Original Articles
Epidemiologic aspects of lipid abnormalities

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Abstract

Existing cholesterol guidelines aimed at preventing cardiovascular disease emphasize the role of total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol in lipid management decisions, with a subsidiary role for high-density lipoprotein (HDL) cholesterol in guiding treatment and little role for triglycerides. In this article, epidemiologic evidence is reviewed relating to the independent value of lipid factors in prediction of cardiovascular disease risk, including TC, LDL cholesterol, HDL cholesterol, very-low-density lipoprotein (VLDL) cholesterol and triglycerides, LDL particle size (“pattern B”), and the TC/HDL-cholesterol ratio. Several observations are highlighted. Triglycerides appear to be an independent risk factor in specific populations. Postprandial triglycerides may be superior to fasting triglycerides as a predictor of risk. LDL particle size does not have independent predictive value after adjustment for triglycerides. Particular emphasis is placed on the observation that the single most predictive lipid factor is the TC/HDL-cholesterol ratio, which implicitly incorporates information on both LDL and triglycerides in the numerator. This is the best predictor both of outcome and of treatment benefit, and its predictive value appears to be maintained into older age. It is concluded that increasing emphasis should be placed on the TC/HDL cholesterol ratio in epidemiologic analyses and in monitoring patients on therapy for dyslipidemia.

Section snippets

Total cholesterol

Early studies focused on the total cholesterol (TC) in the serum or plasma and consistently showed a dose–response relation between the level of TC and the risk of coronary artery disease. For example, data from 361,662 men aged 35–57 screened for the Multiple Risk Factor Intervention Trial (MRFIT) showed that the age-adjusted death rate for coronary artery disease rose from about 3.5/1,000 men at a TC of 140 mg/dL to about 5/1,000 men at a TC of 200 mg/dL.2 The slope of the association in this

Effects of age

In contrast to the predictive value of cholesterol measured in observational analyses, where the relative and often absolute risk differences diminish sharply with age, analysis of the Lipid Research Clinic Coronary Primary Prevention Trial (LRC-CPPT)12 indicated that observational data underpredicted treatment benefit in older men. Relative treatment benefit was equal in older versus younger subjects, and absolute benefit tended to be greater in older subjects.13 This supports the proposition

LDL cholesterol

LDL cholesterol is thought to be the principal atherogenic lipoprotein in atherosclerosis. The Framingham Study15 reported in 1977 that LDL cholesterol was a better predictor than TC of coronary artery disease in both men and women. Multiple studies have confirmed this finding, although the strength of the association is sometimes greater in men than in women. For example, in the Lipid Research Clinics Follow-Up Study, whereas the association between LDL cholesterol and both cardiovascular

HDL cholesterol

Beginning with the pioneering observations of Barr in the 1950s on the inverse relation of alpha-lipoprotein to coronary artery disease,22 epidemiologic and other studies have consistently confirmed an inverse relation for HDL cholesterol; that is, as HDL cholesterol increases, coronary artery disease risk is lower (Figure 4).9 When analyzed with similar methodology, 1 British and 4 US studies were found to show a consistent protective effect for HDL cholesterol; a 1 mg/dL decrement in HDL

VLDL cholesterol and triglycerides

The amount of cholesterol carried on VLDL (VLDL cholesterol) is nearly perfectly correlated with the level of triglycerides in the blood, up to a triglyceride level of 400 mg/dL. Above this level, VLDL cannot be accurately estimated from the triglyceride level. In earlier epidemiologic studies, triglycerides and/or VLDL cholesterol were thought to have a neutral association with cardiovascular disease because, despite a consistent univariate association with cardiovascular disease, this

LDL density and pattern B

Using gel electrophoresis and other techniques, LDL particles can be separated by size.38 A predominance of smaller, denser particles—called “pattern B”—has been shown to be associated with higher coronary artery disease risk.39, 40, 41 In addition, some evidence exists that small dense LDL particles may be more easily oxidized and more atherogenic. However, LDL particle diameter is strongly and inversely correlated with the triglyceride level, with a correlation in the r = −0.7 range.40 In the

TC/HDL cholesterol ratio

Various ratios have been proposed to simplify the classification of hyperlipidemia and/or dyslipidemia to a single number. The ratios most frequently proposed are TC/HDL cholesterol, LDL cholesterol/HDL cholesterol, and recently triglyceride/HDL cholesterol.9, 13, 37, 49, 50 Each of these ratios carries composite information; that is, they have a numerator, which contains ≥1 lipid fractions with a positive association with coronary artery disease, and a denominator of HDL cholesterol, which is

Ratios and treatment benefits

Not only is the TC/HDL cholesterol ratio the best predictor of outcome in epidemiologic studies, it is also the best predictor of treatment benefit.13 In the LRC-CPPT, after considering the change in the TC/HDL-C ratio, there was no additional treatment benefit from changes in any other lipid parameter. Specifically, reduction in LDL cholesterol, the focus of the treatment with cholestyramine, added no additional benefit beyond the contribution to the TC/HDL cholesterol reduction. For example,

Conclusion

The TC/HDL cholesterol ratio is the best single measure to predict outcome in observational studies and carries nearly all of the prognostic information. Triglyceride level may add to prediction, particularly when HDL cholesterol is low and there are other manifestations of syndrome X. Change in TC/HDL cholesterol ratio is the best measure of risk reduction during therapy for dyslipidemia and should be monitored during therapy. A reasonable goal for treatment is a ratio <4, although this may

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