1/3 LETTER TO THE EDITOR

Statins, renal function and homocysteine A letter related to “Intensive statin therapy used alone or in combination with ezetimibe, improves homocysteine level and lipid peroxidation to a similar degree in patients with coronary artery diseases” Vasilios G. Athyros1, Niki Katsiki1, Dimitri P Mikhailidis2 1

Second Propedeutic Department of Internal Medicine, Medical School, Aristotle

University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece 2

Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal Free

Hospital Campus, University College London Medical School, University College London (UCL), London, UK

This Letter was written independently; no company or institution supported the authors financially or by providing a professional writer. VGA has given talks, attended conferences and participated in trials sponsored by MSD, Sanofi, and Amgen; DPM has given talks and attended conferences sponsored by MSD, AstraZeneca and Libytec; NK has given talks, attended conferences and

participated in trials sponsored by for MSD, Novartis, Amgen, Sanofi, Novo Nordisk and Libytec.

CORRESPONDING AUTHOR: DP Mikhailidis BSc MSc MD FCP FRSPH FFPM FRCP FRCPath Academic Head of Dept. Dept. of Clinical Biochemistry (Vascular Disease Prevention Clinics) Royal Free Hospital campus, University College London Medical School

2/3 University College London (UCL), Pond Street, London NW3 2QG, UK Tel: 0044 (0) 20 7830 2258 Fax: 0044 (0) 20 7830 2235 e-mail: [email protected] Pytel et al. [1] report significantly higher levels of homocysteine (Hcy) and lipid peroxidation in coronary artery disease (CAD) patients with a low density lipoprotein cholesterol (LDL-C) >70 mg/dl compared with healthy volunteers. Intensive lipid-lowering therapy [rosuvastatin (R) or atorvastatin (A), or atorvastatin+ezetimibe (A+E) combination therapy] decreased Hcy levels, lipid peroxidation and LDL-C levels [1]. Investigation of changes in renal function in the Pytel et al. study [1] would be of interest given that circulating Hcy levels rise with impaired kidney function [2]. It has been shown that patients with early chronic kidney disease (CKD) benefit from high potency statins [3]. This was shown 12 years ago in a post hoc analysis of a statin survival study [4] and was verified by a larger worldwide study with atorvastatin [5]. In both studies [4,5] CAD patients exhibited an improvement of renal function, especially those with stage 3 CKD and those on a high atorvastatin dose. These patients also had nearly a double CAD risk reduction compared with those with normal renal function [4,5]. These results were reproduced in patients with diabetes [6] or metabolic syndrome [7,8] taking atorvastatin. Also, ezetimibe added to a statin may improve kidney function [9,10]. Finally, the SHARP study in patients with CKD (on or before dialysis) showed a significant decrease in vascular events with the simvastatin + ezetimibe combination compared with placebo [11]. However, the effect of statin treatment on Hcy was not investigated in these studies, and lowering circulating Hcy levels might be involved in CKD improvement and CAD risk reduction. High Hcy levels contribute to the development of glomerular sclerosis similar to that of atherosclerosis [12]. Understanding these mechanisms may contribute to designing new approaches for the treatment of any damage [13] due to high serum Hcy levels.

3/3 References [1] Pytel E, Jackowska P, Chwatko G, Olszewska-Banaszczyk M, Koter-Michalak M, Kubalczyk P, et al. Intensive statin therapy, used alone or in combination with ezetimibe, improves homocysteine level and lipid peroxidation to a similar degree in patients with coronary artery diseases. Pharmacol Rep 2016;68:344-8. [2] Tak YJ, Jeong DW, Kim YJ, Lee SY, Lee JG, Song SH, Cha KS, Kang YH. Hyperhomocysteinaemia as a potential marker of early renal function decline in middleaged Asian people without chronic kidney disease. Int Urol Nephrol 2016;48:239-48 [3] Athyros VG, Katsiki N, Karagiannis A, Mikhailidis DP. Statins can improve proteinuria and glomerular filtration rate loss in chronic kidney disease patients, further reducing cardiovascular risk. Fact or fiction? Expert Opin Pharmacother 2015;16:1449-61. [4] Athyros VG, Mikhailidis DP, Papageorgiou AA, Symeonidis AN, Pehlivanidis AN, Bouloukos VI, et al. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study. J Clin Pathol 2004;57:728-34. [5] Shepherd J, Breazna A, Deedwania PC, LaRosa JC, Wenger NK, Messig M, et al; Treating to New Targets Steering Committee and Investigators. Relation Between Change in Renal Function and Cardiovascular Outcomes in Atorvastatin-Treated Patients (from the Treating to New Targets [TNT] Study). Am J Cardiol 2016 Jan 28. pii: S00029149(16)30136-9. [6] Athyros VG, Papageorgiou AA, Elisaf M, Mikhailidis DP; GREACE Study Collaborative Group. Statins and renal function in patients with diabetes mellitus. Curr Med Res Opin 2003;19:615-7.

4/3 [7] Athyros VG, Mikhailidis DP, Liberopoulos EN, Kakafika AI, Karagiannis A, Papageorgiou AA, et al. Effect of statin treatment on renal function and serum uric acid levels and their relation to vascular events in patients with coronary heart disease and metabolic syndrome: a subgroup analysis of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study. Nephrol Dial Transplant 2007;22:118-27. [8] Athyros VG, Hatzitolios AI, Karagiannis A, Savopoulos C, Katsiki N, Tziomalos K, et al; IMPERATIVE Collaborative Group. IMproving the imPlemEntation of cuRrent guidelines for the mAnagement of major coronary hearT disease rIsk factors by multifactorial interVEntion. The IMPERATIVE renal analysis. Arch Med Sci 2011;7:984-92. [9] Migdalis I, Efthimiadis A, Pappas S, Alexopoulos D, Vlasserou F, Mikhailidis DP. Clinical experience with ezetimibe/simvastatin in a Mediterranean population. Curr Med Res Opin. 2009;25:2571-6. [10] Gazi IF, Daskalopoulou SS, Nair DR, Mikhailidis DP. Effect of ezetimibe in patients who cannot tolerate statins or cannot get to the low density lipoprotein cholesterol target despite taking a statin. Curr Med Res Opin. 2007;23:2183-92. [11] Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al; SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011;377:2181-92. [12] Yi F, Li PL. Mechanisms of homocysteine-induced glomerular injury and sclerosis. Am J Nephrol 2008;28:254-64. [13] Wejksza K, Rzeski W, Turski WA. Kynurenic acid protects against the homocysteineinduced impairment of endothelial cells. Pharmacol Rep 2009;61:751-6.

5/3 Vasilios G. Athyros, Niki Katsiki, Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece Dimitri P Mikhailidis Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, UK