- Email: [email protected]
Combination Therapy with Statins and Omega-3 Fatty Acids
Combination Therapy with Statins and Omega-3 Fatty Acids Vijay Nambi, MD,a and Christie M. Ballantyne, MDb,c,* Combined dyslipidemia is the concurrent presence of multiple abnormalities in various lipid subfractions, including elevated concentrations of low-density lipoprotein (LDL) cholesterol and triglycerides (TGs), as well as decreased concentrations of high-density lipoprotein (HDL) cholesterol. The Adult Treatment Panel III (ATP III) guidelines of the US National Cholesterol Education Program (NCEP) lowered the cut points for classification of TG levels, established non-HDL cholesterol levels as a secondary target of therapy in patients with TGs of >2.26 mmol/L (200 mg/dL), and defined the metabolic syndrome as a secondary target of therapy. Although 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are first-line therapy for most patients with elevated LDL cholesterol, statin monotherapy may not be sufficient to achieve recommended non-HDL cholesterol goals, and statins have only modest effects on reducing TG levels. Similarly, patients whose TG levels remain elevated despite treatment with a TG-lowering agent may require the addition of a statin to provide further TG reduction. In addition, statin therapy may be needed to offset the secondary increase in levels of LDL cholesterol that frequently results from treatment with a TG-lowering agent in patients with marked hypertriglyceridemia. In a number of small studies, the combination of statins and omega-3 fatty acids has been consistently shown to be an effective, safe, and well-tolerated treatment for combined dyslipidemia. Patients with recent myocardial infarction may also benefit from this combination. When considering risks and benefits of adding a second agent to statins for treatment of combined dyslipidemia, omega-3 fatty acids provide additional lipid improvements without requiring additional laboratory tests and do not increase risk for adverse muscle or liver effects. © 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;98[suppl]:34i–38i)
The Adult Treatment Panel III (ATP III) guidelines of the US National Cholesterol Education Program (NCEP) lowered the cut points for classification of triglyceride (TG) levels, established non– high-density lipoprotein (non-HDL) cholesterol levels as a secondary target of therapy in patients with TG levels ⱖ2.26 mmol/L (200 mg/dL), and defined the metabolic syndrome as a secondary target of therapy.1 With this increased emphasis on TGs, more individuals may need combination therapy to comply with the recommendations. Although 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are first-line therapy for most patients with elevated plasma levels of lowdensity lipoprotein (LDL) cholesterol, statin monotherapy may not be sufficient to achieve recommended non-HDL cholesterol goals, and statins have only modest effects on reducing TG levels. Similarly, patients whose TG levels remain elevated despite treatment with a TG-lowering agent may require the addition of a statin to provide further TG reduction. In addition, statin therapy may be needed to a
Section of Cardiology, and bSection of Atherosclerosis and Lipid Research, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA; and cCenter for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center, Houston, Texas, USA. *Address for reprints: Christie M. Ballantyne, MD, Baylor College of Medicine, 6565 Fannin, MS A-601, Houston, Texas 77030. E-mail address: [email protected]. 0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.12.025
offset the secondary increase in LDL cholesterol that frequently results from treatment with a TG-lowering agent in patients with marked hypertriglyceridemia. In this article, we review the data from clinical trials that have studied the efficacy of combination therapy with omega-3 fatty acids and statins to treat mixed hyperlipidemia, as well as evidence supporting the use of omega-3 fatty acids in combination with statins for patients with recent myocardial infarction (MI). In addition, we review data on the antithrombotic and anti-inflammatory effects of omega-3 fatty acids when added to statins and examine some of the clinical issues of adding omega-3 fatty acids to statins in comparison with other options. Combination Therapy for Combined Dyslipidemia Combined dyslipidemia is the concurrent presence of abnormalities in various lipid subfractions, including elevated concentrations of LDL cholesterol and TGs and a decreased concentration of HDL cholesterol. The ATP III guidelines define optimal LDL cholesterol levels as ⬍2.59 mmol/L (100 mg/dL) and normal TG levels as ⬍1.70 mmol/L (150 mg/dL); an HDL cholesterol level ⬍1.04 mmol/L (40 mg/ dL) is defined as low in the algorithm for risk-factor counting, and HDL cholesterol levels ⬍1.04 mmol/L (40 mg/dL) in men and ⬍1.30 mmol/L (50 mg/dL) in women is a www.AJConline.org
Nambi and Ballantyne/Statin Plus Omega-3 Fatty Acid Therapy
