Comparative study of efficacy and safety of omega 3 fatty acids and fenofibrate with background atorvastatin therapy in patients of atherogenic dyslipidaemia
Keywords:Atherogenic dyslipidaemia, Atorvastatin, Fenofibrate, Hypertriglyceridemia, Omega-3 fatty acids
Background: Trials of atorvastatin combined either with fenofibrate or with omega-3 fatty acids (O3FA) have shown promising results in atherogenic dyslipidemia but there are very few studies where both these TGs lowering agents have been compared with each other. This study was conducted to compare efficacy and safety of these two agents on lipid profile of patients of atherogenic dyslipidaemia on background statin therapy and also to monitor effects of these interventions on serum uric acid (SUA) levels.
Methods: About 90 patients of dyslipidemia were randomised to 3 groups and received O3FA (2000 mg), fenofibrate (80 mg) or dietary restrictions, each with atorvastatin (20 mg) in background for a period of 90 days. Total cholesterol (TC), HDL-C,TGs, LDL-C, SGOT and SGPT levels were done at baseline, 6 weeks and 12 weeks. Other parameters (SUA and BMI) were done at baseline and 12 weeks.
Results: Both group 1 (O3FA) and group 2 (fenofibrate) showed highly significant fall in TG levels (p <0.001) in comparison to group 3 (dietary restrictions) whereas comparative TG reduction between groups 1 and group 2 was not significant. Group 2 also showed significant fall in LDL-C levels (p <0.01) in comparison to group 3. LDL-C reduction, TG reduction and SUA reduction was more in group 2 compared to group 1 followed by group 3. No significant difference was observed in the incidence of adverse effects in three study groups.
Conclusions: Combination of fenofibrate and atorvastatin was more effective than that of omega-3 fatty acid and atorvastatin, in lowering serum TG and LDL-C levels. There was a significant reduction in SUA levels in all three groups, but combination of fenofibrate and atorvastatin again showed better outcomes. With respect to the safety, all the 3 groups were comparable. O3FA, however, may be a good alternative to fibrates in patients not tolerating latter.
Chandra SK, Bansal M, Nair T, Iyengar SS, Gupta R, Manchanda SC, et al. Consensus statement on management of dyslipidemia in Indian subjects. Ind Heart J. 2014;66(3):S1-51.
Mulukutla SR, Venkitachalam L, Marroquin OC, Kip KE, Aiyer A, Edmundowicz D, et al. Population variations in atherogenic dyslipidemia: a report from the Heart SCORE and India SCORE Studies. J Clin Lipidol. 2008;2(6):410-7.
Sharma RK, Singh VN, Reddy HK. Thinking beyond low-density lipoprotein cholesterol: strategies to further reduce cardiovascular risk. Vasc Health Risk Manag. 2009;5:793-9.
Ramachandran A, Snehalatha C, Satyavani K, Sivasankari S, Vijay V. Metabolic syndrome in urban Asian Indian adults: a population study using modified ATP III criteria. Diab Res Clin Pract. 2003;60(3):199-204.
Mohan V, Shanthirani S, Deepa R, Premalatha G, Sastry NG, Saroja R, et al. Intra-urban differences in the prevalence of the metabolic syndrome in southern India: the Chennai Urban Population Study (CUPS No. 4). Diab Med J Brit Diab Assoc. 2001;18(4):280-7.
Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype. a proposed genetic marker for coronary heart disease risk. Circulation. 1990;82(2):495-506.
Vinik AI. The metabolic basis of atherogenic dyslipidemia. Clin Cornerstone. 2005;7(2-3):27-35.
Musunuru K. Atherogenic dyslipidemia: cardiovascular risk and dietary intervention. Lipids. 2010;45(10):907-14.
Grundy SM. Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome. Am J Cardiol. 1998;81(4A):18B-25B.
Lehto S, Niskanen L, Rönnemaa T, Laakso M. Serum uric acid is a strong predictor of stroke in patients with non–insulin-dependent diabetes mellitus. Stroke. 1998;29(3):635-9.
Bickel C, Rupprecht HJ, Blankenberg S, Rippin G, Hafner G, Daunhauer A, et al. Serum uric acid as an independent predictor of mortality in patients with angiographically proven coronary artery disease. Am J Cardiol. 2002;89(1):12-7.
Choi HK, Ford ES. Prevalence of the metabolic syndrome in individuals with hyperuricemia. Am J Med. 2007;120(5):442–7.
Uetake D, Ohno I, Ichida K, Yamaguchi Y, Saikawa H, Endou H, et al. Effect of fenofibrate on uric acid metabolism and urate transporter 1. Intern Med Tokyo Jpn. 2010;49(2):89-94.
Ogata N, Fujimori S, Oka Y, Kaneko K. Effects of three strong statins (atorvastatin, pitavastatin, and rosuvastatin) on serum uric acid levels in dyslipidemic patients. Nucleosides Nucleotides Nucleic Acids. 2010;29(4-6):321-4.
Manjunath CN, Rawal JR, Irani PM, Madhu K. Atherogenic dyslipidemia. Indian J Endocrinol Metab. 2013;17(6):969-76.
