Treatment options for the management of hypertriglyceridemia: Strategies based on the best-available evidence

Published:April 16, 2012DOI:https://doi.org/10.1016/j.jacl.2012.04.003

      Abstract

      A severe elevation in triglycerides (TG; ≥500 mg/dL) increases the risk for pancreatitis. TG levels ≥200 mg/dL are associated with a greater risk of atherosclerotic coronary heart disease (CHD). However, no outcomes trials exist to assess the efficacy of TG lowering for preventing pancreatitis in patients with severe hypertriglyceridemia. Similarly, no completed prospective outcomes trial exists to support or refute a reduction in CHD risk resulting from lipid-altering therapy in patients specifically selected for the presence of hypertriglyceridemia. This review examines the available evidence for the use of statins, omega-3 fatty acids, fibrates, and niacin in the management of hypertriglyceridemic patients. Results from CHD outcomes trials support statins as the first-line lipid-altering drug therapy to reduce CHD in hypercholesterolemic patients, and subgroup analyses suggest statins are efficacious in hypertriglyceridemic patients with fasting TG levels <500 mg/dL. Omega-3 fatty acids and fibrates are reasonable first drug options for patients with TG ≥500 mg/dL and often are used to lower TG levels with the objective of reducing pancreatitis risk, although a statin or niacin may also be reasonable options. Combination lipid drug therapy may be needed to achieve both low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol treatment goals for CHD prevention in patients with elevated TG levels, particularly those with TG ≥500 mg/dL. Additional clinical outcomes data are needed to provide a more evidence-based rationale for clinical lipid management of hypertriglyceridemic patients.

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      References

      1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: 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) final report.
        Circulation. 2002; 106: 3143-3421
        • Flegal K.M.
        • Carroll M.D.
        • Ogden C.L.
        • Johnson C.L.
        Prevalence and trends in obesity among US adults, 1999–2000.
        JAMA. 2002; 288: 1723-1727
        • Ford E.S.
        • Li C.
        • Zhao G.
        • Pearson W.S.
        • Mokdad A.H.
        Hypertriglyceridemia and its pharmacologic treatment among US adults.
        Arch Intern Med. 2009; 169: 572-578
        • Miller M.
        • Stone N.J.
        • Ballantyne C.
        • et al.
        • American Heart Association Clinical Lipidology, Thrombosis, and Prevention Committee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Nursing; Council on the Kidney in Cardiovascular Disease
        Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association.
        Circulation. 2011; 123: 2292-2333
      2. U.S. Census Bureau. The 2011 Statistical Abstract. Available at: http://www.census.gov/compendia/statab/. Accessed April 23, 2012.

        • Assmann G.
        • Schulte H.
        • von Eckardstein A.
        Hypertriglyceridemia and elevated lipoprotein (a) are risk factors for major coronary events in middle-aged men.
        Am J Cardiol. 1996; 77: 1179-1184
        • Hokanson J.E.
        • Austin M.A.
        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. 1996; 3: 213-219
        • Sarwar N.
        • Danesh J.
        • Eiriksdottir G.
        • et al.
        Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 prospective studies.
        Circulation. 2007; 115: 450-458
        • Labreuche J.
        • Touboul P.J.
        • Amarenco P.
        Plasma triglyceride levels and risk of stroke and carotid atherosclerosis: a systematic review of the epidemiological studies.
        Atherosclerosis. 2009; 203: 331-345
        • Ginsberg H.N.
        New perspectives on atherogenesis: role of abnormal triglyceride-rich lipoprotein metabolism.
        Circulation. 2002; 106: 2137-2142
        • Goldberg I.J.
        • Eckel R.H.
        • McPherson R.
        Triglycerides and heart disease: Still a hypothesis?.
        Arterioscler Thromb Vasc Biol. 2011; 31: 1716-1725
        • Cromwell W.C.
        • Barringer T.A.
        Low-density lipoprotein and apolipoprotein B: clinical use in patients with coronary heart disease.
        Curr Cardiol Rep. 2009; 11: 468-475
        • Otvos J.D.
        • Mora S.
        • Shalaurova I.
        • Greenland P.
        • Mackey R.H.
        • Goff Jr., D.C.
        Clinical implications of discordance between low-density lipoprotein cholesterol and particle number.
        J Clin Lipidol. 2011; 5: 105-113
        • Rizzo M.
