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BMC Medicine

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Open Access 01-12-2014 | Research article

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

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

Published in: BMC Medicine | Issue 1/2014

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.

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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

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. 10.1001/archinte.159.15.1793.PubMed

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. 10.1001/archinte.166.21.2307.

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. 10.1016/j.amjmed.2004.04.022.PubMed

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. 10.1001/jama.282.24.2340.PubMed

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. 10.1001/jama.1997.03550040069040.PubMed

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.PubMed

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, 371:2084PubMed

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.PubMed

10.

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.PubMed

11.

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: e29849-10.1371/journal.pone.0029849.PubMed

12.

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. 10.1016/S0140-6736(09)61965-6.PubMed

13.

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. 10.1093/qjmed/hcq165.PubMed

14.

FDA expands advice on statin risks. [http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm293330.htm]

15.

Statins: risk of hyperglycaemia and diabetes. Drug safety update January 2012. 5: A2-[http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON140667]

16.

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. 10.1002/pds.1993.PubMed

17.

Yang CC, Jick SS, Jick H: Lipid-lowering drugs and the risk of depression and suicidal behavior. Arch Intern Med. 2003, 163: 1926-1932. 10.1001/archinte.163.16.1926.PubMed

18.

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. 10.1212/01.WNL.0000142963.90204.58.PubMed

19.

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. 10.1212/01.wnl.0000182897.18229.ec.PubMed

20.

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. 10.1001/archopht.124.1.33.PubMed

21.

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.PubMed

22.

Scott HD, Laake K: Statins for the prevention of Alzheimer’s disease and dementia. Cochrane Database Syst Rev. 2001, CD003160.

23.

McGuinness B, O’Hare J, Craig D, Bullock R, Malouf R, Passmore P: Statins for the treatment of dementia. Cochrane Database Syst Rev. 2010, CD007514.

24.

Gehlbach P, Li T, Hatef E: Statins for age-related macular degeneration. Cochrane Database Syst Rev. 2012, CD006927.

25.

Wang J, Xiao Y, Luo M, Luo H: Statins for multiple sclerosis. Cochrane Database Syst Rev. 2011, CD008386.

26.

Li L, Sun T, Zhang P, Tian J, Yang K: Statins for primary prevention of venous thromboembolism. Cochrane Database Syst Rev. 2011, CD008203.

27.

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: d1250-10.1136/bmj.d1250.PubMed

28.

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.PubMed

29.

ClinicalEvidence: Learn, teach, and practise evidence-based medicine. [http://clinicalevidence.bmj.com/x/set/static/ebm/learn/665076.html]

30.

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. 10.1111/j.1471-1842.2011.00972.x.PubMed

31.

Higgins JPT, Green S: Cochrane Handbook for Systematic Reviews of Interventions, Version 5.0.2 [updated September 2009]. The Cochrane Collaboration. 2009, Chichester, UK: John Wiley & Sons, Ltd, [http://www.cochrane-handbook.org]

32.

Egger M, Smith GD, Phillips AN: Meta-analysis: principles and procedures. BMJ. 1997, 315: 1533-1537. 10.1136/bmj.315.7121.1533.PubMedPubMedCentral

33.

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. 10.1016/j.amjcard.2004.12.068.PubMed

34.

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. 10.1093/ageing/afp203.PubMed

35.

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. 10.1093/ndt/gfl244.PubMed

36.

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. 10.2165/00002018-200831050-00004.PubMed

37.

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. 10.1016/S0140-6736(00)02400-4.PubMed

38.

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. 10.1136/annrheumdis-2011-200092.PubMed

39.

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. 10.1136/jech.2003.013409.PubMedPubMedCentral

40.

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. 10.1212/01.wnl.0000319647.15752.7b.PubMedPubMedCentral

41.

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. 10.1001/archinternmed.2011.625.PubMed

42.

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. 10.1136/ard.2011.155622.PubMed

43.

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. 10.1093/ije/dyl147.PubMed

44.

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. 10.1111/j.1538-7836.2004.00696.x.PubMed

45.

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. 10.1093/aje/kwq361.PubMed

46.

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. 10.1017/S0950268810000105.PubMed

47.

Fujii T, Nakabayashi T, Hashimoto S, Kuwano H: Statin use and risk of gastroduodenal ulcer and reflux esophagitis. Hepatogastroenterology. 2009, 56: 641-644.PubMed

48.

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. 10.1007/s002280000248.PubMed

49.

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. 10.1212/WNL.58.9.1333.PubMed

50.

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. 10.1097/00001648-200109000-00017.PubMed

51.

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.

52.

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. 10.1016/j.jalz.2006.02.003.PubMed

53.

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. 10.1111/j.1365-2125.2009.03362.x.PubMedPubMedCentral

54.

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. 10.1136/jnnp.2008.150433.PubMed

55.

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: c2197-10.1136/bmj.c2197.PubMedPubMedCentral

56.

