Non-High-Density Lipoprotein Cholesterol: An Alternate Target for Lipid-Lowering Therapy

Vera Bittner, MD, MSPH

In This Article

Does Non-HDL Cholesterol Correlate With Cardiovascular Risk?

Non-HDL cholesterol, in contrast to LDL cholesterol, includes the cholesterol carried in triglyceride-rich lipoproteins. Why is this important? Although not well accepted in the past, recent meta-analyses suggest triglyceride levels are strongly and independently related to coronary artery disease risk.[12,13] Triglycerides are carried on triglyceride-rich lipoprotein particles that, despite their name, also carry substantial quantities of cholesterol. In vitro data, data from animal models, and data in human beings show that some of the triglyceride-rich lipoproteins (primarily the so-called remnant particles) are highly atherogenic.[14,15] The cardiovascular risk associated with plasma triglyceride concentrations is believed to be mediated through these atherogenic particles.

The link between LDL cholesterol and cardiovascular risk is well established and reviewed in detail in the NCEP ATP III guidelines.[1] Similarly, there is strong evidence for the link between coronary heart disease and lipoprotein(a) and intermediate-density lipoprotein cholesterol, the two lipoprotein fractions included in the LDL cholesterol levels calculated by the Friedewald formula.[16,17] Few studies have specifically examined the link between non-HDL cholesterol levels and measures of atherosclerosis in human beings.[18,19,20,21] In the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study, an autopsy study of 15- to 34-year-old men and women who died of accidents, homicides, or suicides, non-HDL cholesterol levels measured postmortem were positively associated with fatty streaks, raised lesions, and stenoses ≥40%.[18,19] Non-HDL cholesterol levels also relate to coronary disease progression in angiographic studies[20] and to carotid intimal medial thickness as measured by high resolution B-mode ultrasound.[21]

Most, but not all, epidemiologic studies that have examined the relationship between non-HDL cholesterol and cardiovascular morbidity and mortality have concluded that non-HDL cholesterol strongly predicts cardiovascular outcomes.[22,23,24,25,26,27,28,29,30,31,32,33] Prospective cohort studies in middle-aged men in Finland, Italy, and Great Britain showed that non-HDL cholesterol levels related to coronary heart disease morbidity and mortality.[22,23,24] Cross-sectional data from the Framingham Offspring study[25] suggested that non-HDL cholesterol was also a risk factor for coronary heart disease among middle-aged women. In a large cohort of middle-aged men (n=2406) and women (n=2056) who participated in the Lipid Research Clinics program Follow-up Study, both LDL cholesterol and non-HDL cholesterol levels predicted cardiovascular death over 19 years of follow-up.[25] Non-HDL cholesterol level seemed to be a somewhat stronger predictor than LDL cholesterol level in both sexes: a 30 mg/dL difference in non-HDL cholesterol translated to a 19% difference in cardiovascular mortality risk among men and a 11% difference in risk among women; corresponding risks for LDL cholesterol were 15% among men and 8% among women, respectively.[26] High non-HDL cholesterol levels in this study also predicted all-cause mortality in both sexes, whereas LDL cholesterol levels did not.[26] Data from the Stanford Five-City Project suggest the predictive value of non-HDL cholesterol level is independent of LDL particle size.[27]

Data among older persons are less clear. In the Systolic Hypertension in the Elderly Program (SHEP), which enrolled older men and women with hypertension, non-HDL cholesterol level predicted the combined end point of nonfatal myocardial infarction or coronary heart disease death over 4.5 years of follow-up after controlling for age, race, gender, history of coronary disease, diastolic blood pressure, smoking, diabetes, alcohol use, uric acid level, Rose questionnaire angina, presence of carotid bruit, and HDL cholesterol and triglyceride levels.[28] The relative risk was the same as for LDL cholesterol in comparable models.[28] In contrast, investigators from the Rancho Bernardo Study found no relationship between non-HDL cholesterol level and coronary disease and cardiovascular disease mortality at 3, 5, and 10 years of follow-up among older women and only a weak association between non-HDL cholesterol level and these outcomes among older men (these became nonsignificant after adjusting for other cardiovascular risk factors).[28] Interestingly, LDL cholesterol level was also not predictive in this cohort of older patients without a history of cardiovascular disease.[29]

Lehto et al.[30] showed that non-HDL cholesterol level, but not LDL cholesterol level, was a predictor of 7-year coronary heart disease mortality among patients with diabetes; when nonfatal events were included in the analysis, LDL cholesterol level was significant, but the hazard ratio (HR) was higher for non-HDL cholesterol level. In the Strong Heart Study, non-HDL cholesterol level among American-Indian subjects with diabetes predicted cardiovascular events at 9 years of follow-up even after adjusting for age, body mass index, smoking status, study center, systolic blood pressure, glycosylated hemoglobin level, fibrinogen, insulin, and ratio of albumin to creatinine.[31] HRs for non-HDL cholesterol in this study were somewhat higher than those for LDL cholesterol in both sexes (HR 2.23 and 1.80 for the highest tertile of non-HDL cholesterol level among men and women, respectively, vs. 1.71 and 1.61 for the highest tertile of LDL cholesterol level among men and women, respectively). Non-HDL cholesterol levels strongly predicted coronary heart disease, especially myocardial infarction, but not stroke.

Data on the relationship between non-HDL cholesterol and cardiovascular outcomes among patients with established coronary heart disease are more limited.[32,33] In the Scandinavian Simvastatin Survival Study (4S), non-HDL cholesterol levels in the placebo group seemed to be a slightly better predictor of major coronary events at 5.4 years than corresponding LDL cholesterol levels (-16.4% risk reduction vs. -12.8% risk reduction, respectively, for every 1 mmol/L [38.7 mg/dL] lower level).[32] In the Bypass Angioplasty Revascularization Investigation (BARI), a randomized trial of angioplasty vs. coronary artery bypass surgery among patients with multivessel coronary artery disease, baseline non-HDL cholesterol level (but not LDL cholesterol level) was an independent predictor of nonfatal myocardial infarction and angina pectoris at 5 years, even after adjustment for age, sex, race, history of hypertension, history of diabetes, angiographically determined severity of coronary artery disease, and treatment assignment to angioplasty or coronary bypass surgery.[33] In time-dependent analyses, every 10 mg/dL increment in average non-HDL cholesterol level increased the risk of nonfatal myocardial infarction by 5% and the odds of angina pectoris by 10%.[33]