Effect of High-Dose Statin Versus Low-Dose Statin Plus Ezetimibe on Endothelial Function

Background: Combining low-dose statin and ezetimibe reduces the low-density lipoprotein cholesterol (LDL-C) similar to high-dose statin. However, whether there is a difference in the effect of these 2 lipid-lowering regimes on endothelial function is still controversial. Methods: We performed a systematic search of databases (MEDLINE [1950 to September 2011], EMBASE [1966 to September 2011]) and references of identified studies. Completely published randomized controlled trials comparing the effect of high-dose statin with low-dose stain plus ezetimibe on endothelial function (flow-mediated dilation [FMD] method) were included in this study. Results: Six trials with a total of 213 participants were included in the meta-analysis. The pooled weighted mean difference of FMD did not differ between the 2 lipid-lowering regimes (0.22%; 95% confidence interval [CI]: −0.85%-1.29%, P = .68). Furthermore, no significant reduction in LDL-C and C-reactive protein (CRP) occurred with high-dose statin versus low-dose statin plus ezetimibe (pooled weighted mean differences of LDL-C and CRP were −4.12 mg/dL, 95% CI: −9.54-1.12 mg/dL, P = .12, and −0.02 mg/L, 95% CI: −0.31-0.27 mg/L, P = .89, respectively). Conclusions: Based on the currently available evidence, combining a low-dose statin with ezetimibe may provide similar beneficial effects on endothelial function as high-dose statin.

[1]  Paul Welsh,et al.  Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. , 2011, JAMA.

[2]  M. Landray,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 , 2011, The Lancet.

[3]  K. Sugi,et al.  IMPACT OF OXIDIZED LOW DENSITY LIPOPROTEIN CHOLESTEROL UNDER EZETIMIBE OR ROSUVASTATIN THERAPY ON ENDOTHELIAL FUNCTION , 2011 .

[4]  R. Collins,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 , 2010, The Lancet.

[5]  R. Collins,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 , 2010, The Lancet.

[6]  R. Collins,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. , 2010, Lancet.

[7]  W. Krone,et al.  Ezetimibe alone or in combination with simvastatin increases small dense low-density lipoproteins in healthy men: a randomized trial. , 2010, European heart journal.

[8]  C. Tsioufis,et al.  Rosuvastatin but not ezetimibe improves endothelial function in patients with heart failure, by mechanisms independent of lipid lowering. , 2010, International journal of cardiology.

[9]  H. Uzun,et al.  Ezetimibe Therapy and Its Influence on Oxidative Stress and Fibrinolytic Activity , 2010, Southern medical journal.

[10]  M. Bertolami,et al.  Pleiotropic Effects With Equivalent Low-density Lipoprotein Cholesterol Reduction: Comparative Study Between Simvastatin and Simvastatin/Ezetimibe Coadministration , 2010, Journal of cardiovascular pharmacology.

[11]  D. Moher,et al.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement , 2009, BMJ.

[12]  D. Moher,et al.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement , 2009, BMJ : British Medical Journal.

[13]  T. Meinertz,et al.  Flow-mediated dilation in patients with coronary artery disease is enhanced by high dose atorvastatin compared to combined low dose atorvastatin and ezetimibe: results of the CEZAR study. , 2009, Atherosclerosis.

[14]  R. Shamburek,et al.  The pleiotropic effects of statins on endothelial function, vascular inflammation, immunomodulation and thrombogenesis. , 2009, Atherosclerosis.

[15]  Wan Zhang,et al.  Short-term withdrawal of simvastatin induces endothelial dysfunction in patients with coronary artery disease: a dose-response effect dependent on endothelial nitric oxide synthase. , 2009, International journal of cardiology.

[16]  J. Liao,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 , 2009, Circulation.

[17]  J. Chambers,et al.  Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. , 2008, The New England journal of medicine.

[18]  F. Visseren,et al.  The Effects of Low-Dose Simvastatin and Ezetimibe Compared to High-Dose Simvastatin Alone on Post-Fat Load Endothelial Function in Patients With Metabolic Syndrome: A Randomized Double-Blind Crossover Trial , 2008, Journal of cardiovascular pharmacology.

[19]  A. Zwinderman,et al.  Simvastatin with or without ezetimibe in familial hypercholesterolemia. , 2008, The New England journal of medicine.