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. 10.1002/mds.21290.PubMedPubMedCentral

57.

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. 10.1001/archinte.167.9.935.PubMed

58.

Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA: Statins and the risk of dementia. Lancet. 2000, 356: 1627-1631. 10.1016/S0140-6736(00)03155-X.PubMed

59.

Jick SS, Bradbury BD: Statins and newly diagnosed diabetes. Br J Clin Pharmacol. 2004, 58: 303-309. 10.1111/j.1365-2125.2004.02142.x.PubMedPubMedCentral

60.

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. 10.1136/ard.2008.091967.PubMed

61.

Klein BE, Klein R, Lee KE, Grady LM: Statin use and incident nuclear cataract. JAMA. 2006, 295: 2752-2758. 10.1001/jama.295.23.2752.PubMed

62.

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. 10.1001/archopht.121.8.1151.PubMed

63.

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. 10.1016/j.ajo.2007.02.047.PubMedPubMedCentral

64.

Kwong JC, Li P, Redelmeier DA: Influenza morbidity and mortality in elderly patients receiving statins: a cohort study. PLoS One. 2009, 4: e8087-10.1371/journal.pone.0008087.PubMedPubMedCentral

65.

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. 10.7326/0003-4819-139-2-200307150-00009.PubMed

66.

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. 10.1093/gerona/63.4.369.PubMed

67.

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. 10.1016/j.thromres.2007.10.014.PubMed

68.

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. 10.1001/archinte.162.12.1395.PubMed

69.

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. 10.1111/j.1532-5415.2010.02906.x.PubMedPubMedCentral

70.

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. 10.1111/j.1600-0447.2008.01189.x.PubMed

71.

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: e29724-10.1371/journal.pone.0029724.PubMedPubMedCentral

72.

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. 10.1016/j.jclinepi.2006.11.006.PubMed

73.

McGwin G, Owsley C, Curcio CA, Crain RJ: The association between statin use and age related maculopathy. Br J Ophthalmol. 2003, 87: 1121-1125. 10.1136/bjo.87.9.1121.PubMedPubMedCentral

74.

McGwin G, 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. 10.1001/archopht.122.6.822.PubMed

75.

Meier CR, Schlienger RG, Kraenzlin ME, Schlegel B, Jick H: HMG-CoA reductase inhibitors and the risk of fractures. JAMA. 2000, 283: 3205-3210. 10.1001/jama.283.24.3205.PubMed

76.

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. 10.1002/pds.1715.PubMed

77.

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. 10.1001/archoto.2011.15.PubMedPubMedCentral

78.

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. 10.1016/j.clinthera.2007.08.022.PubMed

79.

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. 10.1167/iovs.09-4821.PubMed

80.

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. 10.1111/j.1538-7836.2008.03235.x.PubMed

81.

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. 10.1136/ip.8.4.276.PubMedPubMedCentral

82.

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. 10.1001/archneur.62.7.1047.PubMed

83.

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.PubMed

84.

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. 10.1161/STROKEAHA.109.552760.PubMed

85.

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. 10.1002/mds.23102.PubMedPubMedCentral

86.

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. 10.1159/000111583.PubMed

87.

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. 10.1001/archneur.59.2.223.PubMed

88.

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. 10.1080/15412550903156325.

89.

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. 10.1592/phco.27.3.325.PubMed

90.

Schlienger RG, Haefeli WE, Jick H, Meier CR: Risk of cataract in patients treated with statins. Arch Intern Med. 2001, 161: 2021-2026. 10.1001/archinte.161.16.2021.PubMed

91.

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. 10.1359/JBMR.040607.PubMed

92.

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. 10.1001/archinte.165.17.2007.PubMed

93.

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. 10.1136/bjo.2004.064477.PubMedPubMedCentral

94.

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. 10.1111/j.1365-2125.2008.03308.x.PubMedPubMedCentral

95.

Smeeth L, Hubbard R, Fletcher AE: Cataract and the use of statins: a case–control study. QJM. 2003, 96: 337-343. 10.1093/qjmed/hcg064.PubMed

96.

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. 10.1016/j.neurobiolaging.2007.09.012.PubMed

97.

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. 10.1111/j.1538-7836.2009.03279.x.PubMed

98.

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. 10.1161/CIRCOUTCOMES.110.936278.PubMed

99.

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. 10.1111/j.1464-410X.2010.09598.x.PubMed

100.

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. 10.1016/j.amjcard.2007.11.042.PubMed

101.

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. 10.1212/01.wnl.0000279333.77404.d7.PubMedPubMedCentral

102.

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. 10.1016/j.ajo.2006.11.027.PubMed

103.

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. 10.1016/j.ajo.2006.11.021.PubMed

104.

Tsai C-J, Leitzmann MF, Willett WC, Giovannucci EL: Statin use and the risk of cholecystectomy in women. Gastroenterology. 2009, 136: 1593-1600. 10.1053/j.gastro.2009.01.042.PubMedPubMedCentral

105.

