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Does It Matter How You Lower Your Cholesterol?

By Jeffrey Norris

Recent headlines are shining a hot spotlight on a continually simmering issue - who should be treated for risk factors associated with heart attack and stroke, and what should the prescription be? The headlines were inspired by a cholesterol-lowering drug called Vytorin. Thanks to congressional scrutiny, the apparent failure of the already marketed drug in a recent clinical trial, and the slowness of partners Merck and Schering-Plough in releasing the trial data, the media jumped on a January 14 press release about the drug. In the trial, called ENHANCE, 720 patients with an inherited form of high cholesterol received two years of treatment with either Vytorin or a high-dose statin alone. Vytorin bested the statin when it came to lowering "bad" LDL cholesterol. But improved cholesterol lowering in the study was not matched by a significant decrease in progression of arterial disease. Vytorin is a cholesterol-lowering pill that couples a high dose of a statin with a newer type of cholesterol-lowering drug. The companies' announcement followed prodding by US Congressional representatives, backed by legislation mandating the timely release of clinical trial data. The formulation of Vytorin tested in ENHANCE is a combination of a high dose of a Merck statin called Zocor, now available generically as simvastatin, and a newer type of cholesterol-lowering drug called ezetimibe. Branded Zetia by Schering-Plough, ezetimibe has been marketed since 2002. But in the ENHANCE trial, there was no difference between treatment groups when researchers measured changes in the thickness of the walls of the carotid artery in the neck. The researchers who used CT imaging to obtain data and make measurements were unaware of which treatments individual patients were receiving, as were the patients themselves. On March 30, the American College of Cardiology (ACC) is hosting a session on the ENHANCE study as part of its annual scientific meeting. A statement issued by the ACC soon after the initial flurry of Vytorin press coverage in January was interpreted by some as advocating continued use of Vytorin. However, the ACC subsequently sent to members an email stating that "the ACC and American Heart Association [AHA] have published guidelines which recommend that a statin be given as first-line treatment and that alternatives be used only when statins fail to be effective or are associated with significant side effects. The benefits of statins have been proven in large studies, while the effect of ezetimibe is unproven." Congress has asked the ACC and AHA for records detailing their financial relationships with Merck and Schering-Plough. In a January 24 statement issued by the House Commerce Committee, Bart Stupak (D-MI), chairman of the committee's Subcommittee on Oversight and Investigations, said, "Our subcommittee intends to examine exactly how much funding these two organizations receive from Merck and Schering-Plough, how they use this funding and any potential conflicts of interest." What's a Physician to Do? Endocrinologist Philip Frost, MD, an expert on cholesterol and other fats and a UCSF clinical professor of medicine, returned to his office after a trip abroad in mid-January and was immediately barraged with phone calls from patients with questions about the cholesterol-lowering medications they were taking to prevent heart attacks. But Frost is not shunning Zetia or Vytorin, at least not yet. Frost treats many tough cases - patients whose blood fats are sky-high. "Most of the patients that come to see me are people who do not respond sufficiently to a single drug," he says. He is not ready to abandon a drug that is well tolerated by most patients, and which has an additive cholesterol-lowering effect. Frost, a veteran of many clinical trials going back decades, prefaces his comments with the disclosure that he now serves occasionally as a paid speaker for Merck and Schering-Plough. Frost and cardiologists contacted for this story view the limited information released about ENHANCE as unrevealing. The proof of Vytorin's true effectiveness must await the results of clinical trials designed to compare clinical outcomes - heart attack, for example. These trials will not be completed for a few more years. Drugs Are Approved Without Showing Real Clinical Benefit Measuring LDL lowering in clinical trials is a "surrogate" measure for clinical benefit. It's not the same as identifying a real clinical benefit. The same can be said for measuring blood vessel wall thickness, as was used in ENHANCE, to track progression of atherosclerosis. But using surrogate markers yields results much more quickly than waiting for significant numbers of clinical trial patients to have heart attacks and strokes - called "clinical events" by medical researchers. In fact, the benefits of lowering LDL in patients with coronary artery disease is so highly esteemed that the Food and Drug Administration permits cholesterol lowering to be used to gauge success in studies that serve as the basis of drug approval. Many studies of cholesterol-lowering treatments have shown a relationship between amount of cholesterol lowering and amount of heart attack risk reduction, Frost notes. Fortunately, for the earliest generation of statins, studies demonstrating success in lowering cholesterol have been followed by years of additional studies that have demonstrated that these statins do indeed lower the risk of heart attacks among patients with proven heart disease and among patients at high risk for having a first heart attack. Frost says it remains important to track mortality from all causes in heart drug studies, not just reduction in heart attacks. For instance, he notes a large study in which the drug clofibrate reduced incidence of heart attacks, but did not increase overall life span. Quality and Biases of Studies Probed LDL