Clinical Review

YOU HAVE A NEW JOB: Monitor the lipid profile

OBG Manag. 2008 December;20(12):45-53

References

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2. Biggerstaff KD, Wooten JS. Understanding lipoproteins as transporters of cholesterol and other lipids. Adv Physiol Educ. 2004;28:105-106.

3. Nordestgaard BG, Wooten R, Lewis B. Selective retention of VLDL, IDL and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo. Molecular size as a determinant of fractional loss from the intima-inner media. Arterioscler Thromb Vasc Biol. 1995;15:534-542.

4. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk. Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care. 2008;31:811-822.

5. Barter PJ, Ballantyne CM, Carmena R, et al. ApoB versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel. J Intern Med. 2006;259:247-258.

6. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet. 2001;358:2026-2033.

7. Mudd JO, Borlaug BA, Johnson PV, et al. Beyond low-density lipoprotein cholesterol: defining the role of low-density lipoprotein heterogeneity in coronary artery disease. J Am Coll Cardiol. 2007;50:1735-1741.

8. Executive Summary of the 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). JAMA. 2001;285:2486-2497.

9. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:227-239.

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11. Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. 2007;115:1481.-

12. Sniderman AD. Apolipoprotein B versus non-high-density lipoprotein cholesterol. And the winner is… Circulation. 2005;112:3366-3367.

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15. Cromwell WC, Otvos JD, Keyes MJ, et al. LDL particle number and risk of future cardiovascular disease in the Framingham Off spring Study—implications for LDL management. J Clin Lipidol. 2007;1:583-592.

16. El Harchaoui K, van der Steeg WA, Stroes ES, et al. Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study. J Am Coll Cardiol. 2007;49:547-553.

17. Mora S, Szklo M, Otvos JD, et al. LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis. 2007;192:211-217.

18. Liu J, Sempos CT, Donahue RP, et al. Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their predictive risk values in coronary heart disease. Am J Cardiol. 2006;98:1363-1368.

19. National Cholesterol Education Program. Recommendations on lipoprotein measurement from the Working Group on Lipoprotein Measurement. National Institutes of Health. National Heart, Lung, and Blood Institute. NIH Publication No. 95-3044. Bethesda, Md: September 1995.

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Because LDL is the predominant apoB species, non-HDL-C is the best lipid concentration predictor of LDL-P.¹⁵ Because neither TC nor HDL-C assays require a patient to fast, non-HDL-C is accurate in nonfasting patients, making it a very practical way to screen for CVD risk.⁸ In the Women’s Health Study, which involved mostly healthy women, non-HDL-C predicted the risk of coronary heart disease as well as apoB did, but not as well as LDL-P.^22,23 In independent, separately published analyses from the Framingham Off-spring Study, LDL-P was a better predictor of risk than LDL-C and apoB.^15,24

NCEP ATP-III guidelines introduced non-HDL-C as a secondary goal of therapy in patients with TG >200 mg/dL. Subsequent data indicate that non-HDL-C is always a better predictor of risk than LDL-C is, regardless of TG levels.¹⁸

The AHA Women’s Guideline was the first to set a desired non-HDL-C level (130 mg/dL) independent of the TG value.¹⁰ Because a normal VLDL-C concentration is 30 mg/dL, the non-HDL-C goal is 30 mg/dL above the desired LDL-C goal. For example, if the desired LDL-C value is 100 mg/dL, the non-HDL-C goal is 130 mg/dL. If the desired LDL-C goal is 70 mg/dL—as it is in a patient at very high risk—the non-HDL-C goal would be 100 mg/dL ( FIGURE ).^9,11

Insulin resistance diminishes accuracy of lipid profile

The ability to predict lipoprotein particle concentrations using the lipid profile becomes far less accurate in situations associated with insulin resistance and metabolic syndrome in patients who have TG-HDL axis disorders. In women, these disorders are typified by an elevation of TG >150 mg/dL and a decrease in HDL-C <50 mg/dL, with borderline or normal LDL-C levels.²⁵

As TG begins to rise above 120 mg/dL, hepatic secretion of TG-rich VLDL particles increases. As VLDL-TG is hydrolyzed by lipoprotein lipase in muscle and fat cells, in a process termed lipolysis, VLDL shrinks and transforms into IDL. Ultimately, unless it is cleared by hepatic LDL receptors, the IDL undergoes additional lipolysis by hepatic lipase and transforms into LDL particles. Because of their longer half-life, these LDL particles accumulate, further elevating apoB and LDL-P.

In the presence of TG-rich VLDL and chylomicrons, additional pathologic particle remodeling occurs. By way of a lipid transfer protein called cholesteryl ester transfer protein (CETP), some of the TG molecules present in TG-rich lipoproteins are exchanged for cholesteryl esters in LDL and HDL. This lipid transfer creates LDL and HDL that are TG-rich and cholesterol-poor, enabling additional TG lipolysis by hepatic lipase to create smaller LDL and HDL. The latter is so small that it can pass through renal glomeruli and be excreted, leading to reductions of HDL-P, apoA-I, and HDL-C.

Also created in this process are smaller, atherogenic, cholesterol-rich VLDL and chylomicron remnants, diagnosable by an elevated VLDL-C. Patients who have this pathology typically have elevated TG, reduced HDL-C, variable LDL-C, and an increased TG/HDL-C ratio (>3.8), which are indicative of too many small LDL particles (high apoB, LDL-P) and reduced number of HDL particles (high apoB/A-I ratio).^26,27

Such a scenario, typical of TG-HDL axis disorders, explains much of the risk associated with rising TG levels and is very common in premenopausal women who have insulin-resistant states such as type 2 diabetes or polycystic ovary syndrome and in menopausal women who have insulin resistance and coronary artery disease.¹

LDL-C and LDL-P do not always correlate

Because the volume of a lipoprotein is a function of its radius cubed (V = 4/3πr³),¹⁴ a patient who has small LDL will require up to 40% to 70% more LDL particles to traffic a given amount of LDL-C. In such a patient, there is often little correlation between LDL-C and LDL-P or apoB values. Regardless of the LDL-C, the apoB, LDL-P, or non-HDL-C is often elevated.²⁸ This risk, which cannot be predicted by looking only at LDL-C, is the main reason guidelines advocate the use of non-HDL-C or the TC/HDL-C ratio.^8,11 (See the case studies.)

In summary, a large part of the risk of CVD seen in patients who have low HDL-C derives from the associated increase in the number of apoB particles, mostly composed of small LDL, as well as an increase in remnant particles.^15,21,28 This crucial point explains why treatment of low HDL-C states should always first target apoB or LDL-P (LDL-C and non-HDL-C), rather than apoA-I or HDL-C ( TABLES 3 and 4 ).^8,9

TABLE 3

Lipid markers of small low-density lipoproteins

High-density lipoprotein cholesterol (HDL-C) <50 mg/dL
Triglyceride (TG) >130–150 mg/dL
Total cholesterol/HDL-C ratio >4.0 with normal low-density lipoprotein cholesterol (LDL-C)
TG/HDL-C ratio >3.8 in women
Unremarkable LDL-C but elevated non-HDL-C