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Statins and Cognitive Function: A Systematic Review

Karl Richardson, MD*; Marisa Schoen, BA*; Benjamin French, PhD; Craig A. Umscheid, MD, MSCE; Matthew D. Mitchell, PhD; Steven E. Arnold, MD; Paul A. Heidenreich, MD, MS; Daniel J. Rader, MD; and Emil M. deGoma, MD
[+] Article and Author Information

* Dr. Richardson and Ms. Schoen contributed equally to this study.


From the Perelman School of Medicine, University of Pennsylvania, and University of Pennsylvania Health System, Philadelphia, Pennsylvania, and Stanford University Medical Center, Stanford, California.

Potential Conflicts of Interest: Dr. Arnold: Board membership fees: TEVA Pharmaceuticals; Grants: National Institutes of Health, Pfizer, Bristol Myers Squibb, Johnson and Johnson, Merck. Dr. Rader: Personal fees: AstraZeneca, Pfizer, Merck. Dr. deGoma: Personal fees: Aegerion; Grants: Pfizer, Amgen, Novartis, Regenerol. All other authors have no disclosures. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-3027.

Requests for Single Reprints: Emil M. deGoma, MD, Perelman Center for Advanced Medicine, Heart and Vascular Center, 3400 Civic Center Boulevard, Philadelphia, PA 19104; e-mail, Emil.deGoma@uphs.upenn.edu.

Current Author Addresses: Dr. Richardson, Ms. Schoen, and Dr. deGoma: Heart and Vascular Center, 3400 Civic Center Boulevard, Perelman Center for Advanced Medicine, Philadelphia, PA 19104.

Dr. French: 204 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104.

Drs. Umscheid and Mitchell: 3535 Market Street, Mezzanine, Suite 50, Philadelphia, PA 19104.

Dr. Arnold: Penn Memory Center, 3615 Chestnut Street, Philadelphia, PA 19104.

Dr. Heidenreich: Veterans Affairs Palo Alto Medical Center, 111C Cardiology, 3801 Miranda Avenue, Palo Alto, CA 94304.

Dr. Rader: 11-125 Translational Research Center, 3400 Civic Center Boulevard, Building 421, Philadelphia, PA 19104.

Author Contributions: Conception and design: K. Richardson, M. Schoen, C.A. Umscheid, M.D. Mitchell, E.M. deGoma.

Analysis and interpretation of the data: K. Richardson, M. Schoen, B. French, C.A. Umscheid, M.D. Mitchell, S.E. Arnold, P.A. Heidenreich, D.J. Rader, E.M. deGoma.

Drafting of the article: K. Richardson, M. Schoen, C.A. Umscheid, M.D. Mitchell, E.M. deGoma.

Critical revision of the article for important intellectual content: K. Richardson, M. Schoen, B. French, C.A. Umscheid, M.D. Mitchell, S.E. Arnold, P.A. Heidenreich, D.J. Rader, E.M. deGoma.

Final approval of the article: K. Richardson, M. Schoen, B. French, C.A. Umscheid, M.D. Mitchell, S.E. Arnold, P.A. Heidenreich, D.J. Rader, E.M. deGoma.

Provision of study materials or patients: E.M. deGoma.

Statistical expertise: B. French, C.A. Umscheid, M.D. Mitchell.

Administrative, technical, or logistic support: K. Richardson, M. Schoen, E.M. deGoma.

Collection and assembly of data: K. Richardson, M. Schoen, E.M. deGoma.


Ann Intern Med. 2013;159(10):688-697. doi:10.7326/0003-4819-159-10-201311190-00007
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Background: Despite the U.S. Food and Drug Administration (FDA) warning regarding cognitive impairment, the relationship between statins and cognition remains unknown.

Purpose: To examine the effect of statins on cognition.

Data Sources: PubMed, Embase, and Cochrane Library from inception through October 2012; FDA databases from January 1986 through March 2012.

Study Selection: Randomized, controlled trials (RCTs) and cohort, case–control, and cross-sectional studies evaluating cognition in patients receiving statins.

Data Extraction: Two reviewers extracted data, 1 reviewer assessed study risk of bias, and 1 reviewer checked all assessments.

Data Synthesis: Among statin users, low-quality evidence suggested no increased incidence of Alzheimer disease and no difference in cognitive performance related to procedural memory, attention, or motor speed. Moderate-quality evidence suggested no increased incidence of dementia or mild cognitive impairment or any change in cognitive performance related to global cognitive performance scores, executive function, declarative memory, processing speed, or visuoperception. Examination of the FDA postmarketing surveillance databases revealed a low reporting rate for cognitive-related adverse events with statins that was similar to the rates seen with other commonly prescribed cardiovascular medications.