diagnostic criterion for the metabolic syndrome.1 Combined dyslipidemia may be secondary to genetic disorders, diabetes mellitus, the metabolic syndrome, or the use of drugs such as immunosuppressive agents or protease inhibitors. The presence of this constellation of abnormalities has been shown in multiple studies to confer an increased risk for coronary artery disease (CAD). In the Prospective Cardiovascular Münster Study2 and the Physicians’ Health Study,3 the presence of these abnormalities conferred a 2- to 5-fold increase in the risk of CAD. Other studies such as the Helsinki Heart Study4 and the Quebec Cardiovascular Study5 demonstrated an association between combined dyslipidemia and future cardiovascular events. Although statins— especially the more potent ones and at higher doses—lower TG levels, the addition of omega-3 fatty acids can provide greater TG reductions that may be needed to optimize TG levels in patients with combined dyslipidemia. For TG lowering, omega-3 fatty acids should be administered at a dose of ⱖ3 g/day of eicosapentaenoic acid (EPA) and docosahexaenoic acid. Omega-3 fatty acids reduce serum TG levels by 20% to 40%.6 – 8 The mechanism of action appears to be decreased production of very-lowdensity lipoproteins (VLDLs).9 Omega-3 fatty acids also reduce postprandial lipemia via increased clearance of chylomicron TGs.10 Not infrequently, in patients with marked hypertriglyceridemia, LDL cholesterol levels increase by 5% to 10% with the use of omega-3 fatty acids.8 For the resulting combined dyslipidemia, a statin can be added to reduce LDL cholesterol levels. Several studies have examined the effects of using the combination of statins and omega-3 fatty acids in combined dyslipidemia. In a study in 32 patients with combined dyslipidemia (total cholesterol ⬎5.5 mmol/L [213 mg/dL] and TGs ⬎2.8 mmol/L [248 mg/dL]), patients were randomized to 6 weeks of treatment with pravastatin (40 mg/day), omega-3 fatty acids (3 g/day Himega; formerly manufactured by Sigma Pharmaceuticals, Croydon, Victoria, Australia; no longer on the market), or placebo; then all patients received both active treatments for an additional 12 weeks.11 The addition of omega-3 fatty acids to pravastatin resulted in additional reductions in TGs and apolipoprotein B levels compared with pravastatin alone, but the differences were not statistically significant; the addition of pravastatin to fish oil resulted in significant decreases in total cholesterol (18%), LDL cholesterol (24%), and apolipoprotein B (19%) compared with fish oil alone. Subsequent combination therapy in placebo recipients produced significant decreases in plasma levels of TGs (33%), total cholesterol (25%), LDL cholesterol (26%), and apolipoprotein B (27%). Simvastatin (20 mg) was used alone and in combination with omega-3 fatty acids (4 g/day Omacor; omega-3 acid ethyl esters, Pronova AS Biocare, Oslo, Norway) in 41 patients with combined dyslipidemia (total cholesterol ⬎5.3 mmol/L [205 mg/dL] and TGs 2.0 to 15.0 mmol/L [175 to
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1,330 mg/dL]).12 The addition of omega-3 fatty acids to simvastatin therapy provided a significant further 28% reduction in serum TG level and a borderline-significant reduction in total cholesterol level without adversely affecting the LDL cholesterol–lowering effect of simvastatin. In another study in which omega-3 fatty acids were added to simvastatin therapy, 59 patients with CAD and serum TGs ⬎2.3 mmol/L (205 mg/dL) while taking baseline therapy with simvastatin 10 to 40 mg/day (dosed to reduce total cholesterol to ⬍5.5 mmol/L [213 mg/dL], although not achieved in all patients) were randomized to omega-3 fatty acids (Omacor 4 g/day) or placebo for 1 year.13 The addition of omega-3 fatty acids significantly decreased serum TG levels by 28% at 12 weeks and by 35% at 48 weeks (p ⬍0.0005 for combination therapy versus simvastatin alone). VLDL cholesterol levels were also significantly reduced, by 40% at 12 weeks (p ⬍0.005 compared with simvastatin alone), and non-HDL cholesterol was reduced by approximately 18% at 12 weeks. The addition of omega-3 fatty acids did not have a deleterious effect on levels of LDL cholesterol or HDL cholesterol or, in patients with diabetes, glycemic control. Omega-3 fatty acids (Omacor 2 g/day) were added to atorvastatin (10 mg/day) or placebo (corn oil, 2 g/day) in 42 patients with combined dyslipidemia (total cholesterol ⱖ5.3 mmol/L [205 mg/dL] and TGs 2.0 to 15.0 mmol/L [175 to 1,330 mg/dL]).14 Compared with atorvastatin alone, the addition of omega-3 fatty acids significantly increased levels of HDL cholesterol and significantly reduced small, dense LDL particles and postprandial hypertriglyceridemia. However, there was no significant change in TG or LDL cholesterol levels with combination therapy compared with atorvastatin alone. The effects of atorvastatin and omega-3 fatty acids as monotherapy and in combination were examined in 52 obese men (body mass index ⬎29, waist ⬎40 in [100 cm]) with dyslipidemia (LDL cholesterol ⬎2.59 mmol/L [100 mg/ dL], non-HDL cholesterol ⬎3.37 mmol/L [130 mg/dL], TGs ⬎1.19 mmol/L [105 mg/dL]) in a study with a 2⫻2 factorial design.15 Subjects were randomized to treatment with atorvastatin (40 mg/day), omega-3 fatty acids (Omacor 4 g/day), the combination of both, or placebo for 6 weeks. No statistically significant interaction between atorvastatin and omega-3 fatty acid treatment was found for any lipid variable assessed. Compared with baseline values, TG levels were reduced by 26% with atorvastatin monotherapy, 25% with omega-3 fatty acid monotherapy, and 40% with the combination. In the respective treatment groups, levels of LDL cholesterol were reduced by 52%, 6%, and 47%; levels of non-HDL cholesterol were reduced by 46%, 10%, and 47%; levels of remnant-like particle cholesterol were reduced by 33%, 31%, and 51%; and levels of HDL cholesterol were increased by 4%, 1%, and 14%. The investigators concluded that atorvastatin and omega-3 fatty acid have independent and additive effects on dyslipidemia in obese men.
