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Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease

Robert S Rosenson, MD
Section Editor
Mason W Freeman, MD
Deputy Editor
Gordon M Saperia, MD, FACC


Lipid lowering with statins in patients with hypercholesterolemia has a proven survival benefit for both primary prevention (ie, in patients without clinical evidence of coronary disease) and secondary prevention (ie, in patients with established coronary disease), even when serum cholesterol concentrations are "normal" for the population or borderline high. Statins may also be beneficial in patients with heart failure. (See "Clinical trials of cholesterol lowering for primary prevention of coronary heart disease" and "Clinical trials of cholesterol lowering in patients with cardiovascular disease or diabetes" and "Statin therapy in patients with heart failure", section on 'Potential benefits and harms of statin therapy in HF'.)


The mechanisms by which lipid-lowering therapy (particularly with statins) is beneficial are incompletely explained by the serum low density lipoprotein (LDL) concentration at baseline or after treatment [1-6]. Although statins probably cause regression of atherosclerosis, an improvement in outcome can be demonstrated as early as six months (figure 1) [7,8], a time considered too early for significant regression. In addition, the amount of lesion regression is small compared with the magnitude of the observed clinical benefit.

A case-control study of adults with a first clinical presentation of coronary heart disease found that use of statins was associated with a decreased likelihood of that presentation being an acute myocardial infarction (odds ratio 0.45) and thus an increased likelihood of presenting with stable angina [9]. These observations suggest a mechanism of benefit with statins that might involve unstable coronary lesions.

Among the nonlipid mechanisms that may be involved are plaque stabilization, reduced inflammation, reversal of endothelial dysfunction, and decreased thrombogenicity [10,11].

Regression of atherosclerosis — Regression of the atherosclerotic lesions can occur after lipid lowering, without change in vessel wall thickness or vessel wall area, and may be clinically important [12]. One limitation to arteriographic studies is the relative lack of sensitivity to morphologic changes in atheroma, which can be better characterized by intracoronary ultrasonography (ICUS) [13], or to small changes, which might be detectable by other techniques such as B-mode ultrasonography for measurement of carotid intima thickness [14], electron beam or multidetector row computed tomography to detect coronary artery calcification [15], or high-resolution magnetic resonance imaging (MRI) [12]. (See "Diagnostic and prognostic implications of coronary artery calcification detected by computed tomography" and "Clinical utility of cardiovascular magnetic resonance imaging".)


