Association of statin use with risk of dementia: A meta-analysis of prospective cohort studies

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1 bs_bs_banner Geriatr Gerontol Int 2013; 13: REVIEW ARTICLE Association of statin use with risk of dementia: A meta-analysis of prospective cohort studies Yu Song, 1 Hongwei Nie, 2 * Yong Xu, 1 Ling Zhang 1 and Yan Wu 1 1 Department of Preventive Medicine, School of Public Health, Soochow University, and 2 Department of Public Health, the Second Affiliated Hospital of Soochow University, Suzhou, China Statins are a class of medications that reduce cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which were thought to have a positive impact on dementia. We carried out the present meta-analysis to investigate whether statins might be associated with a reduction on risk of dementia. We carried out a meta-analysis of prospective cohort studies to examine the risk of dementia associated with statins. Ovid-Medline database, PubMed database, Springer Link database and Google Scholar in English search were carried out for relevant studies. Selected studies had to describe an original study defined by strict screening and diagnostic criteria. We included eight prospective cohort studies that reported relative risks with 95% confidence intervals for the association of statins and dementia risk. A random effects model was used to calculate the summary risk estimates. The studies eligible for analysis involved 2851 cases and participants. The summary relative risk of dementia for the use of statins was 0.62 (95% confidence interval ), with evidence of heterogeneity (P = 0.001, I 2 = 70.8%). Findings of the present meta-analysis show that statin use was associated with a reduced risk of dementia. Geriatr Gerontol Int 2013; 13: Keywords: cohort studies, dementia, intervention, meta-analysis, statins. Introduction Dementia is an acquired, global, progressive and usually irreversible deterioration of cognition. 1 It is a loss of cognitive abilities in multiple domains that results in impairment in normal activities of daily living and loss of independence. 2 The dementia illnesses are increasing in prevalence and present a major public health problem for the upcoming decades, 3 which bring heavy burden to the families and society. The diagnosis of dementia must have met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, third or fourth edition, revised. Statins are a class of drugs that inhibit 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) reductase. 4 Statins inhibit cholesterol synthesis, and high serum cholesterol level is a possible risk factor for Alzheimer s disease (AD), 5 7 which is the most common cause of dementia. Some researchers 8 have seen that the number of people who develop dementia is lower among those Accepted for publication 27 December Correspondence: Professor Yong Xu PhD, Department of Preventive Medicine, School of Public Health, Soochow University, Suzhou , China. xuyong59@sohu.com *Contributed equally to this work. taking statins than those not taking statins. However, a previous pooling analysis by Zhou on treatment of dementia by statins failed to detect any significant associations of statins use with incidence of dementia. 9 During the past decade, the number of subsequent original studies on this issue has increased constantly. We carried out a meta-analysis of prospective cohort studies with the following objectives: (i) to review and summarize the epidemiological evidence on the relationship of statins with the risk of dementia; (ii) to examine the statins and dementia association according to study characteristics; and (iii) to analysis the results of the included studies that we have selected. Methods Search strategy We attempted to plan, carry out and report this metaanalysis in accordance with the Meta-Analysis of Observational Studies in Epidemiology guidelines. 10 We carried out Ovid-Medline database, PubMed database, Springer Link database and Google Scholar in English searches to identify relevant studies regarding the association between statin use and risk of dementia, and the date of the last electronic search was July We used searched the terms statins, statin intervention or 2013 Japan Geriatrics Society doi: /ggi

