Unintended effects of statins from observational studies in the general population: systematic review and meta-analysis

Ana Filipa Macedo, Fiona Claire Taylor, Juan P Casas, Alma Adler, David Prieto-Merino, Shah Ebrahim, Ana Filipa Macedo, Fiona Claire Taylor, Juan P Casas, Alma Adler, David Prieto-Merino, Shah Ebrahim

Abstract

Background: Efficacy of statins has been extensively studied, with much less information reported on their unintended effects. Evidence from randomized controlled trials (RCTs) on unintended effects is often insufficient to support hypotheses generated from observational studies. We aimed to systematically assess unintended effects of statins from observational studies in general populations with comparison of the findings where possible with those derived from randomized trials.

Methods: Medline (1998 to January 2012, week 3) and Embase (1998 to 2012, week 6) were searched using the standard BMJ Cohort studies filter. The search was supplemented with reference lists of all identified studies and contact with experts in the field. We included prospective studies with a sample size larger than 1,000 participants, case control (of any size) and routine health service linkage studies of over at least one year duration. Studies in subgroups of patients or follow-up of patient case series were excluded, as well as hospital-based cohort studies.

Results: Ninety studies were identified, reporting on 48 different unintended effects. Statins were associated with lower risks of dementia and cognitive impairment, venous thrombo-embolism, fractures and pneumonia, but these findings were attenuated in analyses restricted to higher quality studies (respectively: OR 0.74 (95% CI 0.62 to 0.87); OR 0.92 (95% CI 0.81 to 1.03); OR 0.97 (95% CI 0.88 to 1.05); OR 0.92 (95% CI 0.83 to 1.02)); and marked heterogeneity of effects across studies remained. Statin use was not related to any increased risk of depression, common eye diseases, renal disorders or arthritis. There was evidence of an increased risk of myopathy, raised liver enzymes and diabetes (respectively: OR 2.63 (95% CI 1.50 to 4.61); OR 1.54 (95% CI 1.47 to 1.62); OR 1.31 (95% CI 0.99 to 1.73)).

Conclusions: Our systematic review and meta-analyses indicate that high quality observational data can provide relevant evidence on unintended effects of statins to add to the evidence from RCTs. The absolute excess risk of the observed harmful unintended effects of statins is very small compared to the beneficial effects of statins on major cardiovascular events.

Figures

Figure 1
Figure 1
Flow chart for identifying eligible studies. The search strategy yielded 12,010 publications, of which 1,674 were duplicates and 10,230 references were not eligible based on abstract and title review. We systematically searched the reference lists of the remaining 110 eligible articles and of 33 reviews, and contacted experts. Ninety-five additional studies were identified that were not captured with our initial search strategy. Of this total, five references of short communications await classification because we were unable to contact the author or received no answer regarding a possible publication. Full papers were obtained for 200 references. From these, 63 were excluded for not fulfilling inclusion criteria. Of the identified 137 references, 51 assessed statin risk of cancer and were excluded from the present analysis; we focused on the remaining 86 references.
Figure 2
Figure 2
Newcastle-Ottawa Quality Assessment: number of studies by number of “stars” assigned, according to study design.
Figure 3
Figure 3
Summary of results from random-effects meta-analyses for each outcome and estimates from Randomized Controlled Trials.

References

    1. Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, Ward K, Ebrahim S. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;1 CD004816.
    1. Ross SD, Allen IE, Connelly JE, Korenblat BM, Smith ME, Bishop D, Luo D. Clinical outcomes in statin treatment trials: a meta-analysis. Arch Intern Med. 1999;159:1793–1802. doi: 10.1001/archinte.159.15.1793.
    1. Thavendiranathan P, Bagai A, Brookhart MA, Choudhry NK. Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials. Arch Int Med. 2006;166:2307–2313. doi: 10.1001/archinte.166.21.2307.
    1. Briel M, Studer M, Glass TR, Bucher HC. Effects of statins on stroke prevention in patients with and without coronary heart disease: a meta-analysis of randomized controlled trials. Am J Med. 2004;117:596–606. doi: 10.1016/j.amjmed.2004.04.022.
    1. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA. 1999;282:2340–2346. doi: 10.1001/jama.282.24.2340.
    1. Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. JAMA. 1997;278:313–321. doi: 10.1001/jama.1997.03550040069040.
    1. Pitrou I, Boutron I, Ahmad N, Ravaud P. Reporting of safety results in published reports of randomized controlled trials. Arch Intern Med. 2009;169:1756–1761.
    1. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–1278. Erratum in: Lancet 2005, 366:1358. Lancet 2008, 371:2084.
    1. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–1681.
    1. Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH, Voysey M, Gray A, Collins R, Baigent C. Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380:581–590.
    1. Emberson JR, Kearney PM, Blackwell L, Newman C, Reith C, Bhala N, Holland L, Peto R, Keech A, Collins R, Simes J, Baigent C. Cholesterol Treatment Trialists’ (CTT) Collaboration. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One. 2012;7:e29849. doi: 10.1371/journal.pone.0029849.