        • Berneis K.
        Low-density lipoprotein size and cardiovascular risk assessment.
        Q J Med. 2006; 99: 1-14
        • Bays H.
        • Conard S.
        • Leiter L.A.
        • et al.
        Are post-treatment low-density lipoprotein subclass pattern analyses potentially misleading?.
        Lipids Health Dis. 2010; 30: 136
        • Lada A.T.
        • Rudel L.L.
        Associations of low density lipoprotein particle composition with atherogenicity.
        Curr Opin Lipidol. 2004; 15: 19-24
        • Austin M.A.
        • King M.C.
        • Vranzan K.M.
        • et al.
        Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk.
        Circulation. 1990; 82: 495-506
        • Davidson M.H.
        • Maki K.C.
        • Bays H.
        • et al.
        Effects of prescription omega-3-acid ethyl esters on lipoprotein particle concentrations, apolipoproteins AI and CIII, and lipoprotein-associated phospholipase A2 mass in statin-treated subjects with hypertriglyceridemia.
        J Clin Lipidol. 2009; 3: 332-340
        • Davidson M.H.
        • Bays H.E.
        • Stein E.
        • et al.
        • TRIMS Investigators
        Effects of fenofibrate on atherogenic dyslipidemia in hypertriglyceridemic subjects.
        Clin Cardiol. 2006; 29: 268-273
        • Reaven G.M.
        • Chen Y.D.
        • Jeppesen J.
        • et al.
        Insulin resistance and hyperinsulinemia in individuals with small, dense, low density lipoprotein particles.
        J Clin Invest. 1993; 92: 141-146
        • Maki K.C.
        Fibrates for the treatment of the metabolic syndrome.
        Curr Atheroscler Rep. 2004; 6: 45-51
        • Maki K.C.
        • Galant R.
        • Davidson M.H.
        Non-high density lipoprotein cholesterol: the forgotten therapeutic target.
        Am J Cardiol. 2005; 96: 59K-64K
        • Davidson M.H.
        Strategies to improve Adult Treatment Panel III guideline adherence and patient compliance.
        Am J Cardiol. 2002; 89: 8C-22C
        • Grundy S.M.
        • Cleeman J.I.
        • Merz C.N.
        • et al.
        • National Heart, Lung, and Blood Institute; American College of Cardiology; American Heart Association
        Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.
        Circulation. 2004; 110: 227-239
        • Sniderman A.
        • McQueen M.
        • Contois J.
        • et al.
        Why is non-high-density lipoprotein cholesterol a better marker of the risk of vascular disease than low-density lipoprotein cholesterol.
        J Clin Lipidol. 2010; 4: 152-155
        • Elovson J.
        • Chatterton J.E.
        • Bell G.T.
        • et al.
        Plasma very-low-density lipoproteins contain a single molecule of apolipoprotein B.
        J Lipid Res. 1988; 29: 1461-1473
        • Liu J.
        • Sempos C.T.
        • Donahue R.P.
        • et al.
        Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease.
        Am J Cardiol. 2006; 98: 1363-1368
        • Davidson M.H.
        Apolipoprotein measurements: is more widespread use clinically indicated?.
        Clin Cardiol. 2009; 32: 482-486
        • Davidson M.H.
        • Ballantyne C.M.
        • Jacobson T.A.
        • et al.
        Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists.
        J Clin Lipidol. 2011; 5: 338-367
        • Bays H.E.
        Rationale for prescription omega-3-acid ethyl ester therapy for hypertriglyceridemia: a primer for clinicians.
        Drugs Today. 2008; 44: 205-246
        • Nordmann A.J.
        • Nordmann A.
        • Briel M.
        • et al.
        Effects of low-carbohydrate vs. low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials.
        Arch Intern Med. 2006; 166: 285-293
        • Gardner C.D.
        • Kiazand A.
        • Alhassan S.
        • et al.
        Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women: the A TO Z Weight Loss Study: a randomized trial.
        JAMA. 2007; 297: 969-977
        • Parks E.J.
        Effect of dietary carbohydrate on triglyceride metabolism in humans.
        J Nutr. 2001; 131: 2772S-2774S
        • Fried S.K.
        • Rao S.P.
        Sugars, hypertriglyceridemia, and cardiovascular disease.
        Am J Clin Nutr. 2003; 78: 873S-880S
        • Stanope K.L.
