Forbes's Matthew Herper Bashes Zetia

Never missing an opportunity to engage in a Zetia (aka ezetimibe) pile-on, Forbes reporter Matthew Herper shows his continued disdain for the drug and its marketing in his most lopsided article yet. Herper's less-than-objective synopsis of Merck's Zetia-related troubles follows results of a recent, small head-to-head study, in which Abbott's Niaspan (extended-release niacin) outperformed Zetia in a highly selected population.

The essential problem with Herper's (and others') coverage of Zetia: He fails to stress that the drug significantly lowers LDL cholesterol—a well-recognized risk factor for vascular disease and a primary target of prevention guidelines. Herper is correct in writing, "No trials show that [Zetia] prevents heart attacks"; but he neglects to remind his readers that, at one time, the same could have been said of Pfizer's blockbuster statin Lipitor (atorvastatin).

Lipitor came to market in 1996 because it significantly lowered LDL-C; but Lipitor had not yet been shown to prevent clinical vascular events like other statins. Nevertheless, Lipitor quickly became the number-one statin because 1) it reduced LDL-C by a relatively greater percentage than other statins and 2) clinicians believe that the LDL-C level is directly related to the risk of vascular events. Lipitor wasn't approved to reduce the risk of vascular events until 2004.

Herper claims, "Merck's clever marketers have spun straw into gold"—a metaphor that wrongly equates the lowering of the LDL-C level with worthless "straw." To support his claim, he cites results of the Niaspan study and the infamous ENHANCE study, both of which enrolled highly selective at-risk populations and used another surrogate marker for vascular disease—the ultrasound measurement of carotid intima media thickness (CIMT). Merck (and Schering-Plough) reportedly struggled with the quality of the CIMT measurements in the ENHANCE study, and some investigators have questioned the usefulness of CIMT generally to assess cholesterol-lowering drugs. For instance, in the placebo-controlled CASHMERE trial, Lipitor failed to significantly alter CIMT in postmenopausal women, despite that fact that the statin undeniably reduces the risk of cardiac events and stroke.

Herper adds Zetia-disparaging quotes from prominent cardiologists, like Sanjay Kaul (who described Zetia as "the miracle of marketing, not the miracle of medicine") and renowned Zetia/Vytorin basher Steve Nissen ("We've spent billions on a drug that may turn out to be a placebo.") Herper also implicitly chastises Merck for waiting 3 years after Zetia approval (in 2002) to begin the IMPROVE-IT study, in which Vytorin (the combination of ezetimibe and simvastatin) is being compared with simvastatin alone to reduce the risk of a composite vascular outcome. Vytorin was FDA approved in 2004.

Herper also unfairly casts aspersions at prominent cardiologists Michael H. Davidson and Antonio M. Gotto, Jr, for providing "lecture and consulting" services to Merck after the results of the ENHANCE study became public. Herper implies that these physicians were paid off to promote the drug, despite the fact that the small and troubled ENHANCE study failed to show the benefit of adding Zetia to statin therapy in a highly select group of patients (ie, individuals with familial hypercholesterolemia). Herper's information was evidently supplied by the office of Senator Grassley, ranking minority member of the Senate Finance Committee.

A quick examination of the medical literature reveals that both physicians (like so many others) endorse the vascular benefits of lowering the LDL-C level. For instance, in a recent editorial, Gotto writes, "Lowering elevated [LDL-C] is a surefire way to reduce cardiovascular risk." But he also acknowledges the potential drawbacks of using surrogate markers to assess the protective benefits of drugs by adding, "As monotherapy, [Zetia] at 10 mg reduces LDL-C by approximately 17%, but when added to any dose of statin, it reduces LDL-C by an additional 25%. Given the well-established log-linear relationship between LDL-C and relative risk for [coronary heart disease], these greater degrees of LDL-C reduction can be expected to result in improved clinical outcomes, although this has not yet been proven in the case of ezetimibe."

In another editorial ("Is LDL-C passed its prime?"), Davidson more clearly lays out the shortcomings of applying general guidelines to what is probably a very heterogenous at-risk population. He notes that the rising number of patients with metabolic syndrome and those currently taking statins present more complex portraits of dyslipidemia and its associated vascular risks. He argues that, in these subgroups, other lipid markers—like apoB, LDL-particle number, and non-HDL levels—become relatively more predictive of coronary heart disease. Consequently drugs that specifically affect these levels (for example, niacin) may be more protective in these specific populations.

CASHMERE = Carotid Atorvastatin Study in Hyperlipidemic Postmenopausal Women; ENHANCE = Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression; IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial; LDL = low-density lipoprotein.