By Michael H. Crawford, MD, Editor

SYNOPSIS: An analysis of the ASPREE database showed that with almost five years of follow-up, statins are not associated with cognitive decline or dementia in a large group of elderly subjects in whom multiple tests of cognition were performed serially.

SOURCE: Zhou Z, Ryan J, Ernst ME, et al. Effect of statin therapy on cognitive decline and incident dementia in older adults. J Am Coll Cardiol 2021;77:3145-3156.

There is little evidence supporting a connection between taking statins and experiencing cognitive decline and dementia. Zhou et al analyzed the systematically collected comprehensive cognitive data in the Aspirin in Reducing Events in the Elderly (ASPREE) trial to determine the association of statin use with incident dementia and mild cognitive impairment (MCI), to assess the influence of statin lipophilicity on neurocognitive effects, and to identify factors that may modify statin effects on cognition.

ASPREE was a large prospective, randomized, placebo-controlled study of daily low-dose aspirin in subjects > age 70 years or > age 65 years in U.S. minorities. Subjects presented with no prior cardiovascular (CV) disease events or dementia and scored > 78 on the Modified Mini-Mental State Examination (3MS). Investigators recruited participants between 2010 and 2014 in Australia and the United States.

Taking a closer look at ASPREE, Zhou et al grouped subjects by their baseline statin use, resulting in 12,948 not on statins and 5,898 on statins for closer examination. The mean age was 74 years, and 56% were women. More subjects in the statin group were diabetic or hypertensive and were on more concomitant medications. Cognitive function was assessed at baseline; at one, three, and five years; and after the final visit (maximum seven years). Multiple covariates were assessed that could affect neurocognitive function or could interact with statins.

During the median follow-up of 4.7 years, Zhou et al identified 566 cases of dementia. Using statins was not associated with the risk of dementia (HR, 1.16; 95% CI, 0.97-1.40; P = not significant). MCI developed in 380 subjects and also was not associated with statin use (HR, 1.44; 95% CI, 0.90-2.29; P = not significant). Although statin users recorded lower global cognition scores at baseline, there was no significant difference between statin users and no use of statins groups over the follow-up period. There were no differences in outcomes among those using lipophilic vs. hydrophilic statins. There were interactions between baseline cognitive scores and statin therapy for the development of dementia. No other interaction effects were found, including baseline LDL cholesterol levels. In addition, sensitivity analyses of the various comorbidities did not alter the results. The authors concluded that in older adults, there was no association between statin use and the development of MCI or dementia.

COMMENTARY

In 2012, the FDA issued a warning indicating statins had been reported in their adverse events reporting system as causing short-term cognitive impairment.1 This caused quite a stir, and it was hard to convince older patients to take statins. Since then, other investigators reviewed the evidence on which the FDA based its decision, drawing different conclusions.2-4

ASPREE focused on patients > age 65 years who completed several cognitive function tests over about five years. Also, the outcomes were adjudicated by a committee, sensitivity analyses were conducted, and researchers explored whether lipophilicity of the statin was of importance. Zhou et al showed statin use was not associated with incident MCI or dementia or that cognitive function declines over time on statins. In addition, they did not find that lipophilicity influenced the results, and sensitivity analyses did not show that comorbidities affected the results. However, in those in the lowest quartile of normal cognitive function at baseline, there was an interaction suggesting a potential statin effect on dementia risk. For this reason, the investigators urged caution in interpreting their data until randomized, controlled trials in progress are completed.

There were other weaknesses to the Zhou et al study. It was a post-hoc analysis of an observational study conducted for other reasons, so there could be residual confounding. There could be an indication bias since the statin group exhibited more CV disease at baseline. Reverse causality is another consideration as declining cognition within the normal range could have been an indication for statins to prevent any CV components to cognitive dysfunction. Also, these were highly selected subjects with few comorbidities, less frailty, and who were taking fewer drugs than an older general population would have been. In addition, there were no data on LDL cholesterol levels, dosage of the statins, and the length of statin use before the study. Finally, this was a relatively short-term study.

The main issue is whether the risk of statins outweighs the benefits for older patients. In this regard, some believe heart failure outweighs CV events in older subjects, making statin use more problematic. Since their introduction, the adverse effects of statins have been of great interest. The most serious, rhabdomyolysis, is rare. Early on, liver function was a concern, but routine testing of liver function is no longer recommended since serious liver disease also is rare. There seems to be a real association with diabetes, but it is believed the benefits of statins outweigh this small risk. Muscle symptoms have become the biggest reason patients quit taking statins, but recent controlled studies have shown most of these symptoms are not reproducible. There has been fear that too low cholesterol levels could adversely affect the nervous system, but studies of the PCSK9 inhibitors, which can lower LDL cholesterol to < 20 mg/dL, have not borne this out. Thus, cognitive dysfunction is the new big worry with statins. The Zhou et al study is reassuring in that over five years, no significant deterioration in cognitive function was observed in a higher-risk elderly population studied serially by multiple cognition tests.

REFERENCES

  1. U.S. Food & Drug Administration. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs.
  2. Richardson K, Schoen MW, French B, et al. Statins and cognitive function: A systematic review. Ann Intern Med 2013;159:688-697.
  3. Swiger KJ, Manalac RJ, Blumenthal RS, et al. Statins and cognition: A systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc 2013;88:1213-1221.
  4. Ott BR, Daiello LA, Dahabreh IJ, et al. Do statins impair cognition? A systematic review and meta-analysis of randomized controlled trials. J Gen Intern Med 2015;30:348-358.