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. 10.1136/bmj.326.7383.255.PubMedPubMedCentral

106.

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. 10.1016/j.ophtha.2003.10.024.PubMed

107.

van Staa T, Wegman S, de Vries F, Leufkens B, Cooper C: Use of statins and risk of fractures. JAMA. 2001, 285: 1850-1855. 10.1001/jama.285.14.1850.PubMed

108.

Wahner AD, Bronstein JM, Bordelon YM, Ritz B: Statin use and the risk of Parkinson disease. Neurology. 2008, 70: 1418-1422. 10.1212/01.wnl.0000286942.14552.51.PubMed

109.

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. 10.1001/jama.283.24.3211.PubMed

110.

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. 10.1161/01.STR.0000127786.16612.A4.PubMed

111.

Yang C-C, Jick SS, Jick H: Statins and the risk of idiopathic venous thromboembolism. Br J Clin Pharmacol. 2002, 53: 101-105. 10.1046/j.0306-5251.2001.01523.x.PubMedPubMedCentral

112.

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. 10.1016/S1726-4901(09)70339-9.PubMed

113.

Zamrini E, McGwin G, Roseman JM: Association between statin use and Alzheimer’s disease. Neuroepidemiology. 2004, 23: 94-98. 10.1159/000073981.PubMed

114.

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. 10.1001/archpsyc.62.2.217.PubMed

115.

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: e1001026-10.1371/journal.pmed.1001026.PubMedPubMedCentral

116.

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: 154-10.1186/1741-7015-10-154.PubMedPubMedCentral

117.

Toh S, Hernández-Díaz S: Statins and fracture risk. A systematic review. Pharmacoepidemiol Drug Saf. 2007, 16: 627-640. 10.1002/pds.1363.PubMed

118.

Sandhu S, Wiebe N, Fried LF, Tonelli M: Statins for improving renal outcomes: a meta-analysis. J Am Soc Nephrol. 2006, 17: 2006-2016. 10.1681/ASN.2006010012.PubMed

119.

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: e1001310-10.1371/journal.pmed.1001310.PubMedPubMedCentral

120.

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. 10.1016/j.mayocp.2013.07.013.PubMed

121.

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. 10.7326/0003-4819-159-10-201311190-00007.PubMed

122.

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. 10.1007/s00228-011-1159-4.PubMed

123.

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. 10.1503/cmaj.111017.PubMedPubMedCentral

124.

Chopra V, Flanders SA: Does statin use improve pneumonia outcomes?. Chest. 2009, 136: 1381-1388. 10.1378/chest.09-0941.PubMed

125.

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. 10.1001/jama.2011.860.PubMed

126.

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. 10.1016/j.jacc.2010.10.047.PubMed

127.

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: f2610-10.1136/bmj.f2610.PubMedPubMedCentral

128.

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. 10.1016/S0140-6736(12)61190-8.PubMedPubMedCentral

129.

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. 10.1007/s00125-006-0269-5.PubMed

130.

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. 10.1007/s00125-010-1691-2.PubMed

131.

Koh KK, Sakuma I, Quon MJ: Differential metabolic effects of distinct statins. Atherosclerosis. 2011, 215: 1-8. 10.1016/j.atherosclerosis.2010.10.036.PubMed

132.

Law M, Rudnicka AR: Statin safety: a systematic review. Am J Cardiol. 2006, 97: 52C-60C.PubMed

133.

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. 10.1161/CIRCULATIONAHA.112.136101.PubMed

134.

Mansi I, Frei CR, Pugh MJ, Makris U, Mortensen EM: Statins and musculoskeletal conditions, arthropathies, and injuries. JAMA. 2013, 173: 1-10.

135.

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. 10.7326/0003-4819-157-4-201208210-00007.PubMedPubMedCentral

136.

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. 10.7326/0003-4819-157-4-201208210-00005.PubMed

137.

Armitage J: The safety of statins in clinical practice. Lancet. 2007, 370: 1781-1790. 10.1016/S0140-6736(07)60716-8.PubMed

138.

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. 10.1161/CIRCOUTCOMES.111.000071.PubMed

139.

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. 10.1161/CIRCULATIONAHA.111.055269.PubMed

140.

Reiner Z: Statins in the primary prevention of cardiovascular disease. Nat Rev Cardiol. 2013, 10: 453-464. 10.1038/nrcardio.2013.80.PubMed

141.

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. 10.1136/heartjnl-2013-303698.PubMedPubMedCentral

142.

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. 10.1161/CIRCULATIONAHA.109.873232.PubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/12/51/prepub

Title: Unintended effects of statins from observational studies in the general population: systematic review and meta-analysis
Authors: Ana Filipa Macedo
Fiona Claire Taylor
Juan P Casas
Alma Adler
David Prieto-Merino
Shah Ebrahim
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: BMC Medicine / Issue 1/2014
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/1741-7015-12-51

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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