Abstract
Background:
Statins represent a group of drugs that are currently indicated in the primary and secondary prevention of cardiovascular events. Their administration can be associated with side effects and the insufficient reduction of triacylglyceride (TAG) levels. This study aimed to assess the effect of the triple combination of statins with omega-3 fatty acids and coenzyme Q10 (CoQ10) on parameters associated with atherogenesis and statin side effects.
Methods:
In this pilot randomized double-blind trial, 105 subjects who met the criteria of combined dislipidemia and elevated TAG levels were randomly divided into three groups. In the control group, unaltered statin therapy was indicated. In the second and third groups, omega-3 PUFA 2.52 g/day (Zennix fa Pleuran) and omega-3 PUFA 2.52 g+CoQ10 200 mg/day (Pharma Nord ApS) were added, res//. At the end of the 3-month period (±1 week), all patients were evaluated.
Results:
Significant reduction of hepatic enzymes activity, systolic blood preasure, inflammatory markers and TAG levels were detected in both groups in comparison to the control group. Activity of SOD and GPx increased significantly after additive therapy. Coenzyme Q10 addition significantly reduced most of the abovementioned parameters (systolic blood preasure, total cholesterol, LDL, hsCRP, IL-6, SOD) in comparison with the statin+omega-3 PUFA group. The intensity of statin adverse effects were significantly reduced in the group with the addition of CoQ10.
Conclusions:
The results of this pilot study suggest the possible beneficial effects of triple combination on the lipid and non-lipid parameters related to atherogenesis and side effects of statin treatment.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: This study was entirely funded by PROBIO ITMS No.26220220104.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Beignet C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Cholesterol Treatment Trialists’ (CTT) Collaborators (2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–78.10.1016/S0140-6736(05)67394-1Search in Google Scholar
2. Shanes JG, Minadeo KN, Moret A, Groner M, Tabaie SA. Statin therapy in heart failure: prognostic effects and potential mechanisms. Am Heart J 2007;154:617–23.10.1016/j.ahj.2007.05.020Search in Google Scholar
3. Schuster H, Fox JC. Investigating cardiovascular risk reduction–the Rosuvastatin GALAXY Programme. Expert Opin Pharmacother 2004;5:1187–200.10.1517/14656566.5.5.1187Search in Google Scholar
4. Chan DC, Watts GF. Dyslipidaemia in the metabolic syndrome and type 2 diabetes: pathogenesis, priorities, pharmacotherapies. Expert Opin Pharma-cother 2011;12:13–30.10.1517/14656566.2010.502529Search in Google Scholar
5. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk 1997;3:213–19.10.1097/00043798-199604000-00014Search in Google Scholar
6. Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G, Wareham N, Bingham S, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation 2007;115:450–8.10.1161/CIRCULATIONAHA.106.637793Search in Google Scholar
7. Schulte H, Cullen P, Assmann G. Obesity, mortality and cardiovascular disease in the Münster Heart Study (PROCAM). Atherosclerosis 1999;144:199–209.10.1016/S0021-9150(99)00055-6Search in Google Scholar
8. Newman JW, Pedersen TL, Brandenburg VR, Harris WS, Shearer GC. Effect of omega-3 fatty acid ethyl esters on the oxylipin composition of lipoproteins in hypertriglyceridemic, statin-treated subjects. PLoS One 2014;9:e111471.10.1371/journal.pone.0111471Search in Google Scholar PubMed PubMed Central
9. Foran JA, Carpenter DO, Hamilton MC, Knuth BA, Schwager SJ. Risk-based consumption advice for farmed Atlantic and wild Pacific salmon contaminated with dioxins and dioxin-like compounds, Environ. Health Perspect 2005;113:552–556.10.1289/ehp.7626Search in Google Scholar PubMed PubMed Central
10. Lim S, Barter P. Antioxidant effects of statins in the management of cardiometabolic disorders. J Atheroscler Thromb 2010;21:997–1010.10.5551/jat.24398Search in Google Scholar PubMed
