Will Zetia Save Your Heart?

In a recent clinical trail, a widely prescribed cholesterol lowering drug was found to offer no further protection against atherosclerosis, a condition that greatly increases the risk of heart attack, when used in combination with traditional statin treatment. The results, published March 30th in The New England Journal of Medicine, ran contrary to widespread expectation and attracted unusual media attention and public scrutiny. At a meeting of the American College of Cardiology that coincided with the release, editorial writer and panelist Harlan M. Krumholz, MD, said they “should change clinical practice,” and reminds us “how thin the evidence really is” for a drug with 34 million prescriptions and sales eclipsing $5 billion in 2007.

The medical community greeted ezetimibe, marketed as Zetia by Merck and Schering-Plough, with enthusiasm because it targeted so-called “bad cholesterol” by a new mechanism. Cholesterol is an important component of cell membranes, but too much of it can have serious consequences for the body, including heart attack and stroke. The bulk of it is produced internally by the tissues themselves, but a portion is also absorbed though the small intestine from the diet. Because cholesterol is not water soluble, this portion is transported in the blood by small particles called lipoproteins. Low-density lipoproteins (LDL), carriers of the infamous “bad cholesterol” are thought to deliver cholesterol to the tissues, while high-density lipoproteins (HDL) carry it away. The risks associated with high LDL cholesterol are complex but often manifest as an inflammatory response in the artery walls that can lead to a build up of plaque, ultimately restricting blood flow. Statins, the stalwart LDL cholesterol reducing agents, inhibit an enzyme responsible for a critical step in the biosynthetic pathway of cholesterol. To compensate for a shortage of cholesterol, cells respond by leaching more LDL cholesterol out of the blood. Ezetimibe, on the other hand, slows the absorption of cholesterol in the small intestine. The hope was that ezetimibe would benefit patients as a second line of defense against high cholesterol, particularly for patients who struggle to stay within range with traditional statin treatment and lifestyle changes.

Ezetimibe was approved by the FDA in 2002 based on evidence from clinical trials that patients who were prescribed both ezetimibe and a statin did, in fact, attain lower circulating LDL cholesterol levels (almost 30 percent lower) than patients taking a statin alone. Because decades of research and clinical testing have shown that statins greatly benefit patients, regulators - and much of the scientific community - accepted the observed reduction in LDL cholesterol as proof that ezetimibe would be similarly beneficial, termed a “surrogate” determinant of efficacy. This more recent trial, unblinded in 2006 but delayed for nearly two years, compared the progression of atherosclerosis by measuring the thickness of artery walls in over 700 patients with genetic predispositions toward high cholesterol. Patients were prescribed either simvastatin (Zocor), or simvastatin and ezetimibe (combined in one pill as Vytorin). After a period of two years, the group taking both drugs fared no better with respect to heart attacks and stroke, in spite of the almost 30 percent lower LDL cholesterol levels. The finding has puzzled scientists and clinicians alike. This caused many to take a hard look at the clinical justifications of ezetimibe and wonder how its use was allowed to balloon after only 4 years on the market.

In his editorial, Dr Krumholz conducted a rigorous comparison of ezetimibe use in Canada and the U.S. What he found was a surprisingly different pattern. Released as Ezetrol in Canada, prescription rates rose quickly, but not nearly as fast as in the United States. And with the release of Vytorin (the combined pill with simvastatin), prescription rates surged for a second time in the U.S., topping 34 million in 2007. Vytorin was never released in Canada and Ezetrol sales remained steady, receiving only a quarter of the number of U.S. prescriptions in 2007. Dr Krumholz estimates that 1 in 6 prescriptions for a cholesterol-lowering agent in the U.S. was ezetimibe, compared to 1 in 26 in Canada. Merck/Schering-Plough aggressively marketed the drug to doctors in both countries, pointing to its proven ability to reduce LDL cholesterol. And many doctors stood behind the drug based on the proven link between LDL cholesterol and heart disease.

The wide disparity between prescription rates in the U.S. and Canada can likely be explained by the millions spent on direct-to-consumer advertising ($200 million in 2007 alone), a practice that is illegal in Canada. The advertising campaign focused on the “two sources of cholesterol: food and family” with the slogan “Vytorin treats both.” This ad campain undoubtedly had a significant effect on prescription rates – but nowhere do they explain the limitations of the evidence. Doctors reported receiving hundreds of phone calls, some as many as 20 per day, from patients asking questions about Vytorin and their cholesterol treatment plans. Furthermore, the considerable delay in the release of the Vytorin results led to accusations that information was being withheld to boost sales.

Under intense pressure, Merck/Schering-Plough released preliminary results in a highly unusual January 15th news conference. Shortly after, New York State Attorney General Andrew Cuomo – who later subpoenaed both companies – quipped “while these companies profited, Americans were left in the dark.” The uproar also prompted two congressional investigations into the delay and what they viewed as the “use of misleading statements in direct-to-consumer advertisements.” With the attention these results have attracted there is little question new ezetimibe prescriptions will plummet, and doctors will think very carefully about prescribing the drug. Barring further proof that ezetimibe use provides a real clinical benefit, it’s time for a return to statins – a drug with a proven record – and a “return to evidence-based medicine,” according to Dr Krumholz . “I’m not saying this drug should go away, but it should definitely go to the end of the line.”

Ben Pedroja is currently working as a researcher in the Ophthalmology department at the Mount Sinai Medical Center in Manhattan. His research focuses on the mechanisms that regulate wound healing in the cornea.