Managing Residual CVD Risk: The Role of HDL Cholesterol – Issue 1

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Issue Author
Robert D. Brook, MD
Associate Professor
Department of Internal Medicine
University of Michigan
Ann Arbor MI


Series Chair
Clinical Professor
University of Illinois
School of Medicine
Peoria, IL
Director of Preventive Cardiology
Sterling Rock Falls Clinic, Ltd.
Sterling, IL

Click Here to read Dr. Tóth’s commentary on this issue.



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The Association Between HDL Cholesterol and CVD Risk: Where Do We Stand?


The relationship between low concentrations of high density lipoprotein-cholesterol (HDL-C) and the risk for cardiovascular (CV) disease has been known for decades. This inverse association persists even after adjusting for multiple concomitant risk factors and has been demonstrated among numerous populations and several meta-analyses. Low HDL-C is an increasingly prevalent disorder of growing public health importance given the worldwide epidemic of the metabolic syndrome and the growing use of HMG CoA reductase inhibitors (statins) to treat low density lipoprotein-cholesterol (LDL-C). Despite the consistent inverse relationship among epidemiological studies, the linkage between a residual low HDL-C among patients treated with statins and excess CV risk is less clearly established. Moreover, recent studies evaluating the importance underlying genetic influences on HDL-C concentration as well as conditions associated with extreme values of HDL-C (high or low) have provided mixed results. These findings illustrate that HDL is not a simple homogenous lipoprotein but rather a complex mixture of particles of varying size, functionality, and composition. Emerging evidence suggests that certain subsets of HDL particles may be more protective against CV disease than others. Given that clinical trials have yet to demonstrate that raising HDL-C per se directly translates into a reduction in hard CV events, more research is still needed to clarify and elucidate the complicated relationship between HDL-C and atherosclerotic vascular disease.


HDL-C and the Risk for CV Diseases

Epidemiological Studies Linking Low HDL-C with Elevated CV Risk

Decades of research has demonstrated an inverse relationship between HDL-C and the risk for CV events.1 The most recent meta-analyses of epidemiological studies have confirmed that this association is graded, monotonic, and evident across a wide range of HDL-C levels without apparent threshold values.2, 3 Importantly, the CV risk due to lower HDL-C values is not obviated by statistically controlling for numerous other CV risk factors (eg, hypertension), as well as circulating atherogenic lipoproteins (eg, LDL-C or non-HDL-C) and triglyceride levels.3 This inverse relationship has been corroborated in men and women as well as across wide ranges of age groups, races, and differing populations worldwide.4-6

Perhaps the most robust epidemiological evidence derives from the recent Emerging Risk Factor Collaboration (ERFC) meta-analysis,2 which showed that each standard deviation increase in HDL-C (15 mg/dL) was related to a 22% decrease in coronary heart disease (CHD) risk (Figure 1).

Figure 1. HDL-C and coronary heart disease risk from ERFC meta-analysis.

The Emerging Risk Factors Collaboration. JAMA. 2009;302:1993-2000. Used with permission.



The findings from the ERFC 2 largely corroborated the earlier results from the Prospective Studies Collaboration.3 In the latter meta-analysis of approximately 150,000 individuals with available HDL-C results, the total cholesterol/HDL-C ratio was the most predictive lipoprotein marker of CV risk. This ratio was more than twice as potent a predictor of ischemic heart disease compared to total cholesterol alone. Other factors, such as the presence of hypertension, did not attenuate this risk but additively increased absolute event rates. These findings confirm that HDL-C is a strong independent risk factor for ischemic heart disease.

The most recent meta-analysis worthy of discussing evaluated the coronary heart disease risk associated with specific low HDL-C phenotypes.7 In 2 large collaborations of prospective cohorts and cross-sectional studies, the prevalence of HDL-C disorders and the associated CV risks were compared in Asians versus non-Asians. Individual-level data from >220,000 participants (87% Asian) from 37 studies were included. Low HDL-C (<40 mg/dL in men and <50 mg/dL in women) was common in both Asians (33.1%) and non-Asians (27%). However, an isolated low HDL-C (normal non-HDL-C and triglycerides) was a far more prevalent lipid disorder among Asians (22.4% versus 14.5% of the populations) (Figure 2). The study also confirmed the known inverse association between HDL-C and coronary heart disease. Individuals with low HDL-C values, regardless of the phenotype and after controlling for other risk factors, had a 57% higher risk of events. Though isolated low HDL-C was not independently related to higher risk (hazard ratio [HR] 1.17; 95% confidence interval [(CI], 0.95-1.46) in the whole populace, this phenotype increased coronary events among Asians (HR 1.67; 95%CI, 1.27-2.19), but not among non-Asians. These interesting findings suggest that while low HDL-C is associated with coronary risk among all individuals, isolated low HDL-C poses a risk in a race-dependent fashion. Further studies are warranted to investigate these novel findings.


Figure 2. Prevalence of low HDL-C phenotypes in Asians and non-Asians.

Huxley RR, et al. Circulation. 2011;142:2056-2064. Used with permission.


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