Thromb Haemost 2004; 92(05): 1129-1135
DOI: 10.1160/TH03-04-0250
Cell Signalling and Vessel Remodelling
Schattauer GmbH

Statin and fibrate treatment of combined hyperlipidemia: the effects on some novel risk factors

Miran Šebeštjen
1   University Clinical Centre, Department of Angiology, Ljubljana, Slovenia
,
Irena Keber
1   University Clinical Centre, Department of Angiology, Ljubljana, Slovenia
,
Branka Žegura
1   University Clinical Centre, Department of Angiology, Ljubljana, Slovenia
,
Saša Simčič
2   Institute of Microbiology and Immunology, Medical Faculty, Ljubljana, Slovenia
,
Mojca Božič
1   University Clinical Centre, Department of Angiology, Ljubljana, Slovenia
,
Martine Migaud Fressart
3   Diagnostica Stago, Asnières, France
,
Mojca Stegnar
1   University Clinical Centre, Department of Angiology, Ljubljana, Slovenia
› Author Affiliations
Further Information

Publication History

Received 28 April 2003

Accepted after revision 05 July 2004

Publication Date:
04 December 2017 (online)

Summary

The effects of cerivastatin and fenofibrate on proteins involved in haemostasis and on markers of inflammation were investigated in otherwise healthy middle-aged males with combined hyperlipidemia. Besides classical risk factors, other so-called novel risk factors for coronary artery disease are seen to be playing an increasingly important role in the development and progression of atherosclerosis. Thirty-eight males, aged 49 ± 5 years were randomised to 12 weeks treatment either with cerivastatin at a daily dose of 0.2 mg to 0.4 mg to achieve the LDL cholesterol goal of <3.0 mM, or with fenofibrate 250 mg daily. Fasting serum lipids, homocysteine, total and free tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor (PAI-1) and tissue plasminogen activator (t-PA) antigen and activity, C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured. No change in homocysteine level was observed in the cerivastatin group, while after fenofibrate administration it increased (p <0.0001).Total TFPI decreased significantly after cerivastatin (p = 0.002), but not after fenofibrate. Free TFPI did not decrease after either drug. Neither drug affected (t-PA) antigen and activity, while fenofibrate increased PAI-1 antigen (p <0.05) and activity (p <0.05). Cerivastatin decreased serum CRP values by 49.5% (p = 0.001), and fenofibrate by 29.8% (p = 0.03). The decreases of CRP in the two groups differed significantly (p = 0.04). IL-6 levels decreased significantly in the fenofibrate group (39%; p <0.0001), but not in the cerivastatin group (15%; p = 0.24) No significant decreases were observed for TNF-α. Cerivastatin had neutral effects on fibrinolysis, homocysteine or coagulation. On the other hand, fenofibrate increased PAI-1 antigen and activity and homocysteine, and did not affect coagulation. Both cerivastatin and fenofibrate reduced CRP levels, the decrease being significantly greater after cerivastatin. Fenofibrate also significantly decreased IL-6.