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Results from the Japan EPA Lipid Intervention Study (JELIS) were presented in November 2005 at the scientific sessions of the American Heart Association (AHA).16 JELIS was a randomized, open-label, blinded study that included patients with (n ⫽ 3,664) or without (n ⫽ 14,981) a history of CAD who were taking statin therapy for hypercholesterolemia. The mean baseline total cholesterol and LDL cholesterol levels were 7.1 mmol/L (275 mg/dL) and 4.6 mmol/L (180 mg/dL), respectively.17 Study patients were randomized to receive either capsules of 1,800 mg of highly purified EPA or placebo and were followed for 4.5 years. The addition of the fish oil capsules significantly decreased the incidence of the primary end point of major coronary events (sudden cardiac death, fatal or nonfatal MI, unstable angina, and revascularization) from 3.5% in the statin monotherapy group to 2.8% in the combination therapy group (hazard ratio, 0.81; 95% confidence interval, 0.69 to 0.95; relative risk reduction [RRR], 19%).16 Further analysis showed that in the secondary prevention group, combination therapy decreased the occurrence of the primary end point from 10.7% to 8.7% (RRR, 19%), whereas in the primary prevention group, a reduction from 1.7% to 1.4% (RRR, 18%) was not statistically significant. LDL cholesterol levels were reduced by 26% in both groups. This is the first study in which clinical benefit of combination therapy with omega-3 fatty acids and statin has been reported. In summary, there are emerging data on clinical outcomes with the use of statins and omega-3 fatty acids in combination therapy for combined dyslipidemia. To date, the combination has consistently been shown to provide significant additional reductions in TGs without serious adverse effects.
Combination Therapy for Patients After Myocardial Infarction In the absence of contraindications, after MI all patients should receive statin therapy. Omega-3 fatty acids have also been found to provide clinical benefit in patients with recent MI. In the largest trial to date, the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSIPrevenzione) trial, 11,324 patients with recent MI (ⱕ3 months) were randomized to open-label treatment with omega-3 fatty acids 1 g/day, vitamin E 300 mg/day, the combination, or neither (control).18 Patients were followed for 3.5 years. At baseline, mean TG level was 1.83 mmol/L (162 mg/dL), and mean LDL cholesterol level was 3.55 mmol/L (137 mg/dL). Omega-3 fatty acids significantly reduced risk for the combined primary end point of death, nonfatal MI, and stroke by 10% by 2-way analysis and 15% by 4-way analysis. The combination of omega-3 fatty acids and vitamin E resulted in a similar 14% decrease in the risk for the primary end point, but treatment with vitamin E alone did not have a significant effect. At the start of this trial, statin use had not yet been established as standard
therapy and only 5% of patients were taking any lipidlowering therapy; this number increased to 46% in all the groups by the end of the trial. It must be noted that the dose of omega-3 fatty acids used in this study was lower than that commonly used in clinical practice for the treatment of elevated TGs (1 g/day Omacor in contrast to 4 g/day Omacor for TG reduction). At 6-month follow-up, TG levels were reduced by 3.4% with omega-3 fatty acids alone and by 0.9% with the combination of omega-3 fatty acids and vitamin E, which was statistically significant compared with controls but not considered clinically significant by the investigators. Therefore, the survival benefit was probably conferred through mechanisms other than lipid changes.
Potential Antithrombotic and Anti-Inflammatory Effects of Combination Therapy Omega-3 fatty acids have been shown to have beneficial biologic effects on the physiologic processes leading to atherothrombosis, including improvement in endothelial function19 and arterial compliance.20 Other potential mechanisms for the cardiovascular benefit observed with omega-3 fatty acids include reductions in arrhythmias,21,22 thrombosis,23 and inflammation.24 –26 Statins have also been shown to have antithrombotic27 and anti-inflammatory28 effects; however, the potential cardiovascular benefit conferred by these nonlipid effects of statins has not been established. The potential antithrombotic effect of combination therapy with omega-3 fatty acids and statins was examined in a study in 42 patients with combined dyslipidemia (total cholesterol ⬎5.3 mmol/L [205 mg/dL] and TGs 2.0 to 15.0 mmol/L [175 to 1330 mg/dL]). Participants received atorvastatin 10 mg/day, to which was added either omega-3 fatty acids 2 g/day or placebo.29 The addition of omega-3 fatty acids to atorvastatin provided reductions in both fasting and postprandial concentrations of the activated form of coagulation factor VII, postprandial factor VII coagulant activity, and postprandial concentrations of factor VII antigen. Combination therapy with atorvastatin and omega-3 fatty acids was also studied for its effect on inflammatory markers in a study in 48 obese men (mean body mass index, 33.6) with combined dyslipidemia (total cholesterol ⬎5.18 mmol/L [200 mg/dL] and TGs ⬎1.19 mmol/L [105 mg/dL]) who were randomized to treatment with atorvastatin 40 mg/day, omega-3 fatty acids 4 g/day, the combination, or placebo for 6 weeks.30 C-reactive protein (CRP) was reduced from baseline by 31% with atorvastatin monotherapy, 0.9% with omega-3 fatty acid monotherapy, and 48% with the combination; changes in interleukin-6 in the respective treatment groups were ⫺17%, ⫹6%, and ⫺26%. Atorvastatin treatment had a statistically significant main effect of lowering concentrations of CRP and interleukin-6, but fish
Nambi and Ballantyne/Statin Plus Omega-3 Fatty Acid Therapy
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Table 1 Clinical considerations when adding a second agent to statin therapy for treatment of mixed dyslipidemia Agent
Baseline Laboratory Tests Needed
Potential Adverse Effects to Monitor
Fibrates (gemfibrozil, fenofibrate)
Liver function tests, blood urea nitrogen/creatinine, consider creatine kinase
Niacin
Liver function tests, blood glucose, consider uric acid
Ezetimibe Omega-3 fatty acids
Liver function tests None
Gallstones; increased levels of liver transaminases; increased myopathy/rhabdomyolysis, particularly with gemfibrozil Increased levels of liver transaminases; hepatitis with sustained-release formulations; increased blood glucose; gout; flushing Increased levels of liver transaminases Increased bleeding time, gastrointestinal symptoms, eg, eructation and taste
oil did not. Tumor necrosis factor–␣ concentration was not significantly affected by atorvastatin or fish oil. The effect on CRP of combination therapy with omega-3 fatty acids and simvastatin was examined in a study in 40 patients with combined dyslipidemia.31 After being treated with simvastatin 10 to 20 mg/day for 6 to 12 weeks, the patients were then randomized to receive, in addition, omega-3 fatty acids 3 g/day or placebo for 2 months. In the group receiving active combination therapy, CRP levels were significantly reduced by 38.5%, and the reduction in CRP was significantly related to the reduction in TG levels.
