- Email: [email protected]
Differential effects of statins on serum CRP levels: implications of recent clinical trials
Atherosclerosis 169 (2003) 349 /351 www.elsevier.com/locate/atherosclerosis
Letter to the Editor Differential effects of statins on serum CRP levels: implications of recent clinical trials Sir, It is unclear whether the clinical benefits of the HMGCoA reductase inhibitors (statins) in reducing coronary risk are attributable to their potent LDLlowering effects alone, and it has been argued that the early separation of survival curves seen in some of these studies is related to the non-lipid effects of these compounds [1,2]. Several publications have reported substantial reductions in plasma inflammatory markers, such as Creactive protein (CRP) following treatment with statin (Table 1), and it has been proposed that their putative anti-inflammatory properties may contribute to plaque stabilisation. However the literature is inconsistent. The intrinsic biological variation of plasma inflammatory markers, especially that due to minor infections, may be partially responsible for this. Investigators have attempted to reduce the impact of the variability by, for example, omitting subjects with high initial levels from the data analysis [2,3]. It is also possible that the statins differ in their potency to reduce CRP. There are very limited data comparing the relative efficacy of different statins for CRP reduction [2,4,5], or
whether the effects of statins on serum CRP concentrations are dose /dependent [2,5,6]. Analysis of data from large trials indicate that at a single dose there is no significant relationship between LDL reduction and CRP change [2,7,8], however, there have been few studies in which a forced titration of dose has been used [1,9,10]. The data from trials in which serum hsCRP levels were measured during statin treatment were reviewed in order to determine whether the various statins differ in their efficacy in reducing CRP, if there is a relationship between this and their LDL-cholesterol lowering effect, and whether they display a dose-dependency. Medline and PubMed were used to identify papers using ‘CRP and statin’ or ‘C-reactive protein and statin’ as the search terms. Only papers reporting the use of fixed doses of statin, or a forced titration over a defined time scale were included in the analysis of dose v change in serum CRP, although change in serum LDL versus change in CRP was analysed for other studies in which a single statin was investigated. Trials of less than 6 weeks duration were excluded. Of the 83 papers listed, 14 reported primary data that could be used in the data analysis. Of these, seven reported the response to atorvastatin, or simvastatin, five to pravastatin and one each to cerivastatin and lovastatin. One used a
Fig. 1. Dose /dependent effects of atorvastatin on serum CRP concentrations.
* Present address: Centre for Clinical Science and Measurement, SBMS University of Surrey, Guildford, Surrey GU2 5XH, UK. Tel.: /44-1483686-419; fax: /44-1483-464-072. 0021-9150/03/$ - see front matter # 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0021-9150(03)00191-6
350
Letter to the Editor
Table 1 Effects of statins on serum CRP and lipid levels Statin
Dose
Duration of Treatment
Subject Group
n
Median base-line CRP (mg/l)
DCRP(%)
DLDL(%)
DHDL(%)
Refs.
Atorvastatin Atorvastatin Atorvastatin Simvastatin Simvastatin Simvastatin Atorvastatin Lovastatin Atorvastatin Simvastatin Atorvastatin Pravastatin Atorvastatin Simvastatin Pravastatin Pravastatin Pravastatin Pravastatin Atorvastatin Atorvastatin Cerivastatin Cerivastatin Atorvastatin Simvastatin Simvastatin Simvastatin Simvastatin Atorvastatin Fluvastatain
20 40 80 40 80 80 10-80 5-10 10-80 20 10 40 10 40 40 40 40 40 10 20 0.4 0.8 40 20 40 40 40 80 20
6 Weeksa 6 Weeks a 24 Weeksa 6 weeksa 6 Weeks a 24 Weeksa 3 Months 12 Months 12 Months 6 Weeksb 6 Weeksb 6 Weeksb 3 Months 3 months 3 Months 5 Years 24 Weeks 24 Weeksb 3 Monthsa 3 Monthsa 8 Weeksa 8 Weeks a 6 Weeksb 8 Weeks 3 Months 3 Months 2 Years 2 Years 24 Weeks
Hypercholesterolaemia Hypercholesterolaemia Hypercholesterolaemia Hypercholesterolaemia Hypercholesterolaemia Hypercholesterolaemia CHD or high risk Stable angina Stable angina Combined dyslipidaemia Combined dyslipidaemia Combined dyslipidaemia Hypercholesterolaemia Hypercholesterolaemia Hypercholesterolaemia Post MI Primary prevention Secondary prevention Diabetes mellitus Diabetes mellitus Hypercholesterolaemia Hypercholesterolaemia Visceral obesity Renal disease Hypercholesterolaemia CHD FH FH CHD and dyslipidaemia
23 23 23 24 24 24 151 33 72 22 22 22 33 33 33 258 865 1182 39 39 162 623 13 28 33 25 133 135
1.15 1.15 1.15 1.2 1.2 1.2 2.25 2.6 2.6 2.5 2.5 2.5 1.9 2.4 2.3 2.30 2.0 2.7 1.98 1.98 1.8 1.5 2.60 2.3 1.02 1.61 2.0 2.1 ?