        • Havel P.
        Fructose consumption: recent results and their potential implications.
        Ann N Y Acad Sci. 2010; 1190: 15-24
        • Theuwissen E.
        • Plat J.
        • van der Kallen C.J.
        • et al.
        Plant stanol supplementation decreases serum triacylglycerols in subjects with overt hypertriglyceridemia.
        Lipids. 2009; 44: 1131-1140
        • Demonty I.
        • Ras R.T.
        • van der Knaap H.C.M.
        • et al.
        Continuous dose-response relationship of the LDL-cholesterol-lowering effect of phytosterol intake.
        J Nutr. 2009; 139: 271-284
        • Eleftheriadou I.
        • Grigoropoulou P.
        • Katsilambros N.
        • et al.
        The effects of medications used for the management of diabetes and obesity on postprandial lipid metabolism.
        Curr Diabetes Rev. 2008; 4: 340-356
        • Crouse 3rd, J.R.
        Hypertriglyceridemia: a contraindication to the use of bile acid binding resins.
        Am J Med. 1987; 83: 243-248
      3. LIPITOR® (atorvastatin calcium) Tablets. Prescribing information.
        Parke-Davis, Division of Pfizer Inc., New YorkJune 2009
      4. CRESTOR® (rosuvastatin calcium) Tablets. Prescribing information.
        AstraZeneca Pharmaceuticals LP, Wilmington, DEMay 2011
      5. ZOCOR® (simvastatin) Tablets. Prescribing information.
        Merck & Co., Inc., Whitehouse Station, NJJune 2011
      6. LESCOL® XL (fluvastatin sodium 80 mg). Prescribing information.
        Novartis Pharmaceuticals Corporation, East Hanover, NJJuly 2011
        • Jones P.H.
        • Davidson M.H.
        • Stein E.A.
        • et al.
        • for the STELLAR Study Group
        Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR) trial.
        Am J Cardiol. 2003; 92: 152-160
        • McKenney J.M.
        • Jones P.H.
        • Adamczyk A.
        • et al.
        • for the STELLAR Study Group
        Comparison of the efficacy of rosuvastatin versus atorvastatin, simvastatin, and pravastatin in achieving lipid goals: results from the STELLAR trial.
        Curr Med Res Opin. 2003; 19: 689-698
        • McKenney J.M.
        Efficacy and safety of rosuvastatin in treatment of dyslipidemia.
        Am J Health Syst Pharm. 2005; 62: 1033-1047
        • Sasaki J.
        Pitavastatin approved for treatment of primary hypercholesterolemia and combined dyslipidemia.
        Vasc Health Risk Manag. 2010; 6: 997-1005
        • Bays H.
        Clinical overview of Omacor: a concentrated formulation of omega-3 polyunsaturated fatty acids.
        Am J Cardiol. 2006; 98: 71i-76i
        • Maki K.C.
        • McKenney J.M.
        • Reeves M.S.
        • et al.
        Effects of adding prescription omega-3 acid ethyl esters to simvastatin (20 mg/day) on lipids and lipoprotein particles in men and women with mixed dyslipidemia.
        Am J Cardiol. 2008; 102: 429-433
        • Ballantyne C.M.
        • Bays H.E.
        • Kastelein J.J.
        • et al.
        AMR101 lowers triglycerides, atherogenic lipoprotein, phospholipase A2, and high-sensitivity C-reactive protein levels in patients with high triglycerides and on background statin therapy (the ANCHOR study).
        Circulation. 2011; 124: A15071
      7. TRICOR 48 mg and 145 mg (fenofibrate tablets). Prescribing information.
        Abbott Laboratories, North Chicago, ILOctober 2010
      8. Trilipix®(fenofibric acid delayed release capsules). Prescribing Information.
        Abbott Laboratories, North Chicago, ILSeptember 2010
      9. Antara® (fenofibrate) Capsules. Prescribing information.
        Lupin Pharma, Baltimore, MDNovember 2009
        • Elisaf M.
        Effects of fibrates on serum metabolic parameters.
        Curr Med Res Opin. 2002; 18: 269-276
        • Knopp R.H.
        • Brown W.V.
        • Dujovne C.A.
        • et al.
        Effects of fenofibrate on plasma lipoproteins in hypercholesterolemia and combined hyperlipidemia.
