LDL Cholesterol - The Lower the Better?

The debate goes on

cholesterol molecule
cholesterol. MediaForMedicine/UIG/Getty Images

There is an ongoing debate among cholesterol experts regarding the treatment of LDL cholesterol levels, and how rigorously doctors should try to push LDL to very low levels in patients who either have, or are at high risk for, cardiovascular disease. Some experts insist that doctors should push their patients’ LDL levels as low as they can get them. Others say, “Not so fast.”

Over the past decade, the pendulum has swung back and forth on this question. Then in 2013, the official cholesterol guidelines were updated, eliminating entirely any “target” LDL levels, much to the dismay of the “lower the better” crowd.

However, since that time new evidence has been developed that appears to suggest, after all, that reducing LDL to very low levels may be an inherently good thing to do. Many prominent cholesterol experts now say that the question is settled and that the guidelines need to be rewritten to reinstate (very low) LDL targets.

The whole question promises to become quite confusing for anyone who is at high risk for CAD (and their doctors), and who is trying to decide on cholesterol therapy.

Why LDL Targets Were Dropped In the First Place

The idea that LDL cholesterol is “bad,” and that reducing LDL levels will help prevent heart disease (known as the Cholesterol Hypothesis) is supported by a lot of experimental and clinical data.

Still, it has become clear that the Cholesterol Hypothesis is too simple. Atherosclerosis is caused by numerous factors, of which LDL cholesterol is only one. In addition, some kinds of LDL (tiny LDL particles ) are worse than other kinds (big LDL particles), and therapies might reduce the wrong kind of LDL.

In eliminating LDL treatment targets, the 2013 guideline writers took into account the following information:

  1. Several studies using several different therapies failed to show that significantly lowering LDL levels reduced cardiovascular risk. Prominent among these were the Women’s Health Initiative (which showed an increase in heart disease despite a substantial LDL reduction with hormone replacement therapy). Furthermore, studies with fibrates, bile acid sequestrants, niacin, ezetimibe and CETP inhibitors showed reductions in LDL cholesterol, with no measurable benefit in clinical outcomes (and in some cases, with worse clinical outcomes).
  2. The only class of LDL-lowering drugs that demonstrated a significant clinical benefit in several clinical trials were the statins. And statins, in addition to lowering cholesterol, also have several other actions that can reduce atherosclerosis. So, it is unclear whether or not the main benefits seen with statins are due to LDL reductions.

    In summary, the 2013 guidelines committee found that the accumulated clinical evidence did not support treating LDL cholesterol to a specific target. Rather, evidence supported addressing a single question: should this patient take statins, or not? And that’s what the guidelines did.

    Is It Dangerous To Drop LDL Levels Too Low?

    This is a question worth asking because some studies have correlated a very low LDL level with an increased risk of cancer, diabetes, and hemorrhagic stroke. While a correlation does not mean there is a causal relation, it is true that cholesterol is a critical component of cell membranes and hormonal balance, among other things. So there is at least a theoretical concern about reducing LDL beyond some undefined “optimal” level.

    What Is the New Evidence In Favor of Very Low LDL Levels?

    Nonetheless, since the 2013 guidelines were published, two new lines of evidence have been developed that appear to support pushing LDL to very low levels in high-risk patients.

    The PCSK9 Inhibitors - This new class of drugs, the first two of which were approved by the FDA in 2015, offer a novel and effective way to reduce LDL to very low levels, and early data suggests that doing so improves clinical outcomes. However, a study designed to measure clinical improvement more definitively will not be finished until 2018. Notably, these new drugs are not being used alone, but only in combination with statins.

    Statins Plus Ezetimibe - In the IMPROVE-IT trial, the addition of ezetimibe to simvastatin, sufficient to drive LDL levels from around 70 mg/dL to around 50 mg/dL, led to a modest improvement in clinical outcomes. In an earlier study, the use of ezetimibe alone appeared to worsen outcomes.

    The Bottom Line

    The bottom line is that the debate continues. While evidence from studies with the PCSK9 inhibitors (and IMPROVE-IT) do offer succor to those who espouse a “lower the better” theory, it will be a few years before we really have the data we need to support this approach. And whether PCSK9 inhibitors alone (instead of combining them with statins) would improve clinical outcomes is not even being studied yet. (We already know that ezetimibe alone does not.)

    Because statins do a lot more than merely lower cholesterol, any study that relies on the use of statins to show clinical improvement cannot truly test the hypothesis that a very low LDL level, by itself, is all that is needed. So we are a long way from settling the great debate among cholesterol experts.

    Fortunately, settling the debate is not really necessary for people whose risk of heart disease is elevated. We already know how to reduce that risk.


    Laufs U, Descamps OS, Catalan AL, et al. Understanding IMPROVE-IT and the Cardinal Role of LDL-C Lowering in CVD Prevention Eur Heart J. 2014;35(30):1996-2000.

    Sabatine MS, Guigliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; DOI:10.1056/NEJMoa1500858.

    Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association. J Am Coll Cardiol 2013.

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