    1. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd J, Davis BR, Pressel SL, Marchioli R, Marfisi RM, Maggioni AP, Tavazzi L, Tognoni G, Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Clearfield MB, Downs JR, Nakamura H, Ohashi Y. et al.Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375:735–742. doi: 10.1016/S0140-6736(09)61965-6.
    1. Mills EJ, Wu P, Chong G, Ghement I, Singh S, Akl EA, Eyawo O, Guyatt G, Berwanger O, Briel M. Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials. QJM. 2011;104:109–124. doi: 10.1093/qjmed/hcq165.
    1. FDA expands advice on statin risks. [ ]
    1. Statins: risk of hyperglycaemia and diabetes. Drug safety update January 2012. p. A2. [ ]
    1. Feng L, Yap KB, Kua EH, Ng TP. Statin use and depressive symptoms in a prospective study of community-living older persons. Pharmacoepidemiol Drug Saf. 2010;19:942–948. doi: 10.1002/pds.1993.
    1. Yang CC, Jick SS, Jick H. Lipid-lowering drugs and the risk of depression and suicidal behavior. Arch Intern Med. 2003;163:1926–1932. doi: 10.1001/archinte.163.16.1926.
    1. Li G, Higdon R, Kukull WA, Peskind E, Van Valen Moore K, Tsuang D, van Belle G, McCormick W, Bowen JD, Teri L, Schellenberg GD, Larson EB. Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study. Neurology. 2004;63:1624–1628. doi: 10.1212/01.WNL.0000142963.90204.58.
    1. Bernick C, Katz R, Smith NL, Rapp S, Bhadelia R, Carlson M, Kuller L. Cardiovascular Health Study. Statins and cognitive function in the elderly: the Cardiovascular Health Study. Neurology. 2005;65:1388–1394. doi: 10.1212/.
    1. McGwin G, Modjarrad K, Andrew Hal T, Xie A, Owsley C. 3-Hydroxy-3-methylglutaryl coenzyme a reductase inhibitors and the presence of age-related macular degeneration in the cardiovascular health study. Arch Ophthalmol. 2006;124:33–37. doi: 10.1001/archopht.124.1.33.
    1. McCarty CA, Mukesh BN, Guymer RH, Baird PN, Taylor HR. Cholesterol-lowering medications reduce the risk of age-related maculopathy progression. Med J Aust. 2001;175:340.
    1. Scott HD, Laake K. Statins for the prevention of Alzheimer’s disease and dementia. Cochrane Database Syst Rev. 2001. p. CD003160.
    1. McGuinness B, O’Hare J, Craig D, Bullock R, Malouf R, Passmore P. Statins for the treatment of dementia. Cochrane Database Syst Rev. 2010. p. CD007514.
    1. Gehlbach P, Li T, Hatef E. Statins for age-related macular degeneration. Cochrane Database Syst Rev. 2012. p. CD006927.
    1. Wang J, Xiao Y, Luo M, Luo H. Statins for multiple sclerosis. Cochrane Database Syst Rev. 2011. p. CD008386.
    1. Li L, Sun T, Zhang P, Tian J, Yang K. Statins for primary prevention of venous thromboembolism. Cochrane Database Syst Rev. 2011. p. CD008203.
    1. Rahimi K, Emberson J, McGale P, Majoni W, Merhi A, Asselbergs FW, Krane V, Macfarlane PW. PROSPER Executive. Effect of statins on atrial fibrillation: collaborative meta-analysis of published and unpublished evidence from randomised controlled trials. BMJ. 2011;342:d1250. doi: 10.1136/bmj.d1250.
    1. Bulbulia R, Bowman L, Wallendszus K, Parish S, Armitage J, Peto R, Collins R. Heart Protection Study Collaborative Group. Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20,536 high-risk individuals: a randomised controlled trial. Lancet. 2011;378:2013–2020.
    1. ClinicalEvidence: Learn, teach, and practise evidence-based medicine. [ ]
    1. Golder S, Loke YK. Sensitivity and precision of adverse effects search filters in MEDLINE and EMBASE: a case study of fractures with thiazolidinediones. Health Info Libr J. 2012;29:28–38. doi: 10.1111/j.1471-1842.2011.00972.x.
    1. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.0.2 [updated September 2009]. The Cochrane Collaboration. Chichester, UK: John Wiley & Sons, Ltd; 2009. [ ]
    1. Egger M, Smith GD, Phillips AN. Meta-analysis: principles and procedures. BMJ. 1997;315:1533–1537. doi: 10.1136/bmj.315.7121.1533.
    1. Anderson JL, Muhlestein JB, Bair TL, Morris S, Weaver AN, Lappé DL, Renlund DG, Pearson RR, Jensen KR, Horne BD. Do statins increase the risk of idiopathic polyneuropathy? Am J Cardiol. 2005;95:1097–1099. doi: 10.1016/j.amjcard.2004.12.068.
    1. Ashfield TA, Syddall HE, Martin HJ, Dennison EM, Cooper C, Aihie Sayer A. Grip strength and cardiovascular drug use in older people: findings from the Hertfordshire Cohort Study. Age Ageing. 2010;39:185–191. doi: 10.1093/ageing/afp203.