        Am J Med. 1987; 83: 50-59
        • Keating G.M.
        Fenofibrate: a review of its lipid-modifying effects in dyslipidemia and its vascular effects in type 2 diabetes mellitus.
        Am J Cardiovasc Drugs. 2011; 11: 227-247
      10. Niaspan® Tablets (niacin extended release tablets). Prescribing information.
        Abbott Laboratories, North Chicago ILDecember 2010
        • Morgan J.M.
        • Capuzzi D.M.
        • Guyton J.R.
        • et al.
        Treatment effect of Niaspan, a controlled-release niacin, in patients with hypercholesterolemia: a placebo-controlled trial.
        J Cardiovasc Pharmacol Ther. 1996; 1: 195-202
        • Capuzzi D.M.
        • Guyton J.R.
        • Morgan J.M.
        • et al.
        Efficacy and safety of an extended-release niacin (Niaspan): a long-term study.
        Am J Cardiol. 1998; 82: 74U-81U
        • McKenney J.
        New perspectives on the use of niacin in the treatment of lipid disorders.
        Arch Intern Med. 2004; 164: 697-705
        • Carlson L.A.
        Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review.
        J Intern Med. 2005; 258: 94-114
        • Bakker-Arkema R.H.
        • Davidson M.H.
        • Goldstein R.J.
        • et al.
        Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia.
        JAMA. 1996; 275: 128-133
        • Hunninghake D.B.
        • Stein E.A.
        • Bays H.E.
        • et al.
        Rosuvastatin improves the atherogenic and atheroprotective lipid profiles in patients with hypertriglyceridemia.
        Coron Artery Dis. 2004; 15: 115-123
        • Harris W.S.
        • Ginsberg H.N.
        • Arunakul N.
        • et al.
        Safety and efficacy of Omacor in severe hypertriglyceridemia.
        J Cardiovasc Risk. 1997; 4: 385-391
        • Balk E.
        Effects of Omega-3-Fatty Acids on Cardiovascular Risk Factors and Intermediate Markers of Cardiovascular Disease.
        Agency for Healthcare Research and Quality, Rockville, MD2004
        • Maki K.C.
        • Dicklin M.R.
        • Lawless A.L.
        • Reeves M.S.
        Omega-3 fatty acids for the treatment of elevated triglycerides.
        Clin Lipidol. 2009; 4: 425-437
        • Bays H.E.
        • Ballantyne C.M.
        • Kastelein J.J.
        • et al.
        Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with very high triglyceride levels [from the Multi-center, plAcebo-controlled, Randomized, double-blINd, 12-week study with open-label Extension (MARINE) trial].
        Am J Cardiol. 2011; 108: 682-690
      11. Lovaza® (omega-3-acid ethyl esters capsules). Prescribing Information.
        Glaxo SmithKline, Research Triangle Park, NCDecember 2010
        • Packard C.J.
        Overview of fenofibrate.
        Eur Heart J. 1998; 19: A62-A65
        • Goldberg A.C.
        • Schonfeld G.
        • Feldman E.B.
        • et al.
        Fenofibrate for the treatment of type IV and V hyperlipoproteinemias: a double-blind, placebo-controlled multicenter US study.
        Clin Ther. 1989; 11: 69-83
        • Ballantyne C.M.
        • Bertolami H.
        • Hernandez Garcia H.R.
        • et al.
        Achieving LDL cholesterol, non-HDL cholesterol and apolipoprotein B target levels in high-risk patients: Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapy (MERCURY) II.
        Am Heart J. 2006; 151: 975.e1-975.e9
        • Shepherd J.
        • Cobbe S.M.
        • Ford I.
        • et al.
        Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.
        N Engl J Med. 1995; 333: 1301-1307
        • Sacks F.M.
        • Pfeffer M.A.
        • Moye L.A.
        • et al.
        The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.
        N Engl J Med. 1996; 335: 1001-1009
        • Sacks F.M.
        • Tonkin A.M.
        • Shepherd J.
        • et al.
        Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project.
        Circulation. 2000; 102: 1893-1900
        • Scandinavian Simvastatin Survival Study Group
        Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
        Lancet. 1994; 344: 1383-1389
        • Ballantyne C.M.
        • Olsson A.G.
        • Cook T.J.
        • et al.
        Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S.
        Circulation. 2001; 104: 3046-3051
        • Ridker P.M.
        • Danielson E.
