Effect of Statins on Serum level of hs-CRP and CRP in Patients with Cardiovascular Diseases: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background Several studies have reported that statins have anti-inflammatory effects. Nevertheless, results of clinical trials concerning the effect of statins on the levels of C-reactive protein (CRP) and high-sensitivity CRP (hs-CRP) have been inconsistent. Therefore, we performed a systematic review and meta-analysis of randomized clinical trials (RCTs) evaluating the effect of statins on CRP and hs-CRP levels in patients with cardiovascular diseases (CVDs). Methods Literature search of the major databases was performed to find eligible RCTs assessing the effect of statins on serum levels of CRP and hs-CRP from the inception until the last week of April 2021. The effect sizes were determined for weighted mean difference (WMD) and 95% confidence intervals (CI). Results 26 studies were identified (3010 patients and 2968 controls) for hs-CRP and 20 studies (3026 patients and 2968 controls) for CRP. Statins reduced the serum levels of hs-CRP (WMD = −0.97 mg/L; 95% CI: -1.26 to -0.68 mg/L; P < 0.001) and CRP (WMD = −3.05 mg/L; 95% CI: -4.86 to -1.25 mg/L; P < 0.001) in patients with CVDs. Statins decreased the serum levels of hs-CRP in patients receiving both high-intensity and moderate/low-intensity treatments with these drugs. In addition, the duration of treatment longer than 10 weeks decreased hs-CRP levels. Only high-intensity statin treatment could marginally decrease serum levels of CRP in CVDs patients. Conclusions This meta-analysis showed the efficacy of statins to reduce the concentrations of CRP and hs-CRP in patients with different types of CVDs.

[1]  A. Sahebkar,et al.  Effect of resveratrol on C‐reactive protein: An updated meta‐analysis of randomized controlled trials , 2021, Phytotherapy research : PTR.

[2]  M. Banach,et al.  Statins as anti-pyroptotic agents , 2021, Archives of medical science : AMS.

[3]  N. Kiaie,et al.  Implications on the Therapeutic Potential of Statins via Modulation of Autophagy , 2021, Oxidative medicine and cellular longevity.

[4]  Lixuan Wang,et al.  A systematic review and meta-analysis on the efficacy of statins in the treatment of atherosclerosis. , 2021, Annals of palliative medicine.

[5]  D. Benaiges,et al.  Hydrophilic or Lipophilic Statins? , 2021, Frontiers in Cardiovascular Medicine.

[6]  J. Kastelein,et al.  New and Emerging Therapies for Reduction of LDL-Cholesterol and Apolipoprotein B: JACC Focus Seminar 1/4. , 2021, Journal of the American College of Cardiology.

[7]  E. Mayo-Wilson,et al.  The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. , 2021, Journal of clinical epidemiology.

[8]  C. Sirtori,et al.  Lipid Lowering Drugs: Present Status and Future Developments , 2021, Current Atherosclerosis Reports.

[9]  M. Banach,et al.  Improved COVID-19 ICU admission and mortality outcomes following treatment with statins: a systematic review and meta-analysis , 2021, Archives of medical science : AMS.

[10]  A. Zambon,et al.  Red Yeast Rice for Hypercholesterolemia: JACC Focus Seminar. , 2021, Journal of the American College of Cardiology.

[11]  A. Szalai,et al.  Therapeutic Lowering of C-Reactive Protein , 2021, Frontiers in Immunology.

[12]  M. Laakso,et al.  Novel biomarkers associated with incident heart failure in 10 106 Finnish men , 2020, ESC heart failure.

[13]  M. Banach,et al.  Statins and C-reactive protein: in silico evidence on direct interaction , 2020, Archives of medical science : AMS.

[14]  S. Wilson,et al.  Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein , 2020, 50 Landmark Papers Every Vascular and Endovascular Surgeon Should Know.

[15]  M. Banach,et al.  Efficacy and safety of bempedoic acid for the treatment of hypercholesterolemia: A systematic review and meta-analysis , 2020, PLoS medicine.

[16]  M. Banach,et al.  Statins and the COVID-19 main protease: in silico evidence on direct interaction , 2020, Archives of medical science : AMS.

[17]  N. Kiaie,et al.  Effects of statins on the biological features of mesenchymal stem cells and therapeutic implications , 2020, Heart Failure Reviews.

[18]  S. Bo,et al.  Effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on ageing: Molecular mechanisms , 2020, Ageing Research Reviews.