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Literature review current through: Sep 2016. | This topic last updated: Dec 16, 2015.
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  1. Thompson GR, Hollyer J, Waters DD. Percentage change rather than plasma level of LDL-cholesterol determines therapeutic response in coronary heart disease. Curr Opin Lipidol 1995; 6:386.
  2. Sacks FM, Gibson CM, Rosner B, et al. The influence of pretreatment low density lipoprotein cholesterol concentrations on the effect of hypocholesterolemic therapy on coronary atherosclerosis in angiographic trials. Harvard Atherosclerosis Reversibility Project Research Group. Am J Cardiol 1995; 76:78C.
  3. Jukema JW, Bruschke AV, van Boven AJ, et al. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation 1995; 91:2528.
  4. Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S). Lancet 1995; 345:1274.
  5. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998; 97:1440.
  6. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004; 109:III39.
  7. Effects of pravastatin in patients with serum total cholesterol levels from 5.2 to 7.8 mmol/liter (200 to 300 mg/dl) plus two additional atherosclerotic risk factors. The Pravastatin Multinational Study Group for Cardiac Risk Patients. Am J Cardiol 1993; 72:1031.
  8. Furberg CD, Byington RP, Crouse JR, Espeland MA. Pravastatin, lipids, and major coronary events. Am J Cardiol 1994; 73:1133.
  9. Go AS, Iribarren C, Chandra M, et al. Statin and beta-blocker therapy and the initial presentation of coronary heart disease. Ann Intern Med 2006; 144:229.
  10. Vaughan CJ, Gotto AM Jr, Basson CT. The evolving role of statins in the management of atherosclerosis. J Am Coll Cardiol 2000; 35:1.
  11. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation 2000; 101:207.
  12. Corti R, Fayad ZA, Fuster V, et al. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation 2001; 104:249.
  13. Schartl M, Bocksch W, Koschyk DH, et al. Use of intravascular ultrasound to compare effects of different strategies of lipid-lowering therapy on plaque volume and composition in patients with coronary artery disease. Circulation 2001; 104:387.
  14. Smilde TJ, van Wissen S, Wollersheim H, et al. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001; 357:577.
  15. Callister TQ, Raggi P, Cooil B, et al. Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron-beam computed tomography. N Engl J Med 1998; 339:1972.
  16. Effect of simvastatin on coronary atheroma: the Multicentre Anti-Atheroma Study (MAAS). Lancet 1994; 344:633.
  17. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001; 345:1583.
  18. Corti R, Fuster V, Fayad ZA, et al. Lipid lowering by simvastatin induces regression of human atherosclerotic lesions: two years' follow-up by high-resolution noninvasive magnetic resonance imaging. Circulation 2002; 106:2884.
  19. Williams JK, Sukhova GK, Herrington DM, Libby P. Pravastatin has cholesterol-lowering independent effects on the artery wall of atherosclerotic monkeys. J Am Coll Cardiol 1998; 31:684.
  20. Crisby M, Nordin-Fredriksson G, Shah PK, et al. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation 2001; 103:926.
  21. Ambrose JA, Martinez EE. A new paradigm for plaque stabilization. Circulation 2002; 105:2000.
  22. Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995; 91:2844.
  23. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995; 92:657.
  24. Aikawa M, Rabkin E, Sugiyama S, et al. An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation 2001; 103:276.
  25. Bellosta S, Via D, Canavesi M, et al. HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages. Arterioscler Thromb Vasc Biol 1998; 18:1671.
  26. Cipollone F, Fazia M, Iezzi A, et al. Suppression of the functionally coupled cyclooxygenase-2/prostaglandin E synthase as a basis of simvastatin-dependent plaque stabilization in humans. Circulation 2003; 107:1479.
  27. Rosenson RS. Pluripotential mechanisms of cardioprotection with HMG-CoA reductase inhibitor therapy. Am J Cardiovasc Drugs 2001; 1:411.
  28. Knapp AC, Huang J, Starling G, Kiener PA. Inhibitors of HMG-CoA reductase sensitize human smooth muscle cells to Fas-ligand and cytokine-induced cell death. Atherosclerosis 2000; 152:217.
  29. Shiomi M, Ito T, Tsukada T, et al. Reduction of serum cholesterol levels alters lesional composition of atherosclerotic plaques. Effect of pravastatin sodium on atherosclerosis in mature WHHL rabbits. Arterioscler Thromb Vasc Biol 1995; 15:1938.
  30. Aikawa M, Rabkin E, Okada Y, et al. Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma: a potential mechanism of lesion stabilization. Circulation 1998; 97:2433.
  31. Aikawa M, Voglic SJ, Sugiyama S, et al. Dietary lipid lowering reduces tissue factor expression in rabbit atheroma. Circulation 1999; 100:1215.
  32. Burke AP, Farb A, Malcom GT, et al. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997; 336:1276.
  33. Ridker PM, Rifai N, Pfeffer MA, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999; 100:230.
  34. Jialal I, Stein D, Balis D, et al. Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation 2001; 103:1933.