2 Y Song et al. statin use in combination with dementia. In addition, we reviewed the reference lists of retrieved studies and recent reviews. No attempt was made to identify unpublished reports. Study selection Study selection was based on an initial screen of identified abstracts or titles and a second screen of full-text articles. Studies were considered eligible if they met the following criteria: The study design was a prospective cohort study, which provides stronger evidence than a retrospective design; The main intervention of the study was statin use; The outcome of interest was dementia risk; Relative risks (RR) with corresponding 95% confidence intervals (CI) for the use of statins on dementia were reported; The article took English as the main language. Data extraction and quality assessment We extracted all data using a standardized datacollection form. Information was recorded as follows: last name of the first author, publication year; country; length of follow up (year); number of cases; and risk estimate from multivariable model for the use of statin on dementia with corresponding 95% CI. We accessed the quality of studies using the framework suggested by the Cochrane Collaboration. For the inclusion decision, quality assessment was carried out independently by at least two reviewers. In the case of disagreement, data were reviewed by two other authors. Any disagreements were resolved by discussion. Statistical analysis Our main analyses were focused on the associations between statin use and risk of dementia. The RR was used as the common measure of association across studies, and the hazard ratio and incidence rate ratio were directly considered as RR. Homogeneity of RR across studies was tested by the Q-statistic (significance level at P < 0.10) and the I 2 -statistic, which is a quantitative measure of inconsistency across studies. 11 If substantial heterogeneity exists, the random-effects model is appropriate; otherwise, the fixed-effects model is preferred. 12 We carried out subgroup analyses stratified by geographic region, length of follow up and number of cases to assess the impacts of these variables on outcomes. Potential publication bias was assessed by both the Begg rank correlation test and Egger linear regression test. 13,14 All analyses were carried out using STATA version 11.0 (StataCorp, College Station, TX, USA). P < 0.05 was considered statistically significant, except where otherwise specified. All statistical tests were twosided. Results Literature search A flow chart showing the study selection is presented in Figure 1. Briefly, we identified 11 potentially relevant studies for full-text review. Three studies 8,15,16 were excluded, because they used a retrospective design or nested case control design. Finally, eight studies were selected for analysis. Study characteristics The characteristics of the selected studies are presented in Table 1. The eight prospective cohort studies were published between 2003 and Of the included studies, the number of cases diagnosed in the original studies ranged from 110 to 582, with a sum of The number of participants ranged from 748 to , with a sum of The length of follow up ranged from 1 to 9 years, with a median of 4 years. Case ascertainments were confirmed by medical records. Adjustment for potential confounding factors differed across studies, and most risk estimates were adjusted for age, sex, education and baseline stroke status. Main analysis The summary RR for statin used in relation to dementia risk is shown in Fig. 2. Results from eight prospective cohort studies were included. The summary RR was 0.62 (95% CI ), with evidence of heterogeneity (P = 0.001, I 2 = 70.8%). A significant association between statin use and risk of dementia was shown. Subgroup analyses Table 2 shows the results of subgroup analyses stratified by duration of follow up and number of cases. Statin use was associated with a significant reduced risk of dementia in longer years of follow up (summary RR = 0.56, 95% CI , RR and 95%CI are shown in Fig. 3) and in a higher number of cases (summary RR = 0.52, 95% CI , RR and 95%CI are shown in Fig. 4). Summary RR were stratified by the number of cases and length of follow up, and analyses among studies with more cases and longer duration yielded significant results. Publication bias There was no evidence of publication bias with regard to statin use in relation to dementia risk, as suggested by the and Egger linear regression test (all P > 0.05) Japan Geriatrics Society