Clinical Considerations Although statins are first-line therapy for patients with mixed hyperlipidemia, other pharmacologic agents with different mechanisms of action are frequently added to provide greater improvements in the atherogenic lipid profile, particularly in patients who are at high risk for cardiovascular disease events.32 Physicians should evaluate both the potential risks and benefits before initiation of a second agent. In contrast to other options, omega-3 fatty acid therapy does not require baseline laboratory tests and does not entail increased risk for serious adverse events such as muscle or liver toxicity (Table 1). The gastrointestinal adverse effects, primarily eructation and taste, can be minimized by highly purified, high-potency formulations that allow for much lower dosing. As we better understand the pathogenesis and underlying risk factors for cardiovascular disease, strategies for cardiovascular disease prevention will continue to evolve. LDL cholesterol–lowering statin therapy has been shown to be effective in primary and secondary prevention of atherosclerotic cardiovascular disease, but the ATP III guidelines place increasing emphasis on TGs and TG-rich lipoproteins. Omega-3 fatty acids are effective TG-lowering agents; they have also been shown to reduce the incidence of clinical events in patients with CAD irrespective of their effect on TG levels. In a number of small studies, the combination of statins and omega-3 fatty acids has been consistently shown to be an effective, safe, and well-tolerated treatment for
combined dyslipidemia. Larger trials with clinical event end points are needed to assess the potential cardiovascular benefit of combination therapy with statins and omega-3 fatty acids as well as to determine the optimal treatment strategy for cardiovascular risk reduction. 1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486 –2497. 2. Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Am J Cardiol 1992;70:733–737. 3. Stampfer MJ, Krauss RM, Ma J, Blanche PJ, Holl LG, Sacks FM, Hennekens CH. A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA 1996;276:882– 888. 4. Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Manttari M, Heinonen OP, Frick MH. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: implications for treatment. Circulation 1992;85:37– 45. 5. Lamarche B, Moorjani S, Lupien PJ, Cantin B, Bernard PM, Dagenais GR, Despres JP. Apolipoprotein A-I and B levels and the risk of ischemic heart disease during a five-year follow-up of men in the Quebec Cardiovascular Study. Circulation 1996;94:273–278. 6. Pownall HJ, Brauchi D, Kilinc C, Osmundsen K, Pao Q, Payton-Ross C, Gotto AM Jr, Ballantyne CM. Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the neutral lipid compositions of high-density and low-density lipoproteins. Atherosclerosis 1999;143:285–297. 7. Weber P, Raederstorff D. Triglyceride-lowering effect of omega-3 LC-polyunsaturated fatty acids—a review. Nutr Metab Cardiovasc Dis 2000;10:28 –37. 8. Harris WS. n-3 Fatty acids and serum lipoproteins: human studies. Am J Clin Nutr 1997;65(suppl):1645S–1654S. 9. Harris WS. Fish oils and plasma lipid and lipoprotein metabolism in humans: a critical review. J Lipid Res 1989;30:785– 807. 10. Park Y, Harris WS. Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance. J Lipid Res 2003;44:455– 463. 11. Contacos C, Barter PJ, Sullivan DR. Effect of pravastatin and omega-3 fatty acids on plasma lipids and lipoproteins in patients with combined hyperlipidemia. Arterioscler Thromb 1993;13:1755–1762. 12. Nordøy A, Bønaa KH, Nilsen H, Berge RK, Hansen JB, Ingebretsen OC. Effects of simvastatin and omega-3 fatty acids on plasma lipoproteins and lipid peroxidation in patients with combined hyperlipidaemia. J Intern Med 1998;243:163–170.
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13. Durrington PN, Bhatnagar D, Mackness MI, Morgan J, Julier K, Khan MA, France M. 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 2001;85:544 –548. 14. Nordøy A, Hansen JB, Brox J, Svensson B. Effects of atorvastatin and omega-3 fatty acids on LDL subfractions and postprandial hyperlipemia in patients with combined hyperlipemia. Nutr Metab Cardiovasc Dis 2001;11:7–16. 15. Chan DC, Watts GF, Mori TA, Barrett PH, Beilin LJ, Redgrave TG. Factorial study of the effects of atorvastatin and fish oil on dyslipidaemia in visceral obesity. Eur J Clin Invest 2002;32:429 – 436. 16. Yokoyama M. Effects of eicosapentaenoic acid (EPA) on major cardiovascular events in hypercholesterolemic patients: the Japan EPA Lipid Intervention Study (JELIS). Presented at the American Heart Association Scientific Sessions; November 14, 2005; Dallas, TX. 17. Yokoyama M, Origasa H, for the JELIS Investigators. Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholesterolemia: rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS). Am Heart J 2003;146:613– 620. 18. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354:447– 455. 19. Chin JP, Dart AM. How do fish oils affect vascular function? Clin Exp Pharmacol Physiol 1995;22:71– 81. 20. McVeigh GE, Brennan GM, Cohn JN, Finkelstein SM, Hayes RJ, Johnston GD. Fish oil improves arterial compliance in non-insulindependent diabetes mellitus. Arterioscler Thromb 1994;14:1425– 1429. 21. Calo L, Bianconi L, Colivicchi F, Lamberti F, Loricchio ML, de Ruvo E, Meo A, Pandozi C, Staibano M, Santini M. N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: a randomized, controlled trial. J Am Coll Cardiol 2005;45:1723–1728. 22. Leaf A, Kang JX, Xiao YF, Billman GE. Clinical prevention of sudden cardiac death by n-3 polyunsaturated fatty acids and mechanism of
23. 24.
