Is ezetimibe/simvastatin no better than simvastatin alone? Lessons learned and clinical implications
Neutral results, negative publicity
On December 31, 2007, the ENHANCE study was unblinded, and on January 14, 2008, Merck/Schering-Plough issued a press release announcing the results. The press release stated that there were no statistically significant differences between the treatment groups in the primary end point or in any of the secondary end points, despite a 16.5% greater reduction in LDL-C (about 50 mg/dL) in the group receiving the ezetimibe/simvastatin combination. The composite intima-media thickness had increased by an average of 0.0111 mm in the combined-therapy group vs 0.0058 mm in the simvastatin-only group (P = .29) over the 24-month treatment period.5
The press release received unprecedented international media attention. One leading cardiologist commented to the media that ENHANCE showed “millions of patients may be taking a drug [ezetimibe] that does not benefit them, raising their risk of heart attacks and exposing them to potential side effects.”6 The perceived message that ezetimibe/simvastatin is harmful resulted in thousands of phone calls from concerned patients to their physicians throughout the United States. The American Heart Association (AHA) and the American College of Cardiology (ACC) issued a joint statement the next day saying that ezetimibe/simvastatin does not appear to be unsafe and that patients should not stop taking the drug on their own. In the following days, Merck/Schering-Plough placed advertisements in newspapers reaffirming the safety of ezetimibe and quoting the AHA/ACC statement.
But the full results of the study were not available at that point. In fact, Senator Charles Grassley (R-Iowa) had launched a congressional investigation into the delays in releasing the results of the ENHANCE trial in December 2007. A focus of the investigation was whether the sponsor was delaying the release either because the data reflected negatively on its product or because it was legitimately concerned about the quality of the measurements of the carotid intima-media thickness. After Merck/Schering-Plough placed the advertisements quoting the AHA/ACC statement, these organizations were criticized for touting the safety of ezetimibe while receiving educational grants and other funds from Merck/Schering-Plough. Senator Grassley sent a letter to the ACC in late March requesting information about the amount of funds the ACC had received.
Full results are published, and the ACC is misquoted
The ENHANCE study was selected for a special presentation at the ACC annual scientific session on March 30, 2008. The full ENHANCE results were presented by Dr. Kastelein, after which an expert panel led by Harlan M. Krumholz, MD, discussed the trial’s implications. The ENHANCE results were simultaneously published in the New England Journal of Medicine,1 accompanied by an editorial by B. Greg Brown, MD, and Allen J. Taylor, MD,7 and another editorial by the editors of that journal, Jeffrey M. Drazen, MD, and colleagues.8 The expert panel and the editorialists concluded that the ENHANCE trial data raised concerns about the cardiovascular benefits of ezetimibe; that statins should be used as initial therapy for hyperlipidemia and titrated to the goal LDL-C level or to the maximally tolerated dose; and that other drugs such as bile acid sequestrants, fibrates, and niacin should be used in combination with statins before considering ezetimibe.9
The next day, stories appeared in the media mistakenly stating that the ACC had recommended that ezetimibe/simvastatin be discontinued. This view was fueled by an article in the ACC’s Scientific Session News, penned by a contract writer and editor, with the headline, “ACC on Vytorin: Go Back to Statins” that said, “After waiting for 18 months for the results of the ENHANCE study, an ACC panel on Sunday encouraged physicians to use statins as a first line and prescribe Vytorin only as a last resort for patients unable to tolerate other cholesterol-lowering agents.”10
The ACC later clarified that this was the opinion of the panelists and not that of the ACC, and they reiterated statements from the AHA/ACC Secondary Prevention Guidelines11 recommending statins in maximally tolerated doses or titrated to a goal LDL-C level for first-line drug treatment of coronary artery disease, and recommending that patients speak with their physicians before discontinuing any therapy.
WHY WERE THE ENHANCE STUDY RESULTS NEUTRAL?
The ACC expert panel concluded that the most likely reason for the neutral ENHANCE results was that ezetimibe lowers LDL-C but does not confer a cardiovascular benefit. In the words of Dr. Krumholz (as quoted by Shannon Pettypiece and Michelle Fay Cortez on bloomberg.com), ezetimibe is “just an expensive placebo.”12
There are at least three potential explanations for the lack of benefit with ezetimibe in the ENHANCE trial. I list them below in order of lowest to highest probability, in my opinion:
Theory 1: Ezetimibe lowers LDL-C but is not antiatherogenic
Since almost all experts agree that lowering LDL-C confers cardiovascular benefits, if ezetimibe does not inhibit atherosclerosis it must have some “off-target” effect that negates its LDL-C-lowering benefit. Critics of ezetimibe point out that oral estrogen and torcetrapib also lower LDL-C but do not improve cardiovascular outcomes.13,14
The lack of benefit with these two other agents can be explained. Oral estrogen does not lower apolipoprotein B (an indication of the number of atherogenic particles), but rather it increases the levels of both triglycerides and C-reactive protein, and it is prothrombotic in some people.15 Torcetrapib increases aldosterone production and substantially raises blood pressure.16 Therefore, both drugs have true off-target effects that could explain their failure to reduce cardiovascular risk despite reductions in LDL-C. (Interestingly, though, oral estrogen has been shown to slow the progression of carotid intima-media thickness in newly postmenopausal women.17
Ezetimibe, however, lowers LDL-C by an ultimate mechanism similar to that of statins and bile acid sequestrants, ie, by up-regulating LDL receptors, although these drugs reach this mechanism via different pathways. Statins inhibit cholesterol synthesis, thereby lowering hepatic intracellular cholesterol and thus up-regulating LDL-receptors and enhancing LDL-C clearance from the plasma. Bile acid sequestrants interrupt bile acid reabsorption in the ileum, thereby decreasing intracellular hepatic cholesterol and up-regulating LDL receptors. Ezetimibe, like bile acid sequestrants, also decreases cholesterol return to the liver, lowering hepatic intracellular levels and thus up-regulating LDL receptors.18
Ezetimibe is unlikely to have an off-target effect because it is only fractionally absorbed systemically, and a recent animal study showed that it enhances macrophage efflux of cholesterol, thereby potentially increasing reverse cholesterol transport.19 Ezetimibe has also been shown to reduce atherosclerosis in animal models.20
In their editorial, Drs. Brown and Taylor7 noted that ezetimibe reduces the expression of adenosine triphosphate binding cassette A1 (ABCA1) in Caco-2 (an intestinal cell line), and this may be an example of an off-target effect. However, statins also reduce ABCA1 expression in macrophages.21 ABCA1 is sensitive to intracellular cholesterol, and when cholesterol levels are decreased, whether by statins or by ezetimibe, ABCA1 expression is down-regulated.22
