Residual Cardiovascular Risk: New Research on Particle Behavior

Two studies have demonstrated novel research directions for LDL-C and LDL-P. The first revealed that when LDL-C and LDL-P are concordant (that is either both high, normal, or low), either can serve as a good measure of CV risk. However, when they are discordant, cardiovascular events increase.

One fact is not up for debate: statins are marvelous therapeutic additions to the primary and secondary prevention of cardiovascular disease.

A cursory retrospective in this regard is worthwhile, specifically addressing trials aimed at secondary prevention. Three major secondary prevention trials each demonstrated a significant reduction in cardiovascular (CV) events (death or non-fatal myocardial infarction) when:
• Simvastatin, 20 mg/d, was administered in the “4S” trial (event rate active drug 19% vs 28% placebo)
• Pravastatin, 40 mg/d, was administered in the CARE Study (10.2% vs 13.2%)
• Pravastatin, at the same dose, was administered in LIPID (12.3% vs 15.9% placebo).1

Look at the numbers more closely. Statins reduce CV events approximately 20% to 30%. What about the remaining 70% or greater? Therein lies the rub of contemporary and future treatment regimens for risks leading to CV disease.

Where are we with addressing these substantial residual risks?

There will be 2 steps in the process-identifying what is responsible for residual risk, and developing drugs that target the appropriate problems. 
Atherosclerosis and one of its major risk factors-increased LDL (or LDL-C)-are much more complicated than previously realized. For example, the term “LDL” represents particles composed of cholesterol, triglycerides, a phospholipid coating, and an apolipoprotein (for LDL apolipoprotein B).2 To further complicate matters, people have different numbers of LDL particles (LDL-P) and possibly differing amounts of LDL-C per particle, not only in the absolute level that is presently measured. So, the LDL-P is the next frontier of prevention.

Two studies have demonstrated novel research directions for LDL-C and LDL-P. The first revealed that when LDL-C and LDL-P are concordant (that is either both high, normal, or low), either can serve as a good measure of CV risk.2,3 However, when they are discordant, for example when the number of LDL-P is high and LDL-C is not, CV events increase. In the MESA, or second trial, when LDL-P was greater than LDL-C in persons free of CV disease at entry, risks were increased in the higher LDL-P group.2,4

As a result of the implications of this study, it was suggested in 2008 that a broader, more scientifically updated view of CV risk be implemented. In higher-risk patients, LDL-P or other additional tests should be considered (such as apolipoprotein-B).2,5 

There is another area to consider. Presently, therapeutic responses to the LDL-C/LDL-P data are limited. Certain drugs (statins, statins plus ezetimibe or bile acid binders, estrogen replacement, and some antiretrovirals) lower LDL-C more than LDL-P.2 Conversely, fibrates, niacin, pioglitazone, and omega-3 fatty acids lower LDL-P more than LDL-C.2   

Are there better drugs on the horizon to target data implicating LDL-P/LDL-C discordancy? There are many new studies and potentially new drugs. This is the subject of part 2-looking at residual cardiovascular risk: the new "magic words." 

1. Chyu K-Y, Shah PK. Emerging therapies for atherosclerosis prevention and  management. Cardiol Clin. 2011;29:123-135.
2. Rader DJ, Underberg JA. Management of dyslipidemia and residual CV risk: importance of lipoprotein particle analysis.
3. Cromwell WC, Otvos JD, Keyes MJ, et al. Particle number and risk of future cardiovascular disease in the Framingham Offspring Study-implications for lDL management. J Clin Lipidology. 2007;1:583-592.
4. Otvos D, Mora S, Shalaurova I, et al. Clinical implications of discordance between low-density lipoprotein and particle number. J Clin Lipidology. 2011;5:105-113.
5. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2008;51:1512-1524.

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