Skip to main content

Advertisement

SpringerLink
Log in

Therapeutic Options to Further Lower C-Reactive Protein for Patients on Statin Treatment

  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Cardiovascular disease remains the leading cause of morbidity and mortality in developed nations. Inflammation plays an increasingly important role in the cardiovascular disease process. Recent statin trials have demonstrated a correlation between the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) and cardiovascular risk. This review describes the results of changes in hsCRP in the major statin outcome trials and the concept of a “dual target” for both low-density lipoprotein cholesterol and hsCRP. The effect on hsCRP of combination statin therapy with ezetimibe, fenofibric acid, niacin, and colesevelam is reviewed. Although some statin combination therapies have additional effects on CRP and other atherogenic lipids, evidence for their effect on cardiovascular risk beyond statin monotherapy is lacking. Ongoing placebo-controlled trials investigating statin combination therapy versus statin monotherapy may provide additional clues to the role of additional changes in lipids versus markers of inflammation on cardiovascular risk reduction. Until these trials are completed, current evidence suggests focusing on low-density lipoprotein cholesterol targets.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as:• Of importance •• Of major importance

  1. Ridker P: C-reactive protein: eighty years from discovery to emergence as a major risk marker for cardiovascular disease. Clin Chem 2009, 55:209–215.

    Article  CAS  PubMed  Google Scholar 

  2. Ledue TB, Rifai N: High sensitivity immunoassays for C-reactive protein: promises and pitfalls. Clin Chem Lab Med 2001, 39:1171–1176.

    Article  CAS  PubMed  Google Scholar 

  3. Roberts WL, Moulton L, Law TC, et al.: Evaluation of nine automated high-sensitivity C-reactive protein methods: implications for clinical and epidemiological applications. Part 2. Clin Chem 2001, 47:418–425.

    CAS  PubMed  Google Scholar 

  4. Sachdeva A, Cannon C, Deedwania P, et al.: Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in Get with the Guidelines. Am Heart J 2009, 157:111–117.

    Article  CAS  PubMed  Google Scholar 

  5. •• Ridker PM, Danielson E, Fonseca FA, et al.: Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Eng J Med 2008, 359:2195–2207. The landmark JUPITER trial was a prospective, randomized controlled trial that evaluated the use of statin therapy in patients considered to have cholesterol levels at target by current guidelines and elevated hsCRP greater than 2.0. The trial was stopped early due to the large risk reduction in the treatment group.

    Article  CAS  Google Scholar 

  6. Hansson GK: Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005, 352:1685–1696.

    Article  CAS  PubMed  Google Scholar 

  7. Pearson TA, Mensah GA, Alexander RW, et al.: Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003, 107: 499–511.

    Article  PubMed  Google Scholar 

  8. Takemoto M, Liao JK: Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arterioscler Thromb Vasc Biol 2001, 21:1712–1719.

    Article  CAS  PubMed  Google Scholar 

  9. Sacks FM, Pfeffer MA, Moye LA, et al.: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.N Engl J Med 1996, 335:1001–1009.

    Article  CAS  PubMed  Google Scholar 

  10. Ridker PM, Rifai N, Pfeffer MA, et al.: Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999, 100:230–235.

    CAS  PubMed  Google Scholar 

  11. 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, 344:1959–1965.

    Article  CAS  PubMed  Google Scholar 

  12. Kinlay S, Schwartz GG, Olsson AG, et al.: High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation 2003, 108:1560–1566.

    Article  CAS  PubMed  Google Scholar 

  13. Nissen SE, Tuzcu EM, Schoenhagen P, et al.: Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis. JAMA 2004, 291:1071–1080.

    Article  CAS  PubMed  Google Scholar 

  14. Morrow DA, de Lemos JA, Sabatine MS, et al.: Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial. Circulation 2006, 114:281–288.

    Article  CAS  PubMed  Google Scholar 

  15. Ridker PM, Cannon CP, Morrow D, et al.: C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005, 352:20–28.

    Article  CAS  PubMed  Google Scholar 

  16. • Kinlay S: Low-density lipoprotein-dependent and –independent effects of cholesterol-lowering therapies on C-reactive protein: a meta-analysis. J Am Coll Cardiol 2007, 49: 2003–2009. This is an important meta-analysis demonstrating the link between LDL-C reduction and hsCRP reduction and the difficulty in separating the two based on current evidence.

