Questioning the Importance of LDL Cholesterol: The ENHANCE Fallout

Michael O'Riordan

The debate surrounding the ENHANCE trial took a bit of a twist this past week when attention turned to the LDL-cholesterol hypothesis, with some experts arguing that lowering LDL cholesterol to prevent clinical events is an unsophisticated premise and that other factors beyond lowering LDL cholesterol are involved. Other reports openly questioned whether this latest evidence suggests it might not be important to reduce cholesterol levels.
"The idea that you’re just going to lower LDL and people are going to get better, that’s too simplistic, much too simplistic," Dr Eric Topol (Scripps Translational Science Institute, La Jolla, CA) told the New York Times last week [1].
Experts say, however, that this is not the dismissal of decades of research, including numerous studies in the past few years adding evidence to the "lower-is-better" cholesterol hypothesis. With many of those trials, researchers used higher and higher doses of statins to drive down cholesterol levels, all with the intention of further reducing clinical events. Instead, some say that how cholesterol is lowered is as important as how much.
"The message for me is not that lowering LDL cholesterol doesn't work to prevent disease progression or to prevent clinical events," Dr Steven Nissen (Cleveland Clinic, OH) told heartwire. "The important thing to remember is how the cholesterol levels are lowered. Statins do a lot more than reduce LDL cholesterol. They also increase HDL cholesterol, decrease triglycerides, and decrease C-reactive protein levels. Ezetimibe doesn’t do any of these things."
The temple of LDL cholesterol
In his most recent video post on theheart.org's TopoLog, entitled "Temple of the LDL cholesterol," Topol called the ENHANCE results surprising but noted that the ezetimibe/simvastatin combination would not even have met the criteria for noninferiority on the primary end point of carotid intima media thickness (IMT).
In terms of what this study means for LDL cholesterol and reducing events in cardiovascular medicine, Topol referenced a 1999 study by Dr Frans Van de Werf (University of Leuven, Belgium) and colleagues that showed that LDL had no predictive value but that oxidized LDL cholesterol was predictive of acute coronary syndrome and MI.
"One of the problems we may indeed be suffering is that we consider all LDL cholesterol the same," said Topol. "We know that the oxidized form is particularly noxious and proinflammatory. We don't know, for example, how different ways of lowering LDL cholesterol, such as with ezetimibe or statins, affect subspecies of LDL cholesterol, and we certainly have no knowledge about ezetimibe's reduction of events."
Is lowering LDL cholesterol important?
With the release of ENHANCE, a study showing that reductions in LDL cholesterol did not translate into improvements in atherosclerosis as measured by carotid IMT, as well as torcetrapib data published last year, questions have been raised about whether or not it is important to reduce LDL-cholesterol levels at all.
Some clinicians, in fact, are quite candid in their interpretation of the newly presented data. Dr Rodney Hayward (University of Michigan, Ann Arbor), for example, told BusinessWeek that the "current evidence supports ignoring LDL cholesterol altogether. [2]"
In case you've been under a rock . . .
The ENHANCE study captured the attention of clinical cardiology, the business world, and the media this past week when the results of the long-awaited and controversial ENHANCE study were presented. Investigators presented data showing no benefit of the combination of ezetimibe (Zetia, Merck/Schering-Plough Pharmaceuticals) and simvastatin (sold together as Vytorin, Merck/Schering-Plough Pharmaceuticals) over simvastatin alone.
ENHANCE, with lead investigator Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands), was conducted in 720 patients with heterozygous familial hypercholesterolemia (FH) and showed no significant difference in the primary end point--mean change in IMT measured at three sites in the carotid arteries--between patients treated with ezetimibe/simvastatin 10/80 mg and patients treated with simvastatin 80 mg alone over a two-year period.
There was also no statistically significant difference between the treatment groups for each of the components of the primary end point, including the common carotid artery. Key secondary imaging end points showed no statistical difference between treatment groups.
Commenting on the current climate following the release of the ENHANCE data, Dr Patrick McBride (University of Wisconsin Medical School, Madison) told heartwire that the LDL hypothesis is irrefutable.
"Anytime you can lower LDL-cholesterol levels safely, you are going to see reductions in the risk of clinical events," he said. "In any of the previously published cholesterol studies, there is always a decrease in cardiovascular risk with reductions in LDL cholesterol."
