Effect of statins on low-density lipoprotein size: a new role in cardiovascular prevention?

To the Editor: Cardiovascular diseases still represent the first cause of death in most of the industrialized countries. An effective prevention includes the treatment of a series of risk factors: smoking, hypertension, diabetes, obesity and dyslipidemia. (1) Statins represent a class of cholesterol-lowering drugs as inhibitors of the hydroxymethylglutaryl-coenzyme A reductase enzyme which catalyzes one of the first steps of the cholesterol metabolic pathway. This class of drugs has been used in a very large number of patients, in both primary and secondary cardiovascular prevention, for its ability to reduce clinical events linked to atherosclerosis, including acute myocardial infarction, unstable angina, coronary revascularization procedures, cardiac death, stroke, symptoms of peripheral arterial disease and total mortality. (1)

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Besides their action on plasma lipid levels, statins have several effects on plasma lipoproteins that are independent from cholesterol reduction, and a number of studies have shown that statins are able to modulate the distribution of low-density lipoprotein (LDL) subclasses. (2) In fact, it seems that the "quality" rather than the "quantity" of LDL exerts a greater influence on cardiovascular risk. Based on the measurement of peak particle diameter, or ultracentrifugal density, individuals generally cluster into two broad subgroups: the majority with a predominance of larger or medium sized LDL (LDL-I and -II) and a substantial minority with a higher proportion of smaller, more dense LDL particles (LDL-III and -IV) (2,3) (Fig.).

Small, dense LDL are associated with an increased risk for cardiovascular diseases and diabetes mellitus, and a reduction in LDL size has been reported in patients with acute myocardial infarction, angina pectoris or noncoronary forms of atherosclerosis. (4) LDL size seems also to be an important predictor of cardiovascular events and progression of coronary artery disease, and the predominance of small, dense LDL has been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III. (1) In addition, small, dense LDL, with elevated triglyceride levels and low HDL-cholesterol concentrations, constitute the "atherogenic lipoprotein phenotype," a form of atherogenic dyslipidemia that is a feature of type 2 diabetes and metabolic syndrome. (5)

Recently, the Coordinating Committee of the National Cholesterol Education Program stated that very high-risk patients may benefit from stronger therapeutical approaches. Screening for the presence of small, dense LDL in patients with coronary or noncoronary forms of atherosclerosis may identify those with even higher vascular risk and may contribute to directing specific anti-atherosclerotic treatments to prevent new vascular events in the same or another district.

Hypolipidemic treatment is able to alter LDL subclass distribution. (2) Medications with triglyceride-lowering effects shift LDL size from small and dense to larger, more buoyant particles, and this may be explained by the fact that reduced availability of triglyceride-rich particles lead to a reduction in the production of small, dense LDL. This type of effect has been shown for both fibrates and niacin: these substances lower preferentially small, dense LDL, but in many studies, the net effect was only moderate. Statins potentially lower all LDL subclasses, but a number of studies have shown that they may strongly reduce atherogenic small, dense LDL, with a greater effect shown by atorvastatin and simvastatin.

In conclusion, the therapeutic modulation of distinct LDL subspecies (eg, small, dense particles) may be of great benefit in reducing the cardiovascular risk, and among all lipid-lowering molecules, statins (in particular, atorvastatin and simvastatin) seem to be very effective agents. Beyond cholesterol reduction, the implications of LDL size modulation by statins may be relevant in both primary and secondary prevention, in particular for patients at high risk for cardiovascular diseases.

Manfredi Rizzo, MD, PhD

Department of Clinical Medicine and Emerging Diseases

University of Palermo 

Palermo, Italy

Kasper Berneis, MD

Division of Endocrinology and Diabetology

University of Zurich 

Zurich, Switzerland

References

1. National Cholesterol Education Program (NCEP). Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106: 3143-3421.

2. Rizzo M, Berneis K. Low-density lipoprotein size and cardiovascular risk assessment. QJM 2006;99:1-14.

3. Griffin BA, Caslake MJ, Yip B, et al. Rapid isolation of low density lipoprotein (LDL) subfractions from plasma by density gradient ultracentrifugation. Atherosclerosis 1990; 83:59-67.

4. Rizzo M, Berneis K, Corrado E, Novo S. The significance of low-density-lipoproteins size in vascular diseases. Int Angiol 2006;25:4-9.

5. Rizzo M, Berneis K. Should we measure routinely the LDL peak particle size? Int J Cardiol 2006;107:166-170.