[20]  L. Rydén,et al.  Cholesterol lowering is more important than pleiotropic effects of statins for endothelial function in patients with dysglycaemia and coronary artery disease. , 2008, European heart journal.

[21]  D. Tribble,et al.  Effects of ezetimibe/simvastatin on lipoprotein subfractions in patients with primary hypercholesterolemia: an exploratory analysis of archived samples using two commercially available techniques. , 2007, Clinical therapeutics.

[22]  I. Wilkinson,et al.  Ezetimibe and simvastatin reduce inflammation, disease activity, and aortic stiffness and improve endothelial function in rheumatoid arthritis. , 2007, Journal of the American College of Cardiology.

[23]  S. Kinlay Low-density lipoprotein-dependent and -independent effects of cholesterol-lowering therapies on C-reactive protein: a meta-analysis. , 2007, Journal of the American College of Cardiology.

[24]  K. Parhofer,et al.  Effect of ezetimibe on low-density lipoprotein subtype distribution: results of a placebo-controlled, double-blind trial in patients treated by regular low-density lipoprotein apheresis and statins. , 2006, Metabolism: clinical and experimental.

[25]  C. Heeschen,et al.  Differential effects of short-term lipid lowering with ezetimibe and statins on endothelial function in patients with CAD: clinical evidence for 'pleiotropic' functions of statin therapy. , 2006, European heart journal.

[26]  R. Collins,et al.  Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins , 2005, The Lancet.

[27]  T. Meinertz,et al.  Systemic Endothelial Dysfunction as an Early Predictor of Adverse Outcome in Heart Failure , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[28]  A. Zeiher,et al.  Endothelial Function: Cardiac Events , 2005, Circulation.

[29]  P. Ganz,et al.  Role of Endothelial Dysfunction in Atherosclerosis , 2004, Circulation.

[30]  R. Karas,et al.  Effects of Statins on Nonlipid Serum Markers Associated with Cardiovascular Disease , 2003, Annals of Internal Medicine.

[31]  P. Sager,et al.  Effect of Ezetimibe Coadministered With Atorvastatin in 628 Patients With Primary Hypercholesterolemia: A Prospective, Randomized, Double-Blind Trial , 2003, Circulation.

[32]  R. Suresh,et al.  Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia. , 2003, The American journal of cardiology.

[33]  M. Watkins,et al.  Risk Stratification for Postoperative Cardiovascular Events via Noninvasive Assessment of Endothelial Function: A Prospective Study , 2002, Circulation.

[34]  F. Perticone,et al.  Prognostic Significance of Endothelial Dysfunction in Hypertensive Patients , 2001, Circulation.

[35]  D. Green,et al.  Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. , 1997, Circulation.

[36]  T. Imaizumi,et al.  Single LDL apheresis improves endothelium-dependent vasodilatation in hypercholesterolemic humans. , 1997, Circulation.

[37]  M. Olschewski,et al.  Cigarette smoking potentiates endothelial dysfunction of forearm resistance vessels in patients with hypercholesterolemia. Role of oxidized LDL. , 1996, Circulation.

[38]  ThomasHeitzer,et al.  Cigarette Smoking Potentiates Endothelial Dysfunction of Forearm Resistance Vessels in Patients With Hypercholesterolemia , 1996 .

[39]  W. Weintraub,et al.  Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. , 1995, The New England journal of medicine.

[40]  C. Lau,et al.  Beneficial effect of cholesterol-lowering therapy on coronary endothelium-dependent relaxation in hypercholesterolaemic patients , 1993, The Lancet.

[41]  H. Drexler,et al.  Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine , 1991, The Lancet.

[42]  J. Loscalzo,et al.  Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. , 1990, The Journal of clinical investigation.

[43]  M. Nakazato,et al.  Ezetimibe ameliorates atherosclerotic and inflammatory markers, atherogenic lipid profiles, insulin sensitivity, and liver dysfunction in Japanese patients with hypercholesterolemia. , 2012, Journal of atherosclerosis and thrombosis.

[44]  Chie Aoki,et al.  Comparative study between high-dose fluvastatin and low-dose fluvastatin and ezetimibe with regard to the effect on endothelial function in diabetic patients. , 2011, Endocrine journal.

[45]  R. Collins,et al.  Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) , 2009 .

[46]  J. Mckenney,et al.  Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). , 2001, JAMA.