McBride stressed, however, the importance of safety. Two exceptions to the LDL hypothesis are estrogen and torcetrapib; both reduced LDL-cholesterol levels, but the reductions were offset with other side effects, he said. Estrogen, for example, resulted in blood clotting and posed a cancer risk, while torcetrapib increased blood pressure. Ezetimibe, he said, is safe in that no known abnormalities have been noted with the drug.
Nissen is skeptical, however, noting that much of the cholesterol hypothesis is based on studies with statins. He is not sure, noting the absence of data and the lack of imaging support, that adding ezetimibe to simvastatin is the most effective means to reduce risk. Moving the patient to a high-dose, highly potent statin, such as atorvastatin (Lipitor, Pfizer) 80 mg, is supported by the evidence.
"There are many advocates out there who espouse lowering LDL cholesterol by any means possible," said Nissen. "But let's be clear: 95% of the studies that form the basis for the cholesterol hypothesis are based on studies of statins. I think, then, extrapolating from these statin trials to ezetimibe is a mistake."
Speaking with heartwire, most experts echoed the notion that it is still too early to determine whether using ezetimibe to lower LDL cholesterol is an effective means to reduce hard clinical events, such as MI. They point out that the ENHANCE study was small, enrolled difficult-to-treat FH patients, and was a surrogate-end-point study. Although the imaging end points were nonsignificant, it had been hoped that the ezetimibe and simvastatin combination, which reduced LDL cholesterol 58% compared with a 41% reduction with simvastatin alone, would lead to slower disease progression.
Dr Roger Blumenthal (Johns Hopkins University Medical Center, Baltimore, MD) said that while it is certainly possible that not all the methods of reducing LDL cholesterol will be equally beneficial, he said that many statements made in the media have been alarmist.
"We are going to have a lot more data in the years to come, such as the completion of the IMPROVE-IT study, and it is only then that we're going to be able to know whether or not this particular method of lowering LDL is clinically beneficial."
The IMPROVE-IT study coming not so soon . . .
IMPROVE-IT is a multicenter, randomized, double-blind study that is enrolling 10 000 patients with ACS, including unstable angina, NSTEMI, and STEMI. Patients will be randomized to either ezetimibe 10 mg/simvastatin 40 mg or simvastatin 40 mg per day. Patients will be followed for over two years. The trial was not initiated until 2006, four years after the FDA approval of drug, and is not expected to be completed until 2011.
"I'll be blunt," Nissen told heartwire. "This was a case of the company putting all of their money into advertising instead of the needed clinical trials."
FH patients treated aggressively in the past
Commenting on the LDL hypothesis for heartwire, Dr Michael Blazing (Duke Clinical Research Institute, Durham, NC), who is involved in the IMPROVE-IT study, said that the ENHANCE study enrolled very-difficult-to-treat patients, those with FH and LDL-cholesterol levels exceeding 300 mg/dL. He stressed that the two-year change in mean carotid IMT between the treatment arms was neutral, and not doubled in the ezetimibe/simvastatin arm, as reported commonly in the media.
"In the meantime, some people are really going out on a limb," said Blazing. "At this point, we have data only from a surrogate-end-point trial and have no way of knowing what type of clinical effect the reductions in LDL will have. Moreover, we're extrapolating from a difficult patient population who has been treated aggressively in the past."
Dr Christie Ballantyne (Baylor College of Medicine, Houston, TX) told heartwire that too much has been made of an unpublished study. He agreed, however, that there are many questions that must be answered, such as what is the most effective way to lower LDL cholesterol after a high-dose statin failed to knock levels down low enough.
"I still think ezetimibe is a good option," said Ballantyne. "What I don't want people saying is that LDL is not important, although we know that it's not everything. This is a complex disease, but we want to avoid swinging too far, placing too much emphasis on an unpublished study, and dismissing 20 years of published research."
In his video blog, Topol also pointed to the new BusinessWeek article that questioned the value of statins, particularly the event protection conferred by atorvastatin. In the lengthy article, reporter John Carey crunches the numbers and shows that the number needed to treat to prevent one MI is 100, not a very impressive number. With reduction in strokes and longer-term follow-up, this benefit might increase, but the vast majority of patients are not really deriving protection from events, even though nearly all patients have a reduction of LDL cholesterol, said Topol.
"We've seen punching of holes in this whole LDL story, on multiple fronts," he said.
Berenson A. New questions on treating cholesterol. New York Times, January 17, 2008. Available at: http://www.nytimes.com.
Carey J. Do cholesterol drugs do any good? BusinessWeek, January 17, 2008. Available at: http://www.businessweek.com.