/36.4 /59 /63.6 33 41.7 /8.0 /18.7 /7.7 /34.6 /22.8 /28.3 /20.3 0 /20.8 0 /17.4 /16.9 /13.1 /18.2 /37.9 /11.1 /13.1 /30.8 /47.8 /49 /27.3 /19.7 /40.1 0
/51.3 /59.4 /60.6 /47.3 /53.8 /53.2 /45.3 /17.6 /45.9 /30.3 /32.9 /21.7 /37.3 /44.7 /31.2 /32 /21.5 /24.2 /43.4 /48.8 /37.3 /42.2 /52.6 /41 /41 /40 /44.0 /52.6
7.1 8.7 /0.6 11.9 14.1 9.6 9.1 ? 2.3 2.2 0.2 2.5 7.8 4.5 0 ? 6.6 6.5 0.8 /4.2 6.7 8.0 2.8 2.8 7.5 0 13.8 14.3
[1] [1] [1] [1] [1] [1] [3] [4] [4] [5] [5] [5] [6] [6] [6] [6] [8] [8] [9] [9] [10] [10] [11] [12] [13] [13] [14] [14] [15]
a b
Forced titration. Crossover design.
crossover design and two used forced titration. The duration of treatment ranged between 6 weeks and 5 years. Changes in LDL and CRP were expressed as percentage changes from baseline. The reduction in LDL varied from 21.5% (using 40 mg/day of pravastatin) to 60.9% (for 80 mg/day atorvastatin); and the change in CRP ranged from an increase of 41.7% (80 mg/day simvastatin) to a decrease of 63.6% (for 80 mg/ day atorvastatin). There was a significant log-linear relationship between dose of atorvastatin and CRP reduction (r2 / 0.69, P B/0.01) (Fig. 1) and a linear relationship between %LDL reduction and %CRP reduction (r2 /0.67, P B/ 0.01), but this was not observed for simvastatin (P / 0.05), nor for the pooled data from all statins. Although comparative data for the effects of the different statins on serum CRP levels are very limited, it appears that they may differ in their potency; that the response, at least to atorvastatin, is dose /dependent and related to the reduction in LDL achieved. In patients with elevated levels of CRP it may be necessary to use a higher dose of statin than required to attain the target LDL-cholesterol concentration, for an
optimal anti-inflammatory/plaque stabilising effect; and this may vary between the currently available statins.
References [1] Wiklund O, Mattsson-Hulten L, Hurt-Camejo E, Oscarsson J. Effects of simvastatin and atorvastatin on inflammation markers in plasma. J Int Med 2002;251:338 /47. [2] Koh KK. Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability. Cardiovasc Res 2000;47:648 / 57. [3] Riesen WF, Engler H, Risch M, Korte W, Noseda G. Short-term effects of atorvastatin on C-reactive protein. Eur Heart J 2002;23:794 /9. [4] Kinley S, Timms T, Clark M, et al. Comparison of effect of intensive lipid lowering with atorvastatin to less intensive lowering with lovastatin on C-reactive protein in patients with stable angina pectoris and inducible myocardial ischemia. Am J Cardiol 2002;89:1205 /7. [5] Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S. Effects of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitivity C-reactive protein levels. Circulation 2001;103:1933 /5. [6] Joukhadar C, Klein N, Prinz M, et al. Similar effects of atorvastatin, simvastatin and pravastatin on thrombogenic and
Letter to the Editor
[7]
[8]
[9]
[10]
[11]
[12]
[13]
inflammatory parameters in patients with hypercholesterolemia. Thromb Haemost 2000;85:47 /51. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Longterm effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999;100:230 /5. Albert MA, Danielson E, Rifai N, Ridker PM. 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 /70. Tan KCB, Chow WS, Tam SCF, Ai VHG, Lam CHL, Lam KSL. Atorastatin lowers-reactive protein and improves endothelium dependent vasodilation in type2 diabetes mellitus. J Clin Endocrinol Metab 2002;87:563 /8. Ridker PM, Rifai N, Pitman Lowenthal S. Rapid reduction in Creactive protein with cerivastatin among 785 patients with primary hypercholesterolaemia. Circulation 2001;103:1191 /3. Chan DC, Watts GF, Barrett PHR, Beilin LJ, Mori TA. Effect of atorvastatin and fish oil on plasma high-sensitivity C-reactive protein concentrations in individuals with visceral obesity. Clin Chem 2002;48:877 /83. Chang JW, Yang WS, Min WK, Lee SK, Park JS, Kim SB. Effects of simvastatin on high-sensitivity C-reactive protein and serum albumin in hemodialysis patients. Am J Kidney Dis 2002;39:1213 /7. Musial J, Undas A, Gajewski P, Jankowski M, Sydor W, Szczeklik A. Ant-inflammatory effects of simvastatin in subjects with hypercholesterolaemia. Int J Cardiol 2001;77:247 /53.
351
[14] van Weissen S, Trip MD, Smilde TJ, deGraaf J, Stalenhoef AF, Kastelwin JJ. Differential hs-CRP reduction in patients with familial hypercholesterolaemia treated with aggressive or conventional statin therapy. Atherosclerosis 2002;165:361 /6. [15] Cortellaro M, Cofrancesco E, Boschetti C, et al. Effects of fluvastatin and bezafibrate combination on plasma fibrinogen, t -plasminogen activator inhibitor and C reactive protein levels in coronary artery disease patients with mixed hyperlipidaemia (FACT study). Thromb Haemost 2000;83:549 /53.
Received 1 May 2003; accepted 9 May 2003 Gordon A.A. Ferns * School of Biomedical and Molecular Science, University of Surrey, Guildford, Surrey GU2 5XH, UK Department of Clinical Biochemistry, Royal Surrey County Hospital, Egerton Road, Guildford, Surrey GU2 5XX, UK E-mail address: [email protected]
Letter to the Editor Differential effects of statins on serum CRP levels: implications of recent clinical trials Sir, It is unclear whether the clinical benefits of the HMGCoA reductase inhibitors (statins) in reducing coronary risk are attributable to their potent LDLlowering effects alone, and it has been argued that the early separation of survival curves seen in some of these studies is related to the non-lipid effects of these compounds [1,2]. Several publications have reported substantial reductions in plasma inflammatory markers, such as Creactive protein (CRP) following treatment with statin (Table 1), and it has been proposed that their putative anti-inflammatory properties may contribute to plaque stabilisation. However the literature is inconsistent. The intrinsic biological variation of plasma inflammatory markers, especially that due to minor infections, may be partially responsible for this. Investigators have attempted to reduce the impact of the variability by, for example, omitting subjects with high initial levels from the data analysis [2,3]. It is also possible that the statins differ in their potency to reduce CRP. There are very limited data comparing the relative efficacy of different statins for CRP reduction [2,4,5], or
whether the effects of statins on serum CRP concentrations are dose /dependent [2,5,6]. Analysis of data from large trials indicate that at a single dose there is no significant relationship between LDL reduction and CRP change [2,7,8], however, there have been few studies in which a forced titration of dose has been used [1,9,10]. The data from trials in which serum hsCRP levels were measured during statin treatment were reviewed in order to determine whether the various statins differ in their efficacy in reducing CRP, if there is a relationship between this and their LDL-cholesterol lowering effect, and whether they display a dose-dependency. Medline and PubMed were used to identify papers using ‘CRP and statin’ or ‘C-reactive protein and statin’ as the search terms. Only papers reporting the use of fixed doses of statin, or a forced titration over a defined time scale were included in the analysis of dose v change in serum CRP, although change in serum LDL versus change in CRP was analysed for other studies in which a single statin was investigated. Trials of less than 6 weeks duration were excluded. Of the 83 papers listed, 14 reported primary data that could be used in the data analysis. Of these, seven reported the response to atorvastatin, or simvastatin, five to pravastatin and one each to cerivastatin and lovastatin. One used a
Fig. 1. Dose /dependent effects of atorvastatin on serum CRP concentrations.