    1. Atthobari J, Brantsma AH, Gansevoort RT, Visser ST, Asselbergs FW, van Gilst WH, de Jong PE, de Jong-van den Berg LT. PREVEND study group. The effect of statins on urinary albumin excretion and glomerular filtration rate: results from both a randomized clinical trial and an observational cohort study. Nephrol Dial Transplant. 2006;21:3106–3114. doi: 10.1093/ndt/gfl244.
    1. Becker C, Jick SS, Meier CR. Use of statins and the risk of Parkinson’s disease: a retrospective case–control study in the UK. Drug Saf. 2008;31:399–407. doi: 10.2165/00002018-200831050-00004.
    1. Chan KA, Andrade SE, Boles M, Buist DS, Chase GA, Donahue JG, Goodman MJ, Gurwitz JH, LaCroix AZ, Platt R. Inhibitors of hydroxymethylglutaryl-coenzyme A reductase and risk of fracture among older women. Lancet. 2000;355:2185–2188. doi: 10.1016/S0140-6736(00)02400-4.
    1. Clockaerts S, Van Osch GJ, Bastiaansen-Jenniskens YM, Verhaar JA, Van Glabbeek F, Van Meurs JB, Kerkhof HJ, Hofman A, Stricker BH, Bierma-Zeinstra SM. Statin use is associated with reduced incidence and progression of knee osteoarthritis in the Rotterdam study. Ann Rheum Dis. 2012;71:642–647. doi: 10.1136/annrheumdis-2011-200092.
    1. Corrao G, Zambon A, Bertù L, Botteri E, Leoni O, Contiero P. Lipid lowering drugs prescription and the risk of peripheral neuropathy: an exploratory case–control study using automated databases. J Epidemiol Community Health. 2004;58:1047–1051. doi: 10.1136/jech.2003.013409.
    1. 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;71:344–350. doi: 10.1212/01.wnl.0000319647.15752.7b.
    1. Culver AL, Ockene IS, Balasubramanian R, Olendzki BC, Sepavich DM, Wactawski-Wende J, Manson JE, Qiao Y, Liu S, Merriam PA, Rahilly-Tierny C, Thomas F, Berger JS, Ockene JK, Curb JD, Ma Y. Statin use and risk of diabetes mellitus in postmenopausal women in the Women’s Health Initiative. Arch Intern Med. 2012;172:144–152. doi: 10.1001/archinternmed.2011.625.
    1. de Jong HJ, Klungel OH, van Dijk L, Vandebriel RJ, Leufkens HG, van der Laan JW, Cohen Tervaert JW, van Loveren H. Use of statins is associated with an increased risk of rheumatoid arthritis. Ann Rheum Dis. 2012;71:648–654. doi: 10.1136/ard.2011.155622.
    1. de Vries F, de Vries C, Cooper C, Leufkens B, van Staa TP. Reanalysis of two studies with contrasting results on the association between statin use and fracture risk: the General Practice Research Database. Int J Epidemiol. 2006;35:1301–1308. doi: 10.1093/ije/dyl147.
    1. Doggen CJ, Lemaitre RN, Smith NL, Heckbert SR, Psaty BM. HMG CoA reductase inhibitors and the risk of venous thrombosis among post-menopausal women. J Thromb Haemost. 2004;2:700–701. doi: 10.1111/j.1538-7836.2004.00696.x.
    1. Erichsen R, Frøslev T, Lash TL, Pedersen L, Sorensen HT. Long-term statin use and the risk of gallstone disease: a population-based case-control study. Am J Epidemiol. 2011;173:162–170. doi: 10.1093/aje/kwq361.
    1. Fleming DM, Verlander NQ, Elliot AJ, Zhao H, Gelb D, Jehring D, Nguyen-Van-Tam JS. An assessment of the effect of statin use on the incidence of acute respiratory infections in England during winters 1998–1999 to 2005–2006. Epidemiol Infect. 2010;138:1281–1288. doi: 10.1017/S0950268810000105.
    1. Fujii T, Nakabayashi T, Hashimoto S, Kuwano H. Statin use and risk of gastroduodenal ulcer and reflux esophagitis. Hepatogastroenterology. 2009;56:641–644.
    1. Gaist D, Garcia Rodriguez LA, Huerta C, Hallas J, Sindrup SH. Are users of lipid-lowering drugs at increased risk of peripheral neuropathy? Eur J Clin Pharmacol. 2001;56:931–933. doi: 10.1007/s002280000248.
    1. Gaist D, Jeppesen U, Andersen M, García Rodríguez LA, Hallas J, Sindrup SH. Statins and risk of polyneuropathy: a case–control study. Neurology. 2002;58:1333–1337. doi: 10.1212/WNL.58.9.1333.
    1. Gaist D, Rodriguez LA, Huerta C, Hallas J, Sindrup SH. Lipid-lowering drugs and risk of myopathy: a population-based follow-up study. Epidemiology. 2001;12:565–569. doi: 10.1097/00001648-200109000-00017.
