Cholesterol Is Associated With Stroke, but Is Not a Risk Factor
Proponents of cholesterol as a risk factor for stroke usually support their argument by citing evidence from clinical trials of the beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (“statins”) in reducing stroke risk among people with prior cardiovascular disease. Although such studies may provide some supportive evidence, causation can really only be established between a risk factor and a disease when certain criteria are met.1 These include the criteria that the association between the risk factor and the disease must be temporal and biologically plausible. Although there may be little or no debate about whether cholesterol is a biologically plausible risk factor for stroke or that high cholesterol levels precede (rather than follow) stroke, some of the other criteria are more ambiguous. These other “guidelines for causation” are discussed below:
1. Strong Association Between Risk Factor and Disease
There have been numerous major prospective epidemiological studies of cholesterol and the risk of stroke. However, at best, the results have provided evidence for a minimal association. Initially, part of this may have been because stroke was treated as a homogeneous entity. This may have resulted in an association being masked by the opposing effects of cholesterol on ischemic stroke and intracerebral hemorrhage. In a meta-analysis that was limited to ischemic stroke, cholesterol levels of more than ≈5.7 mmol/L were associated with a relative risk of ischemic stroke of 1.3.2 One must be extremely cautious in interpreting findings with such weak associations as they could be influenced by confounding factors or bias. This is particularly important given that this risk ratio is unadjusted for any potentially confounding factors.
2. Consistency of Results Between Studies
The association between cholesterol and stroke has not always been consistent. In an analysis of the results of 45 cohort studies, no association was found between cholesterol and stroke. However, the fact that many of these studies included only fatal strokes as an endpoint may have resulted in bias.3 In contrast, authors of a recent meta-analysis of 7 cohort studies reported a positive association between cholesterol and ischemic stroke.4 The fact that the former analysis of cohort studies mainly included fatal events, and that there was no differentiation between ischemic and hemorrhagic stroke, may explain these disparate findings.
3. Dose–Response Relationship
In a recent meta-analysis of cohort studies conducted in the Asia-Pacific region, there was a positive association between cholesterol levels and ischemic stroke.5 Each increase of 1 mmol/L to the “usual cholesterol” level was associated with a 25% greater risk of fatal or nonfatal ischemic stroke. Although adjusted for the important and potentially confounding factors of age, systolic blood pressure, and smoking status, other equally important confounding factors have not been considered. Such factors may include the so-called inflammation-sensitive plasma proteins. In the Framingham study, cholesterol was associated with ischemic stroke among people who had high levels of inflammation-sensitive plasma proteins, but not among people with low levels of these markers.6 Thus, cholesterol may not be a risk factor in isolation, but may interact with other factors to aid the progression of atherosclerosis.
4. Removing the Risk Factor Reduces Disease Risk
Meta-analysis of early trials of lipid-lowering therapy with the use of dietary or drug intervention (eg, fibrates and resins) provides evidence that, among people with elevated cholesterol levels, reducing cholesterol levels per se does not reduce the risk of stroke.7 In contrast, use of HMG-CoA reductase inhibitors (“statins”) among such patients has been reported to produce about a 24% relative risk reduction of all stroke and a 30% relative risk reduction of ischemic stroke. The disparity between the dramatic effects of statins in reducing stroke risk compared with the more modest effects of other methods of lowering cholesterol levels may reflect the possibility that statins have greater cholesterol-lowering efficacy. However, it is also likely that other pharmacological effects of statins such as amelioration of endothelial dysfunction, promotion of atherosclerotic plaque stability, and modification of both inflammatory responses and thrombus formation play a major role.8
Further evidence for a major role of nonlipid properties is provided by the observation that, among high risk patients with average or below-average cholesterol levels, both the development of carotid atherosclerosis9 and coronary and stroke events10 can be reduced by statins.
In summary, the prevailing evidence is not supportive of the hypothesis that cholesterol is an important risk factor for stroke. This is based on the observation that the association between cholesterol and stroke is weak, inconsistent, and that lowering cholesterol levels does not necessarily result in a reduction in the risk of stroke. It is clear that this issue has been clouded by the observation of a reduced risk of stroke with use of statins.
- Received February 24, 2004.
- Accepted February 24, 2004.
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