* Present address: Centre for Clinical Science and Measurement, SBMS University of Surrey, Guildford, Surrey GU2 5XH, UK. Tel.: /44-1483686-419; fax: /44-1483-464-072. 0021-9150/03/$ - see front matter # 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0021-9150(03)00191-6
350
Letter to the Editor
Table 1 Effects of statins on serum CRP and lipid levels Statin
Dose
Duration of Treatment
Subject Group
n
Median base-line CRP (mg/l)
DCRP(%)
DLDL(%)
DHDL(%)
Refs.
Atorvastatin Atorvastatin Atorvastatin Simvastatin Simvastatin Simvastatin Atorvastatin Lovastatin Atorvastatin Simvastatin Atorvastatin Pravastatin Atorvastatin Simvastatin Pravastatin Pravastatin Pravastatin Pravastatin Atorvastatin Atorvastatin Cerivastatin Cerivastatin Atorvastatin Simvastatin Simvastatin Simvastatin Simvastatin Atorvastatin Fluvastatain
20 40 80 40 80 80 10-80 5-10 10-80 20 10 40 10 40 40 40 40 40 10 20 0.4 0.8 40 20 40 40 40 80 20
6 Weeksa 6 Weeks a 24 Weeksa 6 weeksa 6 Weeks a 24 Weeksa 3 Months 12 Months 12 Months 6 Weeksb 6 Weeksb 6 Weeksb 3 Months 3 months 3 Months 5 Years 24 Weeks 24 Weeksb 3 Monthsa 3 Monthsa 8 Weeksa 8 Weeks a 6 Weeksb 8 Weeks 3 Months 3 Months 2 Years 2 Years 24 Weeks
Hypercholesterolaemia Hypercholesterolaemia Hypercholesterolaemia Hypercholesterolaemia Hypercholesterolaemia Hypercholesterolaemia CHD or high risk Stable angina Stable angina Combined dyslipidaemia Combined dyslipidaemia Combined dyslipidaemia Hypercholesterolaemia Hypercholesterolaemia Hypercholesterolaemia Post MI Primary prevention Secondary prevention Diabetes mellitus Diabetes mellitus Hypercholesterolaemia Hypercholesterolaemia Visceral obesity Renal disease Hypercholesterolaemia CHD FH FH CHD and dyslipidaemia
23 23 23 24 24 24 151 33 72 22 22 22 33 33 33 258 865 1182 39 39 162 623 13 28 33 25 133 135
1.15 1.15 1.15 1.2 1.2 1.2 2.25 2.6 2.6 2.5 2.5 2.5 1.9 2.4 2.3 2.30 2.0 2.7 1.98 1.98 1.8 1.5 2.60 2.3 1.02 1.61 2.0 2.1 ?
/36.4 /59 /63.6 33 41.7 /8.0 /18.7 /7.7 /34.6 /22.8 /28.3 /20.3 0 /20.8 0 /17.4 /16.9 /13.1 /18.2 /37.9 /11.1 /13.1 /30.8 /47.8 /49 /27.3 /19.7 /40.1 0
/51.3 /59.4 /60.6 /47.3 /53.8 /53.2 /45.3 /17.6 /45.9 /30.3 /32.9 /21.7 /37.3 /44.7 /31.2 /32 /21.5 /24.2 /43.4 /48.8 /37.3 /42.2 /52.6 /41 /41 /40 /44.0 /52.6
7.1 8.7 /0.6 11.9 14.1 9.6 9.1 ? 2.3 2.2 0.2 2.5 7.8 4.5 0 ? 6.6 6.5 0.8 /4.2 6.7 8.0 2.8 2.8 7.5 0 13.8 14.3
[1] [1] [1] [1] [1] [1] [3] [4] [4] [5] [5] [5] [6] [6] [6] [6] [8] [8] [9] [9] [10] [10] [11] [12] [13] [13] [14] [14] [15]
a b
Forced titration. Crossover design.