 
  • References

  • 1 Kannel WB, McGee D, Gordon T. A general cardiovascular risk profile: the Framingham study. Am J Cardiol 1976; 38: 46-51.
  • 2 Stampfer MJ, Malinow M, Willett MC. et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992; 268: 877-81.
  • 3 Nygard O, Nordrehaug JE, Refsum H. et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997; 337: 230-6.
  • 4 Koenig W, Sund M, Frölich M. et al. C-reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men. Circulation 1999; 99: 237-42.
  • 5 Ridker PM, Rifai N, Pfeffer MA. et al. for the Cholesterol and recurrent events (CARE) investigators. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation 1998; 98: 839-44.
  • 6 Ridker PM, Rifai N, Stampfer MJ. et al. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101: 1767-72.
  • 7 Ridker PM, Rifai N, Pfeffer M. et al. Elevation of tumor necrosis factor-α and increased risk of recurrent coronary events after myocardial infarction. Circulation 2000; 101: 2149-53.
  • 8 Welch GN, Lascalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998; 338: 1042-50.
  • 9 Chambers JC, Obeid OA, Kooner JS. Physiological increments in plasma homocysteine induce vascular endothelial dysfunction in normal human subjects. Arterioscler Thromb Vasc Biol 1999; 19: 2922-7.
  • 10 MRFIT Research Group. Kuller LH, Tracy RP, Shaten J. et al. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Am J Epidemiol 1996; 144: 537-47.
  • 11 Heinrich PC, Castell JV, Andus T. Interleukin- 6 and the acute phase response. Biochem J 1990; 265: 621-36.
  • 12 Abbas AK, Lichtman AH. eds. Cellular and molecular immunology. 5th . ed. Philadelphia: Saunders; 2003
  • 13 Walsh BW, Cox DA, Sashegyi A. et al. Role of tumor necrosis factor-a and interleukin-6 in the effects of hormone replacement therapy and raloxifene on C-reactive protein in postmenopausal women. Am J Cardiol 2001; 88: 825-8.
  • 14 Fuster V, Badimon L, Badimon JJ. et al. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992; 326: 242-50.
  • 15 Lindahl AK. Tissue factor pathway inhibitor: from unknown coagulation inhibitor to major antithrombotic principle. Cardiovasc Res 1997; 33: 286-91.
  • 16 Broze Jr GJ. Tissue factor pathway inhibitor and the current concept of blood coagulation. Blood Coagul Fibrinol 1995; 06 (01) S7-S13.
  • 17 Folsom AR. Hemostatic risk factors for atherothrombotic disease: an epidemiologic view. Thromb Haemost 2001; 86: 366-73.
  • 18 Morishita E, Asakura H, Saito M. et al. Elevated plasma levels of free-form of TFPI antigen in hypercholesterolemic patients. Atherosclerosis 2001; 154: 203-12.
  • 19 Folsom AR. Hemostatic risk factors for atherothrombotic disease: an epidemiologic view. Thromb Haemost 2001; 86: 366-73.
  • 20 Janson JH, Olofsson BO, Nilsson TK. Predictive value of tissue plasminogen activator mass concentration on long-term mortality in patients with coronary arterydisease: a 7-year follow-up. Circulation 1993; 88: 2030-4.
  • 21 Hamsten A, De Faire U, Walldius G. et al. Plasminogen activator inhibitorin plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 02: 3-9.
  • 22 Gaw A. Evidence based approach for the management of mixed hyperlipidemia. Atherosclerosis 1998; 137: S97-S100.
  • 23 Friedwald WT, Levy RI, Frederickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of preparative ultracentrifuge. Clin Chem 1972; 18: 499-502.
  • 24 Roberts WL, Sedrick R, Moulton L. et al. Evaluation of four automated high-sensitivity C-reactive protein methods: Implications for clinical and epidemiological applications. Clin Chem 2000; 46 (04) 461-8.
  • 25 de Lorgeril M, Salen P, Paillard F. et al. Lipidlowering drugs and homocysteine. Lancet 1999; 353: 209-10.
  • 26 Dierkes J, Westphal S, Luley C. Serum homocysteine increases after therapy with fenofibrate or bezafibrate. Lancet 1999; 354: 219-20.
  • 27 Hansen JB, Huseby KR, Huseby NR. et al. Effect of cholesterol lowering on intravascular pools of TFPI and its anticoasgulant potential in type II hyperlipoproteinemia. Arterioscler Thromb Vasc Biol 1995; 15: 879-85.
  • 28 Bevilacqua M, Bettica P, Milani H. et al. Effect of fluvastatin on lipids and fibrinolysis in coronary artery disease. Am J Cardiol 1997; 79: 84-7.
  • 29 Dangas G, Smith DA, Unger AH. et al. Pravastatin: an antithrombotic effect independent of the cholesterol-lowering effect. Thromb Haemost 2000; 83: 688-92.
  • 30 Mitropoulos KA, Armitage JM, Collins R. et al. Randomized placebo-controlled study of the effects of simvastatin on haemostatic variables, lipoproteins and free fatty acids. Eur Heart J 1997; 17: 235-41.
  • 31 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: 217-25.
  • 32 Kockx M, de Maat MPM, Knipscheer HC. et al. Effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator, plasminogen activator inhibitor-1 and fibrinogen in hyperlipidaemic patients. Thromb Haemost 1997; 78: 1167-72.
  • 33 Keber I, Lavre J, Šuc S. et al. The decrease of plasminogen activator inhibitor after normalization of triglycerides during treatment with fibrates. Fibrinol 1994; 08: 57-9.
  • 34 Ridker PM, Rifai N, Lowenthal SP. Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia. Circulation 2001; 103: 1191-3.
  • 35 Ridker PM, Rifai N, Pfeffer MA. et al. For the Cholesterol and recurrent events (CARE) investigators. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999; 1000: 230-5.
  • 36 Strandberg TE, Vanhanen H, Tikkanen MJ. Associations between change in C-reactive protein and serum lipids during statin treatment. Ann Med 2000; 32: 579-83.
  • 37 Kinaly 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: 1560-6.
  • 38 Cortellaro M, Cofrancesco E, Boschetti C. et al. Effects of fluvastatin and bezafibrate combination on plasma fibrinogen, plasminogen activator inhibitor and C reactive protein levels in coronary artery disease patients with mixed hyperlipidemia (FACT study). Thromb Haemost 2000; 83: 549-53.
  • 39 Weinhold B, Ruether U. Interleukin-6-dependent and –independent regulation of the human C-reactive protein gene. Biochem J 1997; 327: 425-9.
  • 40 Staels B, Koenig W, Habib A. et al. Activation of human aortic smooth-muscle is inhibited PPAR alpha but not by PPAR gamma activators. Nature 1998; 393 (6687) 790-3.
  • 41 Wang TD, Chen WJ, Lin JW. et al. Efficacy of fenofibrate and simvastatin on endothelial function and inflammatory markers in patients with combined hyperlipidemia: relations with baseline lipid profiles. Atherosclerosis 2003; 170: 315-23.