Statins and Dementia: Are Some Folks More Prone to Harm?

Beyond my pay grade.

Statins and Dementia: Are Some Folks More Prone to Harm?

ASPREE neurocognition analysis largely neutral for most people

by Nicole Lou, Staff Writer, MedPage Today June 21, 2021

Statin users provided reassuring longer-term data on cognition in ASPREE, but even that large study could not exclude statin-related dementia in some older people.

People who entered the ASPREE trial on baseline statin therapy were not at a significantly elevated risk of incident dementia, mild cognitive impairment, or changes in domain-specific cognition over a median 4.7 years of follow-up, according to Zhen Zhou, PhD, of Menzies Institute for Medical Research, University of Tasmania in Hobart, Australia, and colleagues.

Yet statin users had lower baseline cognition function compared with non-users, and baseline neurocognitive ability turned out to be an effect modifier for the associations between statins and dementia (P<0.001 for interaction) and statins and memory change (P=0.02 for interaction).

The increased dementia risk with statin use at lower baseline cognition was attributable mainly to the increased risk for Alzheimer's disease (AD), Zhou and colleagues reported in the Journal of the American College of Cardiology.

"It is possible that the increased dementia risk with statin use seen in the lowest cognition quartile reflected reverse causality or an indication bias whereby participants with lower cognition have been prescribed statins in the hope of preventing deterioration in the vascular component of dementia," the authors suggested.

"It is also possible that participants with lower cognitive function might have their statin treatment initiated too late to produce any measurable functional improvement, and indeed if disease is already present, the statin may exacerbate it further," they continued.

Statins are an established therapy for primary and secondary cardiovascular prevention.

FDA warned of apparent short-term cognitive impairment with statin use in 2012, but more recent observational and randomized data have largely been neutral. Thus, the link between statins and dementia remains unsettled.

One hypothesis is that lipophilic statins can be expected to have a greater harm on neurocognition due to their greater blood-brain barrier penetrance compared with hydrophilic statins.

In ASPREE, however, neurocognition outcomes were similar between users of the two statin types.

For now, it appears that lipid lowering in the short term does not appear to improve or worsen cognition irrespective of baseline LDL cholesterol levels and medication used, commented Christie Ballantyne, MD, and Vijay Nambi, MD, PhD, both of Baylor College of Medicine in Houston, in an accompanying editorial.

"However, the potential increased risk for Alzheimer's disease (AD), especially among patients with baseline cognitive impairment, requires further investigation," the duo urged.

Zhou's group had performed a post hoc analysis of ASPREE, a randomized trial that found daily low-dose aspirin to be no better than placebo for older patients hoping to reduce their risk of disability-free survival and cardiovascular disease. Aspirin also reportedly had no neurocognitive benefit in the trial.

The present analysis included 18,846 adults over age 65 in the ASPREE trial who had been recruited in 2010-2014 in Australia and the U.S. Participants were required to have no prior cardiovascular events, major physical disability, or dementia at baseline.

Median age was 74. Women and white individuals accounted for 56.4% and 91.3%, respectively, of the cohort.

The 31.3% of people who were on statins at baseline differed from the rest of the group: they were more likely to be women, have less education, take more medications, and have higher prevalence of cardiovascular risk factors; they were also less likely to be white, current drinkers, or report a family history of dementia.

Residual confounding is a chief limitation of such an observational study, which also lacked records on length of statin use or statin dose. Moreover, ASPREE participants had been highly selected, the investigators cautioned.

"Finally, the apolipoprotein E genotype was missing in about 35% of the study population, and hence the investigators did not factor this into their analysis; however, a subanalysis would be useful, especially in light of their findings regarding AD," according to Ballantyne and Nambi.

More answers regarding statins and cognition may come from STAREE and PREVENTABLE, two ongoing randomized statin trials of primary prevention in older populations that include dementia as a study endpoint.

Even so, these trials will still leave unanswered questions given their inclusion criteria, the editorialists said.

"In the meantime, practicing clinicians can have confidence and share with their patients that short-term lipid-lowering therapy in older patients, including with statins, is unlikely to have a major impact on cognition," the pair concluded.

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  Nicole Lou is a reporter for MedPage Today, where she covers cardiology news and other developments in medicine. Follow

Disclosures

ASPREE had been supported by grants from the National Institute on Aging and the National Cancer Institute of the NIH, the National Health and Medical Research Council of Australia, and by Monash University and the Victorian Cancer Agency.

Zhou had no disclosures.

Ballantyne reported receiving an NIH grant and institutional research support from Abbott Diagnostic, Akcea, Amgen, Esperion, Ionis, Novartis, Regeneron, and Roche Diagnostics; and having consulted to Abbott Diagnostics, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Corvidia, Denka Seiken, Esperion, Genentech, Gilead, Matinas BioPharma, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche Diagnostics, and Sanofi-Synthelabo.

Nambi is named as a coinvestigator on a provisional patent (along with Baylor College of Medicine and Roche); and serves as a site principal investigator for studies sponsored by Amgen and Merck.

Primary Source

Journal of the American College of Cardiology

Source Reference: Zhou Z, et al "Effect of statin therapy on cognitive decline and incident dementia in older adults" J Am Coll Cardiol 2021; DOI: 10.1016/j.jacc.2021.04.075.

Secondary Source

Journal of the American College of Cardiology

Source Reference: Ballantyne CM, Nambi V "Statins and your memory: 'forget' about it?" J Am Coll Cardiol 2021; DOI: 10.1016/j.jacc.2021.04.076.