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prevention of arrhythmias by n-3 fish oils. Circulation 2003;107:2646 –2652. Calder PC. n-3 Fatty acids and cardiovascular disease: evidence explained and mechanisms explored. Clin Sci (Lond) 2004;107:1–11. Abe Y, El-Masri B, Kimball KT, Pownall H, Reilly CF, Osmundsen K, Smith CW, Ballantyne CM. Soluble cell adhesion molecules in hypertriglyceridemia and potential significance on monocyte adhesion. Arterioscler Thromb Vasc Biol 1998;18:723–731. Lopez-Garcia E, Schulze MB, Manson JE, Meigs JB, Albert CM, Rifai N, Willett WC, Hu FB. Consumption of (n-3) fatty acids is related to plasma biomarkers of inflammation and endothelial activation in women. J Nutr 2004;134:1806 –1811. Zhao G, Etherton TD, Martin KR, West SG, Gillies PJ, Kris-Etherton PM. Dietary ␣-linolenic acid reduces inflammatory and lipid cardiovascular risk factors in hypercholesterolemic men and women. J Nutr 2004;134:2991–2997. Krysiak R, Okopien B, Herman Z. Effects of HMG-CoA reductase inhibitors on coagulation and fibrinolysis processes. Drugs 2003;63: 1821–1854. Schönbeck U, Libby P. Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents? Circulation 2004;109(suppl1):II18 –II26. Nordøy A, Svensson B, Hansen JB. Atorvastatin and omega-3 fatty acids protect against activation of the coagulation system in patients with combined hyperlipemia. J Thromb Haemost 2003;1:690 – 697. Chan DC, Watts GF, Barrett PH, 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– 883. Hong H, Xu ZM, Pang BS, Cui L, Wei Y, Guo WJ, Mao YL, Yang XC. Effects of simvastain combined with omega-3 fatty acids on high sensitive C-reactive protein, lipidemia, and fibrinolysis in patients with mixed dyslipidemia. Chin Med Sci J 2004;19:145–149. Xydakis AM, Ballantyne CM. Combination therapy for combined dyslipidemia. Am J Cardiol 2002;90:21K–29K.
The Adult Treatment Panel III (ATP III) guidelines of the US National Cholesterol Education Program (NCEP) lowered the cut points for classification of triglyceride (TG) levels, established non– high-density lipoprotein (non-HDL) cholesterol levels as a secondary target of therapy in patients with TG levels ⱖ2.26 mmol/L (200 mg/dL), and defined the metabolic syndrome as a secondary target of therapy.1 With this increased emphasis on TGs, more individuals may need combination therapy to comply with the recommendations. Although 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are first-line therapy for most patients with elevated plasma levels of lowdensity lipoprotein (LDL) cholesterol, statin monotherapy may not be sufficient to achieve recommended non-HDL cholesterol goals, and statins have only modest effects on reducing TG levels. Similarly, patients whose TG levels remain elevated despite treatment with a TG-lowering agent may require the addition of a statin to provide further TG reduction. In addition, statin therapy may be needed to a
Section of Cardiology, and bSection of Atherosclerosis and Lipid Research, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA; and cCenter for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center, Houston, Texas, USA. *Address for reprints: Christie M. Ballantyne, MD, Baylor College of Medicine, 6565 Fannin, MS A-601, Houston, Texas 77030. E-mail address: [email protected]. 0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.12.025
offset the secondary increase in LDL cholesterol that frequently results from treatment with a TG-lowering agent in patients with marked hypertriglyceridemia. In this article, we review the data from clinical trials that have studied the efficacy of combination therapy with omega-3 fatty acids and statins to treat mixed hyperlipidemia, as well as evidence supporting the use of omega-3 fatty acids in combination with statins for patients with recent myocardial infarction (MI). In addition, we review data on the antithrombotic and anti-inflammatory effects of omega-3 fatty acids when added to statins and examine some of the clinical issues of adding omega-3 fatty acids to statins in comparison with other options. Combination Therapy for Combined Dyslipidemia Combined dyslipidemia is the concurrent presence of abnormalities in various lipid subfractions, including elevated concentrations of LDL cholesterol and TGs and a decreased concentration of HDL cholesterol. The ATP III guidelines define optimal LDL cholesterol levels as ⬍2.59 mmol/L (100 mg/dL) and normal TG levels as ⬍1.70 mmol/L (150 mg/dL); an HDL cholesterol level ⬍1.04 mmol/L (40 mg/ dL) is defined as low in the algorithm for risk-factor counting, and HDL cholesterol levels ⬍1.04 mmol/L (40 mg/dL) in men and ⬍1.30 mmol/L (50 mg/dL) in women is a www.AJConline.org
Nambi and Ballantyne/Statin Plus Omega-3 Fatty Acid Therapy
