Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 141 No. 4748 (2011)

Statins in clinical medicine

  • Jonas Rutishauser
DOI
https://doi.org/10.4414/smw.2011.13310
Cite this as:
Swiss Med Wkly. 2011;141:w13310
Published
21.11.2011

Summary

Statins inhibit cholesterol biosynthesis. Their main effect is a decrease in circulating levels of LDL cholesterol, which translates into a ~ 20% relative reduction of major vascular events and coronary mortality per mmol/L LDL reduction achieved. Statins are efficient in preventing first cardiovascular events, but the cost-efficiency of primary prevention remains controversial. In primary prevention particularly, the pros and cons of statin therapy should be weighted by considering patient-specific life circumstances and assessing the individual cardiovascular risk, as provided by risk calculators. Since diabetes mellitus poses a high risk even in the absence of known coronary artery disease, statin treatment is generally indicated in these patients. There is no lower LDL threshold defining the limit of treatment benefit; rather, LDL target levels should be sought according to individual cardiovascular risk. If the necessary precautions are taken, e.g., by considering age, co-morbidities and co-medication when choosing the dose, statins are well tolerated and safe, as evidenced by many randomised controlled trials and meta-analyses. If a patient will not tolerate a statin dose necessary to achieve his or her LDL target level, ezetimibe may be added. There is no indication that statins alter cancer risk. Despite recent evidence that statin treatment is associated with a small risk of incident diabetes mellitus, this disadvantage is outweighed by the vascular benefits. Statins have pleiotropic effects, such as anti-inflammatory properties. It is still debated to what extent these effects translate into cardiovascular risk reduction beyond that conferred by LDL reduction.