    Article  CAS  PubMed  Google Scholar 

  17. •• Ridker PM, Danielson E, Fonseca FA, 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, 373:1175–1182. This study from the JUPITER trial supports the concept of a dual target for LDL-C and hsCRP. Those who achieved levels of both LDL-C and hsCRP below target were found to have the best outcomes.

    Article  CAS  PubMed  Google Scholar 

  18. Milani RV, Lavie CJ, Mehra MR: Reduction in C-reactive protein through cardiac rehabilitation and exercise training. J Am Coll Cardiol 2004, 43:1056–1061.

    Article  CAS  PubMed  Google Scholar 

  19. Pearson TA, Denke MA, McBride PE, et al.: Effectiveness of ezetimibe added to ongoing statin therapy in modifying lipid profiles and low-density lipoprotein cholesterol goal attainment in patients of different races and ethnicities: a substudy of the ezetimibe add-on to statin for effectiveness trial. Mayo Clin Proc 2006, 81:1177–1185.

    Article  CAS  PubMed  Google Scholar 

  20. Goldberg RB, Guyton JR, Mazzone T, et al.: Ezetimibe/simvastatin vs atorvastatin in patients with type 2 diabetes mellitus and hypercholesterolemia. Mayo Clin Proc 2006, 81:1579–1588.

    Article  CAS  PubMed  Google Scholar 

  21. Catapano AL, Davidson MH, Ballantyne CM, et al.: Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus rosuvastatin in hypercholesterolemic patients. Curr Med Res Opin 2006, 22:2041–2053.

    Article  CAS  PubMed  Google Scholar 

  22. • Pearson TA, Ballantyne CM, Sisk C, et al.: Comparison of effects of ezetimibe/simvastatin versus simvastatin versus atorvastatin in reducing C-Reactive protein and LDL-C levels. Am J Cardiol 2007, 99:1706–1713. This is a combination of trials revealing a significant difference in hsCRP reduction between ezetimibe/simvastatin versus simvastatin monotherapy. The reason for the significant difference is not completely understood and suggests the need for more investigation.

    Article  CAS  PubMed  Google Scholar 

  23. Kastelein JJ, Akdim F, Stroes ES, et al.: Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008, 358:1431–1443.

    Article  CAS  PubMed  Google Scholar 

  24. Muhlestein JB, May HT, Jensen JR, et al.: The reduction of inflammatory biomarkers by statin, fibrate, and combination therapy among diabetic patients with mixed dyslipidemia: the DIACOR (Diabetes and Combined Lipid Therapy Regimen) study. J Am Coll Cardiol 2006, 48:396–401.

    Article  CAS  PubMed  Google Scholar 

  25. • Jones PH, Davidson MH, Kashyap ML, et al.: Efficacy and safety of ABT-335 (fenofibric acid) in combination with rosuvastatin in patients with mixed dyslipidemia: a phase 3 study. Atherosclerosis 2009, 204:208–215. This trial examined the combination of fenofibric acid with rosuvastatin. LDL-C reduction was greatest with high-dose statin therapy but there was a trend for greater hsCRP reduction with combination therapy.

    Article  CAS  PubMed  Google Scholar 

  26. • Goldberg AC, Bays HE, Ballantyne CM, et al.: Efficacy and safety of ABT-335 (fenofibric acid) in combination with atorvastatin in patients with mixed dyslipidemia. Am J Cardiol 2009, 103:515–522. This trial examined the combination of fenofibric acid with atorvastatin. LDL-C reduction was greatest with high-dose statin therapy but there was a trend for greater hsCRP reduction with combination therapy.

    Article  CAS  PubMed  Google Scholar 

  27. • Mohiuddin SM, Pepine CJ, Kelly MT, et al.: Efficacy and safety of ABT-335 (fenofibric acid) in combination with simvastatin in patients with mixed dyslipidemia: a phase 3, randomized, controlled study. Am Heart J 2009, 157:195–203. This trial examined the combination of fenofibric acid with simvastatin. LDL-C reduction was greatest with high-dose statin therapy but there was a trend for greater hsCRP reduction with combination therapy.