diagnostic criterion for the metabolic syndrome.1 Combined dyslipidemia may be secondary to genetic disorders, diabetes mellitus, the metabolic syndrome, or the use of drugs such as immunosuppressive agents or protease inhibitors. The presence of this constellation of abnormalities has been shown in multiple studies to confer an increased risk for coronary artery disease (CAD). In the Prospective Cardiovascular Münster Study2 and the Physicians’ Health Study,3 the presence of these abnormalities conferred a 2- to 5-fold increase in the risk of CAD. Other studies such as the Helsinki Heart Study4 and the Quebec Cardiovascular Study5 demonstrated an association between combined dyslipidemia and future cardiovascular events. Although statins— especially the more potent ones and at higher doses—lower TG levels, the addition of omega-3 fatty acids can provide greater TG reductions that may be needed to optimize TG levels in patients with combined dyslipidemia. For TG lowering, omega-3 fatty acids should be administered at a dose of ⱖ3 g/day of eicosapentaenoic acid (EPA) and docosahexaenoic acid. Omega-3 fatty acids reduce serum TG levels by 20% to 40%.6 – 8 The mechanism of action appears to be decreased production of very-lowdensity lipoproteins (VLDLs).9 Omega-3 fatty acids also reduce postprandial lipemia via increased clearance of chylomicron TGs.10 Not infrequently, in patients with marked hypertriglyceridemia, LDL cholesterol levels increase by 5% to 10% with the use of omega-3 fatty acids.8 For the resulting combined dyslipidemia, a statin can be added to reduce LDL cholesterol levels. Several studies have examined the effects of using the combination of statins and omega-3 fatty acids in combined dyslipidemia. In a study in 32 patients with combined dyslipidemia (total cholesterol ⬎5.5 mmol/L [213 mg/dL] and TGs ⬎2.8 mmol/L [248 mg/dL]), patients were randomized to 6 weeks of treatment with pravastatin (40 mg/day), omega-3 fatty acids (3 g/day Himega; formerly manufactured by Sigma Pharmaceuticals, Croydon, Victoria, Australia; no longer on the market), or placebo; then all patients received both active treatments for an additional 12 weeks.11 The addition of omega-3 fatty acids to pravastatin resulted in additional reductions in TGs and apolipoprotein B levels compared with pravastatin alone, but the differences were not statistically significant; the addition of pravastatin to fish oil resulted in significant decreases in total cholesterol (18%), LDL cholesterol (24%), and apolipoprotein B (19%) compared with fish oil alone. Subsequent combination therapy in placebo recipients produced significant decreases in plasma levels of TGs (33%), total cholesterol (25%), LDL cholesterol (26%), and apolipoprotein B (27%). Simvastatin (20 mg) was used alone and in combination with omega-3 fatty acids (4 g/day Omacor; omega-3 acid ethyl esters, Pronova AS Biocare, Oslo, Norway) in 41 patients with combined dyslipidemia (total cholesterol ⬎5.3 mmol/L [205 mg/dL] and TGs 2.0 to 15.0 mmol/L [175 to
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1,330 mg/dL]).12 The addition of omega-3 fatty acids to simvastatin therapy provided a significant further 28% reduction in serum TG level and a borderline-significant reduction in total cholesterol level without adversely affecting the LDL cholesterol–lowering effect of simvastatin. In another study in which omega-3 fatty acids were added to simvastatin therapy, 59 patients with CAD and serum TGs ⬎2.3 mmol/L (205 mg/dL) while taking baseline therapy with simvastatin 10 to 40 mg/day (dosed to reduce total cholesterol to ⬍5.5 mmol/L [213 mg/dL], although not achieved in all patients) were randomized to omega-3 fatty acids (Omacor 4 g/day) or placebo for 1 year.13 The addition of omega-3 fatty acids significantly decreased serum TG levels by 28% at 12 weeks and by 35% at 48 weeks (p ⬍0.0005 for combination therapy versus simvastatin alone). VLDL cholesterol levels were also significantly reduced, by 40% at 12 weeks (p ⬍0.005 compared with simvastatin alone), and non-HDL cholesterol was reduced by approximately 18% at 12 weeks. The addition of omega-3 fatty acids did not have a deleterious effect on levels of LDL cholesterol or HDL cholesterol or, in patients with diabetes, glycemic control. Omega-3 fatty acids (Omacor 2 g/day) were added to atorvastatin (10 mg/day) or placebo (corn oil, 2 g/day) in 42 patients with combined dyslipidemia (total cholesterol ⱖ5.3 mmol/L [205 mg/dL] and TGs 2.0 to 15.0 mmol/L [175 to 1,330 mg/dL]).14 Compared with atorvastatin alone, the addition of omega-3 fatty acids significantly increased levels of HDL cholesterol and significantly reduced small, dense LDL particles and postprandial hypertriglyceridemia. However, there was no significant change in TG or LDL cholesterol levels with combination therapy compared with atorvastatin alone. The effects of atorvastatin and omega-3 fatty acids as monotherapy and in combination were examined in 52 obese men (body mass index ⬎29, waist ⬎40 in [100 cm]) with dyslipidemia (LDL cholesterol ⬎2.59 mmol/L [100 mg/ dL], non-HDL cholesterol ⬎3.37 mmol/L [130 mg/dL], TGs ⬎1.19 mmol/L [105 mg/dL]) in a study with a 2⫻2 factorial design.15 Subjects were randomized to treatment with atorvastatin (40 mg/day), omega-3 fatty acids (Omacor 4 g/day), the combination of both, or placebo for 6 weeks. No statistically significant interaction between atorvastatin and omega-3 fatty acid treatment was found for any lipid variable assessed. Compared with baseline values, TG levels were reduced by 26% with atorvastatin monotherapy, 25% with omega-3 fatty acid monotherapy, and 40% with the combination. In the respective treatment groups, levels of LDL cholesterol were reduced by 52%, 6%, and 47%; levels of non-HDL cholesterol were reduced by 46%, 10%, and 47%; levels of remnant-like particle cholesterol were reduced by 33%, 31%, and 51%; and levels of HDL cholesterol were increased by 4%, 1%, and 14%. The investigators concluded that atorvastatin and omega-3 fatty acid have independent and additive effects on dyslipidemia in obese men.
