Just How Important is Reducing LDL Cholesterol?

The fallout from the results of the ENHANCE trial, announced last week, has continued unabated. Much of the fallout has had to do with the question of corporate ethics, as was predicted in this space. Somewhat surprisingly, however, the ENHANCE trial has also caused a general "cholesterol backlash." Illustrative of this backlash are articles appearing last week in the New York Times and BusinessWeek, which ask the question: in the face of the ENHANCE trial, just how useful is it to reduce LDL cholesterol levels?

What has triggered this question is that in the ENHANCE trial, despite the significant reductions in LDL levels achieved with both simvastatin (41% reduction) and Vytorin (58% reduction), atherosclerosis progressed in both groups, and more so (though not statistically significantly so) in the Vytorin group. Why did this happen if LDL levels are so important? Both the New York Times and the BusinessWeek articles quote experts who now wonder aloud whether we've placed too much emphasis on reducing LDL levels.

So the ENHANCE trial has done more than just throw a monkey wrench in the Vytorin (and Zetia) marketing plans (for which, for reasons mentioned before, we can all be thankful). It has caused some to begin questioning the well-entrenched, dearly-held, lower-is-better paradigm.

DrRich Comments:

It ought to be noted that the ENHANCE trial was not the first to question the ultimate importance of LDL cholesterol. 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 cholesterol, but in 2006 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 as 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 by several mechanisms 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, apparently can arrest the progression of atherosclerosis in some patients. Whether this effect is due to low LDL levels or to some other effect of the statin itself is unknown.

To summarize, while reducing LDL levels may be extremely important, much of the available evidence is also consistent with the theory that it's the statins themselves that reduce cardiac risk, rather than primarily the reduction in cholesterol levels achieved by statins.

Sorting all of this out will take some time. So, 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? In DrRich's opinion, we should act according to what is known:

1) For everyone: take every available non-pharmacologic opportunity to reduce cardiac risk, including weight control, a good diet, plenty of exercise, not smoking, blood pressure control, and (admittedly controversial but reasonably well-documented) moderate alcohol (i.e., at least one drink per week, but no more than two drinks per day). These measures will reduce your cholesterol levels, but more importantly, they'll substantially reduce your risk despite your cholesterol levels.

2) For patients with established CAD (probably without regard to baseline cholesterol levels): statin therapy.

3) For patients at high risk for CAD: aggressive risk factor control, and discuss the utility of statin therapy with your doctor.

4) For patients with LDL cholesterol levels currently recommended for treatment according to latest guidelines, and who do not have established CAD: first try non-prescription control , and if that fails discuss statin therapy with your doctor.

5) For patients who should be considered for statin therapy (see items 2 - 4) but who cannot tolerate statins: Consider alternate pharmacologic therapy to reduce cholesterol, keeping in mind that the scientific evidence for such therapy is less well established.

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 called Familial Hypercholesterolemia. 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 that 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.