ASPREE post hoc analysis answers some, but not all, questions about statins and cognition

Almost a decade ago, the FDA issued a warning about reports of “apparent short-term cognitive impairment” among statin users, but systematic reviews have failed to find evidence to support this so-called statin brain. Now, an analysis of data from a trial of almost 19,000 adults age 65 or older suggested that, in healthy adults with normal cognitive function, statins don’t increase risk of dementia.

Zhen Zhou, PhD, of the Menzies Institute for Medical Research at the University of Tasmania, in Hobart, Australia, and co-investigators of the Aspirin in Reducing Events in the Elderly (ASPREE) trial looked at statin use versus nonuse to “(1) determine the prospective associations of baseline statin use with incident dementia, mild cognitive impairment (MCI) and cognition over time; (2) assess the role of statin lipophilicity in mediating any statin-related neurocognitive effects; and (3) identify potential effect modifiers of the statin-related changes.” They published their results in The Journal of the American College of Cardiology.

They found no association between statin use and dementia, MCI, or declines in individual cognitive domains. Also, this lack of association held regardless of the type of statin, hydrophilic or lipophilic, even though lipophilic statins—atorvastatin, simvastatin, lovastatin, fluvastatin, cerivastatin and pitavastatin—are known to cross the blood-brain barrier more than hydrophilic statins such as rosuvastatin and pravastatin.

ASPREE was a prospective, randomized, placebo-controlled trial of low-dose aspirin versus placebo in older adults enrolled in Australia and the U.S. The participants had no history of CVD, dementia, or major disabilities. The observational cohort study reported by Zhou and colleagues included 18,846 who had a baseline score of 78 or higher on the Modified Mini-Mental State Examination (3MS). Participants were followed for a median of 4.7 years.

At enrollment and follow-up, participants were asked to bring a list of currently used medications. The median age of participants was 74 and more than half were women. More than two-thirds of the cohort, 12,948, were statin nonusers. The rate of statin use was greater among women (60.9%), Australians (86%), and White patients (89.4%P<0.001 for each). Other factors significantly associated with statin use were diabetes, obesity, hypertension, and chronic kidney disease, which are also factors associated with cognitive decline.

“During 85,557 person-years of follow-up, 566 incident cases of dementia were recorded (probable AD, n=235; mixed presentations, n=331). Compared with no statin use, statin use was not associated with risk for all-cause dementia (HR: 1.16; 95% CI: 0.97-1.40; P=0.11), probable AD (HR: 1.33; 95% CI: 1.00-1.77; P=0.05), or mixed presentations of dementia (HR: 1.06; 95% CI: 0.82-1.35; P=0.67)”, they wrote.

There were 380 incident cases of MCI, and again there was no increased risk for statin users versus nonusers.

Of note, baseline 3MS, episode memory (Hopkins Verbal Learning Test-Revised delayed recall), and composite cognition scores were significantly lower among statin users compared to nonusers. But over follow-up, “there was no statistically significant difference in the change of composite cognition and any individual cognitive domains between the 2 groups (P>0.01 for all).” That said, the researchers did observe an interaction between baseline cognition scores, statin use and memory changes with “the outcome risks for statin use increasing as baseline cognitive levels decreased.”

That trend for AD and the interaction between baseline cognitive scores and outcome caught the attention of Christie M. Ballantyne, MD, and Vijay Nambi, MD, PhD, from the Baylor College of Medicine in Houston, who wrote an editorial published with the study.

“Over a median follow-up period of 4.5 years, statins were not associated with incident dementia, mild cognitive impairment, or cognitive change, although there was a trend toward an increase in AD (hazard ratio: 1.33; 95% confidence interval: 1.00-1.77; P=0.05) in 18,846 participants (median age 74 years, 56.4% women, 31.3% on statins). In addition, a significant interaction between baseline cognitive ability and statins was noted: patients in the lowest quartile of baseline cognitive ability on statins had higher hazards for dementia and change in episodic memory, one component of cognitive testing most associated with AD,” Ballantyne and Nambi wrote.

Thus, while answering some questions, the analysis by ASPREE investigators raises others that can only be answered in randomized controlled trials, the editorialists concluded.

Zhou et al also noted a number of limitations, some of which are common to all observational trials. Their analysis was a post-hoc exercise and the ASPREE trial itself was not designed to answer questions about statin use, but rather to test the value of aspirin to reduce the risk of cardiovascular events. The investigators didn’t collect data on duration of statin therapy, nor did they collect information about statin doses. Moreover, there was no adjustment for apolipoprotein E genotype. “Finally, as ASPREE participants were highly selected, with few morbidities, drug intolerances, and with less frailty and taking fewer concomitant drugs than older people in the general populations, our study findings may not be generalizable to broader, unselected older populations,” they wrote.

  1. In an observational cohort study of adults age 65 or older, statin therapy was not associated with incident dementia, MCI, or functional declines in cognition.

  2. Be aware that randomized trials are needed to clarify the neurological effects of statin therapy in elderly populations.

Peggy Peck, Editor-in-Chief, BreakingMED™

The ASPREE trial was supported by a grant from the National Institute on Aging and the National Cancer Institute atthe National Institutes of Health, by grants from the National Health and Medical Research Council of Australia, and by Monash University and the Victorian Cancer Agency.

Zhou had no disclosures.

Ballantyne is supported by National Institutes of Health and has received grant and research support (to his institution) from Abbott Diagnostic, Akcea, Amgen, Esperion, Ionis, Novartis, Regeneron, and Roche Diagnostics; and has been a consultant for 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 a coinvestigator on a provisional patent along with Baylor College of Medicine and Roche on the use of biomarkers to predict heart failure and a site principal investigator for studies sponsored by Amgen and Merck.

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Topic ID: 398,404,282,404,730,4,914,33,361,192,925