    1. Gao X, Simon K, Schwarzschild MA, Ascherio A. A prospective study of statin use and risk of Parkinson disease. Parkinsonism Relat D. 2012;18:S40.
    1. Green RC, McNagny SE, Jayakumar P, Cupples LA, Benke K, Farrer LA. MIRAGE Study Group. Statin use and the risk of Alzheimer’s disease: the MIRAGE study. Alzheimers Dement. 2006;2:96–103. doi: 10.1016/j.jalz.2006.02.003.
    1. Gulmez SE, Lassen AT, Aalykke C, Dall M, Andries A, Andersen BS, Hansen JM, Andersen M, Hallas J. Do statins protect against upper gastrointestinal bleeding? Br J Clin Pharmacol. 2009;67:460–465. doi: 10.1111/j.1365-2125.2009.03362.x.
    1. Haag MD, Hofman A, Koudstaal PJ, Stricker BH, Breteler MM. Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study. J Neurol Neurosurg Psychiatry. 2009;80:13–17. doi: 10.1136/jnnp.2008.150433.
    1. Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ. 2010;340:c2197. doi: 10.1136/bmj.c2197.
    1. Huang X, Chen H, Miller WC, Mailman RB, Woodard JL, Chen PC, Xiang D, Murrow RW, Wang YZ, Poole C. Lower low-density lipoprotein cholesterol levels are associated with Parkinson’s disease. Mov Disord. 2007;22:377–381. doi: 10.1002/mds.21290.
    1. Huerta C, Johansson S, Wallander MA, Garcıa Rodrıguez LA. Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom. Arch Intern Med. 2007;167:935–943. doi: 10.1001/archinte.167.9.935.
    1. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet. 2000;356:1627–1631. doi: 10.1016/S0140-6736(00)03155-X.
    1. Jick SS, Bradbury BD. Statins and newly diagnosed diabetes. Br J Clin Pharmacol. 2004;58:303–309. doi: 10.1111/j.1365-2125.2004.02142.x.
    1. Jick SS, Choi H, Li L, McInnes IB, Sattar N. Hyperlipidaemia, statin use and the risk of developing rheumatoid arthritis. Ann Rheum Dis. 2009;68:546–551. doi: 10.1136/ard.2008.091967.
    1. Klein BE, Klein R, Lee KE, Grady LM. Statin use and incident nuclear cataract. JAMA. 2006;295:2752–2758. doi: 10.1001/jama.295.23.2752.
    1. Klein R, Klein BE, Tomany SC, Danforth LG, Cruickshanks KJ. Relation of statin use to the 5-year incidence and progression of age-related maculopathy. Arch Ophthalmol. 2003;121:1151–1155. doi: 10.1001/archopht.121.8.1151.
    1. Klein R, Knudtson MD, Klein BE. Statin use and the five-year incidence and progression of age-related macular degeneration. Am J Ophthalmol. 2007;144:1–6. doi: 10.1016/j.ajo.2007.02.047.
    1. Kwong JC, Li P, Redelmeier DA. Influenza morbidity and mortality in elderly patients receiving statins: a cohort study. PLoS One. 2009;4:e8087. doi: 10.1371/journal.pone.0008087.
    1. LaCroix AZ, Cauley JA, Pettinger M, Hsia J, Bauer DC, McGowan J, Chen Z, Lewis CE, McNeeley SG, Passaro MD, Jackson RD. Statin use, clinical fracture, and bone density in postmenopausal women: results from the Women’s Health Initiative Observational Study. Ann Intern Med. 2003;139:97–104. doi: 10.7326/0003-4819-139-2-200307150-00009.
    1. LaCroix AZ, Gray SL, Aragaki A, Cochrane BB, Newman AB, Kooperberg CL, Black H, Curb JD, Greenland P, Woods NF. Statin use and incident frailty in women aged 65 years or older: prospective findings from the Women’s Health Initiative Observational Study. J Gerontol A Biol Sci Med Sci. 2008;63:369–375. doi: 10.1093/gerona/63.4.369.
    1. Lacut K, Le Gal G, Abalain JH, Mottier D, Oger E. Differential associations between lipid-lowering drugs, statins and fibrates, and venous thromboembolism: role of drug induced homocysteinemia? Thromb Res. 2008;122:314–319. doi: 10.1016/j.thromres.2007.10.014.
    1. Lemaitre RN, Psaty BM, Heckbert SR, Kronmal RA, Newman AB, Burke GL. Therapy with hydroxymethylglutaryl coenzyme a reductase inhibitors (statins) and associated risk of incident cardiovascular events in older adults: evidence from the Cardiovascular Health Study. Arch Intern Med. 2002;162:1395–1400. doi: 10.1001/archinte.162.12.1395.
    1. Li G, Shofer JB, Rhew IC, Kukull WA, Peskind ER, McCormick W, Bowen JD, Schellenberg GD, Crane PK, Breitner JC, Larson EB. Age-varying association between statin use and incident Alzheimer’s disease. J Am Geriatr Soc. 2010;58:1311–1317. doi: 10.1111/j.1532-5415.2010.02906.x.
