Stymied by statin data? Some studies suggest they help prevent dementia, others suggest they do not. A paper from Ben Wolozin, Boston University, and colleagues is the latest to weigh in on the debate. Writing in the July 18 Biomed Central Medicine, the researchers report that at least one statin, simvastatin, significantly lowers the risk of both dementia and Parkinson disease. The findings are likely to reinvigorate the debate over the potential fringe benefits of statin therapy.

Statins, developed as lipid-lowering agents, are some of the most widely prescribed drugs in the world. Since they are used to treat cardiovascular diseases that have been associated with increased risk for dementia, there was some initial optimism that they may also help protect against Alzheimer disease. But the data so far have been equivocal. Cross-sectional data generally show benefit, whereas prospective trials have failed to show that statins reduce dementia incidence (see ARF related news story). “There is a lot of ambiguity in the literature, but most of the studies that looked at incidence of dementia among people taking statins suffer from lack of power,” said Wolozin. To address that, he and his colleagues have looked at data from the decision support system of the U.S. Veterans Affairs database, which covers around 4.5 million individuals.

The researchers analyzed data for people aged 65 with no prior diagnosis of AD and who had been taking simvastatin (over 700,000 patients), atorvastatin (over 53,000 patients), or lovastatin (just over 54,000 patients) for at least 7 months. “We figured a 7-month window might be long enough to see an effect, and we were also concerned that if we made that window longer, we would have less time for follow-up analysis,” said Wolozin. For controls, the researchers compared people taking statins with those taking other cardiovascular disease drugs or warfarin, a blood thinner. They also used the Charlson Index of chronic disease to test for covariates that might account for any effect. Those who subsequently developed dementia were identified by the International Classification of Diseases, revision 9 (ICD-9) code for senile dementia of the Alzheimer type (331.0). Wolozin admits that this does not have the diagnostic rigor of the NINDS criteria, for example, and for this reason the researchers use the term dementia, rather than AD. Parkinson disease was identified by ICD-9 code 332.0.

The researchers found no difference in incidence for either disease between controls and those taking lovastatin. The incidence of dementia in those taking atorvastatin was about 10 percent lower than in controls, but after adjusting for covariates, this effect was eliminated. The effect of simvastatin, however, was robust. Patients taking this statin were 55 percent less likely to develop dementia, an effect that remained significant even after adjusting for covariates. Simvastatin also lowered the hazard ratio for newly developed Parkinson disease to 0.51.

It is not clear why simvastatin should perform so much better than other statins, but Wolozin noted that atorvastatin, while slightly more potent, does not penetrate the blood-brain barrier as well as simvastatin. So what does this mean for patients who may be already taking statins to lower plasma lipids? “I would say look at your parents. If there is a family history of AD and you are on a statin, then you should talk to your doctor about switching to simvastatin,” said Wolozin. “But if your father had a heart attack and you don’t have dementia in your family, then I would recommend atrovastin because it reduces morbidity.”

John Breitner, University of Washington, Seattle, suggests a different explanation for the apparent differences among the statins. “The VA Decision Support System is a wonderful resource for this sort of study, but its limitations should be recognized. VA specifies ‘first line’ drugs based on cost and empirical evidence of efficacy and safety. Simvastatin is a typical ‘first line’ therapy for the VA. Assignment to simvastatin or other statins is far from random. Veterans who receive other drugs are probably different in some ways from those receiving simvastatin. Caution is therefore warranted in the interpretation of these results: it may be the particular qualities of the patients receiving simvastatin versus other statins that account for their different apparent effects,” he wrote in an e-mail to ARF.

Whatever the explanation, Wolozin admits that there is more work to be done. “The next step,” he said, “is to look at disease progression.” It seems that with statins and dementia, things are far from static.—Tom Fagan.

Reference:
Wolozin B, Wang SW, Li N-C, Lee A, Lee TA, Kazis LE. Simvastatin is associated with a reduced incidence of dementia and Parkinson’s disease. Biomed Central Medicine. J. Neurosci. 2007 June 27;27:6859-6867. Abstract

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  1. The Percival Effect

    Ben Wolozin did it again. Whenever he and his colleagues turn to statins and epidemiology something unexpected happens. The data by themselves are stunning. Stunning because of the enormous sample size, stunning because of the extreme risk reduction in the simvastatin population, stunning because of the unexpected PD effect (maybe not as much unexpected to those who listened to Eliezer Masliah's talk in Salzburg). Moreover, the work shows how urgently more studies are needed to explore and validate these effects within prospective clinical trials—studies aimed to explore and validate the modes of action of statins in dementia, and studies that compare the effectiveness of different statins.

    But the vast sample size came at a cost. Predominantly, the absence of a good control group, the increased likelihood of bias (because the database used does not reflect an average U.S.-American population), and missing resolution when it comes to the details.
    One example that highlights this is the cardiovascular risk group (CV). Statins are given to patients with what is considered to represent too high blood LDL-cholesterol levels. This factor alone introduces a major bias and even the comparison between the CV and statin users does not remove this bias. Obviously CV patients who aren't given a statin differ from those who are. This example could be extended endlessly, e.g., different dosages for different statins, different population profiles for different statins, etc.

    At the end of the day the value of this work is not that it would provide us with new answers, rather that the value of this work is the new and important questions it raises. Sometimes a question can be more relevant than an answer. The tragedy of Percival on his quest for the holy grail was that he failed to ask the relevant question.

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References

News Citations

  1. Statin Use and Alzheimer Disease: A Tale of Two Methodologies?

Paper Citations

  1. . Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease. BMC Med. 2007;5:20. PubMed.

Further Reading

Papers

  1. . Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease. BMC Med. 2007;5:20. PubMed.

News

  1. Philadelphia: All Is Not Well with the Statin Story
  2. Statin Use and Alzheimer Disease: A Tale of Two Methodologies?

Primary Papers

  1. . Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease. BMC Med. 2007;5:20. PubMed.