3 Association of statin use with risk of dementia Potentially relevant studies identified through database search (n = 176) 165 articles excluded by screen of titles or abstracts Not cohort studies Endpoint not rel evant Full-text articles reviewed for more detailed evaluation (n = 11) 3 articles excluded Retrospective cohort studies (n = 1) Nested case-control studies (n = 1) Subset of other studies (n = 1) Figure 1 selection. Flow chart of study Articles accepted for analysis (n = 8) Discussion Since 1994, six large clinical trials have shown that (HMG-CoA) reductase inhibitors (statins) significantly reduce the incidence of coronary heart disease-related morbidity and mortality, and strokes in patients undergoing treatment for an average of 5 years Furthermore, epidemiological studies suggested that cardiovascular diseases were the important risk factor for the development of dementia Statins are increasingly popular drugs for cardiovascular indications, and they might also have protective effects against dementing illness. Statins are also effective treatments for hypercholesterolemia, a possible risk factor for both vascular dementia and AD. 35 Studies show that statins lower the level of 24S-hydroxycholesterol, a major product of brain cholesterol metabolism, in patients with AD. 36,37 Statin has long been thought to play a role in the vascular improvement on dementia patients, yet evidence from the studies is not conclusive. The results of some observational and randomized-controlled studies 8,16,38 44 provide evidence of an association, whereas others found no association Although a previous meta-analysis by Zhou et al. 9 in 2007 concluded that statin use did not show a beneficial effect on the risk of dementia or Alzheimer s disease, the present findings of the present meta-analysis of prospective cohort studies showed that the use of statin was associated with a reduced risk of dementia. Furthermore, the results of stratified analyses also showed statin use was associated with a significant reduced risk of dementia in longer years of follow up and a higher number of cases. In a Multi-Institutional Research in Alzheimer s Genetic Epidemiology study, Robert and Green provided evidence that statin medications were associated with lowered risk of AD in the elderly population (OR 0.61; 95% CI ). 45 An editorial by Sparks concluded that it is clear that somewhere between normal cognitive performance and profound dementia of AD, statin therapy exerts a beneficial effect. 46 These are consistent with the aforementioned conclusions. Meta-analyzing of these studies is a powerful tool to assess small sample size or low incidence of individual smaller studies. A limitation of a meta-analysis is that absolute numbers of the outcomes of single studies are entered, whereas no effect sizes that are controlled for major confounding factors are entered. 47 The present study had strengths. With the metaanalysis using STATA software, we enhanced the statistical power to detect any associations between statin use and risk of dementia, and to obtain expected results. In addition, all the original studies enrolled in the present meta-analysis used a prospective cohort design, which 2013 Japan Geriatrics Society 819

4 Y Song et al. Table 1 Characteristics of the included studies First author and year Age and sex distribution Type of dementia Mean follow up (year) Cases Adjusted RR (95% CI) Adjustment Carl No mentioned VD ( ) Body mass index, smoking, hypertension, previous history of coronary artery disease, coronary artery bypass surgery, diabetes mellitus, and transient cerebral ischemia GLi AD ( ) Age at entry, years of education, APOE-e4 status, and male: 40.2%; female: 59.8% use of other LLA (for analyses with statins) or use of statins (for analyses of other LLA) Peter AD ( ) Age and sex, education, the number ofapoe-e4 alleles, male: 47.3% female: 52.7% age APOE genotype, and a history of hypertension or diabetes Thomas Dementia ( ) Age, sex, educational level, baseline alcohol male: 33.7% consumption, baseline Modified Mini-Mental State female: 67.3% Examination score, baseline coronary heart disease status and baseline stroke status GLi AD ( ) Age at death, sex, CASI score at entry, presence of male: 45% MVL (0 vs 1 MVL) and brain weight female: 55% Cramer Dementia ( ) Statins, baseline diabetes and stroke male: 42% female: 58% Haag AD ( ) Education, systolic blood pressure, smoking, total male: 40% serum cholesterol, body mass index, diabetes female: 60% mellitus and cardiovascular and cerebrovascular Smeeth Dementia ( ) Age, sex, propensity score, year of index date, first male: 49.8% diagnosis of any of the following post-index date: female: 50.2% diabetes, cerebrovascular disease and coronary heart disease disease AD, Alzheimer s disease; APOE, apolipoprotein; CASI, Cognitive Abilities Screening Instrument; LLA, lipid-lowering agent; MVL, microvascular lesions; VD, vascular disease Japan Geriatrics Society

