Do Statin Drugs Prevent Dementia? Data from the PROSPER Study

Abstract & Commentary

Synopsis: Pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals. The PROSPER study therefore extends to elderly individuals the treatment strategy currently used in middle aged people.

Source: Shepherd J, et al. Lancet. 2002;360:1623-1630.

Among patients with coronary artery disease, HMG CoA reductase inhibitors (statins) are a mainstay of therapy. These drugs have also become widely prescribed with a low threshold to patients with elevated cholesterol and even minimal cardiac risk factors. The role of statins in patients with stroke and other forms of neurological disease is less well defined. Because statins inhibit the activity of beta and gamma secretases, enzymes involved with the cleavage of amyloid precursor protein, they are now thought to be potentially efficacious in preventing the formation of amyloid plaques and the onset of clinical Alzheimer’s disease (AD). Cholesterol lowering may further protect against dementia by limiting the damaging effects of apolipoprotein E, specifically in those patients with the APO e4 allele, a known risk factor for AD. Statins may furthermore be beneficial in the prevention of "vascular" or "multi-infarct" dementia by preventing small vessel strokes or by endothelial remodeling on a microvascular level.

In the pravastatin in elderly individuals at risk of vascular disease (PROSPER) study, 5804 individuals aged 70-82 were randomized to pravastatin 40 mg/d or placebo. Subjects either had a history of vascular disease or had vascular risk factors. The primary outcome measure was a composite end point of coronary death, nonfatal myocardial infarction, or stroke, measured after 3 years of therapy. Pravastatin reduced LDL cholesterol by 34%, from a mean of 146 mg/dL to approximately 100 mg/dL. Statin therapy reduced the risk of a primary end point by 15%. In subgroup analysis, coronary events were reduced by 19%, while no discernable effect was found for stroke. Transient ischemic attack was reduced by 25% but was of borderline significance. The overall incidence of stroke outcomes was low, occurring in 116 treated patients and 119 in the placebo group.

Cognitive outcomes were studied by multiple measures, including digit span, picture-word recall, Stroop test, and mini-mental status examination. Functional outcomes were also explored, including the Barthel index and the instrumental activities of daily living score. Statin therapy had no significant effect on any of these outcomes.

Comment by Alan Z. Segal, MD

The results of the PROSPER study are taken in the context of those of the larger British Heart Protection Study (HPS), which was also reported in Lancet this year.1 Unlike PROSPER, the HPS study did show a decrease in stroke risk. HPS followed patients for a longer period of time (5 years) and had more cerebrovascular outcomes, 444 treated vs 585 placebo (P = 0.002). These differences, however, did not impact cognitive decline. As in PROSPER, statin therapy (in the case of HPS-simvastatin) did not prevent dementia. Although pravastatin and simvastatin are quite similar, it is intriguing that the latter is a possibly more efficacious cerebrovascular drug since it is more lipophilic and may have greater CNS penetration.

These data provide further support to the concept that statin therapy should be prescribed to prevent coronary events in patients with known disease or with risk factors, regardless of age. Both PROSPER and HPS indicate that older age patients (older than 70) derive similar cardiac benefits to younger patients.

These data are less clear about the prevention of stroke and dementia. Part of this problem lies in the heterogeneity of the dementing disorders. Do statins prevent vascular dementia through the prevention of small vessel strokes and microvascular disease? Or do they prevent AD through effects on amyloid? Do other forms of dementia such as Diffuse Lewy Body Disease factor into this equation in any important way?

In addition to their high cost, statins are not free of side effects. Particularly when taking atorvastatin, patients develop often-disabling myalgias, even with normal measurements of CPK. Perhaps as more elderly individuals are treated with statins we may be able to glean information from observational studies. There does not seem justification to begin widespread prophylactic use at this time.

Dr. Segal is Assistant Professor, Department of Neurology, Weill-Cornell Medical College, Attending Neurologist, New York Presbyterian Hospital, New York, NY.

Reference

1. Lancet. 2002;360:7-22.