[19]  Q. Jia,et al.  Clinical efficacy and safety of statin treatment after carotid artery stenting , 2019, Artificial cells, nanomedicine, and biotechnology.

[20]  P. Kovanen,et al.  Mast cell tryptase - Marker and maker of cardiovascular diseases. , 2019, Pharmacology & therapeutics.

[21]  Daniel E Forman,et al.  2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. , 2019, Journal of the American College of Cardiology.

[22]  Su Liu,et al.  Preoperative statins as modifiers of cardiac and inflammatory outcomes following coronary artery bypass graft surgery: a meta-analysis. , 2017, Interactive cardiovascular and thoracic surgery.

[23]  M. Pencina,et al.  Impact of statin therapy on plasma adiponectin concentrations: A systematic review and meta-analysis of 43 randomized controlled trial arms. , 2016, Atherosclerosis.

[24]  S. Boytsov,et al.  Atorvastatin Therapy Modulates Telomerase Activity in Patients Free of Atherosclerotic Cardiovascular Diseases , 2016, Front. Pharmacol..

[25]  O. Barbarash,et al.  Early Effects of Treatment Low-Dose Atorvastatin on Markers of Insulin Resistance and Inflammation in Patients with Myocardial Infarction , 2016, Front. Pharmacol..

[26]  J. C. Arévalo-Lorido Clinical relevance for lowering C-reactive protein with statins , 2016, Annals of medicine.

[27]  Stefan Störk,et al.  EUROASPIRE IV: A European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries , 2016, European journal of preventive cardiology.

[28]  A. Sahebkar,et al.  The impact of statin therapy on plasma levels of von Willebrand factor antigen , 2015, Thrombosis and Haemostasis.

[29]  A. Sahebkar,et al.  Effect of statin therapy on paraoxonase-1 status: A systematic review and meta-analysis of 25 clinical trials. , 2015, Progress in lipid research.

[30]  Naifeng Liu,et al.  Efficacy and Safety of Loading-Dose Rosuvastatin Therapy in Elderly Patients with Acute Coronary Syndromes Undergoing Elective Percutaneous Coronary Intervention , 2015, Clinical Drug Investigation.

[31]  A. Sahebkar,et al.  Association between statin use and plasma D-dimer levels , 2015, Thrombosis and Haemostasis.

[32]  M. Banach,et al.  Statin therapy reduces plasma endothelin-1 concentrations: A meta-analysis of 15 randomized controlled trials. , 2015, Atherosclerosis.

[33]  Christos G Mihos,et al.  Cardiovascular effects of statins, beyond lipid-lowering properties. , 2014, Pharmacological research.

[34]  J. Salazar,et al.  C-Reactive Protein: Clinical and Epidemiological Perspectives , 2014, Cardiology research and practice.

[35]  Wolfgang Koenig,et al.  High-sensitivity C-reactive protein and atherosclerotic disease: from improved risk prediction to risk-guided therapy. , 2013, International journal of cardiology.

[36]  G. Watts,et al.  New Therapies Targeting apoB Metabolism for High-Risk Patients with Inherited Dyslipidaemias: What Can the Clinician Expect? , 2013, Cardiovascular Drugs and Therapy.

[37]  A. Sahebkar,et al.  New LDL-cholesterol lowering therapies: pharmacology, clinical trials, and relevance to acute coronary syndromes. , 2013, Clinical therapeutics.

[38]  Q. Wang,et al.  Effects of atorvastatin on serum lipids, serum inflammation and plaque morphology in patients with stable atherosclerotic plaques , 2012, Experimental and therapeutic medicine.

[39]  K. Mizuno,et al.  Effects of statin therapy on the production of monocyte pro-inflammatory cytokines, cardiac function, and long-term prognosis in chronic heart failure patients with dyslipidemia. , 2012, Circulation journal : official journal of the Japanese Circulation Society.

[40]  Min Chul Kim,et al.  Comparison of Clinical Outcomes of Hydrophilic and Lipophilic Statins in Patients with Acute Myocardial Infarction , 2011, The Korean journal of internal medicine.

[41]  Eun Mi Lee,et al.  Effect of Previous Statin Therapy in Patients With Acute Coronary Syndrome and Percutaneous Coronary Intervention , 2011, Korean circulation journal.

[42]  Richard Kones,et al.  Primary prevention of coronary heart disease: integration of new data, evolving views, revised goals, and role of rosuvastatin in management. A comprehensive survey , 2011, Drug design, development and therapy.