    1. Luijendijk HJ, Stricker BH, Hofman A, Witteman JCM, Tiemeier H. Cerebrovascular risk factors and incident depression in community-dwelling elderly. Acta Psychiatr Scand. 2008;118:139–148. doi: 10.1111/j.1600-0447.2008.01189.x.
    1. Marcus MW, Müskens RP, Ramdas WD, Wolfs RC, De Jong PT, Vingerling JR, Hofman A, Stricker BH, Jansonius NM. Cholesterol-lowering drugs and incident open-angle glaucoma: a population-based cohort study. PLoS ONE. 2012;7:e29724. doi: 10.1371/journal.pone.0029724.
    1. McClure DL, Valuck RJ, Glanz M, Murphy JR, Hokanson JE. Statin and statin-fibrate use was significantly associated with increased myositis risk in a managed care population. J Clin Epidemiol. 2007;60:812–818. doi: 10.1016/j.jclinepi.2006.11.006.
    1. McGwin G Jr, Owsley C, Curcio CA, Crain RJ. The association between statin use and age related maculopathy. Br J Ophthalmol. 2003;87:1121–1125. doi: 10.1136/bjo.87.9.1121.
    1. McGwin G Jr, McNeal S, Owsley C, Girkin C, Epstein D, Lee PP. Statins and other cholesterol-lowering medications and the presence of glaucoma. Arch Ophthalmol. 2004;122:822–826. doi: 10.1001/archopht.122.6.822.
    1. Meier CR, Schlienger RG, Kraenzlin ME, Schlegel B, Jick H. HMG-CoA reductase inhibitors and the risk of fractures. JAMA. 2000;283:3205–3210. doi: 10.1001/jama.283.24.3205.
    1. Myles PR, Hubbard RB, McKeever TM, Pogson Z, Smith CJ, Gibson JE. Risk of community-acquired pneumonia and the use of statins, ace inhibitors and gastric acid suppressants: a population-based case-control study. Pharmacoepidemiol Drug Saf. 2009;18:269–275. doi: 10.1002/pds.1715.
    1. Nash SD, Cruickshanks KJ, Klein R, Klein BE, Nieto FJ, Huang GH, Pankow JS, Tweed TS. The prevalence of hearing impairment and associated risk factors: the Beaver Dam Offspring Study. Arch Otolaryngol Head Neck Surg. 2011;137:432–439. doi: 10.1001/archoto.2011.15.
    1. Nichols GA, Koro CE. Does statin therapy initiation increase the risk for myopathy? An observational study of 32,225 diabetic and nondiabetic patients. Clin Ther. 2007;29:1761–1770. doi: 10.1016/j.clinthera.2007.08.022.
    1. Owen CG, Carey IM, Shah S, de Wilde S, Wormald R, Whincup PH, Cook DG. Hypotensive medication, statins, and the risk of glaucoma. Invest Ophthalmol Vis Sci. 2010;51:3524–3530. doi: 10.1167/iovs.09-4821.
    1. Ramcharan AS, van Stralen KJ, Snoep JD, Mantel-Teeuwisse AK, Rosendaal FR, Doggen CJ. HMG-CoA reductase inhibitors are associated with a reduced risk of venous thrombosis. J Thromb Haemost. 2009;7:514–520. doi: 10.1111/j.1538-7836.2008.03235.x.
    1. Ray WA, Daugherty JR, Griffin MR. Lipid-lowering agents and the risk of hip fracture in a Medicaid population. Inj Prev. 2002;8:276–279. doi: 10.1136/ip.8.4.276.
    1. Rea TD, Breitner JC, Psaty BM, Fitzpatrick AL, Lopez OL, Newman AB, Hazzard WR, Zandi PP, Burke GL, Lyketsos CG, Bernick C, Kuller LH. Statin use and the risk of incident dementia: the Cardiovascular Health Study. Arch Neurol. 2005;62:1047–1051. doi: 10.1001/archneur.62.7.1047.
    1. Rejnmark L, Olsen ML, Johnsen SP, Vestergaard P, Sørensen HT, Mosekilde L. Hip fracture risk in statin users-a population-based Danish case-control study. Osteoporos Int. 2004;15:452–458.
    1. Risselada R, Straatman H, van Kooten F, Dippel DW, van der Lugt A, Niessen WJ, Firouzian A, Herings RM, Sturkenboom MC. Withdrawal of statins and risk of subarachnoid hemorrhage. Stroke. 2009;40:2887–2892. doi: 10.1161/STROKEAHA.109.552760.
    1. Ritz B, Manthripragada AD, Qian L, Schernhammer E, Wermuth L, Olsen J, Friis S. Statin use and Parkinson’s disease in Denmark. Mov Disord. 2010;25:1210–1216. doi: 10.1002/mds.23102.
    1. Rockwood K, Howlett S, Fisk J, Darvesh S, Tuokko H, Hogan DB, Wolfson C, McDowell I. Lipid-lowering agents and the risk of cognitive impairment that does not meet criteria for dementia, in relation to apolipoprotein E status. Neuroepidemiology. 2007;29:201–207. doi: 10.1159/000111583.
