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Determining best cholesterol-based surrogate marker for lowering CHD
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Current treatment of hyperlipidemia is focused on decreasing LDL cholesterol to predetermined treatment goals using various antihyperlipidemic agents to decrease future or recurrent CHD event risk.
Although many statin trials have demonstrated a significant 25% to 35% CHD event risk reduction, there remains residual risk despite appropriate therapy, which has led to debate regarding the best cholesterol-based surrogate marker for assessing and lowering CHD risk.
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LDL cholesterol vs. particle
Currently, LDL cholesterol is the surrogate marker commonly used to assess and lower CHD risk. However, LDL cholesterol does not directly enter the coronary subendothelial space to build up and form plaques. Instead, LDL cholesterol is packaged into LDL particles, which enter the subendothelial space and eventually form arterial plaques. Thus, LDL cholesterol is used as a surrogate for LDL particles and, ultimately, as a surrogate for CHD. LDL cholesterol would be a good surrogate for LDL particles if the LDL particle population is homogeneous, meaning that the amount of LDL cholesterol in each particle is consistent. However, because the LDL concentration in LDL particles is variable, or heterogeneous, then LDL cholesterol may not be an adequate surrogate for LDL particles. LDL particle heterogeneity stems primarily from triglyceride variability, natural variability in LDL particle size and variability in LDL cholesterol level, whereby very low or high LDL can result in LDL-poor or –rich LDL particles.
To illustrate this point, two patients with LDL cholesterol of 100 mg/dL may have very different LDL particle size. This variance in LDL particle size creates a variance in the amount of LDL cholesterol contained in each particle. Patient A may have 10 particles of 10 mg/dL each and patient B may have 20 particles of 5 mg/dL each. Although both present with the same LDL cholesterol, patient B would be at an increased risk for future CHD due to the increased LDL particle number. A post-hoc analysis of the Framingham Offspring Study investigated the association between level of LDL cholesterol, LDL particles and mortality. Patients with low LDL particles had the lowest mortality regardless of level of LDL cholesterol, whereas patients with high LDL particles had the highest mortality regardless of LDL cholesterol level, suggesting that LDL particles may be a better surrogate marker for future CHD or mortality than LDL cholesterol.
Useful methods
Effective strategies to reduce LDL particles are the same strategies as those used to reduce LDL cholesterol. In one study that assessed various statin trials’ comparative efficacy in decreasing LDL cholesterol and LDL particles, statins decreased LDL cholesterol by an average of 35.9% (to 105.2 mg/dL) and LDL particles by an average of 30.6% (to 1,459.2 nmol/L). At these levels, the LDL cholesterol mean correlated with the 27th percentile for the population, whereas the LDL particles mean correlated to the 51st percentile, suggesting that LDL particle goal was not achieved by most. Statins remain an effective tool to reduce LDL particles, although larger doses may be needed to achieve the same results compared with LDL cholesterol.
There are no data with regard to other available cholesterol-lowering therapies, such as bile acid sequestrants or ezetimibe (Zetia, Merck), and LDL particle reduction. However, there are some data on extended-release niacin and fibrates and the effect on LDL particles. A small study (n=54) comparing ER niacin 1 g per day vs. placebo in patients with stable CAD and LDL cholesterol <100 mg/dL demonstrated that after 3 months niacin significantly decreased medium and small LDL particles compared with baseline (P≤.005) and placebo (P≤.05). Niacin 1 g per day also raised HDL cholesterol levels by 2.7%, significantly increased the number of large HDL particles (P≤.001) and decreased the number of small HDL particles (P=.027) compared with baseline and placebo; however, there was no net increase in total HDL particles. Confirmation of the effect of niacin on LDL particles in larger studies is necessary, but there may be a role for niacin in some patients with difficult-to-treat LDL cholesterol.
Lastly, a prospective, nested, case-control analysis from the VA-HIT trial demonstrated that gemfibrozil 600 mg twice daily (n=364) vs. placebo (n=697) in secondary prevention patients significantly increased HDL particles (P=.0005), increased HDL cholesterol (P≤.0001), decreased LDL particles (P≤.0001) and had no significant effect on LDL cholesterol (P=.14). Furthermore, when calculating OR for new CHD events, neither baseline nor on-treatment levels of LDL and HDL cholesterol were significant predictors of CHD risk. However, both LDL particles and HDL particles were significant predictors of CHD risk at baseline and on-treatment, suggesting particle number may be a more effective means of determining CHD risk in secondary prevention patients.
Guiding therapy
The American Association for Clinical Chemistry (AACC), in a position statement, supports the use of particle number through LDL particles or apolipoprotein B and has suggested treatment goals for both LDL particles and ApoB (see Table above). Because LDL particle is more expensive to measure (approximately $150 per test) than LDL cholesterol (approximately $40 per lipid panel), measuring LDL particles has not been widely embraced, although the AACC guidelines recommend using LDL particles or ApoB, besides LDL cholesterol, in all patients.
Clinically, patients who are most likely to benefit from LDL particle measurement are those with high triglycerides, diabetes, metabolic syndrome, low LDL cholesterol or those with moderate to moderately high-risk National Cholesterol Education Program (NCEP) risk category. LDL particles may assist in the determination of how aggressive to be with lipid-lowering therapy.
Eric Gupta, PharmD, BCPS, CLS, FCPhA, is an associate professor of pharmacy practice and administration at Western University of Health Sciences in Pomona, Calif.
Rhonda M. Cooper-DeHoff, PharmD, MS, is associate professor in the department of pharmacotherapy and translational research, College of Pharmacy, and division of cardiovascular medicine, College of Medicine, University of Florida, Gainesville. Dr. Cooper-DeHoff is Cardiology Today’s Pharmacology Consult column editor and a member of the CHD and Prevention section of the Editorial Board. For suggestions for future topics for this column, contact her at dehoff@cop.ufl.edu.
For more information:
- Contois JH. Clin Chem. 2009;55:407-419.
- Cromwell WC. J Clin Lipidol. 2007;1:583-592.
- Jafri H. J Clin Lipidol. 2009;3:45-50.
- Libby P. J Am Coll Cardiol. 2005;46:1225-1228.
- Otvos JD. Am J Cardiol. 2002;90:22i-29i.
- Otvos JD. Circulation. 2006;113:1556-1563.
- Sniderman AD. J Clin Lipidol. 2008;2:36-42.
Disclosure: Dr. Gupta reports no relevant financial disclosures.