This question, which until recently most cardiologists would have considered settled, has been reopened after the results of the ENHANCE trial were made public. The ENHANCE trial compared the use of the statin drug Zocor (simvastatin) to the widely advertised anti-cholesterol drug Vytorin (which consists of Zocor plus ezetimbe, a drug that blocks cholesterol absorption from the gut) in patients with a severe inherited cholesterol disorder called familial hypercholesterolemia.
In the trial, despite the significant reductions in LDL levels achieved with both Zocor (41%) and Vytorin (58%), atherosclerosis progressed in both groups, and more so in the Vytorin group (though the result was not statistically significant). Why did this happen if LDL levels are so important? In response to the ENHANCE trial, popular articles appearing in both The New York Times and BusinessWeek found experts who wondered aloud whether we've placed too much emphasis on reducing LDL levels.
It ought to be noted that the ENHANCE trial was not the first to question the ultimate importance of LDL cholesterol. For instance, estrogen therapy reduces LDL cholesterol, but at least in some subgroups of postmenopausal women its use significantly increases cardiac risk. Similarly, torcetrapib reduces LDL and increases HDL ("good") cholesterol. In 2006, however, this projected blockbuster drug was nonetheless shown to result in increased cardiovascular risk, and has now been abandoned. At the very least, doctors have known (or should have known) for some time that the "cholesterol story" we've all been taught since we were babes in arms is not quite as simple and straightforward as it seemed.
So let's briefly review what we do know:
- For patients with established coronary artery disease (CAD), reducing cholesterol with statins significantly and substantially reduces the subsequent risk of heart attack and death. (This is called secondary prevention.)
- For some patients with elevated risk for CAD, reducing cholesterol with statins statistically reduces that risk. (This is called primary prevention.) Whether that risk reduction is substantial, however, is debatable. (See the BusinessWeek article cited above.)
- Obviously (from estrogen studies and torcetrapib studies), the method by which cholesterol reduction is achieved is important in determining whether risk reduction is thereby also achieved. Very few studies exist showing that cholesterol reduction using anything other than statins reduces cardiac risk.
- Statins work in several ways to reduce cardiac risk (including plaque stabilization, reduction in CRP levels, reduction in inflammation, as well as others). How much of the benefit seen with statins is actually due to cholesterol reduction, and how much is due to some of these other mechanisms? That's an open question. Indeed, for patients with established CAD, treatment with statins reduces subsequent risk even if their baseline cholesterol levels are not substantially elevated.
- Achieving very low levels of LDL cholesterol, using high doses of statins, can apparently arrest the progression of atherosclerosis in some patients. Whether this effect is due to low LDL levels or some other effect of the statin itself is unknown.
To summarize, while reducing LDL levels may indeed be very important, much of the available evidence is also consistent with the theory that it's the statins themselves that reduce cardiac risk, rather than the reduction in cholesterol levels achieved by statins.
Sorting all of this out will take some time. While the experts spend the next several years deciding how much benefit there actually is in reducing LDL cholesterol levels (as opposed to simply taking statins), what about those of us (doctors and patients) who need to decide what to do now? Recommendations on what we ought to do about cholesterol and statins today can be found here.
Finally, an irony. The ENHANCE trial, which triggered this latest round of LDL angst, enrolled patients with a severe form of genetically elevated cholesterol levels. Indeed, the average baseline LDL cholesterol level of patients enrolled in this study was an astoundingly high 318 mg/DL. This means that even after effectively reducing their LDL cholesterol levels by about 50%, these patients were left with post-treatment LDL levels that remained sufficiently high. The continued progression of atherosclerosis would still be expected (even if you subscribe to the low-cholesterol paradigm). In other words, given the relatively high levels of post-treatment LDL cholesterol, there appears to be no particular reason this study should have caused anyone to question the real value of low LDL levels, as legitimate as the question may be.
Sources:
American College of Cardiology Statement on the ENHANCE trial: http://www.acc.org/enhance.htm
Helfrand M, Carson S, Kelley C. Drug Class Review on HMG-CoA Reductase Inhibitors (Statins). Oregon Evidence-based Practice Center, Oregon Health and Science University. Available online at: http://www.ohsu.edu/drugeffectiveness/reports/documents/Statins%20Final%20Report%20u2.pdf%20Report%20u2.pdf