    1. Rockwood K, Kirkland S, Hogan DB, MacKnight C, Merry H, Verreault R, Wolfson C, McDowell I. Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol. 2002;59:223–227. doi: 10.1001/archneur.59.2.223.
    1. Rodríguez GL, Wallander MA, Tolosa LB, Johansson S. Chronic obstructive pulmonary disease in UK primary care: incidence and risk factors. COPD. 2009;6:369–379. doi: 10.1080/15412550903156325.
    1. Schlienger RG, Fedson DS, Jick SS, Jick H, Meier CR. Statins and the risk of pneumonia: a population-based, nested case–control study. Pharmacotherapy. 2007;27:325–332. doi: 10.1592/phco.27.3.325.
    1. Schlienger RG, Haefeli WE, Jick H, Meier CR. Risk of cataract in patients treated with statins. Arch Intern Med. 2001;161:2021–2026. doi: 10.1001/archinte.161.16.2021.
    1. Schoofs MW, Sturkenboom MC, van der Klift M, Hofman A, Pols HA, Stricker BH. HMG-CoA reductase inhibitors and the risk of vertebral fracture. J Bone Miner Res. 2004;19:1525–1530. doi: 10.1359/JBMR.040607.
    1. Scranton RE, Young M, Lawler L, Solomon DH, Gagnon DR, Gaziano JM. Statin use and fracture risk: study of a US veterans population. Arch Intern Med. 2005;165:2007–2012. doi: 10.1001/archinte.165.17.2007.
    1. Smeeth L, Cook C, Chakravarthy U, Hubbard R, Fletcher AE. A case control study of age related macular degeneration and use of statins. Br J Ophthalmol. 2005;89:1171–1175. doi: 10.1136/bjo.2004.064477.
    1. Smeeth L, Douglas I, Hall AJ, Hubbard 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;67:99–109. doi: 10.1111/j.1365-2125.2008.03308.x.
    1. Smeeth L, Hubbard R, Fletcher AE. Cataract and the use of statins: a case–control study. QJM. 2003;96:337–343. doi: 10.1093/qjmed/hcg064.
    1. Solomon A, Kåreholt I, Ngandu T, Wolozin B, MacDonald SW, Winblad B, Nissinen A, Tuomilehto J, Soininen H, Kivipelto M. Serum total cholesterol, statins and cognition in non-demented elderly. Neurobiol Aging. 2009;30:1006–1009. doi: 10.1016/j.neurobiolaging.2007.09.012.
    1. Sørensen HT, Horvath-Puho E, Søgaard KK, Christensen S, Johnsen SP, Thomsen RW, Prandoni P, Baron JA. Arterial cardiovascular events, statins, low dose aspirin and subsequent risk of venous thromboembolism: a population-based case-control study. J Thromb Haemost. 2009;7:521–528. doi: 10.1111/j.1538-7836.2009.03279.x.
    1. Sørensen HT, Riis AH, Lash TL, Pedersen L. Statin use and risk of amyotrophic lateral sclerosis and other motor neuron disorders. Circ Cardiovasc Qual Outcomes. 2010;3:413–417. doi: 10.1161/CIRCOUTCOMES.110.936278.
    1. St Sauver JL, Jacobsen SJ, Jacobson DJ, McGree ME, Girman CJ, Girman CJ, Nehra A, Roger VL, Lieber MM. Statin use and decreased risk of benign prostatic enlargement and lower urinary tract symptoms. BJU Int. 2011;107:443–450. doi: 10.1111/j.1464-410X.2010.09598.x.
    1. Sukhija R, Bursac Z, Kakar P, Fink L, Fort C, Satwani S, Aronow WS, Bansal D, Mehta JL. Effect of statins on the development of renal dysfunction. Am J Cardiol. 2008;101:975–979. doi: 10.1016/j.amjcard.2007.11.042.
    1. Szwast SJ, Hendrie HC, Lane KA, Gao S, Taylor SE, Unverzagt F, Murrell J, Deeg M, Ogunniyi A, Farlow MR, Hall KS. Association of statin use with cognitive decline in elderly African Americans. Neurology. 2007;69:1873–1880. doi: 10.1212/01.wnl.0000279333.77404.d7.
    1. Tan JS, Mitchell P, Rochtchina E, Wang JJ. Statin use and the long-term risk of incident cataract: the Blue Mountains Eye Study. Am J Ophthalmol. 2007;143:687–689. doi: 10.1016/j.ajo.2006.11.027.
    1. Tan JS, Mitchell P, Rochtchina E, Wang JJ. Statins and the long-term risk of incident age-related macular degeneration: the Blue Mountains Eye Study. Am J Ophthalmol. 2007;143:685–687. doi: 10.1016/j.ajo.2006.11.021.
    1. Tsai C-J, Leitzmann MF, Willett WC, Giovannucci EL. Statin use and the risk of cholecystectomy in women. Gastroenterology. 2009;136:1593–1600. doi: 10.1053/j.gastro.2009.01.042.