11. Cao J, Schwichtenberg KA, Hanson NQ, Tsai MY. Incorporation and clearance of omega-3 fatty acids in erythrocyte membranes and plasma phospholipids. Clin Chem 2006;52:2265–72.10.1373/clinchem.2006.072322Search in Google Scholar PubMed
12. Rudkowska I, Caron-Dorval D, Verreault M, Couture P, Deshaies Y, Barbier O, et al. PPARalpha L162V polymorphism alters the potential of n-3 fatty acids to increase lipoprotein lipaseactivity. Mol Nutr Food Res 2010;54:543–50.10.1002/mnfr.200900085Search in Google Scholar PubMed
13. Marai I, Massalha S. Effect of omega-3 polyunsaturated fatty acids and vitamin D on cardiovascular diseases. Isr Med Assoc J 2014;16:117–21.Search in Google Scholar
14. Maresta A, Balduccelli M, Varani E, Marzilli M, Galli C, Heiman F, et al. Prevention of postcoronary angioplasty restenosis by omega-3 fatty acids: main results of the Esapent for Prevention of Restenosis Italian Study (ESPRIT). Am Heart J 2002;143:E5.10.1067/mhj.2002.121805Search in Google Scholar PubMed
15. Harris WS. n-3 fatty acids and serum lipoproteins: human studies. Am J Clin Nutr 1997;65:1645–54.10.1093/ajcn/65.5.1645SSearch in Google Scholar
16. Littlefield N, Beckstrand RL, Luthy KE. Statins’ effect on plasma levels of Coenzyme Q10 and improvement in myopathy with supplementation. J Am Assoc Nurse Pract 2014;26:85–90.10.1002/2327-6924.12046Search in Google Scholar
17. Wyman M, Leonard M, Morledge T. Coenzyme Q10: a therapy for hypertension and statin–induced myalgia? Cleve Clin J Med 2010;77:435–42.10.3949/ccjm.77a.09078Search in Google Scholar
18. Fitzgerald JP. Comparative analysis of superoxide dismutase activities in a range of temperate and tropical teleost fish. Comp Biochem Physiol 1992;101:111–14.10.1016/0305-0491(92)90166-OSearch in Google Scholar
19. Macchia A, Romero M, D’Ettorre A, Tognoni G, Mariani J. Exploratory analysis on the use of statins with or without n-3 PUFA and major events in patients dis–charged for acute myocardial infarction: an observational retrospective study. PLoSOne 2013;8:e62772.10.1371/journal.pone.0062772Search in Google Scholar
20. Nambi V, Ballantyne CM. Combination therapy with statins and omega-3 fatty acids. Am J Cardiol 2006;98:34–8.10.1016/j.amjcard.2005.12.025Search in Google Scholar
21. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090–8.10.1016/S0140-6736(07)60527-3Search in Google Scholar
22. Davidson MH, Stein EA, Bays HE, Maki KC, Doyle RT, Shalwitz RA, et al. COMBination of prescription Omega-3 with Simvastatin (COMBOS) Investigators Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study. Clin Ther 2007;29:1354–67.10.1016/j.clinthera.2007.07.018Search in Google Scholar PubMed
23. Levy Y. Beyond cholesterol lowering: effect of statins on markers of cardiovascular disease. Isr Med Assoc J 2004;6:490–91.Search in Google Scholar
24. Schmelzer C, Niklowitz P, Okun JG, Haas D, Menke T, Döring F. Ubiquinol–induced gene expression signatures are translated into altered parameters of erythropoiesis and reduced low density lipoprotein cholesterol levels in humans. IUBMB Life 2011;64:42–8.10.1002/iub.413Search in Google Scholar PubMed
25. Mabuchi H, Nohara A, Kobayashi J, Kawashiri MA, Katsuda S, Inazu A, et al. Effects of CoQ10 supplementation on plasma lipoprotein lipid, CoQ10 and liver and muscle enzyme levels in hypercholesterolemic patients treated with atorvastatin: a randomized double-blind study. Atherosclerosis 2007;195:182–9.10.1016/j.atherosclerosis.2007.06.010Search in Google Scholar PubMed
26. Garrido-Maraver J, Cordero MD, Oropesa-Ávila M, Fernández Vega A, de la Mata M, Delgado Pavón A, et al. Coenzyme q10 therapy. Mol Syndromol 2014;5:187–97.10.1159/000360101Search in Google Scholar PubMed PubMed Central
27. Fedacko J, Pella D, Fedackova P, Hänninen O, Tuomainen P, Jarcuska P, et al. Coenzyme Q(10) and selenium in statin-associated myopathy treatment. Can J Physiol Pharmacol 2013;91:165–70.10.1139/cjpp-2012-0118Search in Google Scholar PubMed