    Article  CAS  PubMed  Google Scholar 

  28. Bays HE, Jones PH, Mohiuddin SM, et al.: Long-term safety and efficacy of fenofibric acid in combination with statin therapy for the treatment of patients with mixed dyslipidemia. J Clin Lipidology 2008, 2:426–435.

    Article  Google Scholar 

  29. Zambon A, Gervois P, Pauletto P, et al.: Modulation of hepatic inflammatory risk markers of cardiovascular diseases by PPAR-α activators: clinical and experimental evidence. Arteroscler Thromb Vasc Biol 2006, 26:977–986.

    Article  CAS  Google Scholar 

  30. Taylor AJ, Sullenberger LE, Lee HJ, et al.: Arterial biology for the investigation of the treatment effects of reducing cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004, 110: 3512–3517.

    Article  CAS  PubMed  Google Scholar 

  31. Airan-Javia SL, Wolf RL, Wolfe ML, et al.: Atheroprotective lipoprotein effects of a niacin-simvastatin combination compared to low- and high-dose simvastatin monotherapy. Am Heart J 2009, 157:687.e1–687.e8.

    Google Scholar 

  32. • Guyton JR, Brown BG, Fazio S, et al.: Lipid-altering efficacy and safety of ezetimibe/simvastatin coadministered with extended-release niacin in patients with type IIa or type IIb hyperlipidemia. J Am Coll Cardiol 2008, 51:1564–1572. This was a large trial demonstrating no effect on hsCRP with the addition of niacin to ezetimibe/statin therapy, reinforcing the findings from prior investigations of combination therapy with niacin/statins.

    Article  CAS  PubMed  Google Scholar 

  33. Yu B, Zhao S: Anti-inflammatory effect is an important property of niacin on atherosclerosis beyond it lipid-altering effects. Med Hypotheses 2007, 69:90–94.

    Article  CAS  PubMed  Google Scholar 

  34. Bays HE, Davidson M, Jones MR, Abby SL: Effects of colesevelam hydrochloride on low-density lipoprotein cholesterol and high-sensitivity C-reactive protein when added to statins in patients with hypercholesterolemia. Am J Cardiol 2006, 97:1198–1205.

    Article  CAS  PubMed  Google Scholar 

  35. Ridker PM: The time for cardiovascular inflammation reduction trials has arrived: how low to go for hsCRP? Arterioscler Thromb Vasc Biol 2008, 28:1222–1224.

    Article  CAS  PubMed  Google Scholar 

  36. Robinson JR, Wang S, Smith BJ, Jacobson TA.: Meta-analysis of the relationship between non-high density lipoprotein cholesterol reduction and coronary heart disease risk. J Am Coll Cardiol 2009, 53:316–322.

    Article  CAS  PubMed  Google Scholar 

  37. • Ridker PM: Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the cardiovascular inflammation reduction trial (CIRT). J Thromb Haemost 2009, 7:332–339. This is an important proposal for a trial to investigate the role inflammation plays in atherosclerosis from a clinical perspective. A positive study could potentially have large implications on the current approach to therapy for cardiovascular risk.

    Article  CAS  PubMed  Google Scholar 

Download references

Disclosure

Dr. Jacobson is a consultant for Abbott, AstraZeneca, Merck, Schering-Plough, GlaxoSmithKline, and Merck/Schering Plough. No other potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Department of Medicine, Emory University, 69 Jesse Hill Jr Drive, Atlanta, GA, 30303, USA

    Parag H. Joshi

  2. Department of Medicine, Emory University, 49 Jesse Hill Jr Drive, Atlanta, GA, 30303, USA

    Terry A. Jacobson

Authors
  1. Parag H. Joshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Terry A. Jacobson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Parag H. Joshi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Joshi, P.H., Jacobson, T.A. Therapeutic Options to Further Lower C-Reactive Protein for Patients on Statin Treatment. Curr Atheroscler Rep 12, 34–42 (2010). https://doi.org/10.1007/s11883-009-0075-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11883-009-0075-x

Keywords

Search

Navigation