    1. van Leeuwen R, Vingerling JR, Hofman A, de Jong PT, Stricker BH. Cholesterol lowering drugs and risk of age related maculopathy: prospective cohort study with cumulative exposure measurement. BMJ. 2003;326:255–256. doi: 10.1136/bmj.326.7383.255.
    1. van Leeuwen R, Tomany SC, Wang JJ, Klein R, Mitchell P, Hofman A, Klein BE, Vingerling JR, Cumming RG, de Jong PT. Is medication use associated with the incidence of early age-related maculopathy? Pooled findings from 3 continents. Ophthalmology. 2004;111:1169–1175. doi: 10.1016/j.ophtha.2003.10.024.
    1. van Staa T, Wegman S, de Vries F, Leufkens B, Cooper C. Use of statins and risk of fractures. JAMA. 2001;285:1850–1855. doi: 10.1001/jama.285.14.1850.
    1. Wahner AD, Bronstein JM, Bordelon YM, Ritz B. Statin use and the risk of Parkinson disease. Neurology. 2008;70:1418–1422. doi: 10.1212/01.wnl.0000286942.14552.51.
    1. Wang PS, Solomon DH, Mogun H, Avorn J. HMG-CoA reductase inhibitors and the risk of hip fractures in elderly patients. JAMA. 2000;283:3211–3216. doi: 10.1001/jama.283.24.3211.
    1. Woo D, Kissela BM, Khoury JC, Sauerbeck LR, Haverbusch MA, Szaflarski JP, Gebel JM, Pancioli AM, Jauch EC, Schneider A, Kleindorfer D, Broderick JP. Hypercholesterolemia, HMG-CoA reductase inhibitors, and risk of intracerebral hemorrhage: a case-control study. Stroke. 2004;35:1360–1364. doi: 10.1161/01.STR.0000127786.16612.A4.
    1. Yang C-C, Jick SS, Jick H. Statins and the risk of idiopathic venous thromboembolism. Br J Clin Pharmacol. 2002;53:101–105. doi: 10.1046/j.0306-5251.2001.01523.x.
    1. Yang CC, Kao CC. Cardiovascular diseases and the risk of venous thromboembolism: a hospital-based case-control study. J Chin Med Assoc. 2007;70:103–109. doi: 10.1016/S1726-4901(09)70339-9.
    1. Zamrini E, McGwin G, Roseman JM. Association between statin use and Alzheimer’s disease. Neuroepidemiology. 2004;23:94–98. doi: 10.1159/000073981.
    1. Zandi PP, Sparks DL, Khachaturian AS, Tschanz J, Norton M, Steinberg M, Welsh-Bohmer KA, Breitner JC. Cache County Study investigators. Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study. Arch Gen Psychiatry. 2005;62:217–224. doi: 10.1001/archpsyc.62.2.217.
    1. Golder S, Loke YK, Bland M. Meta-analyses of adverse effects data derived from randomised controlled trials as compared to observational studies: methodological overview. PLoS Med. 2011;8:e1001026. doi: 10.1371/journal.pmed.1001026.
    1. O’Neil A, Sanna L, Redlich C, Sanderson K, Jacka F, Williams LJ, Pasco JA, Berk M. The impact of statins on psychological wellbeing: a systematic review and meta-analysis. BMC Med. 2012;10:154. doi: 10.1186/1741-7015-10-154.
    1. Toh S, Hernández-Díaz S. Statins and fracture risk. A systematic review. Pharmacoepidemiol Drug Saf. 2007;16:627–640. doi: 10.1002/pds.1363.
    1. Sandhu S, Wiebe N, Fried LF, Tonelli M. Statins for improving renal outcomes: a meta-analysis. J Am Soc Nephrol. 2006;17:2006–2016. doi: 10.1681/ASN.2006010012.
    1. Rahimi K, Bhala N, Kamphuisen P, Emberson J, Biere-Rafi S, Krane V, Robertson M, Wikstrand J, McMurray J. Effect of statins on venous thromboembolic events: a meta-analysis of published and unpublished evidence from randomised controlled trials. PLoS Med. 2012;9:e1001310. doi: 10.1371/journal.pmed.1001310.
    1. Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS. Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc. 2013;88:1213–1221. doi: 10.1016/j.mayocp.2013.07.013.
    1. Richardson K, Schoen M, French B, Umscheid CA, Mitchell MD, Arnold SE, Heidenreich PA, Rader DJ, de Goma EM. Statins and cognitive function: a systematic review. Ann Int Med. 2013;159:688–697. doi: 10.7326/0003-4819-159-10-201311190-00007.
    1. Kwok CS, Yeong JK, Turner RM, Cavallazzi R, Singh S, Loke YK. Statins and associated risk of pneumonia: a systematic review and meta-analysis of observational studies. Eur J Clin Pharmacol. 2012;68:747–755. doi: 10.1007/s00228-011-1159-4.
    1. Novack V, MacFadyen J, Malhotra A, Almog Y, Glynn R, Ridker PM. The effect of rosuvastatin on incident pneumonia: results from the JUPITER trial. CMAJ. 2012;184:E367–E372. doi: 10.1503/cmaj.111017.