28. Ansell BJ, Watson KE, Weiss RE, Fonarow GC. hsCRP and HDL effects of statins trial (CHEST): rapid effect of statin therapy on C-reactive protein and high-density lipoprotein levels A clinical investigation. Heart Dis 2003;5:2–7.10.1097/01.HDX.0000050407.62572.DESearch in Google Scholar
29. Du B, Xu G, Cao H, Cui W, Lin S, Liu Y, et al. Effects of atorvastatin on expression of ICAM-1 in atherosclerotic rabbits. J Cardiovasc Med 2013;14:120–26.10.2459/JCM.0b013e3283541fcaSearch in Google Scholar
30. Ylä-Herttuala S, Bentzon JF, Daemen M, Falk E, Garcia-Garcia HM, Herrmann J, et al. Stabilization of atherosclerotic plaques: an update. Eur Heart J 2013;34:3251–58.10.1093/eurheartj/eht301Search in Google Scholar
31. Ridker PM. Moving beyond JUPITER: will inhibiting inflammation reduce vascular event rates? Curr Atheroscler Rep 2013;15:295.10.1007/s11883-012-0295-3Search in Google Scholar
32. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes (PROVE IT – TIMI). N Engl J Med 2004;350:1495–504.10.1056/NEJMoa040583Search in Google Scholar
33. Witting PK, Pettersson K, Letters J, Stocker R. Anti-atherogenic effect of coenzyme Q10 in apolipoprotein E gene knockout mice. Free Radic Biol Med 2000;29:295–305.10.1016/S0891-5849(00)00311-7Search in Google Scholar
34. Lee BJ, Huang YC, Chen SJ, Lin PT. Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme activity in patients with coronary artery disease. Nutrition 2012;28:250–55.10.1016/j.nut.2011.06.004Search in Google Scholar PubMed
35. Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol 2011;58:2047–67.10.1016/j.jacc.2011.06.063Search in Google Scholar PubMed
36. Lee BJ, Huang YC, Chen SJ, Lin PT. Effects of co-enzyme Q10 supplementation on inflammatory markers (high-sensitivity C-reactive protein, interleukin-6, and homocysteine) in patients with coronary artery disease. Nutrition 2012;28:767–72.10.1016/j.nut.2011.11.008Search in Google Scholar PubMed
37. Kris-Etherton PM, Harris WS, Appel LJ, American Heart Association. Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747–57.10.1161/01.CIR.0000038493.65177.94Search in Google Scholar
38. Ohara Y, Peterson TE, Sayegh HS, Subramanian RR, Wilcox JN, Harrison DG. Dietary correction of hypercholesterolemia in the rabbit normalizes endothelial superoxide anion production. Circulation 1995;92:898–903.10.1161/01.CIR.92.4.898Search in Google Scholar PubMed
39. Ledoux S, Laouari D, Essig M, Runembert I, Trugnan G, Michel JB, et al. Lovastatin enhances ecto-5′-nucleotidase activity and cell surface expression in endothelial cells: implication of Rho–family GTPases. Circ Res 2002;90:420–27.10.1161/hh0402.105668Search in Google Scholar PubMed
40. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, et al. Effect of intensive compared with moderate lipid-owering therapy on progression of coronary atherosclerosis: a randomized controlled trial. J Am Med Assoc 2004;9:1071–80.10.1001/jama.291.9.1071Search in Google Scholar PubMed
41. Ridker PM. The JUPITER trial: results, controversies, and implications for prevention. Circ Cardiovasc Qual Outcomes 2009;2:279–85.10.1161/CIRCOUTCOMES.109.868299Search in Google Scholar PubMed
42. Brooks JD, Musiek ES, Koestner TR, Stankowski JN, Howard JR, Brunoldi EM, et al. The fatty acid oxidation product 15-A3t-isoprostane is a potent inhibitor of NFκB transcription and macrophage transformation. J Neurochem 2011;119:604–16.10.1111/j.1471-4159.2011.07422.xSearch in Google Scholar PubMed PubMed Central
43. Graham I, Atar D, Borch-Johnsen K, Boysen G, Burell G, Cifkova R, et al.: European guidelines on cardiovascular disease prevention in clinical practise: executive summary: Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practise. Eur Heart J 2007;28:2375–414.10.1093/eurheartj/ehm316Search in Google Scholar PubMed
44. Hamilton SJ, Chew GT, Watts GF. Coenzyme Q10 improves endothelial dysfunction in statin-treated type 2 diabetic patients. Diabetes Care 2009;32:810–12.10.2337/dc08-1736Search in Google Scholar PubMed PubMed Central
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