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Results from the Japan EPA Lipid Intervention Study (JELIS) were presented in November 2005 at the scientific sessions of the American Heart Association (AHA).16 JELIS was a randomized, open-label, blinded study that included patients with (n ⫽ 3,664) or without (n ⫽ 14,981) a history of CAD who were taking statin therapy for hypercholesterolemia. The mean baseline total cholesterol and LDL cholesterol levels were 7.1 mmol/L (275 mg/dL) and 4.6 mmol/L (180 mg/dL), respectively.17 Study patients were randomized to receive either capsules of 1,800 mg of highly purified EPA or placebo and were followed for 4.5 years. The addition of the fish oil capsules significantly decreased the incidence of the primary end point of major coronary events (sudden cardiac death, fatal or nonfatal MI, unstable angina, and revascularization) from 3.5% in the statin monotherapy group to 2.8% in the combination therapy group (hazard ratio, 0.81; 95% confidence interval, 0.69 to 0.95; relative risk reduction [RRR], 19%).16 Further analysis showed that in the secondary prevention group, combination therapy decreased the occurrence of the primary end point from 10.7% to 8.7% (RRR, 19%), whereas in the primary prevention group, a reduction from 1.7% to 1.4% (RRR, 18%) was not statistically significant. LDL cholesterol levels were reduced by 26% in both groups. This is the first study in which clinical benefit of combination therapy with omega-3 fatty acids and statin has been reported. In summary, there are emerging data on clinical outcomes with the use of statins and omega-3 fatty acids in combination therapy for combined dyslipidemia. To date, the combination has consistently been shown to provide significant additional reductions in TGs without serious adverse effects.
Combination Therapy for Patients After Myocardial Infarction In the absence of contraindications, after MI all patients should receive statin therapy. Omega-3 fatty acids have also been found to provide clinical benefit in patients with recent MI. In the largest trial to date, the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSIPrevenzione) trial, 11,324 patients with recent MI (ⱕ3 months) were randomized to open-label treatment with omega-3 fatty acids 1 g/day, vitamin E 300 mg/day, the combination, or neither (control).18 Patients were followed for 3.5 years. At baseline, mean TG level was 1.83 mmol/L (162 mg/dL), and mean LDL cholesterol level was 3.55 mmol/L (137 mg/dL). Omega-3 fatty acids significantly reduced risk for the combined primary end point of death, nonfatal MI, and stroke by 10% by 2-way analysis and 15% by 4-way analysis. The combination of omega-3 fatty acids and vitamin E resulted in a similar 14% decrease in the risk for the primary end point, but treatment with vitamin E alone did not have a significant effect. At the start of this trial, statin use had not yet been established as standard
therapy and only 5% of patients were taking any lipidlowering therapy; this number increased to 46% in all the groups by the end of the trial. It must be noted that the dose of omega-3 fatty acids used in this study was lower than that commonly used in clinical practice for the treatment of elevated TGs (1 g/day Omacor in contrast to 4 g/day Omacor for TG reduction). At 6-month follow-up, TG levels were reduced by 3.4% with omega-3 fatty acids alone and by 0.9% with the combination of omega-3 fatty acids and vitamin E, which was statistically significant compared with controls but not considered clinically significant by the investigators. Therefore, the survival benefit was probably conferred through mechanisms other than lipid changes.