  35. Albert MA, Danielson E, Rifai N, et al. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001; 286:64.
  36. Plenge JK, Hernandez TL, Weil KM, et al. Simvastatin lowers C-reactive protein within 14 days: an effect independent of low-density lipoprotein cholesterol reduction. Circulation 2002; 106:1447.
  37. McCarey DW, McInnes IB, Madhok R, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet 2004; 363:2015.
  38. Rosenson RS, Brown AS. Statin use in acute coronary syndromes: cellular mechanisms and clinical evidence. Curr Opin Lipidol 2002; 13:625.
  39. Nissen SE. High-dose statins in acute coronary syndromes: not just lipid levels. JAMA 2004; 292:1365.
  40. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001; 285:1711.
  41. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350:1495.
  42. de Lemos JA, Blazing MA, Wiviott SD, 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; 292:1307.
  43. Ridker PM, Rifai N, Pfeffer MA, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1998; 98:839.
  44. Horne BD, Muhlestein JB, Carlquist JF, et al. Statin therapy, lipid levels, C-reactive protein and the survival of patients with angiographically severe coronary artery disease. J Am Coll Cardiol 2000; 36:1774.
  45. Chan AW, Bhatt DL, Chew DP, et al. Relation of inflammation and benefit of statins after percutaneous coronary interventions. Circulation 2003; 107:1750.
  46. Ridker PM, Rifai N, Clearfield M, et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001; 344:1959.
  47. Horne BD, Muhlestein JB, Carlquist JF, et al. Statin therapy interacts with cytomegalovirus seropositivity and high C-reactive protein in reducing mortality among patients with angiographically significant coronary disease. Circulation 2003; 107:258.
  48. Weitz-Schmidt G, Welzenbach K, Brinkmann V, et al. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 2001; 7:687.
  49. Frenette PS. Locking a leukocyte integrin with statins. N Engl J Med 2001; 345:1419.
  50. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000; 6:1399.
  51. Ferro D, Parrotto S, Basili S, et al. Simvastatin inhibits the monocyte expression of proinflammatory cytokines in patients with hypercholesterolemia. J Am Coll Cardiol 2000; 36:427.
  52. Egashira K, Hirooka Y, Kai H, et al. Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. Circulation 1994; 89:2519.
  53. Anderson TJ, Meredith IT, Yeung AC, et al. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med 1995; 332:488.
  54. Treasure CB, Klein JL, Weintraub WS, et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995; 332:481.
  55. Tsunekawa T, Hayashi T, Kano H, et al. Cerivastatin, a hydroxymethylglutaryl coenzyme a reductase inhibitor, improves endothelial function in elderly diabetic patients within 3 days. Circulation 2001; 104:376.
  56. Vita JA, Yeung AC, Winniford M, et al. Effect of cholesterol-lowering therapy on coronary endothelial vasomotor function in patients with coronary artery disease. Circulation 2000; 102:846.
  57. Yokoyama I, Momomura S, Ohtake T, et al. Improvement of impaired myocardial vasodilatation due to diffuse coronary atherosclerosis in hypercholesterolemics after lipid-lowering therapy. Circulation 1999; 100:117.
  58. Lefer AM, Campbell B, Shin YK, et al. Simvastatin preserves the ischemic-reperfused myocardium in normocholesterolemic rat hearts. Circulation 1999; 100:178.
  59. Dupuis J, Tardif JC, Cernacek P, Théroux P. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (reduction of cholesterol in ischemia and function of the endothelium) trial. Circulation 1999; 99:3227.
  60. Landmesser U, Bahlmann F, Mueller M, et al. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 2005; 111:2356.
  61. Liu PY, Liu YW, Lin LJ, et al. Evidence for statin pleiotropy in humans: differential effects of statins and ezetimibe on rho-associated coiled-coil containing protein kinase activity, endothelial function, and inflammation. Circulation 2009; 119:131.
  62. John S, Schlaich M, Langenfeld M, et al. Increased bioavailability of nitric oxide after lipid-lowering therapy in hypercholesterolemic patients: a randomized, placebo-controlled, double-blind study. Circulation 1998; 98:211.
  63. Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 1998; 273:24266.
  64. Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998; 97:1129.
  65. Kaesemeyer WH, Caldwell RB, Huang J, Caldwell RW. Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions. J Am Coll Cardiol 1999; 33:234.
  66. Hernández-Perera O, Pérez-Sala D, Navarro-Antolín J, et al. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest 1998; 101:2711.
  67. Hernández-Perera O, Pérez-Sala D, Soria E, Lamas S. Involvement of Rho GTPases in the transcriptional inhibition of preproendothelin-1 gene expression by simvastatin in vascular endothelial cells. Circ Res 2000; 87:616.
  68. Laufs U, Liao JK. Targeting Rho in cardiovascular disease. Circ Res 2000; 87:526.
  69. van Nieuw Amerongen GP, Vermeer MA, Nègre-Aminou P, et al. Simvastatin improves disturbed endothelial barrier function. Circulation 2000; 102:2803.
