HDL markers in cardiovascular risk prediction: ethnicity matters
High-density lipoprotein (HDL) has had a chequered history. Epidemiologic evidence supports HDL cholesterol (HDL-C) as a marker for cardiovascular risk, providing the rationale for its incorporation in SCORE, a cardiovascular risk algorithm1,2 Investigation of the potential of HDL-targeted therapies to reduce cardiovascular events in high-risk patients has, however, proved disappointing in clinical trials.3-6
Over the last few years it has been suggested that rather than measuring the cholesterol content of HDL, the concentration of particles may a better predictor of ASCVD risk. Epidemiologic studies have suggested this for low-density lipoprotein (LDL)7 and more recently HDL8,9. There are, however, gaps in evidence for the consistency of the association between HDL particle concentration and cardiovascular risk in different vascular territories, as well as for the impact of gender and ethnicity. A recent pooled cohort analysis in over 15,000 subjects offered insights.10
This study analysed individual-level data from four large population studies in subjects without atherosclerotic cardiovascular disease at baseline: the Dallas Heart Study (n=2,535), the Atherosclerotic Risk in Communities Study (n=1,595), the Multi Ethnic Study of Atherosclerosis (n=6,632), and Prevention of Renal and Vascular Endstage Disease (n=5,022). The main HDL markers of interest were HDL particle concentration, measured using the same nuclear magnetic resonance algorithm in each cohort, and HDL-C, and the primary outcomes were first fatal and non-fatal myocardial infarction (MI); and fatal and non-fatal ischaemic stroke, individually and as a composite. All cases of definite or probable haemorrhagic and embolic stroke events in the cohorts were excluded from the analysis. Cox proportional hazards models were used to determine hazard ratios (HR) per increasing race- and gender-specific quartiles of HDL-C and HDL particle concentration, with quartile 1 as the reference. Models were adjusted for traditional risk factors including age, hypertension, diabetes, smoking, lipid medications, LDL cholesterol (LDL-C), triglycerides, body mass index, waist circumference and high sensitivity C-reactive protein.
The analysis included 15,784 subjects (median age 56 years, 46% male); there were 8,550 women and 3,520 (22%) Black subjects. In total, 20% were smokers, 10% had diabetes and mean LDL-C was 115 mg/dL (2.97 mmol/L). Median (interquartile range) for HDL-C was 48 (40-57) mg/dL and for HDL particle concentration was 32.5 (28.8-36.8) μmol/L.
Over the mean follow-up period of 8 to 12 years across the cohorts, there were 515 MI events, 321 ischaemic stroke events and overall 1,242 ASCVD events. HDL particle concentration was inversely associated with both MI (HR for quartile 4 versus quartile 1: 0.63, 95% confidence interval [CI] 0.49- 0.81) and ischaemic stroke (HR for quartile 4 versus quartile 1: 0.66, 95% CI 0.48-0.93) For each 1 standard deviation increase in HDL particle concentration there was 16% decrease in the risk of ischaemic stroke. These associations between HDL particle concentration and risk for ischaemic stroke or MI were also observed in women. Ethnicity was, however, a modifier of this association. Specifically, the association between HDL particle concentration and MI was evident in White subjects (quartile 4 versus quartile 1, HR 0.49, 95% CI 0.35-0.69) but not in Black subjects (HR 1.22, 95% CI 0.76-1.98).
For the overall study population, HDL-C was associated with the composite endpoint of MI and ischaemic stroke (HR for quartile 4 versus quartile 1: 0.76, 95 CI 0.61-0.94); the relationship with the individual endpoints was more modest (HR for quartile 4 versus quartile 1: 0.79, 95% CI 0.61 -1.02 for MI and 0.77, 95% CI 0.54-1.10 for ischaemic stroke). These associations were consistent in men and women. In contrast, ethnicity modified the association between HDL-C and ASCVD risk, in particular MI. HDL-C was inversely associated with MI in White subjects (HR for quartile 4 versus quartile 1; 0.53, 95%CI 0.36-0.78) but there was no association in Black subjects. Moreover, there was no association between HDL-C and risk for ischaemic stroke in either group.
Traditionally, lipid assessment for risk estimation has focused on measurement of the cholesterol content of lipoproteins, such as LDL-C and HDL-C. There is, however, accumulating evidence that the association with ASCVD risk may be stronger for lipoprotein particle concentration, especially in the context of hypertriglyceridaemia associated with insulin resistant conditions.11,12 Thus, it was suggested that HDL particle concentration may show a better association with ASCVD risk than HDL-C. The results of the overall analysis are supportive of this, as HDL particle concentration was more consistently associated with ASCVD risk than HDL-C; this was also observed for ischaemic stroke in women. The other key point from this study is that neither HDL particle concentration nor HDL-C are likely to have clinical utility for predicting MI risk in Black subjects.
What are the take home messages from the clinical perspective?
The findings from this analysis suggest that HDL particle concentration may be a better risk predictor than HDL-C, although this warrants further evaluation. On the totality of available evidence, however, HDL-C remains a key risk marker in algorithms such as SCORE as it is easily measured and necessary for calculation of non-HDL-C, an important lipid target.
Finally, neither HDL-C nor HDL particle concentration was associated with MI risk in Black subjects. While recognising heterogeneity between the individual cohorts, the findings imply the need to take account of ethnicity in future refinements of risk prediction algorithms.
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