Limitations: The absence of many well-powered RCTs for most outcomes resulted in final strengths of evidence that were low or moderate. Imprecision, inconsistency, and risk of bias also limited the strength of findings.

Conclusion: Larger and better-designed studies are needed to draw unequivocal conclusions about the effect of statins on cognition. Published data do not suggest an adverse effect of statins on cognition; however, the strength of available evidence is limited, particularly with regard to high-dose statins.

Primary Funding Source: None.

Figures

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Figure 1.

Summary of evidence search and selection.

RCT = randomized, controlled trial.

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Figure 2.

Meta-analyses of risk ratios from cohort studies for dementia, Alzheimer disease, and mild cognitive impairment.

NA = not available.* Pooled analysis as follows: Wolozin et al, 2007: atorvastatin, lovastatin, simvastatin; Hippisley-Cox and Coupland, 2010: atorvastatin/men, atorvastatin/women, fluvastatin/men, fluvastatin/women, pravastatin/men, pravastatin/women, rosuvastatin/men, rosuvastatin/women, simvastatin/men, simvastatin/women; Ancelin et al, 2012: men, women. Adjustments as follows: Rea et al, 2005: age, sex, education, baseline modified Mini-Mental State Examination, cardiovascular disease, cerebrovascular disease, alcohol use; Zandi et al, 2005: age, sex, education, number of ApoE4 alleles, hypertension, diabetes mellitus; Szwast et al, 2007: age, sex, education, ApoE4; Wolozin et al, 2007: age, cardiovascular disease, hypertension, diabetes mellitus, Charlson Index (a measure of chronic disease); Smeeth et al, 2008: age, sex, likelihood of statin use, date of statin initiation, new diagnoses or drug therapies; Hippisley-Cox and Coupland, 2010: age, cardiovascular disease, cerebrovascular disease, diabetes mellitus, depression, use of tricyclic antidepressants or selective serotonin reuptake inhibitors, body mass index; Beydoun et al, 2011: age, sex, race, education, cardiovascular disease, cerebrovascular disease, hypertension, diabetes mellitus, atrial fibrillation, dyslipidemia, body mass index, blood pressure, smoking status; Parikh et al, 2011: medical comorbid conditions defined by the Centers for Medicare & Medicaid Services Hierarchical Condition Categories risk-adjustment model; Ancelin et al, 2012: age, location, education; Bettermann et al, 2012: age, sex, race, education, ApoE4, cardiovascular disease, cerebrovascular disease, baseline mild cognitive impairment, treatment group, location; Sparks, 2008: age, sex, education, ApoE4; Haag et al, 2009: age, sex, education, ApoE4, cardiovascular disease, cerebrovascular disease, diabetes mellitus, other lipid-lowering agents, smoking status, blood pressure, body mass index, total cholesterol; Li et al, 2010: age, cohort, sex, race, education, ApoE4, baseline Cognitive Abilities Screening Instrument, cardiovascular disease, cerebrovascular disease, hypertension, diabetes mellitus, other lipid-lowering agents, smoking status, body mass index; Yaffe et al, 2002: age, education, treatment group, coronary artery bypass grafting, total cholesterol, smoking status; Cramer et al, 2008: education, ApoE4, cerebrovascular disease, diabetes mellitus, smoking status.

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Figure 3.

Meta-analyses of risk ratios from case–control studies (top ) and cross-sectional studies (bottom) for dementia, Alzheimer disease, and mild cognitive impairment.

NA = not available.* Adjustments as follows: Jick et al, 2000: age, sex, cardiovascular disease, cerebrovascular disease, hypertension, diabetes mellitus, date of dementia/Alzheimer disease diagnosis, years of recorded history in General Practice Research Database, practice, body mass index, smoking status; Rockwood et al, 2002: unadjusted results reported; Zamrini et al, 2004: cardiovascular disease, cerebrovascular disease, hypertension, diabetes mellitus, lipid metabolism disorders; Green et al, 2006: age, sex, race, education; Rockwood et al, 2007: sex, education, self-rated health; Rodriguez et al, 2002: age, sex, education, cardiovascular disease, cerebrovascular disease, hypertension, alcohol use, smoking status, primary care physician visit; Wolozin et al, 2000: unadjusted results reported; Carlsson et al, 2009: age, sex, education, mean carotid intima–media thickness; Glasser et al, 2010: age, sex, race, education, income, cardiovascular disease.