lowering is a less useful endpoint in studies comparing one statin with another. A team led by Lisa Bero, PhD, a professor of clinical pharmacy at UCSF, found that in about 90 percent of journal reports on statin clinical trials, drug comparisons were based on measurements of surrogate markers, such as cholesterol lowering. Studies like that do not really indicate which of the tested drugs actually is better for preventing heart attacks. In the analysis, reported in the scientific journal PLoS Medicine last year, Bero and co-authors reviewed 192 clinical trials. Bero's research also suggested the possibility of bias in the publication of results from pharmaceutical company-funded clinical trials that evaluated statins. Published trial results that favored an experimental statin treatment over a comparison drug were 20 times as likely to be funded by the maker of the experimental statin. Similarly, when conclusions favoring the experimental drug were reported by trial investigators - who are expected to be unbiased and to take precautions to remain unbiased - studies were 35 times as likely to be funded by the company that made the drug. Different Paths to Cholesterol Lowering May Be Important ENHANCE has spurred speculation that drug treatments which lower cholesterol - but through distinctly different biochemical pathways - may not yield comparable clinical benefits. Statins put the brakes on cholesterol synthesis in a variety of organs, including the liver. In response, the cells make more of the molecules called LDL receptors, which then remove LDL from the blood. In contrast, Zetia works in the gut, where it reduces absorption of cholesterol from food. Dietary cholesterol is thereby prevented from going to the liver. In response, the liver then makes more LDL receptors to take LDL out of the blood. UCSF epidemiologist and internist Mark Pletcher, MD, MPH, says he is not surprised that the increased cholesterol lowering resulting from Vytorin treatment has not been associated with a better blood vessel outcome. Drugs that work differently to achieve the same goal - in this case, lowering cholesterol - may have unanticipated side effects or interactions that influence outcomes in unanticipated ways. "I think it makes more sense to use surrogate endpoints within a class of drugs than it does to use them to compare different classes of drugs. But with any use of surrogate endpoints, investigators run the risk of making the wrong conclusion about the effects of a drug," he says. In addition to conducting epidemiologic research and cost-effectiveness modeling on primary prevention of heart disease, Pletcher treats patients at risk for heart disease in the UCSF Mount Zion General Medicine Practice. "I almost never use Zetia," he says. "It's expensive and essentially unproven, especially in comparison with statins." Statins Have Anti-inflammatory Effects Statins have been shown by UCSF researchers and others to have anti-inflammatory effects. Inflammation contributes to the progression of cardiovascular disease, so some researchers believe that the anti-inflammatory effects of statins are responsible, at least in part, for their clinical effectiveness in treating ailing arteries. Researchers are exploring the possibility of using statins to treat a variety of diseases in which inflammation plays a role. For instance, Scott Zamvil, MD, PhD, a UCSF neurologist, discovered that statins have anti-inflammatory effects on the T cells that are instrumental in mounting an immune response. Zamvil is deploying the anti-inflammatory effects of atorvastatin in a clinical trial to prevent symptoms of multiple sclerosis, an autoimmune disease that strikes the nervous system. It appears that statins lower levels of a blood marker of inflammation called C-reactive protein, or CRP. Some evidence indicates that high levels of CRP are a risk factor for heart disease. But Frost notes that the association observed between statin treatment and CRP lowering is not good evidence that a reduction of inflammation due to statin treatment contributes to statins' effectiveness in lowering heart attack risk. At a UCSF-hosted symposium in January for reporters on inflammation in disease, Peter Libby, MD, of Harvard Medical School, a leading expert on the role of inflammation in heart disease, presented some of the newest findings in the field. When it comes to gauging coronary artery disease risk, Libby says, "The traditional markers - like high blood pressure, good cholesterol, bad cholesterol, age, sex, smoking - they work." But, he adds, "no matter what your level of traditional risk factors, if you also have the inflammation, it puts you in double jeopardy." Related Links: Mark J. Pletcher, MD, MPH Department of Epidemiology & Biostatistics Lisa Bero: Drug Company Funding of Drug Trials Greatly Influences Outcome UCSF News Release, June 4, 2007 Scott Zamvil: Anti-inflammatory Effects of Statins UCSF News Release, Nov. 4, 2002 "Introduction to Surrogate Markers," Circulation, 2004 ENHANCE Trial and Results, Cardiosource, American College of Cardiology Cardiosource Dingell, Stupak to Continue ENHANCE Trial Investigation Committee on Energy and Commerce Merck and Schering-Plough Respond to Issues Raised About ENHANCE Clinical Trial MERCK Press Release Peter Libby: UCSF-Hosted Symposium, "Inflammation as a Cause and Consequence of Disease" UCTV


Related Links

Mark J. Pletcher, MD, MPH
Department of Epidemiology & Biostatistics
Lisa Bero: Drug company funding of drug trials greatly influences outcome
UCSF News Release, Nov. 4, 2002
“Introduction to Surrogate Markers,”
Circulation, 2004
ENHANCE Trial and Results, Cardiosource, American College of Cardiology
Dingell, Stupak to Continue ENHANCE Trial Investigation
Committee on Energy and Commerce
Merck and Schering-Plough Respond to Issues Raised About ENHANCE Clinical Trial
MERCK Press Release
Peter Libby: UCSF-Hosted Symposium, “Inflammation as a Cause and Consequence of Disease”