  70. Kalinowski L, Dobrucki LW, Brovkovych V, Malinski T. Increased nitric oxide bioavailability in endothelial cells contributes to the pleiotropic effect of cerivastatin. Circulation 2002; 105:933.
  71. Evans M, Anderson RA, Graham J, et al. Ciprofibrate therapy improves endothelial function and reduces postprandial lipemia and oxidative stress in type 2 diabetes mellitus. Circulation 2000; 101:1773.
  72. Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA 1998; 279:1643.
  73. Eto M, Kozai T, Cosentino F, et al. Statin prevents tissue factor expression in human endothelial cells: role of Rho/Rho-kinase and Akt pathways. Circulation 2002; 105:1756.
  74. Undas A, Brummel KE, Musial J, et al. Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation. Circulation 2001; 103:2248.
  75. Szczeklik A, Musiał J, Undas A, et al. Inhibition of thrombin generation by simvastatin and lack of additive effects of aspirin in patients with marked hypercholesterolemia. J Am Coll Cardiol 1999; 33:1286.
  76. Dangas G, Badimon JJ, Smith DA, et al. Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile. J Am Coll Cardiol 1999; 33:1294.
  77. Lacoste L, Lam JY, Hung J, et al. Hyperlipidemia and coronary disease. Correction of the increased thrombogenic potential with cholesterol reduction. Circulation 1995; 92:3172.
  78. Mayer J, Eller T, Brauer P, et al. Effects of long-term treatment with lovastatin on the clotting system and blood platelets. Ann Hematol 1992; 64:196.
  79. Pignatelli P, Carnevale R, Pastori D, et al. Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2. Circulation 2012; 126:92.
  80. Henn V, Slupsky JR, Gräfe M, et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391:591.
  81. Lindmark E, Tenno T, Siegbahn A. Role of platelet P-selectin and CD40 ligand in the induction of monocytic tissue factor expression. Arterioscler Thromb Vasc Biol 2000; 20:2322.
  82. Aukrust P, Müller F, Ueland T, et al. Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation 1999; 100:614.
  83. Schönbeck U, Varo N, Libby P, et al. Soluble CD40L and cardiovascular risk in women. Circulation 2001; 104:2266.
  84. Cipollone F, Mezzetti A, Porreca E, et al. Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy. Circulation 2002; 106:399.
  85. Sanguigni V, Pignatelli P, Lenti L, et al. Short-term treatment with atorvastatin reduces platelet CD40 ligand and thrombin generation in hypercholesterolemic patients. Circulation 2005; 111:412.
  86. Mitchell LB, Powell JL, Gillis AM, et al. Are lipid-lowering drugs also antiarrhythmic drugs? An analysis of the Antiarrhythmics versus Implantable Defibrillators (AVID) trial. J Am Coll Cardiol 2003; 42:81.
  87. De Sutter J, Tavernier R, De Buyzere M, et al. Lipid lowering drugs and recurrences of life-threatening ventricular arrhythmias in high-risk patients. J Am Coll Cardiol 2000; 36:766.
  88. Weber C, Erl W, Weber KS, Weber PC. HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol 1997; 30:1212.
  89. Hussein O, Schlezinger S, Rosenblat M, et al. Reduced susceptibility of low density lipoprotein (LDL) to lipid peroxidation after fluvastatin therapy is associated with the hypocholesterolemic effect of the drug and its binding to the LDL. Atherosclerosis 1997; 128:11.
  90. Girona J, La Ville AE, Solà R, et al. Simvastatin decreases aldehyde production derived from lipoprotein oxidation. Am J Cardiol 1999; 83:846.
  91. Dimmeler S, Aicher A, Vasa M, et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest 2001; 108:391.
  92. Llevadot J, Murasawa S, Kureishi Y, et al. HMG-CoA reductase inhibitor mobilizes bone marrow--derived endothelial progenitor cells. J Clin Invest 2001; 108:399.
  93. Rosenson RS, Tangney CC. Beneficial effects of statins. Lancet 1996; 348:1583.
  94. Marais AD, Firth JC, Bateman ME, et al. Atorvastatin: an effective lipid-modifying agent in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 1997; 17:1527.
  95. Durrington PN, Mackness MI, Bhatnagar D, et al. Effects of two different fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb hyperlipoproteinaemia. Atherosclerosis 1998; 138:217.
  96. Iakoubova OA, Tong CH, Rowland CM, et al. Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease in 2 prospective trials: the CARE and WOSCOPS trials. J Am Coll Cardiol 2008; 51:435.
  97. Iakoubova OA, Robertson M, Tong CH, et al. KIF6 Trp719Arg polymorphism and the effect of statin therapy in elderly patients: results from the PROSPER study. Eur J Cardiovasc Prev Rehabil 2010; 17:455.
  98. Assimes TL, Hólm H, Kathiresan S, et al. Lack of association between the Trp719Arg polymorphism in kinesin-like protein-6 and coronary artery disease in 19 case-control studies. J Am Coll Cardiol 2010; 56:1552.
  99. Stewart AF, Dandona S, Chen L, et al. Kinesin family member 6 variant Trp719Arg does not associate with angiographically defined coronary artery disease in the Ottawa Heart Genomics Study. J Am Coll Cardiol 2009; 53:1471.
  100. Ridker PM, MacFadyen JG, Glynn RJ, Chasman DI. Kinesin-like protein 6 (KIF6) polymorphism and the efficacy of rosuvastatin in primary prevention. Circ Cardiovasc Genet 2011; 4:312.