Trial testing benefits of raising HDL cholesterol to be launched by Oxford researchers

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Trial testing benefits of raising HDL cholesterol to be launched by Oxford researchers

May 31, 2006 | Michael O'Riordan

Oxford, UK - A new, very large, clinical trial assessing whether raising HDL-cholesterol levels protects against cardiovascular events is currently set to be launched by the renowned trialists at the Clinical Trial Service Unit (CTSU) of Oxford University.

The study, known as Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), will assess whether a new combination tablet, containing extended-release niacin and a specific blocker of prostaglandin D2 to prevent flushing, prevents myocardial infarction, stroke, or revascularization procedures in patients with existing vascular disease. Recruitment will begin later this year, and investigators plan to enroll approximately 20 000 patients.

"In addition to encouraging preventive lifestyle measures, we need to find even better preventive treatments," commented Dr Jane Armitage (University of Oxford, UK), one of the HPS2-THRIVE principal investigators, in a release announcing the study. "This new treatment should produce an average increase in HDL cholesterol of around 20%, which might realistically translate into a reduction of about one fifth in the risk of suffering a heart attack or stroke or of being killed by vascular disease."

Raising HDL cholesterol the next front in heart-disease battle

The combination tablet, currently known as MK-0524A, is designed to help patients tolerate the long-term use of the HDL-cholesterol-raising treatment. The study will be funded by a $42 million grant to Oxford University from Merck and Co (Whitehouse Station, NJ), the makers of the combination tablet.

Investigators plan to recruit men and women between the ages of 50 and 80 years with a history of myocardial infarction, stroke, or peripheral arterial disease; approximately 7000 will have diabetes. Of the 20 000 patients, 7500 people will be recruited in the UK, 7500 in China, and 5000 in Denmark, Norway, Finland, and Sweden. LDL-cholesterol levels will be optimized with statin therapy before randomization to either placebo or the combination HDL-raising drug. Patients will be followed for a minimum of four years.

Although raising HDL cholesterol, thus far, has been a relatively neglected area, there have been limited data demonstrating a benefit with HDL-raising therapies, the HPS2-THRIVE investigators note. One large randomized study of niacin was conducted before the introduction of statins, but patients find it difficult to take niacin long term because it produces an uncomfortable side effect of flushing, they add.

"It has long been known that higher levels of good cholesterol are correlated with lower risks of heart disease," writes Armitage. "Unfortunately, there is little evidence to date that raising HDL cholesterol with drugs is beneficial. Most studies have used fibrates, which raise HDL only modestly, and results have been mixed."

The HDL-cholesterol-raising scene

Published in 2001 in the New England Journal of Medicine, the HDL Atherosclerosis Treatment Study (HATS) highlighted the benefits of combining statin therapy with niacin. In this three-year, placebo-controlled trial, investigators showed that simvastatin plus niacin—with mean daily doses of 13 mg and 2.4 g, respectively—halted angiographic atherosclerosis progression and reduced major clinical events [1].

Data from the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER-2) study also showed that the addition of extended-release niacin to statin therapy could slow the progression of atherosclerosis, as measured by carotid intima-media thickness (IMT) among coronary heart disease patients with low HDL cholesterol levels [2].

Fibrates, in a statin-dominated era, have not completely disappeared either. A recent editorial suggested there has been a resurgence of interest in fibrates [3], pointing out that the Veteran Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT), published in 1999, showed for the first time that raising HDL and lowering triglycerides with gemfibrozil reduced major cardiovascular events even without any LDL lowering [4]. Fibrates could become important given the dramatic increase in obesity, diabetes, and metabolic syndrome, the editorial notes.

However, raising HDL-cholesterol levels appeared to get its biggest boost from the small 47-person ApoA-1 Milano study first published in 2003 [5]. Using intravascular ultrasound (IVUS), Dr Steven Nissen (Cleveland Clinic, OH) and colleagues reported that just five weekly infusions of a recombinant version of ApoA-1 Milano produced a modest but significant regression of coronary atherosclerosis.

Early data on torcetrapib, a novel cholesteryl ester transfer protein (CETP) inhibitor, are also promising. In one study, previously reported by heartwire, torcetrapib used alone and in combination with atorvastatin increased HDL cholesterol in healthy patients without vascular disease but with low levels of HDL cholesterol. Pfizer, the maker of torcetrapib, has come under fire for its development strategy with the drug because the major outcome study, known as ILLUMINATE, is being tested only with the company's best-selling statin, atorvastatin, the patent on which is due to expire in 2010.

Nissen is also currently leading the ILLUSTRATE study, a multicenter, randomized, 1200-person trial comparing atorvastatin/torcetrapib combination therapy with atorvastatin alone in preventing the progression of coronary atherosclerosis as measured by IVUS in coronary heart disease patients.

More HDL-raising studies are also planned. The US National Institutes of Health (NIH) is sponsoring a trial that evaluates the merits of simultaneously lowering LDL and raising HDL cholesterol levels. The trial, known as Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH), will compare the incidence of major cardiovascular events in patients randomized to extended-release niacin plus simvastatin or to simvastatin alone. Another study, known as the ACCORD trial, is testing fenofibrate plus a statin vs a statin alone in patients with type 2 diabetes.

Sources

Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001; 345:1583-1592.
Taylor AJ, Sullenberger LE, Lee HJ, et al. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: A double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004; 110:3512-3517.
Bloomfield HE. The role of fibrates in a statin world. Arch Intern Med 2006; 166:715-716.
Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999; 341:410-418.
Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: A randomized controlled trial. JAMA 2003; 290:2292-2300.

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