        • Fonseca F.A.
        • et al.
        • JUPITER Study Group
        Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.
        N Engl J Med. 2008; 359: 2195-2207
        • Glynn R.J.
        • Koenig W.
        • Nordestgaard B.G.
        • et al.
        Rosuvastatin for primary prevention in older individuals with high C-reactive protein and low LDL levels: exploratory analysis of a randomized trial.
        Ann Intern Med. 2010; 152: 488-496
        • Cholesterol Treatment Trialists’ (CTT) Collaborators
        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: 1267-1278
        • Downs J.R.
        • Clearfield M.
        • Weis S.
        • et al.
        Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.
        JAMA. 1998; 279: 1615-1622
        • The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group
        Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.
        N Engl J Med. 1998; 339: 1349-1357
        • Pedersen T.R.
        • Olsson A.G.
        • Faergeman O.
        • et al.
        • for the Scandinavian Simvastatin Survival Study Group
        Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S).
        Circulation. 1998; 97: 1453-1460
        • Heart Protection Study Collaborative Group
        MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,535 high-risk individuals: a randomized placebo-controlled trial.
        Lancet. 2002; 360: 7-22
        • Sever P.S.
        • Dahlöf B.
        • Poulter N.R.
        • et al.
        • ASCOT Investigators
        Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.
        Lancet. 2003; 361: 1149-1158
        • Topol E.J.
        Intensive statin therapy—a sea change in cardiovascular prevention.
        N Engl J Med. 2004; 305: 1562-1564
        • Pedersen F.R.
        • Faergeman O.
        • Kastelein J.J.
        • et al.
        • Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group
        High-dose atorvastatin vs. usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.
        JAMA. 2005; 294: 2437-2445
        • Shepherd J.
        • Barter P.
        • Carmena R.
        • et al.
        Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study.
        Diabetes Care. 2006; 29: 1220-1226
        • Miller M.
        • Cannon C.P.
        • Murphy S.A.
        • et al.
        • for the PROVE IT-TIMI 22 Investigators
        Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 Trial.
        J Am Coll Cardiol. 2008; 51: 724-730
        • Frick M.H.
        • Elo O.
        • Haapa K.
        • et al.
        Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease.
        N Engl J Med. 1987; 317: 1237-1245
        • Manninen V.
        • Tenkanen L.
        • Koskinen P.
        • et al.
        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
        • Tenkanen L.
        • Manttari M.
        • Kovanen P.T.
        • et al.
        Gemfibrozil in the treatment of dyslipidemia: An 18-year mortality follow-up of the Helsinki Heart Study.
        Arch Intern Med. 2006; 166: 743-748
        • The BIP Study Group
        Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study.
        Circulation. 2000; 102: 21-27
        • Rubins H.B.
        • Robins S.J.
        • Collins D.
        • et al.
        • for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group
        Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol.
        N Engl J Med. 1999; 341: 410-418
        • Keech A.
        • Simes R.J.
        • Barter P.
        • et al.
        • FIELD study investigators
        Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.
        Lancet. 2005; 366: 1849-1861
        • Scott R.
        • O’Brien R.
        • Fulcher G.
        • et al.
        • Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study Investigators
        Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.
        Diabetes Care. 2009; 32: 493-498
        • Ginsberg H.N.
        • Elam M.B.
        • Lovato L.C.
        • et al.
        • ACCORD Study Group
        Effects of combination lipid therapy in type 2 diabetes mellitus.
        N Engl J Med. 2010; 362: 1563-1564
        • Yokoyama M.
        • Origasa H.
        • Matsuzaki M.
        • et al.
        • Japan EPA lipid intervention study (JELIS) Investigators
        Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
        Lancet. 2007; 369: 1090-1098
        • Saito Y.
        • Yokoyama M.
        • Origasa H.
        • et al.
        • for the JELIS Investigators, Japan
        Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS).
        Atherosclerosis. 2008; 200: 135-140
        • Boden W.E.
        • Probstfield J.L.
        • Anderson T.
        • et al.
        • AIM-HIGH Investigators
        Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
        N Engl J Med. 2011; 365: 2255-2267
        • Bays H.E.
        • Roth E.M.
        • McKenney J.M.
        • et al.
        The effects of fenofibric acid alone and with statins on the prevalence of metabolic syndrome and its diagnostic components in patients with mixed dyslipidemia.