5 Association of statin use with risk of dementia Figure 2 Forest plot of studies examining the association between statin use and risk of dementia. Table 2 Results of stratified analyses of dementia incidence Group No. studies Summary relative risk (95% CI) P-value for heterogeneity All ( ) Mean follow up (years) < ( ) ( ) No. cases < ( ) ( ) I 2 (%) minimizes recall, and interviewer and selection biases that can always be concerns in retrospective studies. Furthermore, several limitations also involved in the present study should be considered. First, unmeasured or uncontrolled confounding inherited from the original studies was a concern in the present meta-analysis. Second, the high degree of heterogeneity, which made the results complicated to interpret, was a limitation of the present study. Finally, potential publication bias might have influenced the findings. In conclusion, we found a significant association between statin use and a reduced risk of dementia, and our findings, therefore, provide some support to the hypothesis that statins might protect against the development of dementia. However, prospective clinical trials 48,49 do not show enough evidence to support the use of statins to delay progression of AD. More basic experimental research studies and larger, multicenter trials are warranted to confirm the potential benefits of statins in the treatment of AD. 50 Acknowledgments All authors critically revised the manuscript for important intellectual content and approved the final manuscript. Thank you very much for their assistance. This study had no sponsor and no external funding. Disclosure statement No potential conflicts of interest were disclosed Japan Geriatrics Society 821

6 Y Song et al. Figure 3 Forest plot of studies examining the association between statin use and risk of dementia in longer years of follow up. Figure 4 Forest plot of studies examining the association between statin use and risk of dementia in a higher number of cases. References 1 Ilkin I, Ignat P. Dementia. Self Management of Chronic Disease 2009; Williams JW, Plassman BL, Burke J, Holsinger T, Benjamin S. Preventing Alzheimer disease and cognitive decline: evidence report/technology assessment, NO.193. Duke Evidence-based Practice Center Peter VR, Nancy LM, Mary JL. The impact of dementia on the family. JAMA 1982; 248: Bernadette MG, Peter P. Can statins prevent or help treat Alzheimer s disease? J Alzheimers Dis Other Demen 2010; 20: Notkola IL, Sulkava R, Pekkanen J et al. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer s disease. Neuroepidemiology 1998; 17: Evans RM, Emsley CL, Gao S et al. Serum cholesterol, APOE genotype, and the risk of Alzheimer s disease: a population-based study of African Americans. Neurology 2000; 54: Hall K, Murrell J, Ogunniyi A et al. Cholesterol, APOE genotype, and Alzheimer disease: an epidemiologic study of Nigerian Yoruba. Neurology 2006; 66: Jick H, Zornberg GL, Jick S, Sesharia S, Drachman DA. Statins and the risk of dementia. Lancet 2000; 356: Japan Geriatrics Society

7 Association of statin use with risk of dementia 9 Zhou B, Teramukai S, Fukushima M. Prevention and treatment of dementia or Alzheimer s disease by statins: a meta-analysis. Dement Geriatr Cogn Disord 2007; 23: Stroup DF, Berlin JA, Morton SC et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA 2000; 283: Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327 (7414): DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50: Egger M, Davey SG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315 (7109): McGuinness B, O Hare J, Craig D, Bullock R, Malouf R, Passmore P. Statins for the treatment of dementia. Geriatr Med 2008; 6 (8): CD Hajjar I, Schumpert J, Hirth V, Wieland D, Eleazer GP. The impact of the use of statins on the prevalence of dementia and the progression of cognitive impairment. J Gerontol Ser A Biol Sci Med Sci 2002; 57: M414 M Carl JV. Prevention of stroke and dementia with statins: effects beyond lipid lowering. Am J Cardiol 2003; 91 (Suppl): 23B 29B. 18 Li G, Higdon R, Kukull WA et al. Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study. Neurology 2004; 63: Peter PZ, Larry D, Khachaturian AS et al. Do statins Reduce Risk of Incident Dementia and Alzheimer Disease? Arch Gen Psychiatry 2005; 62: Thomas DR, John CB, Bruce MP et al. Statin use and the risk of incident dementia: the cardiovascular health study. Arch Neurol 2005; 62: Li G, Larson EB, Sonnen JA et al. Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease. Neurology 2007; 69: Cramer C, Haan MN, Galea S, Langa KM, Kalbfleisch JD. Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study. Neurology 2008; 71: Haag M, Hofman A, Koudstaal PJ, Stricker C, Breteler B. Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. J Neurol Neurosurg Psychiatry 2009; 80: Smeeth L, Douglas I, Hall AJ, Hubbardd R, Evans S. Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials. Br J Clin Pharmacol 2009; 67: The Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: Shepherd J, Cobbe SM, Ford I et al. for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease in men with hypercholesterolemia. N Engl J Med 1995; 333: Sacks FM, Pfeffer MA, Moye LA et al. for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339: Downs JR, Clearfield M, Weis S et al. for the AFCAPS/ TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998; 279: Robins SJ, Despres JP. MRC/BHF Heart Protection Study. Lancet; 360 (9374): Nash DT, Fillit H. Cardiovascular disease risk factors and cognitive impairment. Am J Cardiol 2006; 97: Luchsinger JA, Reitz C, Honig LS et al. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology 2005; 65: Newman AB, Fitzpatrick AL, Lopez O et al. Dementia and Alzheimer s disease incidence in relationship to cardiovascular disease in the Cardiovascular Health Study cohort. J Am Geriatr Soc 2005; 53: Breteler MM, Claus JJ, Grobbee DE, Hofman A. Cardiovascular disease and distribution of cognitive function in elderly people: the Rotterdam Study. BMJ 1994; 308 (6944): Szwast SJ, Hendrie HC, Lane KA et al. Association of statin use with cognitive decline in elderly African Americans. Neurology 2007; 69: Vega GL, Weiner MF, Lipton AM et al. Reduction in levels of 24S-hydroxycholesterol by statin treatment inpatients with Alzheimer disease. Arch Neurol 2003; 60: Simons M, Schwarzler F, Lutjohann D et al. Treatment with simvastatin in normocholesterolemic patients with Alzheimer s disease: a 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol 2002; 52: Dufouil C, Richard F, Fievet N et al. APOE genotype, cholesterol level, lipid-lowering treatment, and dementia: the Three-City Study. Neurology 2005; 64: Green RC, McNagny SE, Jayakumar P et al. Statin use and the risk of Alzheimer s disease: the MIRAGE Study. Alzheimers Dement 2006; 2: Rockwood K, Kirkland S, Hogan DB et al. Use of lipidlowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol 2002; 59: Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors [see comment]. Arch Neurol 2000; 57: Zamrini E, McGwin G, Roseman JM. Association between statin use and Alzheimer s disease. Neuroepidemiology 2004; 23: Bernick C, Katz R, Smith NL et al. Statins and cognitive function in the elderly. The Cardiovascular Health Study. Neurology 2005; 65: Sparks DL, Sabbagh MN, Connor DJ et al. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol 2005; 62: Robert C, Green SE. Statin use and the risk of Alzheimer s disease: the MIRAGE Study. Alzheimers Dement 2006; 2: Sparks L. Statins and cognitive function. J Neurol Neurosurg Psychiatry 2009; 80: Weih M, Degirmenci Ü, Kreil S, Kornhuber J. Physical activity and Alzheimer s disease: a meta-analysis of cohort studies. Gero Psych 2010; 23: Japan Geriatrics Society 823

8 Y Song et al. 48 MRC/BHF Heat Protection Study of cholesterol lowering with simvastatin in high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: Shepherd J, Blauw GJ, Murphy MB et al. Pravastatin in Elderly Individuals at Risk of Vascular Disease(PROSPER): a randomised controlled trial. Lancet 2002; 360: Alba R, Jordi P, Marta A. Cholesterol lowering and beyond: role of statin in Alzheimer s Disease. Aging Health 2008; 4: Japan Geriatrics Society