Taskinen M-R. Diabetic dyslipidaemia: from basic research to clinical practice. Diabetol. 2003;46(6):733-49.
Adiels M, Olofsson S-O, Taskinen M-R, Borén J. Overproduction of very low-density lipoproteins is the hallmark of the dyslipidemia in the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008;28(7):1225-36.
Packard C, Caslake M, Shepherd J. The role of small, dense low-density lipoprotein (LDL): a new look. Int J Cardiol. 2000;74:S17-22.
Witztum JL, Steinberg D. Role of oxidized low-density lipoprotein in atherogenesis. J Clin Invest. 1991;88(6):1785-92.
Witztum JL, Steinberg D. The oxidative modification hypothesis of atherosclerosis: does it hold for humans? Trends Cardiovasc Med. 2001;11(3-4):93-102.
Gurgle HE, Blumenthal DK. Drug Therapy for Dyslipidemias. In: Brunton LB, Dandan RH, Knollman BC, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics 12th ed. New York, NY: Mc Graw-Hill; 2018:605-18.
Noce MA, Bertucci P, Villahermosa MS, Zenobi R, Castagnola V. Atherosclerosis, dyslipidemia, and inflammation: the significant role of polyunsaturated fatty acids. Int Sch Res Not. 2013;2013:e191823.
Barter P, Ginsberg HN. Effectiveness of combined statin plus omega-3 fatty acid therapy for mixed dyslipidemia. Am J Cardiol. 2008;102(8):1040-5.
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 Lond Engl. 2007;369(9567):1090-8.
Durrington PN, Bhatnagar D, Mackness MI, Morgan J, Julier K, Khan MA, et al. An omega-3 polyunsaturated fatty acid concentrate administered for one-year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia. Heart Br Card Soc. 2001;85(5):544-8.
Shuhaili MF, Samsudin IN, Stanslas J, Hasan S, Thambiah SC. Effects of different types of statins on lipid profile: a perspective on Asians. Int J Endocrinol Metab. 2017;15(2).
Abourbih S, Filion KB, Joseph L, Schiffrin EL, Rinfret S, Poirier P, et al. Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review. Am J Med. 2009;122(10):962.e1-8.
Caniato RN, Alvarenga ME, Garcia-Alcaraz MA. Effect of omega-3 fatty acids on the lipid profile of patients taking clozapine. Aust N Z J Psychiatry. 2006;40(8):691-7.
Agouridis AP, Kostapanos MS, Tsimihodimos V, Kostara C, Mikhailidis DP, Bairaktari ET, et al. Effect of rosuvastatin monotherapy or in combination with fenofibrate or ω-3 fatty acids on lipoprotein subfraction profile in patients with mixed dyslipidaemia and metabolic syndrome. Int J Clin Pract. 2012;66(9):843-53.
Jones PH, Cusi K, Davidson MH, Kelly MT, Setze CM, Thakker K, et al. Efficacy and safety of fenofibric acid co-administered with low- or moderate-dose statin in patients with mixed dyslipidemia and type 2 diabetes mellitus: results of a pooled subgroup analysis from three randomized, controlled, double-blind trials. Am J Cardiovasc Drugs Drugs Devices Interv. 2010;10(2):73-84.
Bradberry JC, Hilleman DE. Overview of omega-3 fatty acid therapies. Pharm Ther. 2013;38(11):681-91.
Serna DL. Fenofibrate decreases plasma fibrinogen, improves lipid profile, and reduces uricemia. Clin Pharmacol. 1999;66(2):7.
Backes J, Anzalone D, Hilleman D, Catini J. The clinical relevance of omega-3 fatty acids in the management of hypertriglyceridemia. Lipids Heal Dis. 2016;15(1):118.
Chang C-H, Tseng P-T, Chen N-Y, Lin P-C, Lin P-Y, Chang JP-C, et al. Safety and tolerability of prescription omega-3 fatty acids: A systematic review and meta-analysis of randomized controlled trials. Prostaglandins Leukot Essent Fatty Acids. 2018;129:1-12.
Tarantino N, Santoro F, De Gennaro L, Correale M, Guastafierro F, Gaglione A, et al. Fenofibrate/simvastatin fixed-dose combination in the treatment of mixed dyslipidemia: safety, efficacy, and place in therapy. Vasc Health Risk Manag. 2017;13:29-41.
Whitfield LR, Porcari AR, Alvey C, Abel R, Bullen W, Hartman D. Effect of gemfibrozil and fenofibrate on the pharmacokinetics of atorvastatin. J Clin Pharmacol. 2011;51(3):378-88.
Li H, Wang C, Zhang S, Sun S, Li R, Zou M, et al. Safety Profile of Atorvastatin 80 mg: A Meta-Analysis of 17 Randomized Controlled Trials in 21,910 Participants. Drug Saf. 2016;39(5):409-19.
Chan JCN, Kong APS, Bao W, Fayyad R, Laskey R. Safety of atorvastatin in Asian patients within clinical trials. Cardiovasc Ther. 2016;34(6):431-40.