    1. Chopra V, Flanders SA. Does statin use improve pneumonia outcomes? Chest. 2009;136:1381–1388. doi: 10.1378/chest.09-0941.
    1. Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, DeMicco DA, Barter P, Cannon CP, Sabatine MS, Braunwald E, Kastelein JJ, de Lemos JA, Blazing MA, Pedersen TR, Tikkanen MJ, Sattar N, Ray KK. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011;305:2556–2564. doi: 10.1001/jama.2011.860.
    1. Waters DD, Ho JE, de Micco DA, Breazna A, Arsenault BJ, Wun CC, Kastelein JJ, Colhoun H, Barter P. Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials. J Am Coll Cardiol. 2011;57:1535–1545. doi: 10.1016/j.jacc.2010.10.047.
    1. Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM. Risk of incident diabetes among patients treated with statins: population based study. BMJ. 2013;346:f2610. doi: 10.1136/bmj.f2610.
    1. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012;380:565–571. doi: 10.1016/S0140-6736(12)61190-8.
    1. Nakata M, Nagasaka S, Kusaka I, Matsuoka H, Ishibashi S, Yada T. Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control. Diabetologia. 2006;49:1881–1892. doi: 10.1007/s00125-006-0269-5.
    1. Kruit JK, Kremer PH, Dai L, Tang R, Ruddle P, de Haan W, Brunham LR, Verchere CB, Hayden MR. Cholesterol efflux via ATP-binding cassette transporter A1 (ABCA1) and cholesterol uptake via the LDL receptor influences cholesterol-induced impairment of beta cell function in mice. Diabetologia. 2010;53:1110–1119. doi: 10.1007/s00125-010-1691-2.
    1. Koh KK, Sakuma I, Quon MJ. Differential metabolic effects of distinct statins. Atherosclerosis. 2011;215:1–8. doi: 10.1016/j.atherosclerosis.2010.10.036.
    1. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol. 2006;97:52C–60C.
    1. Parker BA, Capizzi JA, Grimaldi AS, Clarkson PM, Cole SM, Keadle J, Chipkin S, Pescatello LS, Simpson K, White CM, Thompson PD. Effect of statins on skeletal muscle function. Circulation. 2013;127:96–103. doi: 10.1161/CIRCULATIONAHA.112.136101.
    1. Mansi I, Frei CR, Pugh MJ, Makris U, Mortensen EM. Statins and musculoskeletal conditions, arthropathies, and injuries. JAMA. 2013;173:1–10.
    1. Palmer SC, Craig JC, Navaneethan SD, Tonelli M, Pellegrini F, Strippoli GF. Benefits and harms of statin therapy for persons with chronic kidney disease: a systematic review and meta-analysis. Ann Int Med. 2012;157:263–275. doi: 10.7326/0003-4819-157-4-201208210-00007.
    1. Upadhyay A, Earley A, Lamont JL, Haynes S, Wanner C, Balk EM. Lipid-lowering therapy in persons with chronic kidney disease: a systematic review and meta-analysis. Ann Int Med. 2012;157:251–262. doi: 10.7326/0003-4819-157-4-201208210-00005.
    1. Armitage J. The safety of statins in clinical practice. Lancet. 2007;370:1781–1790. doi: 10.1016/S0140-6736(07)60716-8.
    1. Naci H, Brugts J, Ades T. Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246 955 participants from 135 randomized, controlled trials. Circ Cardiovasc Qual Outcomes. 2013;6:390–399. doi: 10.1161/CIRCOUTCOMES.111.000071.
    1. Hackam DG, Woodward M, Newby LK, Bhatt DL, Shao M, Smith EE, Donner A, Mamdani M, Douketis JD, Arima H, Chalmers J, MacMahon S, Tirschwell DL, Psaty BM, Bushnell CD, Aguilar MI, Capampangan DJ, Werring DJ, De Rango P, Viswanathan A, Danchin N, Cheng CL, Yang YH, Verdel BM, Lai MS, Kennedy J, Uchiyama S, Yamaguchi T, Ikeda Y, Mrkobrada M. Statins and intracerebral hemorrhage: collaborative systematic review and meta-analysis. Circulation. 2011;124:2233–2242. doi: 10.1161/CIRCULATIONAHA.111.055269.
    1. Reiner Z. Statins in the primary prevention of cardiovascular disease. Nat Rev Cardiol. 2013;10:453–464. doi: 10.1038/nrcardio.2013.80.
    1. van Staa TJ, Smeeth L, Ng ES, Goldacre B, Gulliford M. The efficiency of cardiovascular risk assessment: do the right patients get statin treatment? Heart. 2013;99:1597–1602. doi: 10.1136/heartjnl-2013-303698.
    1. Lonn E, Bosch J, Teo KK, Pais P, Xavier D, Yusuf S. The polypill in the prevention of cardiovascular diseases: key concepts, current status, challenges, and future directions. Circulation. 2010;122:2078–2088. doi: 10.1161/CIRCULATIONAHA.109.873232.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren