HDL cholesterol: new light on stroke risk?

Findings from a meta-analysis of statin studies suggest a role for systematic measurement of high-density lipoprotein (HDL) cholesterol in stroke patients. This is not routinely undertaken at present. The data are reviewed by HDL Forum Editor Professor Philip Barter in this commentary.

Amarenco P, Labreuche J. Lipid management in the prevention of stroke: a review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 2009;8:453-63.

Previous epidemiological studies have found an inconsistent association between total cholesterol and stroke risk. In the Prospective Study Collaboration meta-analysis of data from 45 observational cohorts (n=450,000), there was no evidence of any association between total cholesterol levels and risk of fatal stroke (1). However, this analysis failed to take account of non-fatal stroke, an important source of bias, as well as the nature of the stroke. This latter point is highlighted by data from the Multiple Risk Factor Intervention Trial (MRFIT), which demonstrated a positive association between cholesterol and ischaemic stroke but an inverse association between cholesterol and haemorrhagic stroke (Fig 1) (2).

Epidemiological evidence also supports a weak association between low-density lipoprotein (LDL) cholesterol and stroke risk (3). However, until recently, little attention has been paid to HDL cholesterol.

Drs Pierre Amarenco and Julien Labreuche, INSERM U-698 and Bichat University Hospital, Paris-Diderot University, Paris, France undertook a meta-analysis of 24 randomized studies of statins in combination with other preventive strategies (n=165,792 patients in primary and secondary prevention settings). While reduction in LDL cholesterol levels by 1 mmol/L (39 mg/dL) led to a 21% reduction in stroke risk (95% CI 6.3-33.5, p=0.009), the authors also highlighted a need for further study, In particular, the authors suggested a potential role for raising HDL cholesterol levels to reduce stroke risk. ‘Clinicians might need to take into account the ratio of LDL to HDL cholesterol rather than just the standard LDL cholesterol concentration. Future epidemiological studies should focus on this ratio.’

The authors summarised the evidence to support this statement.

The weight of evidence in the literature supports an inverse association between HDL cholesterol levels and risk for stroke or carotid atherosclerosis

In a systematic review of 18 studies (4), 8 of 10 prospective cohort studies (n=238,739) and 3 of 8 case-control studies (n=3604 cases, 8220 controls) showed an association between elevated HDL cholesterol levels and decreased risk of stroke. Prospective cohort studies showed an 11-15% decrease in stroke risk per 10 mg/dL increase in HDL cholesterol (Fig 2). Additionally, in 37 studies involving measurement of intima-media thickness (IMT), 31 reported associations between HDL cholesterol level and carotid atherosclerosis.

In the secondary prevention setting, low HDL cholesterol at baseline was the only lipid abnormality associated with risk of recurrent stroke

The Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) study was the only randomized study that assessed statin use (atorvastatin 80 mg/day) for secondary prevention of stroke (n=4,731 patients). Subgroup analysis of patients with carotid stenosis at entry showed that baseline levels of HDL cholesterol (hazard ratio 0.87, 95% CI 0.79-0.97, p=0.012) and the ratio of LDL to HDL cholesterol (hazard ratio 1.31, 95% CI 1.06-1.62, p=0.012) were predictive of stroke risk. The protective effect of increasing HDL cholesterol levels was even more beneficial in patients with ischaemic stroke (Fig. 3) (5).

 In subjects without prior stroke, evidence supports the value of measuring the ratio of total to HDL cholesterol as a predictor of stroke risk

The Prospective Study Collaboration meta-analysis (6) included data from 61 prospective observational studies comprising almost 900,000 adults without previous disease and with baseline measurements of total cholesterol and blood pressure (3). Information about HDL cholesterol was available for 150,000 participants, among whom there were 5000 vascular deaths (3000 ischaemic heart disease, 1000 stroke, 1000 other). Of various simple measures involving HDL cholesterol, the ratio total/HDL cholesterol was the strongest predictor of ischaemic heart disease mortality (40% more informative than non-HDL cholesterol and more than twice as informative as total cholesterol). The ratio of total to HDL cholesterol was also more predictive of future stroke than HDL, non-HDL or total cholesterol.

However, measuring the ratio of apolipoproteins (apo) B/A-I may be a more robust marker of stroke risk. In the AMORIS study (7), involving over 175,000 subjects, low apoA-I was a common abnormality in all stroke subtypes. In multivariate analyses the ratio of apoB/apoA-I was a stronger predictor of risk of stroke than either the total/HDL cholesterol or LDL/HDL cholesterol ratios. The odds ratio comparing the upper 10th versus the 1st decile of the apoB/apoA-I ratio for all strokes was 2.07 (95% CI: 1.49-2.88), p<0.0001 (adjusted for age, gender, total cholesterol and triglycerides). The association was strongest for ischaemic stroke. These data therefore suggest a potential role for measuring apoA-I as a predictor of stroke risk.

There are, however, practical issues. Before recommending routine measurement of levels of HDL cholesterol and apoA-I, calibration and standardization of assays are essential to reliably identify an individual at risk of stroke due to low HDL cholesterol. In this context, the HDL Forum highlights the need for development of validated assays with appropriate international standardization.

References

1. Prospective studies collaboration: cholesterol, diastolic blood pressure, and stroke: 13000 strokes in 450,000 people in 45 prospective cohorts. Lancet 1995;346:1647-53.

2. Iso H, Jacobs DR, Wentworth D, et al. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med 1989;320:904-10.

 

3. Amarenco P, Lavallee P, Touboul PJ. Stroke prevention, blood cholesterol, and statins. Lancet Neurol 2004;3:271-8.

4. Amarenco P, Labreuche J, Touboul PJ. High-density lipoprotein-cholesterol and risk of stroke and carotid atherosclerosis: a systematic review. Atherosclerosis 2008;196:489-96.

5. Amarenco P, Goldstein LB, Callahan A et al. Baseline blood pressure, low- and high-density lipoproteins, and triglycerides and the risk of vascular events in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Atherosclerososis 2008;DOI: 10.1016/j.atherosclerosis.2008.09.008.

6. Lewington S, Whitlock C, Clark R et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55000 vascular deaths. Lancet 2007;370:1829-39.

7. Walldius G, Aastvelt AH, Jungner I. Stroke mortality and the apoB/apoA-I ratio: results of the AMORIS prospective study. J Intern Med 2006;259:259-66.


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