising good cholesterol and to determine whether higher levels of HDL do in fact reduce the risk of heart attack and stroke.

"Clearly, HDL has become the new frontier, said William Boden, MD, director of cardiology at Hartford (Conn.) Hospital and a lead investigator in one of the new studies.

No one is disputing that low levels of LDL cholesterol are good. That has been the primary focus of heart disease prevention for decades. But intriguing findings have also pointed to high levels of HDL cholesterol as being part of a beneficial lipid profile, and researchers are out to prove this. "Clearly, everybody is now getting on the bandwagon," Dr. Boden said.

Dr. Boden is co-investigator of a six-year study funded by the National Heart, Lung, and Blood Institute to evaluate whether a combination of an extended-release version of niacin, marketed as Niaspan, plus simvastatin is better able to prevent heart disease than is simvastatin alone.

Kos Pharmaceuticals, the manufacturer of Niaspan, is also contributing funds to the trial.

The study is called AIM-HIGH, the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes. The majority of patients enrolled are expected to have metabolic syndrome.

In recognition of the fact that heart disease is a leading killer of women, especially in the years after menopause, AIM-HIGH intends to include at least 30% women in its enrollment of about 3,300. The enrollees will have established vascular disease and low levels of HDL and high triglycerides. Enrollment is expected to begin in the fall at 60 to 80 centers across the country.

AIM-HIGH will build on findings from an earlier study that suggested a correlation between raising HDL levels and the slowing or halting of atherosclerosis. That study also showed that HDL levels were raised among participants who took simvastatin and niacin.

B. Greg Brown, MD, PhD, professor of medicine in the division of cardiology at the University of Washington School of Medicine in Seattle, was the lead investigator in that study and is also a lead investigator in this trial.

"The goal of AIM-HIGH is to see if combined extended-release niacin plus simvastatin will cause significant improvement in the entire lipid profile and reduce cardiac events," Dr. Brown said. The events under review will include coronary death, heart attack, stroke or hospitalization for acute coronary syndromes.

Different approaches

Another trial, the Action to Control Cardiovascular Risk in Diabetes, or ACCORD, study began enrolling approximately 10,000 participants in 2003. It is scheduled to conclude in 2009.

Among the strategies being tested in ACCORD is the improvement of lipid profiles among a group of participants who are taking a fibrate and a statin. Fibrates have been shown to improve levels of HDL cholesterol and lower levels of another heart health risk, triglycerides.

In addition, the pharmaceutical giant Pfizer announced in June that it was about to launch a study of torcetrapib, a medicine developed by the company to increase HDL cholesterol levels. The new drug will be used in trials with atorvastatin, or Lipitor, and studied in 25,000 patients at hundreds of medical centers worldwide at a cost of about $800 million.

Pfizer began work on the torcetrapib/atorvastatin program more than 15 years ago, according to a company statement. Researchers found that the new drug had helped raise HDL levels by inhibiting the production of cholesteryl ester transfer protein (CETP), a protein in the liver that transfers cholesterol.

Despite the flurry of interest in HDL cholesterol, LDL cholesterol is still revealing its secrets. A recent study found that high levels of oxidized phospholipid molecules, a major component of LDL cholesterol, were found to be a good early predictor of coronary blockages, especially among patients younger than 60.

The role of Lp(a)

Although the test used in the research is not commercially available to physicians, the findings do open the possibility for wider use of a test for the cholesterol-containing protein Lp(a) which is available, said lead investigator Sotirios Tsimikas, MD, associate professor of cardiology and director of vascular medicine at the University of California, San Diego.

His study indicated that oxidized phospholipid particles are strongly bound to Lp(a) which, in turn, has a strong affinity for binding to blood vessel walls and may play a key role in the development of atherosclerosis.

Lp(a) was discovered in the 1960s but has received little recent attention from researchers.

The study "demonstrates that these molecules could be promising targets for pharmaceutical research, particularly in developing new drugs to reduce their levels in the bloodstream and in the vessel wall," Dr. Tsimikas said. His study is in the July 7 issue of the New England Journal of Medicine.

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Small tools, but powerful

Washington -- Almost unimaginably small, three to five times the diameter of a single atom, nanoparticles carry a lot of hope for the early diagnosis and improved treatment of illness.

Isaac Asimov had it just about right in his 1966 novel, Fantastic Voyage. But instead of tiny people journeying through the human body, researchers are setting their sights on minute diagnostic tools.

Consider the application for heart disease, responsible for 700,000 deaths a year, half of which occur without warning, said Samuel A. Wickline, MD, a professor of medicine at Washington University School of Medicine in St. Louis. "We don't have early enough diagnosis," he said at a July 13 Capitol Hill briefing on nanotechnology and its implications for medicine.

"We can tell you if you've already had a heart attack. We're pretty good at that," Dr. Wickline said. "But what good is that? What we really want to say is, 'You're going to have a heart attack, and we need to do something about it.' " That's where nanotechnology could have an important role, he added.

"We are trying to develop new approaches to localizing and profiling molecular causes of disease," he said. Instead of just employing an MRI or CT scan and noting that disease or a tissue abnormality is present, nanotechnology would image the source of the disease and quantify biological activity.

The technology may work for new methods of drug delivery. It could evolve into a site-targeted therapeutics delivery system like little "medical guided missiles" to go where they are needed and deliver a payload, he said.

The device could mean new drugs for individuals rather than groups of patients. The technology is being studied that would allow replacement parts to be installed in cells, he added.

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