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Statins and Cognitive Function
Posted on December 4, 2013
Robert P. Young, MD, PhD, Raewyn J. Hopkins
University of Auckland
Conflict of Interest: None Declared
TO THE EDITOR:
Based on an extensive review of the literature, Richardson and colleagues 1 conclude that statins do not cause an increased risk of dementia (D), Alzheimer’s (A) or mild cognitive impairment (MCI). Although their conclusions are based on only low-to-moderate quality evidence, we suggest their results more accurately favour a protective effect and justify this in our comments below.

The evidence from Richardson et.al. suggests to us the relationship between statin use and dementia appears neutral in the cross-sectional studies [RRs:D=0.54(95%CI=0.22-1.33), A=0.45(95%CI=0.35-0.58)*, MCI=0.97(95%CI=0.87-.09), *P<0.05], moderately protective in the cohort studies [RRs:D=0.87 (95%CI=0.82-0.92)*, A=0.79(95%CI=0.63-0.99)*, MCI=0.66(95%CI=0.51-0.86)*,*P<0.05] and strongly protective in the case-control studies [RRs:D=0.25(95%CI=0.14-0.46)*, A=0.56(95%CI=0.41-0.78)*, MCI=0.37(95%CI=0.16-0.84)*, *P<0.05]. While cross sectional studies can be subject to bias (by confounding effects), the cohort studies best reflect a moderately beneficial effect of statins across healthy people (ie. not selected for any particular reason).1 The clinically significant protective effect seen in the case-control meta-analysis,1 where subjects were selected based on their elevated risk of vascular disease,1 suggests a profoundly protective effect in those at greatest risk.2 Conversely, in accumulated case series where there is an absence of a control group of unexposed people at comparable risk, it is not surprising that statin use might be spuriously linked to dementia (through confounding by drug indication). We suggest that the results of Richardson and colleagues1 are highly suggestive of a protective effect and outline below the possible mechanism underlying this observation.2-5

There is now strong evidence from pre-clinical, invitro and prospective clinical studies that systemic inflammation is linked to cognitive decline.2-5 Several studies show that by inhibiting this systemic inflammation, changes in neurobiology associated with loss of cognitive function and memory is significantly reduced.2 As statins are powerful inhibitors of systemic inflammation, particularly in those with elevated inflammatory markers (“high risk”), it is plausible that statins might confer a protective effect on cognitive decline by attenuating the damaging effects of systemic inflammation on the brain. 2 If one accepts the epidemiological data linking coronary artery disease (CAD) with dementia,2 and that in case control studies1 the dementia risk is matched in subjects randomly allocated to statin or placebo, the results reported by Richardson and colleagues provide compelling evidence of a significant protective effect (Dementia=75% reduction, Alzheimer Disease=44% reduction, Mild Cognitive Impairment=63% reduction, all P<0.05). We conclude that the evidence supports the view that statins confer a protective benefit on dementia and long-term studies in “high risk” populations is warranted.

RP Young1,2, RJ Hopkins2. 1Schools of Biological Sciences and 2Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

Affiliations: Dr Robert P Young and Ms Raewyn J Hopkins are affiliated with the Schools of Biological Science and Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
Financial/nonfinancial disclosures: RPY, and the funding of his research, has been supported by grants from the University of Auckland, Health Research Council of New Zealand and Synergenz BioSciences Ltd.
Correspondence to: Dr Robert P Young, BMedSc, MBChB, DPhil, FRACP, FRCP, Director, Respiratory Genetics Group, PO Box 26161, Epsom 1344, Auckland, New Zealand; e-mail: roberty@adhb.govt.nz


References
1. Richardson K, Schoen M, French B, et al. Statins and cognitive function: A systematic review. Ann Intern Med 2013; 159: 688-697.
2. Casserly I, Topol E. Convergence of atherosclerosis and Alzheimer’s disease: inflammation, cholesterol, and misfolded proteins. Lancet 2004; 363: 1139-1146.
3. Perry VH, Cunningham C, Holmes C. Systemic infections and inflammation affect chronic neurodegeneration. Nature Rev 2007; 7: 161-167.
4. Troller JN, Smith E, Baune BT, et al. Systemic inflammation is associated with MCI and its subtypes: The Sydney Memory and Aging Study. Dement Geriatr Cogn Disord 2010; 30: 569-578.
5. Koyama A, O’Brien J, Weuve J, et al. The role of peripheral inflammatory markers in dementia and Alzheimer’s disease: A meta-analysis. J Gerontol 2013; 68; 433-440.


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