The study, dubbed ARBITER 6, was designed to understand the comparative effects of different approaches to cholesterol management, beyond statin therapy, explained lead study author Allen Taylor, MD, director, Advanced Cardiovascular Imaging, Lipid/Prevention Clinic, Dept. of Medicine (Cardiology), Cardiovascular Research Institute at Washington Hospital Center in Washington, D.C. “Two common secondary treatments, niacin and ezetimibe were compared—one that clinically focuses primarily on HDL (niacin) and one that focuses primarily on LDL (ezetimibe),” he said. “The comparative-effectiveness trial showed that the use of extended-release niacin caused a significant regression of carotid intima–media thickness when combined with a statin and that niacin is superior to ezetimibe.”
Patients enrolled in the study had coronary heart disease or a coronary heart disease risk equivalent and were receiving long-term statin therapy. Patients had an LDL cholesterol level under 100 mg per deciliter (2.6 mmol per liter) and an HDL cholesterol level under 50 mg per deciliter for men or 55 mg per deciliter for women (1.3 or 1.4 mmol per liter, respectively), and received either 2000 mg per day of extended-release niacin or 10 mg of ezetimibe per day.
“The primary end point was the between-group difference in the change from baseline in the mean common carotid intima–media thickness after 14 months,” the study said. The trial was terminated early, on the basis of efficacy, according to a prespecified analysis conducted after 208 patients had completed the trial.
Researchers found that the mean HDL cholesterol level in the niacin group increased by 18.4% over the 14-month study period, to 50 mg per deciliter, and the mean LDL cholesterol level in the ezetimibe group decreased by 19.2%, to 66 mg per deciliter.
“Niacin therapy significantly reduced LDL cholesterol and triglyceride levels; ezetimibe reduced the HDL cholesterol and triglyceride levels,” the study stated. “As compared with ezetimibe, niacin had greater efficacy regarding the change in mean carotid intima–media thickness over 14 months, leading to significant reduction of both mean and maximal carotid intima–media thickness. Paradoxically, greater reductions in the LDL cholesterol level in association with ezetimibe were significantly associated with an increase in the carotid intima–media thickness. The incidence of major cardiovascular events was lower in the niacin group than in the ezetimibe group.”
The ARBITER 6 study results found favor among supplement suppliers, especially vitamin B producer, Lonza. “These findings represent additional validation in what is a wealth of scientific studies supporting niacin. As one of the earliest effective products for managing one’s blood lipid profile, the amount of research conducted on niacin is abundant,” commented Lonza’s Kevin Owen, PhD, Nafta head of technical marketing and scientific affairs. “[While] many consumers do not understand cholesterol and blood fat problems well enough to treat themselves, the use of low-cost niacin therapy as a special dietary measure to address cholesterol and blood fat problems should be considered and conducted under a physician's supervision.”
At a November American Heart Association meeting, Merck & Co., Inc. took issue with the study, which it termed to be “a small 200-patient imaging study,” and expressed confidence in the safety and efficacy profiles of Zetia (ezetimibe) and Vytorin (ezetimibe/simvastatin).
“The results of the small ARBITER 6 study do not, in any way, change our view of Zetia and Vytorin as effective medicines for fighting high LDL cholesterol,” said Peter Kim, PhD, president, Merck Research Laboratories.
“Nothing from this study, which a New England Journal of Medicine editorial says has ‘several limitations,’ changes the well established understanding that lowering LDL cholesterol is the primary target of therapy according to the guidelines. Zetia and Vytorin, when used as a supplement to a healthy diet, are effective in reducing LDL cholesterol,” he said. “We encourage patients to continue taking their medication as prescribed by their physicians, and of course to speak to their physician if they have concerns.”
The results of the ARBITER 6, said Merck, “were widely predicted because the study design favored niacin as the patient population selected had well-controlled LDL cholesterol and relatively low HDL cholesterol. Also, it is important to remember that ARBITER 6 is not an outcomes study, and does not have the rigor or size to provide meaningful insight into the effect of either niacin or ezetimibe on clinical outcomes.”
The company pointed out that it had reviewed the data from 43 completed shorter term clinical trials involving approximately 2,400 patients who received ezetimibe alone and 13,600 patients who received ezetimibe with statins, as well as two longer-term studies, and expressed confidence that the data support the safety profiles of Zetia and Vytorin.
“Any suggestion that the results of ARBITER 6 can definitively answer the question of the impact of ezetimibe on cardiovascular outcomes or that its results have implications for clinical use should be met with skepticism,” said Dr. Kim. “Given the broadly accepted, scientifically validated importance of lowering LDL and the millions of people in the United States alone who are not at their recommended treatment goals, Vytorin and Zetia remain effective options for physicians to treat their appropriate patients.”
During a press conference to discuss the results of the ARBITER 6 study, Dr. Taylor affirmed his confidence in the effect of niacin. “Niacin had a superior effect on the artery wall,” he said. “The take-home message is clear: niacin should be the choice when considering an add-on therapy.”
He also said that with the growing concern about the cost of healthcare, niacin is the most economical choice too. He noted that in 2008, 9 million Americans were taking Zetia, as opposed to just 2.5 million who were taking niacin even though Niaspan, the branded formulation used in the trial, is less expensive than Zetia.
When asked by Nutraceuticals World how his findings impact the pharmaceutical and dietary supplement world and if doctors might be compelled to gravitate more toward niacin supplements as a cost effective alternative, Dr. Taylor cautioned that his study findings were limited to the effect of the specific drugs tested, namely prescription extended release niacin, and ezetimibe. “While one might hope that supplement niacin could be an alternative, these compounds are not medically recommended due to limited understanding of their safety and clinical effects,” he said. “Patients should clearly understand that supplement niacin is not a substitute in this instance.”
It’s also worth noting that during the press conference, Dr. Taylor’s objectivity was questioned by reporters who queried his receipt of about $10,000 in lecture fees from Abbott, the makers of Niaspan. When offered the opportunity to clarify the situation, Dr. Taylor told Nutraceuticals World that his lecture fees were “fully disclosed according to the satisfaction and standards of our professional organizations,” and that all of his lecture fees, including those donated by Abbott were subsequently donated to charity.