Lipids and stroke: Looking for risk in all the wrong places?

The report of Varbo and colleagues in this month’s Annals of Neurology adds another interesting chapter to the long saga in the literature characterizing the relationship between lipid levels and stroke risk. As late as 1996, there was general agreement that lipids were at most a very modest risk factor for stroke events. The Framingham Study had recently reported the multivariate risk function for stroke, a report that was silent on a role for lipids as a stroke risk factor despite the focus on lipid levels as the most powerful coronary heart disease risk factor for >15 years. In 1996, the authors of Cardiovascular Health Study published their multivariate stroke risk factor function for stroke, finding factors that were predictive of stroke to be strikingly similar to the Framingham Study, and explicitly noting that they assessed a potential role for total, triglyceride, and low-density lipoprotein cholesterol, finding them to not be related to stroke. There were, however, a few scattered reports supporting a lipid–stroke relationship such as the positive relationship for nonhemorrhagic stroke and a negative effect for intracranial hemorrhage reported in 1989 among the 350,977 men screened for the MRFIT study. However, selection of these participants was not population based (they were recruited from union lists, shopping centers, civic clubs, and other sources), and events were based on fatal events retrieved from death certificates (with a high ratio of hemorrhagic deaths [55 subarachnoid hemorrhages and 83 intracerebral hemorrhages] in comparison to nonhemorrhagic strokes [92 infarctions þ ill-defined]). During this period, the lack of a consistent lipid– stroke association in the observational epidemiological studies was supported by meta-analyses of lipid-lowering trials (13 trials with 1 colestipol treatment, 3 clofibrate, 1 cholestyramine, 1 gemfibrozil, and 7 diet) for prevention of coronary heart disease showing strong evidence that lowering lipids protected against fatal coronary heart disease (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.79–0.95). However, in secondary analyses these same studies showed no benefit for lipid lowering for stroke risk (OR, 0.98; 95% CI, 0.80–1.19), and a nonsignificant suggestion of increased risk for fatal stroke (OR, 1.32; 95% CI, 0.94–1.86). Collectively the state of knowledge led to a general acceptance that lipids were at most a weak stroke risk factor. In 1994, the American Heart Association guidelines for the management of transient ischemic attacks concluded that although there was strong evidence of cholesterol and triglycerides being related to coronary artery disease, their relationship with stroke was ‘‘less clear.’’ They concluded that ‘‘Medications for hyperlipidemia reduce the risk of coronary artery disease; therefore, cholesterol lowering may be recommended for these patients for reasons other than stroke reduction.’’ Subsequently in 1997 (just a bit out of the period), the first American Heart Association guidelines for the prevention and rehabilitation of stroke also concluded that ‘‘the link to ischemic stroke remains uncertain.’’ Despite this uncertainty, interest in investigation of the role of lipids was so weak that it was not mentioned in a litany of 14 research priorities to advance the understanding of risk factors for stroke. Understanding of the stroke–lipid relationship was shook to the foundation by a flurry of reports between 1993 and 1997 examining the impact of statin treatment for the prevention of coronary heart disease, many of which also reported secondary stroke outcomes. Blauw and colleagues were among several groups that produced meta-analyses examining the impact of statin therapy for lipid lowering on fatal stroke risk, summarizing secondary analysis of stroke and TIA risk among 13 studies, including: