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High-intensity statin monotherapy versus moderate-intensity statin plus ezetimibe therapy: Effects on vascular biomarkers
International Journal of Cardiology 180 (2015) 78–79
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the editor
High-intensity statin monotherapy versus moderate-intensity statin plus ezetimibe therapy: Effects on vascular biomarkers C.E.S. Ferreira a,b,1, C.N. França a,1, M.C.O. Izar a, L.M. Camargo a, R.M. Roman c, F.A.H. Fonseca a,⁎ a b c
Department of Medicine, Cardiology Division, Federal University of Sao Paulo, Sao Paulo, Brazil Albert Einstein Israeli Hospital, Sao Paulo, Brazil Federal University of Rio Grande do Sul, Porto Alegre, Brazil
a r t i c l e
i n f o
Article history: Received 26 October 2014 Accepted 23 November 2014 Available online 26 November 2014 Keywords: Biomarkers Atherosclerosis Lipids Endothelial microparticles
Intensive LDL-cholesterol lowering has been proposed to decrease cardiovascular events. However, some effects on vascular biology may explain part of statin benefits, and are less reported with other lipid lowering therapies [1,2]. This study aimed to compare the effects of atorvastatin 80 mg with atorvastatin 20 mg plus ezetimibe 10 mg on cardiovascular biomarkers. The trial included high-risk subjects of both genders (n = 75), aging 35–80 years. Subjects were initially treated with atorvastatin 10 mg for 30 days. After this period, blood samples were collected and the subjects were randomized into two groups (atorvastatin 80 mg or atorvastatin 20 mg plus ezetimibe 10 mg). The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by our institution's human research committee. Written informed consent was obtained from all participants. Lipids were measured by enzymatic kinetics, the cholesterol content of small dense LDL particles tested by microparticle immunoassay (Singulex-Erenna®, Singulex). Myeloperoxidase plasma
levels were quantified by immunoassay (Dimension RXL Max®, Siemens); troponin I (3rd generation), interleukin 6, interleukin 17A, and TNF-alpha by microparticle immunoassay (Singulex-Erenna®, Singulex), NT-proBNP by chemiluminescence, and hsCRP by turbidimetry (Fusion 5600®, Ortho Diagnostics). Endothelial progenitor cells (EPC), and endothelial microparticles (EMP) were quantified by flow cytometry [3–5]. After 30 days of therapy with atorvastatin 10 mg, lipids and lipoproteins were similar in the two study arms. However, despite similar decrease in LDL-cholesterol after 6-months of therapy, only subjects treated with atorvastatin 80 mg decreased apolipoprotein B levels and cholesterol content of small-dense LDL particles (Table 1). No changes were observed on several inflammatory biomarkers, but myeloperoxidase increased with both therapies, whereas NT-proBNP levels augmented in those subjects treated with atorvastatin 80 mg. Therapies did not change EPC (%), but EMP increased with the combined therapy (Fig. 1). Thus, despite similar decrease in LDL-cholesterol, there were interesting differences in the lipoprotein pattern and in the amount of EMP. The effect of statins on myeloperoxidase levels is controversial [6,7], but seems related to the intensity and time of exposure [8]. We found a small increase in the NT-proBNP levels in the atorvastatin 80 mg arm, while troponin levels remained unchanged. Indeed, studies have shown decreased benefit from statins in subjects with high levels of these biomarkers [9,10]. Summarizing, despite similar LDL-C reduction, subjects treated with high-dose statin monotherapy presented more favorable effects in vascular biomarkers than those seen when atorvastatin was combined with ezetimibe. This study was supported by a grant from the Research Foundation of the State of Sao Paulo (FAPESP) (Grant # 573560/2008-0). The Albert Einstein Israeli Hospital of Sao Paulo supported and performed all laboratory assays.
Disclosures ⁎ Corresponding author at: Disciplina de Cardiologia, Universidade Federal de São Paulo, Rua Pedro de Toledo, 276, São Paulo, CEP: 04039-030 SP, Brasil. E-mail address: [email protected] (F.A.H. Fonseca). 1 Dr. Ferreira and Dr. França contributed equality to this study.
http://dx.doi.org/10.1016/j.ijcard.2014.11.177 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Fonseca FA: Consultant and speaker for MSD, Astra Zeneca, Bayer, Amgen, Novartis, Novo Nordisk, Ache, Biolab, Abbott, and EMS. Izar MC: Consultant and speaker for Abbott, Genzyme, and Aegerion; speaker for MSD, Amgen, Aegerion, Ache, Biolab. Other authors: None.
C.E.S. Ferreira et al. / International Journal of Cardiology 180 (2015) 78–79
79
Table 1 Baseline and final laboratory parameters of each study group. ATV baseline
ATV final
ATV/EZE baseline
ATV/EZE final
p value
Total cholesterola LDL-Ca HDL-Ca Triglyceridesa Apo Ba sdLDLa Troponin Ib IL-6b IL-17Ab TNF-alphab NT-proBNPb Myeloperoxidasec hsCRPd
163 (7) 84 (7) 48 (2) 156 (15) 85 (5) 31 (3) 1.8 (0.4) 4.1 (1.7) 0.9 (0.1) 1.9 (0.2) 136 (52) 339 (22) 1.4 (0.5–3.7)
140 (7) 65 (6) 49 (2) 129 (13) 69 (5) 24 (3) 1.8 (0.5) 2.4 (0.3) 1.0 (0.1) 2.5 (0.4) 188 (71) 697 (66) 1.0 (0.5–2.2)
176 (7) 91 (6) 54 (2) 154 (12) 83 (3) 31 (2) 1.3 (0.3) 2.1 (0.3) 1.1 (0.3) 1.6 (0.1) 116 (32) 373 (39) 1.1 (0,7–2.1)
143 (6) 68 (5) 53 (2) 112 (7) 68 (5) 26 (4) 1.0 (0.2) 1.7 (0.2) 1.1 (0.2) 1.5 (0.2) 189 (98) 630 (65) 1.3 (0.5–2.5)
b0.001e b0.001e ns 0.002e 0.005f 0.006f ns ns ns ns 0.04f 0.0001e ns
EPC, % CD34+/KDR+ CD34+/CD133+ CD133+/KDR+
0.25 (0.06) 0.03 (0.02) 0.07 (0.05)
0.21 (0.07) 0.03 (0.01) 0.20 (0.14)
0.13 (0.03) 0.03 (0.01) 0.02 (0.01)
0.21 (0.07) 0.03 (0.01) 0.03 (0.02)
ns ns ns
Values are mean (SE) or median (IQR). ATV = atorvastatin 80 mg; ATV/EZE = atorvastatin 20 mg plus ezetimibe 10 mg; sdLDL = small dense cholesterol content of LDL; TNF-alpha = tumor necrosis factor alpha; NT-proBNP — N terminal pro-brain natriuretic peptide; IL = interleukin; hsCRP = high sensitivity C-reactive protein; EPC — endothelial progenitor cells. a mg/dL. b pg/mL. c pmol/mL. d mg/L, median (IQR). e Paired t-test final vs. baseline for both groups of treatment. f Paired t-test final vs. baseline for atorvastatin 80 mg group.
References
Fig. 1. Number of endothelial microparticles (EMC) after six months of therapies. ATV — atorvastatin 80 mg; ATV/EZE — atorvastatin 20 mg plus ezetimibe 10 mg; ⁎p = 0.005 (Wilcoxon test).
Conflicts of interest The authors report no relationships that could be construed as a conflict of interest.
[1] S.P. Barbosa, L.C. Lins, F.A. Fonseca, et al., Effects of ezetimibe on markers of synthesis and absorption of cholesterol in high-risk patients with elevated C-reactive protein, Life Sci. 92 (2013) 845–851. [2] S.H. Kasmas, M.C. Izar, C.N. França, et al., Differences in synthesis and absorption of cholesterol of two effective lipid-lowering therapies, Braz. J. Med. Biol. Res. 45 (2012) 1095–1101. [3] E.F. da Silva, F.A. Fonseca, C.N. França, et al., Imbalance between endothelial progenitors cells and microparticles in HIV-infected patients naive for antiretroviral therapy, AIDS 25 (2011) 1595–1601. [4] L.F. Pinheiro, C.N. França, M.C. Izar, et al., Pharmacokinetic interactions between clopidogrel and rosuvastatin: effects on vascular protection in subjects with coronary heart disease, Int. J. Cardiol. 158 (2012) 125–129. [5] C.N. França, L.F. Pinheiro, M.C. Izar, et al., Endothelial progenitor cell mobilization and platelet microparticle release are influenced by clopidogrel plasma levels in stable coronary artery disease, Circ. J. 76 (2012) 729–736. [6] S. Sugiyama, Y. Okada, G.K. Sukhova, R. Virmani, J.W. Heinecke, P. Libby, Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes, Am. J. Pathol. 158 (2001) 879–891. [7] R.M. Roman, P.V. Camargo, F.K. Borges, A.P. Rossini, C.A. Polanczyk, Prognostic value of myeloperoxidase in coronary artery disease: comparison of unstable and stable angina patients, Coron. Artery Dis. 21 (2010) 129–136. [8] M.C. Meuwese, M.D. Trip, S. van Wissen, J.N. van Miert, J.J. Kastelein, E.S. Stroes, Myeloperoxidase levels are not associated with carotid atherosclerosis progression in patients with familial hypercholesterolemia, Atherosclerosis 197 (2008) 916–921. [9] J.G. Cleland, J.J. McMurray, J. Kjekshus, et al., Plasma concentration of aminoterminal pro-brain natriuretic peptide in chronic heart failure: prediction of cardiovascular events and interaction with the effects of rosuvastatin. A report from CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure), J. Am. Coll. Cardiol. 54 (2009) 1850–1859. [10] J.G. Cleland, K. Hutchinson, P. Pellicori, A. Clark, Lipid-modifying treatments for heart failure: is their use justified? Heart Fail Clin. 10 (2014) 621–634.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the editor
High-intensity statin monotherapy versus moderate-intensity statin plus ezetimibe therapy: Effects on vascular biomarkers C.E.S. Ferreira a,b,1, C.N. França a,1, M.C.O. Izar a, L.M. Camargo a, R.M. Roman c, F.A.H. Fonseca a,⁎ a b c
Department of Medicine, Cardiology Division, Federal University of Sao Paulo, Sao Paulo, Brazil Albert Einstein Israeli Hospital, Sao Paulo, Brazil Federal University of Rio Grande do Sul, Porto Alegre, Brazil
a r t i c l e
i n f o
Article history: Received 26 October 2014 Accepted 23 November 2014 Available online 26 November 2014 Keywords: Biomarkers Atherosclerosis Lipids Endothelial microparticles
Intensive LDL-cholesterol lowering has been proposed to decrease cardiovascular events. However, some effects on vascular biology may explain part of statin benefits, and are less reported with other lipid lowering therapies [1,2]. This study aimed to compare the effects of atorvastatin 80 mg with atorvastatin 20 mg plus ezetimibe 10 mg on cardiovascular biomarkers. The trial included high-risk subjects of both genders (n = 75), aging 35–80 years. Subjects were initially treated with atorvastatin 10 mg for 30 days. After this period, blood samples were collected and the subjects were randomized into two groups (atorvastatin 80 mg or atorvastatin 20 mg plus ezetimibe 10 mg). The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by our institution's human research committee. Written informed consent was obtained from all participants. Lipids were measured by enzymatic kinetics, the cholesterol content of small dense LDL particles tested by microparticle immunoassay (Singulex-Erenna®, Singulex). Myeloperoxidase plasma
levels were quantified by immunoassay (Dimension RXL Max®, Siemens); troponin I (3rd generation), interleukin 6, interleukin 17A, and TNF-alpha by microparticle immunoassay (Singulex-Erenna®, Singulex), NT-proBNP by chemiluminescence, and hsCRP by turbidimetry (Fusion 5600®, Ortho Diagnostics). Endothelial progenitor cells (EPC), and endothelial microparticles (EMP) were quantified by flow cytometry [3–5]. After 30 days of therapy with atorvastatin 10 mg, lipids and lipoproteins were similar in the two study arms. However, despite similar decrease in LDL-cholesterol after 6-months of therapy, only subjects treated with atorvastatin 80 mg decreased apolipoprotein B levels and cholesterol content of small-dense LDL particles (Table 1). No changes were observed on several inflammatory biomarkers, but myeloperoxidase increased with both therapies, whereas NT-proBNP levels augmented in those subjects treated with atorvastatin 80 mg. Therapies did not change EPC (%), but EMP increased with the combined therapy (Fig. 1). Thus, despite similar decrease in LDL-cholesterol, there were interesting differences in the lipoprotein pattern and in the amount of EMP. The effect of statins on myeloperoxidase levels is controversial [6,7], but seems related to the intensity and time of exposure [8]. We found a small increase in the NT-proBNP levels in the atorvastatin 80 mg arm, while troponin levels remained unchanged. Indeed, studies have shown decreased benefit from statins in subjects with high levels of these biomarkers [9,10]. Summarizing, despite similar LDL-C reduction, subjects treated with high-dose statin monotherapy presented more favorable effects in vascular biomarkers than those seen when atorvastatin was combined with ezetimibe. This study was supported by a grant from the Research Foundation of the State of Sao Paulo (FAPESP) (Grant # 573560/2008-0). The Albert Einstein Israeli Hospital of Sao Paulo supported and performed all laboratory assays.
Disclosures ⁎ Corresponding author at: Disciplina de Cardiologia, Universidade Federal de São Paulo, Rua Pedro de Toledo, 276, São Paulo, CEP: 04039-030 SP, Brasil. E-mail address: [email protected] (F.A.H. Fonseca). 1 Dr. Ferreira and Dr. França contributed equality to this study.
http://dx.doi.org/10.1016/j.ijcard.2014.11.177 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Fonseca FA: Consultant and speaker for MSD, Astra Zeneca, Bayer, Amgen, Novartis, Novo Nordisk, Ache, Biolab, Abbott, and EMS. Izar MC: Consultant and speaker for Abbott, Genzyme, and Aegerion; speaker for MSD, Amgen, Aegerion, Ache, Biolab. Other authors: None.
C.E.S. Ferreira et al. / International Journal of Cardiology 180 (2015) 78–79
79
Table 1 Baseline and final laboratory parameters of each study group. ATV baseline
ATV final
ATV/EZE baseline
ATV/EZE final
p value
Total cholesterola LDL-Ca HDL-Ca Triglyceridesa Apo Ba sdLDLa Troponin Ib IL-6b IL-17Ab TNF-alphab NT-proBNPb Myeloperoxidasec hsCRPd
163 (7) 84 (7) 48 (2) 156 (15) 85 (5) 31 (3) 1.8 (0.4) 4.1 (1.7) 0.9 (0.1) 1.9 (0.2) 136 (52) 339 (22) 1.4 (0.5–3.7)
140 (7) 65 (6) 49 (2) 129 (13) 69 (5) 24 (3) 1.8 (0.5) 2.4 (0.3) 1.0 (0.1) 2.5 (0.4) 188 (71) 697 (66) 1.0 (0.5–2.2)
176 (7) 91 (6) 54 (2) 154 (12) 83 (3) 31 (2) 1.3 (0.3) 2.1 (0.3) 1.1 (0.3) 1.6 (0.1) 116 (32) 373 (39) 1.1 (0,7–2.1)
143 (6) 68 (5) 53 (2) 112 (7) 68 (5) 26 (4) 1.0 (0.2) 1.7 (0.2) 1.1 (0.2) 1.5 (0.2) 189 (98) 630 (65) 1.3 (0.5–2.5)
b0.001e b0.001e ns 0.002e 0.005f 0.006f ns ns ns ns 0.04f 0.0001e ns
EPC, % CD34+/KDR+ CD34+/CD133+ CD133+/KDR+
0.25 (0.06) 0.03 (0.02) 0.07 (0.05)
0.21 (0.07) 0.03 (0.01) 0.20 (0.14)
0.13 (0.03) 0.03 (0.01) 0.02 (0.01)
0.21 (0.07) 0.03 (0.01) 0.03 (0.02)
ns ns ns
Values are mean (SE) or median (IQR). ATV = atorvastatin 80 mg; ATV/EZE = atorvastatin 20 mg plus ezetimibe 10 mg; sdLDL = small dense cholesterol content of LDL; TNF-alpha = tumor necrosis factor alpha; NT-proBNP — N terminal pro-brain natriuretic peptide; IL = interleukin; hsCRP = high sensitivity C-reactive protein; EPC — endothelial progenitor cells. a mg/dL. b pg/mL. c pmol/mL. d mg/L, median (IQR). e Paired t-test final vs. baseline for both groups of treatment. f Paired t-test final vs. baseline for atorvastatin 80 mg group.