[43]  M. Azarpazhooh,et al.  Simvastatin Therapy Reduces Prooxidant-Antioxidant Balance: Results of a Placebo-Controlled Cross-Over Trial , 2011, Lipids.

[44]  T. Kurata,et al.  Early intensive statin treatment for six months improves long-term clinical outcomes in patients with acute coronary syndrome (Extended-ESTABLISH trial): a follow-up study. , 2010, Atherosclerosis.

[45]  G. Biondi-Zoccai,et al.  Meta-analysis of randomized controlled trials of statins versus placebo in patients with heart failure. , 2009, The American journal of cardiology.

[46]  Jose J. Galvez,et al.  C-reactive protein impairs the endothelial glycocalyx resulting in endothelial dysfunction. , 2009, Cardiovascular research.

[47]  J. McMurray,et al.  Effects of Statin Therapy According to Plasma High-Sensitivity C-Reactive Protein Concentration in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA): A Retrospective Analysis , 2009, Circulation.

[48]  Eun Mi Lee,et al.  The beneficial effect of high loading dose of rosuvastatin before percutaneous coronary intervention in patients with acute coronary syndrome. , 2009, International journal of cardiology.

[49]  J. Liao,et al.  Statins and cardiovascular diseases: from cholesterol lowering to pleiotropy. , 2009, Current pharmaceutical design.

[50]  T. Nozawa,et al.  Atorvastatin-induced changes in plasma coenzyme q10 and brain natriuretic peptide in patients with coronary artery disease. , 2008, International heart journal.

[51]  P. Libby,et al.  Diversity of denizens of the atherosclerotic plaque: not all monocytes are created equal. , 2008, Circulation.

[52]  M. Chou,et al.  Atorvastatin Administration after Percutaneous Coronary Intervention in Patients with Coronary Artery Disease and Normal Lipid Profiles: Impact on Plasma Adiponectin Level , 2008, Clinical cardiology.

[53]  E. Vasilieva,et al.  The antiplatelet effect of atorvastatin in patients with acute coronary syndrome depends on the hs-CRP level , 2008, Acute cardiac care.

[54]  V. Pasceri,et al.  Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: results of the ARMYDA-ACS randomized trial. , 2007, Journal of the American College of Cardiology.

[55]  Jian‐Jun Li,et al.  Reduction of C-reactive protein by a single 80 mg of simvastatin in patients with unstable angina. , 2007, Clinica chimica acta; international journal of clinical chemistry.

[56]  M. Böhm,et al.  Rapid immunomodulation by rosuvastatin in patients with acute coronary syndrome. , 2006, European heart journal.

[57]  Amy Shui,et al.  Clinical Relevance of C-Reactive Protein During Follow-Up of Patients With Acute Coronary Syndromes in the Aggrastat-to-Zocor Trial , 2006, Circulation.

[58]  C. Ferrario,et al.  Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease. , 2006, The American journal of cardiology.

[59]  Jiang Li,et al.  The effect of different doses of fluvastatin on inflammatory markers in the early phase of acute coronary syndrome. , 2006, Clinica chimica acta; international journal of clinical chemistry.

[60]  D. Spevack,et al.  Effects of statins beyond lipid lowering: potential for clinical benefits. , 2006, International journal of cardiology.

[61]  P. Libby,et al.  C-reactive protein induces matrix metalloproteinase-1 and -10 in human endothelial cells: implications for clinical and subclinical atherosclerosis. , 2006, Journal of the American College of Cardiology.

[62]  Peter Libby,et al.  Inflammation and cardiovascular disease mechanisms. , 2006, The American journal of clinical nutrition.

[63]  S. Lerakis,et al.  Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure. , 2006, Journal of the American College of Cardiology.

[64]  O. Pachinger,et al.  Reduction of soluble P-selectin by statins is inversely correlated with the progression of coronary artery disease. , 2006, International journal of cardiology.

[65]  Jian‐Jun Li,et al.  Effects of 4 weeks of atorvastatin administration on the antiinflammatory cytokine interleukin-10 in patients with unstable angina. , 2005, Clinical chemistry.

[66]  C. Tajer,et al.  Atorvastatin has an important acute anti-inflammatory effect in patients with acute coronary syndrome: results of a randomized, double-blind, placebo-controlled study. , 2005, American heart journal.