crossover design and two used forced titration. The duration of treatment ranged between 6 weeks and 5 years. Changes in LDL and CRP were expressed as percentage changes from baseline. The reduction in LDL varied from 21.5% (using 40 mg/day of pravastatin) to 60.9% (for 80 mg/day atorvastatin); and the change in CRP ranged from an increase of 41.7% (80 mg/day simvastatin) to a decrease of 63.6% (for 80 mg/ day atorvastatin). There was a significant log-linear relationship between dose of atorvastatin and CRP reduction (r2 / 0.69, P B/0.01) (Fig. 1) and a linear relationship between %LDL reduction and %CRP reduction (r2 /0.67, P B/ 0.01), but this was not observed for simvastatin (P / 0.05), nor for the pooled data from all statins. Although comparative data for the effects of the different statins on serum CRP levels are very limited, it appears that they may differ in their potency; that the response, at least to atorvastatin, is dose /dependent and related to the reduction in LDL achieved. In patients with elevated levels of CRP it may be necessary to use a higher dose of statin than required to attain the target LDL-cholesterol concentration, for an
optimal anti-inflammatory/plaque stabilising effect; and this may vary between the currently available statins.
References [1] Wiklund O, Mattsson-Hulten L, Hurt-Camejo E, Oscarsson J. Effects of simvastatin and atorvastatin on inflammation markers in plasma. J Int Med 2002;251:338 /47. [2] Koh KK. Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability. Cardiovasc Res 2000;47:648 / 57. [3] Riesen WF, Engler H, Risch M, Korte W, Noseda G. Short-term effects of atorvastatin on C-reactive protein. Eur Heart J 2002;23:794 /9. [4] Kinley S, Timms T, Clark M, et al. Comparison of effect of intensive lipid lowering with atorvastatin to less intensive lowering with lovastatin on C-reactive protein in patients with stable angina pectoris and inducible myocardial ischemia. Am J Cardiol 2002;89:1205 /7. [5] Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S. Effects of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitivity C-reactive protein levels. Circulation 2001;103:1933 /5. [6] Joukhadar C, Klein N, Prinz M, et al. Similar effects of atorvastatin, simvastatin and pravastatin on thrombogenic and
Letter to the Editor
[7]
[8]
[9]
[10]
[11]
[12]
[13]
inflammatory parameters in patients with hypercholesterolemia. Thromb Haemost 2000;85:47 /51. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Longterm effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999;100:230 /5. Albert MA, Danielson E, Rifai N, Ridker PM. 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 /70. Tan KCB, Chow WS, Tam SCF, Ai VHG, Lam CHL, Lam KSL. Atorastatin lowers-reactive protein and improves endothelium dependent vasodilation in type2 diabetes mellitus. J Clin Endocrinol Metab 2002;87:563 /8. Ridker PM, Rifai N, Pitman Lowenthal S. Rapid reduction in Creactive protein with cerivastatin among 785 patients with primary hypercholesterolaemia. Circulation 2001;103:1191 /3. Chan DC, Watts GF, Barrett PHR, Beilin LJ, Mori TA. Effect of atorvastatin and fish oil on plasma high-sensitivity C-reactive protein concentrations in individuals with visceral obesity. Clin Chem 2002;48:877 /83. Chang JW, Yang WS, Min WK, Lee SK, Park JS, Kim SB. Effects of simvastatin on high-sensitivity C-reactive protein and serum albumin in hemodialysis patients. Am J Kidney Dis 2002;39:1213 /7. Musial J, Undas A, Gajewski P, Jankowski M, Sydor W, Szczeklik A. Ant-inflammatory effects of simvastatin in subjects with hypercholesterolaemia. Int J Cardiol 2001;77:247 /53.
351
[14] van Weissen S, Trip MD, Smilde TJ, deGraaf J, Stalenhoef AF, Kastelwin JJ. Differential hs-CRP reduction in patients with familial hypercholesterolaemia treated with aggressive or conventional statin therapy. Atherosclerosis 2002;165:361 /6. [15] Cortellaro M, Cofrancesco E, Boschetti C, et al. Effects of fluvastatin and bezafibrate combination on plasma fibrinogen, t -plasminogen activator inhibitor and C reactive protein levels in coronary artery disease patients with mixed hyperlipidaemia (FACT study). Thromb Haemost 2000;83:549 /53.
Received 1 May 2003; accepted 9 May 2003 Gordon A.A. Ferns * School of Biomedical and Molecular Science, University of Surrey, Guildford, Surrey GU2 5XH, UK Department of Clinical Biochemistry, Royal Surrey County Hospital, Egerton Road, Guildford, Surrey GU2 5XX, UK E-mail address: [email protected]