Potential Antithrombotic and Anti-Inflammatory Effects of Combination Therapy Omega-3 fatty acids have been shown to have beneficial biologic effects on the physiologic processes leading to atherothrombosis, including improvement in endothelial function19 and arterial compliance.20 Other potential mechanisms for the cardiovascular benefit observed with omega-3 fatty acids include reductions in arrhythmias,21,22 thrombosis,23 and inflammation.24 –26 Statins have also been shown to have antithrombotic27 and anti-inflammatory28 effects; however, the potential cardiovascular benefit conferred by these nonlipid effects of statins has not been established. The potential antithrombotic effect of combination therapy with omega-3 fatty acids and statins was examined in a study in 42 patients with combined dyslipidemia (total cholesterol ⬎5.3 mmol/L [205 mg/dL] and TGs 2.0 to 15.0 mmol/L [175 to 1330 mg/dL]). Participants received atorvastatin 10 mg/day, to which was added either omega-3 fatty acids 2 g/day or placebo.29 The addition of omega-3 fatty acids to atorvastatin provided reductions in both fasting and postprandial concentrations of the activated form of coagulation factor VII, postprandial factor VII coagulant activity, and postprandial concentrations of factor VII antigen. Combination therapy with atorvastatin and omega-3 fatty acids was also studied for its effect on inflammatory markers in a study in 48 obese men (mean body mass index, 33.6) with combined dyslipidemia (total cholesterol ⬎5.18 mmol/L [200 mg/dL] and TGs ⬎1.19 mmol/L [105 mg/dL]) who were randomized to treatment with atorvastatin 40 mg/day, omega-3 fatty acids 4 g/day, the combination, or placebo for 6 weeks.30 C-reactive protein (CRP) was reduced from baseline by 31% with atorvastatin monotherapy, 0.9% with omega-3 fatty acid monotherapy, and 48% with the combination; changes in interleukin-6 in the respective treatment groups were ⫺17%, ⫹6%, and ⫺26%. Atorvastatin treatment had a statistically significant main effect of lowering concentrations of CRP and interleukin-6, but fish
Nambi and Ballantyne/Statin Plus Omega-3 Fatty Acid Therapy
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Table 1 Clinical considerations when adding a second agent to statin therapy for treatment of mixed dyslipidemia Agent
Baseline Laboratory Tests Needed
Potential Adverse Effects to Monitor
Fibrates (gemfibrozil, fenofibrate)
Liver function tests, blood urea nitrogen/creatinine, consider creatine kinase
Niacin
Liver function tests, blood glucose, consider uric acid
Ezetimibe Omega-3 fatty acids
Liver function tests None
Gallstones; increased levels of liver transaminases; increased myopathy/rhabdomyolysis, particularly with gemfibrozil Increased levels of liver transaminases; hepatitis with sustained-release formulations; increased blood glucose; gout; flushing Increased levels of liver transaminases Increased bleeding time, gastrointestinal symptoms, eg, eructation and taste
oil did not. Tumor necrosis factor–␣ concentration was not significantly affected by atorvastatin or fish oil. The effect on CRP of combination therapy with omega-3 fatty acids and simvastatin was examined in a study in 40 patients with combined dyslipidemia.31 After being treated with simvastatin 10 to 20 mg/day for 6 to 12 weeks, the patients were then randomized to receive, in addition, omega-3 fatty acids 3 g/day or placebo for 2 months. In the group receiving active combination therapy, CRP levels were significantly reduced by 38.5%, and the reduction in CRP was significantly related to the reduction in TG levels.
Clinical Considerations Although statins are first-line therapy for patients with mixed hyperlipidemia, other pharmacologic agents with different mechanisms of action are frequently added to provide greater improvements in the atherogenic lipid profile, particularly in patients who are at high risk for cardiovascular disease events.32 Physicians should evaluate both the potential risks and benefits before initiation of a second agent. In contrast to other options, omega-3 fatty acid therapy does not require baseline laboratory tests and does not entail increased risk for serious adverse events such as muscle or liver toxicity (Table 1). The gastrointestinal adverse effects, primarily eructation and taste, can be minimized by highly purified, high-potency formulations that allow for much lower dosing. As we better understand the pathogenesis and underlying risk factors for cardiovascular disease, strategies for cardiovascular disease prevention will continue to evolve. LDL cholesterol–lowering statin therapy has been shown to be effective in primary and secondary prevention of atherosclerotic cardiovascular disease, but the ATP III guidelines place increasing emphasis on TGs and TG-rich lipoproteins. Omega-3 fatty acids are effective TG-lowering agents; they have also been shown to reduce the incidence of clinical events in patients with CAD irrespective of their effect on TG levels. In a number of small studies, the combination of statins and omega-3 fatty acids has been consistently shown to be an effective, safe, and well-tolerated treatment for
combined dyslipidemia. Larger trials with clinical event end points are needed to assess the potential cardiovascular benefit of combination therapy with statins and omega-3 fatty acids as well as to determine the optimal treatment strategy for cardiovascular risk reduction. 1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486 –2497. 2. Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Am J Cardiol 1992;70:733–737. 3. Stampfer MJ, Krauss RM, Ma J, Blanche PJ, Holl LG, Sacks FM, Hennekens CH. A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA 1996;276:882– 888. 4. Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Manttari M, Heinonen OP, Frick MH. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: implications for treatment. Circulation 1992;85:37– 45. 5. Lamarche B, Moorjani S, Lupien PJ, Cantin B, Bernard PM, Dagenais GR, Despres JP. Apolipoprotein A-I and B levels and the risk of ischemic heart disease during a five-year follow-up of men in the Quebec Cardiovascular Study. Circulation 1996;94:273–278. 6. Pownall HJ, Brauchi D, Kilinc C, Osmundsen K, Pao Q, Payton-Ross C, Gotto AM Jr, Ballantyne CM. Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the neutral lipid compositions of high-density and low-density lipoproteins. Atherosclerosis 1999;143:285–297. 7. Weber P, Raederstorff D. Triglyceride-lowering effect of omega-3 LC-polyunsaturated fatty acids—a review. Nutr Metab Cardiovasc Dis 2000;10:28 –37. 8. Harris WS. n-3 Fatty acids and serum lipoproteins: human studies. Am J Clin Nutr 1997;65(suppl):1645S–1654S. 9. Harris WS. Fish oils and plasma lipid and lipoprotein metabolism in humans: a critical review. J Lipid Res 1989;30:785– 807. 10. Park Y, Harris WS. Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance. J Lipid Res 2003;44:455– 463. 11. Contacos C, Barter PJ, Sullivan DR. Effect of pravastatin and omega-3 fatty acids on plasma lipids and lipoproteins in patients with combined hyperlipidemia. Arterioscler Thromb 1993;13:1755–1762. 12. Nordøy A, Bønaa KH, Nilsen H, Berge RK, Hansen JB, Ingebretsen OC. Effects of simvastatin and omega-3 fatty acids on plasma lipoproteins and lipid peroxidation in patients with combined hyperlipidaemia. J Intern Med 1998;243:163–170.
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