References
Fig. 1. Number of endothelial microparticles (EMC) after six months of therapies. ATV — atorvastatin 80 mg; ATV/EZE — atorvastatin 20 mg plus ezetimibe 10 mg; ⁎p = 0.005 (Wilcoxon test).
Conflicts of interest The authors report no relationships that could be construed as a conflict of interest.
[1] S.P. Barbosa, L.C. Lins, F.A. Fonseca, et al., Effects of ezetimibe on markers of synthesis and absorption of cholesterol in high-risk patients with elevated C-reactive protein, Life Sci. 92 (2013) 845–851. [2] S.H. Kasmas, M.C. Izar, C.N. França, et al., Differences in synthesis and absorption of cholesterol of two effective lipid-lowering therapies, Braz. J. Med. Biol. Res. 45 (2012) 1095–1101. [3] E.F. da Silva, F.A. Fonseca, C.N. França, et al., Imbalance between endothelial progenitors cells and microparticles in HIV-infected patients naive for antiretroviral therapy, AIDS 25 (2011) 1595–1601. [4] L.F. Pinheiro, C.N. França, M.C. Izar, et al., Pharmacokinetic interactions between clopidogrel and rosuvastatin: effects on vascular protection in subjects with coronary heart disease, Int. J. Cardiol. 158 (2012) 125–129. [5] C.N. França, L.F. Pinheiro, M.C. Izar, et al., Endothelial progenitor cell mobilization and platelet microparticle release are influenced by clopidogrel plasma levels in stable coronary artery disease, Circ. J. 76 (2012) 729–736. [6] S. Sugiyama, Y. Okada, G.K. Sukhova, R. Virmani, J.W. Heinecke, P. Libby, Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes, Am. J. Pathol. 158 (2001) 879–891. [7] R.M. Roman, P.V. Camargo, F.K. Borges, A.P. Rossini, C.A. Polanczyk, Prognostic value of myeloperoxidase in coronary artery disease: comparison of unstable and stable angina patients, Coron. Artery Dis. 21 (2010) 129–136. [8] M.C. Meuwese, M.D. Trip, S. van Wissen, J.N. van Miert, J.J. Kastelein, E.S. Stroes, Myeloperoxidase levels are not associated with carotid atherosclerosis progression in patients with familial hypercholesterolemia, Atherosclerosis 197 (2008) 916–921. [9] J.G. Cleland, J.J. McMurray, J. Kjekshus, et al., Plasma concentration of aminoterminal pro-brain natriuretic peptide in chronic heart failure: prediction of cardiovascular events and interaction with the effects of rosuvastatin. A report from CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure), J. Am. Coll. Cardiol. 54 (2009) 1850–1859. [10] J.G. Cleland, K. Hutchinson, P. Pellicori, A. Clark, Lipid-modifying treatments for heart failure: is their use justified? Heart Fail Clin. 10 (2014) 621–634.