[67]  G. Cho,et al.  Effect of preexisting statin use on expression of C‐reactive protein, adhesion molecules, interleukin‐6, and antioxidized low‐density lipoprotein antibody in patients with unstable angina undergoing coronary stenting , 2005, Clinical cardiology.

[68]  E. Salamé,et al.  Effects of tirofiban and statins on high-sensitivity C-reactive protein, interleukin-6, and soluble CD40 ligand following percutaneous coronary interventions in patients with stable coronary artery disease. , 2005, The American journal of cardiology.

[69]  M. Pfeffer,et al.  C-reactive protein levels and outcomes after statin therapy. , 2005, The New England journal of medicine.

[70]  Liying Li,et al.  Changes in serum interleukin-6 and high-sensitivity C-reactive protein levels in patients with acute coronary syndrome and their responses to simvastatin , 2004, Heart and Vessels.

[71]  J. Cauley,et al.  Use of statins and fracture: results of 4 prospective studies and cumulative meta-analysis of observational studies and controlled trials. , 2004, Archives of internal medicine.

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

[73]  P. Libby,et al.  High-Dose Atorvastatin Enhances the Decline in Inflammatory Markers in Patients With Acute Coronary Syndromes in the MIRACL Study , 2003, Circulation.

[74]  M. Hori,et al.  Short-Term Statin Therapy Improves Cardiac Function and Symptoms in Patients With Idiopathic Dilated Cardiomyopathy , 2003, Circulation.

[75]  R. Klein,et al.  Relation of statin use to the 5-year incidence and progression of age-related maculopathy. , 2003, Archives of ophthalmology.

[76]  L. Passos,et al.  Anti-inflammatory effect of atorvastatin (80 mg) in unstable angina pectoris and non-Q-wave acute myocardial infarction. , 2003, The American journal of cardiology.

[77]  H. Makino,et al.  HMG-CoA reductase inhibitor ameliorates diabetic nephropathy by its pleiotropic effects in rats. , 2003, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[78]  P. Hájek,et al.  The effect of early treatment by cerivastatin on the serum level of C-reactive protein, interleukin-6, and interleukin-8 in patients with unstable angina and non-Q-wave myocadial infarction , 2003, Molecular and Cellular Biochemistry.

[79]  R. Madhok,et al.  A Novel Anti-Inflammatory Role for Simvastatin in Inflammatory Arthritis 1 , 2003, The Journal of Immunology.

[80]  M. Pekdemir,et al.  Atorvastatin affects C-reactive protein levels in patients with coronary artery disease , 2003, Current medical research and opinion.

[81]  W. Seeger,et al.  Simvastatin Inhibits Inflammatory Properties of Staphylococcus aureus &agr;-Toxin , 2002, Circulation.

[82]  S. Thompson,et al.  Quantifying heterogeneity in a meta‐analysis , 2002, Statistics in medicine.

[83]  V. Fuster,et al.  Statins and cardiovascular diseases: the multiple effects of lipid-lowering therapy by statins. , 2000, Atherosclerosis.

[84]  B. Halmos,et al.  Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[85]  K. Williams,et al.  Atherosclerosis--an inflammatory disease. , 1999, The New England journal of medicine.

[86]  M. Pfeffer,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. , 1998, Circulation.

[87]  G. Smith,et al.  Bias in meta-analysis detected by a simple, graphical test , 1997, BMJ.

[88]  A R Jadad,et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary? , 1996, Controlled clinical trials.

[89]  C. Begg,et al.  Operating characteristics of a rank correlation test for publication bias. , 1994, Biometrics.

[90]  N. Laird,et al.  Meta-analysis in clinical trials. , 1986, Controlled clinical trials.

[91]  D. Phelan,et al.  Long-term statin therapy in patients with systolic heart failure and normal cholesterol: effects on elevated serum markers of collagen turnover, inflammation, and B-type natriuretic peptide. , 2012, Clinical therapeutics.

[92]  Małgorzata Czechowska,et al.  The influence of low dose atorvastatin on inflammatory marker levels in patients with acute coronary syndrome and its potential clinical value. , 2008, Cardiology journal.

[93]  R. Madhok,et al.  A Novel Anti-Inflammatory Role for Simvastatin in Inflammatory Arthritis , 2003 .

[94]  M. Moskowitz,et al.  Neuroprotection mediated by changes in the endothelial actin cytoskeleton. , 2000, The Journal of clinical investigation.

[95]  M. Pfeffer,et al.  Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. , 1999, Circulation.