References

  1. Endo A. The discovery and development of HMG-CoA reductase inhibitors. J Lipid Res. 1992;33(11):1569–82.
  2. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundamental and Clinical Pharmacology. 2005;19(1):117–25.
  3. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344(8934):1383–9.
  4. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333(20):1301–7.
  5. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279(20):1615–22.
  6. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):7–22.
  7. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361(9364):1149–58.
  8. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AM, Kastelein JJP, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–207.
  9. Zhou Q, Liao JK. Pleiotropic effects of statins. – Basic research and clinical perspectives. Circulation Journal. 2010;74(5):818–26.
  10. Lardizabal JA, Deedwania P. Lipid-lowering therapy with statins for the primary and secondary prevention of cardiovascular disease. Cardiol Clin. 2011;29(1):87–103.
  11. Cholesterol Treatment Trialists’ (CTT) Collaborators. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. 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(9493):1267–78.
  12. Mills EJ, Wu P, Chong G, Ghement I, Singh S, Akl EA, et al. Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials. QJM. 2011;104(2):109–24.
  13. Amarenco P, Bogousslavsky J, Callahan A, Goldstein LB, Hennerici M, Rudolph AE, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355(6):549–59.
  14. Cholesterol Treatment Trialists’ (CTT) Collaborators. Kearney PM, Blackwell L, Collins R, Keech A, Simes J, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371(9607):117–25.
  15. Executive summary: Standards of medical care in diabetes – 2010. Diabetes Care. 2010;33(Suppl 1):S4–10.
  16. Holdaas H, Fellström B, Jardine AG, Holme I, Nyberg G, Fauchald P, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet. 2003;361(9374):2024–31.
  17. Wanner C, Krane V, März W, Olschewski M, Mann JFE, Ruf G, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353(3):238–48.
  18. Fellström BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360(14):1395–407.
  19. SHARP Collaborative Group. Study of Heart and Renal Protection (SHARP): Randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease. Am Heart J. 2010;160(5):785–94.e10.
  20. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377(9784):2181–92.
  21. Stevens KK, Jardine AG. SHARP: a stab in the right direction in chronic kidney disease. Lancet. 2011;377(9784):2153–4.
  22. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335(14):1001–9.
  23. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495–504.
  24. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart J-C, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352(14):1425–35.
  25. Grundy SM, Cleeman JI, Merz CNB, Brewer HB, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. In: Circulation. 2004:227–39.
  26. SEARCH Collaborative Group. Armitage J, Bowman L, Wallendszus K, Bulbulia R, Rahimi K, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010;376(9753):1658–69.
  27. Cholesterol Treatment Trialists’ (CTT) Collaboration. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670–81.
  28. Kjekshus J, Apetrei E, Barrios V, Böhm M, Cleland JGF, Cornel JH, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007;357(22):2248–61.
  29. GISSI-HF Investigators. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9645):1231–9.
  30. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285(13):1711–8.
  31. Sato H, Kinjo K, Ito H, Hirayama A, Nanto S, Fukunami M, et al. Effect of early use of low-dose pravastatin on major adverse cardiac events in patients with acute myocardial infarction: the OACIS-LIPID Study. Circulation Journal. 2008;72(1):17–22.
  32. Thompson PL, Meredith I, Amerena J, Campbell TJ, Sloman JG, Harris PJ, et al. Effect of pravastatin compared with placebo initiated within 24 hours of onset of acute myocardial infarction or unstable angina: the Pravastatin in Acute Coronary Treatment (PACT) trial. Am Heart J. 2004;148(1):e2.
  33. Liem A, van Boven AJ, M VNIG, Withagen AJ, Robles de Medina RM, Tijssen JGP, et al. Effect of fluvastatin on ischaemia following acute myocardial infarction: a randomized trial. Eur Heart J. 2002;23(24):1931–7.
  34. de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KAA, White HD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004;292(11):1307–16.
  35. Briel M, Schwartz GG, Thompson PL, de Lemos JA, Blazing MA, van Es G-A, et al. Effects of early treatment with statins on short-term clinical outcomes in acute coronary syndromes: a meta-analysis of randomized controlled trials. JAMA. 2006;295(17):2046–56.
  36. Briel M, Vale N, Schwartz GG, de Lemos JA, Colivicchi F, den Hartog FR, et al. Updated evidence on early statin therapy for acute coronary syndromes: Meta-analysis of 18 randomized trials involving over 14000 patients. Int J Cardiol. 2011; epub ahead of print.
  37. Vale N, Nordmann AJ, Schwartz GG, de Lemos J, Colivicchi F, den Hartog F, et al. Statins for acute coronary syndrome. Cochrane database of systematic reviews (Online) 2011;6CD006870.
  38. Schouten O, Boersma E, Hoeks SE, Benner R, van Urk H, van Sambeek MRHM, et al. Fluvastatin and perioperative events in patients undergoing vascular surgery. N Engl J Med. 2009;361(10):980–9.
  39. Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota T, et al. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet. 2006;368(9542):1155–63.
  40. Shepherd J, Blauw GJ, Murphy MB, Bollen ELEM, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360(9346):1623–30.
  41. 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(8):596–606.
  42. Ridker PM, JUPITER Study Group. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation. 2003;108(19):2292–7.
  43. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;373(9670):1175–82.
  44. Heart Protection Study Collaborative Group. C-reactive protein concentration and the vascular benefits of statin therapy: an analysis of 20536 patients in the Heart Protection Study. Lancet. 2011;377(9764):469–76.
  45. Greving JP, Visseren FLJ, de Wit GA, Algra A. Statin treatment for primary prevention of vascular disease: whom to treat? Cost-effectiveness analysis. BMJ. 2011;342d1672.
  46. Taylor F, Ward K, Moore TH, Burke M, Davey Smith G, Casas J-P, et al. Statins for the primary prevention of cardiovascular disease. Cochrane database of systematic reviews (Online) 2011(1):CD004816.
  47. Cooper A, Nherera L, Calvert N, O'Flynn N, Turnbull N, Robson J, et al. Clinical Guidelines and evidence review for lipid modification: cardiovascular risk assessment and the primary and secondary prevention of cardiovascular disease. London: National Collaborating Centre for Primary Care and Royal College of General Practitioners 2008.
  48. Davidson MH, McGarry T, Bettis R, Melani L, Lipka LJ, LeBeaut AP, et al. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. JAC. 2002;40(12):2125–34.
  49. Gagné C, Bays HE, Weiss SR, Mata P, Quinto K, Melino M, et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol. 2002;90(10):1084–91.
  50. Rossebø AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359(13):1343–56.
  51. Cannon CP, Giugliano RP, Blazing MA, Harrington RA, Peterson JL, Sisk CM, et al. Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Am Heart J. 2008;156(5):826–32.
  52. Rutishauser J. The role of statins in clinical medicine – LDL – cholesterol lowering and beyond. Swiss Med Wkly. 2006;136(3-4):41–9.
  53. Bodmer M, Brauchli YB, Krähenbühl S, Jick SS, Meier CR. Statin use and risk of gallstone disease followed by cholecystectomy. JAMA. 2009;302(18):2001–7.
  54. Tleyjeh IM, Kashour T, Hakim FA, Zimmerman VA, Erwin PJ, Sutton AJ, et al. Statins for the prevention and treatment of infections: a systematic review and meta-analysis. Arch Int Med. 2009;169(18):1658–67.
  55. Douglas I, Evans S, Smeeth L. Effect of statin treatment on short term mortality after pneumonia episode: cohort study. BMJ. 2011;342d1642.
  56. Dobler CC, Wong KK, Marks GB. Associations between statins and COPD: a systematic review. BMC Pulmonary Medicine. 2009;932.
  57. Glynn RJ, Danielson E, Fonseca FAH, Genest J, Gotto AM, Kastelein JJP, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med. 2009;360(18):1851–61.
  58. Rahimi K, Emberson J, Mcgale P, Majoni W, Merhi A, Asselbergs FW, et al. Effect of statins on atrial fibrillation: collaborative meta-analysis of published and unpublished evidence from randomised controlled trials. BMJ. 2011;342d1250.
  59. McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet. 2004;363(9426):2015–21.
  60. Lee T-M, Lin M-S, Chang N-C. Usefulness of C-reactive protein and interleukin-6 as predictors of outcomes in patients with chronic obstructive pulmonary disease receiving pravastatin. Am J Cardiol. 2008;101(4):530–5.
  61. Oskarsson B. Myopathy: five new things. Neurology. 2011;76(7 Suppl 2):S14–9.
  62. SEARCH Collaborative Group. Link E, Parish S, Armitage J, Bowman L, Heath S, et al. SLCO1B1 variants and statin-induced myopathy – a genomewide study. N Engl J Med. 2008;359(8):789–99.
  63. Poynter JN, Gruber SB, Higgins PDR, Almog R, Bonner JD, Rennert HS, et al. Statins and the risk of colorectal cancer. N Engl J Med. 2005;352(21):2184–92.
  64. Peto R, Emberson J, Landray M, Baigent C, Collins R, Clare R, et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med. 2008;359(13):1357–66.
  65. Strandberg TE, Pyörälä K, Cook TJ, Wilhelmsen L, Faergeman O, Thorgeirsson G, et al. Mortality and incidence of cancer during 10-year follow-up of the Scandinavian Simvastatin Survival Study (4S). Lancet. 2004;364(9436):771–7.
  66. Dale KM, Coleman CI, Henyan NN, Kluger J, White CM. Statins and cancer risk: a meta-analysis. JAMA. 2006;295(1):74–80.
  67. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735–42.