        Diabetes Care. 2010; 33: 2113-2116
        • Preiss D.
        • Seshasai S.R.
        • Welsh P.
        • et al.
        Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.
        JAMA. 2011; 305: 2556-2564
        • Sattar N.
        • Preiss D.
        • Murray H.M.
        • et al.
        Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.
        Lancet. 2010; 375: 735-742
        • Culver A.L.
        • Ockene I.S.
        • Balasubramanian R.
        • et al.
        Statin use and risk of diabetes mellitus in postmenopausal women in the Women’s Health Initiative.
        Arch Intern Med. 2012; 172: 144-152
        • Musa-Veloso K.
        • Binns M.A.
        • Kocenas A.C.
        • et al.
        Long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid dose-dependently reduce fasting serum triglycerides.
        Nutr Rev. 2010; 68: 155-167
        • Maki K.C.
        • Rains T.M.
        Low-dose eicosapentaenoic acid and/or docosahexaenoic acid and triglyceride lowering.
        Nutr Rev. 2010; 68: 567-568
        • Kris-Etherton P.M.
        • Harris W.S.
        • Appel L.J.
        • for the American Heart Association Nutrition Committee
        Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease.
        Circulation. 2002; 106: 2747-2757
        • Bays H.E.
        Fish oils in the treatment of dyslipidemia and cardiovascular disease.
        in: Kwiterovich Jr., P.O. The John Hopkins Textbook of Dyslipidemia. Lippincott Williams & Wilkins, Philadelphia2010: 245-257
        • Skulas-Ray A.C.
        • Kris-Etherton P.M.
        • Harris W.S.
        • et al.
        Dose-response effects of omega-3 fatty acids on triglycerides, inflammation, and endothelial function in healthy persons with moderate hypertriglyceridemia.
        Am J Clin Nutr. 2011; 93: 243-252
        • De Backer G.
        • Ambrosioni E.
        • Borch-Johnsen K.
        • et al.
        European Guidelines on Cardiovascular Disease Prevention in Clinical Practice. Third Joint Task Force of European and Other Societies on Cardiovascular Prevention in Clinical Practice.
        Eur Heart J. 2003; 24: 1601-1610
        • Von Schacky C.
        • Harris W.S.
        Cardiovascular benefits of omega-3 fatty acids.
        Cardiovasc Res. 2007; 73: 310-315
        • Chan D.C.
        • Watts G.F.
        • Barrett P.H.R.
        • et al.
        Regulatory effects of HMG CoA reductase inhibitors and fish oils on Apo B-100 kinetics in insulin-resistant obese male subjects with dyslipidemia.
        Diabetes. 2002; 51: 2377-2386
        • Chan D.C.
        • Watts G.F.
        • Mori T.A.
        • et al.
        Randomized controlled trial of the effect of n-3 fatty acid supplementation on the metabolism of apolipoprotein B-100 and chylomicron remnants in men with visceral obesity.
        Am J Clin Nutr. 2003; 77: 300-307
        • Bays H.E.
        • Tighe A.P.
        • Sadovsky R.
        • et al.
        Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications.
        Expert Rev Cardiovasc Ther. 2008; 6: 391-409
        • Harris W.S.
        • Miller M.
        • Tighe A.P.
        • Davidson M.H.
        • Schaefer E.J.
        Omega-3 fatty acids and coronary heart disease risk: Clinical and mechanistic perspectives.
        Atherosclerosis. 2008; 187: 12-24
        • Maki K.C.
        • Bays H.E.
        • Dicklin M.R.
        • et al.
        Effects of prescription omega-3-acid ethyl esters coadministered with atorvastatin, on circulating levels of lipoprotein particles, apolipoprotein CIII, and lipoprotein-associated phospholipase A2 mass in men and women with mixed dyslipidemia.
        J Clin Lipidol. 2011; 5: 483-492
        • Harris W.S.
        n-3 fatty acids and serum lipoproteins: human studies.
        Am J Clin Nutr. 1997; 65: 1645S-1654S
        • Pownall H.J.
        • Brauchi D.
        • Kilinc C.
        • et al.
        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
        • Calabresi L.
        • Donati D.
        • Pazzucconi F.
        • et al.
        Omacor in familial combined hyperlipidemia: effects on lipids and low density lipoprotein subclasses.
        Atherosclerosis. 2000; 148: 387-396
        • Davidson M.H.
        • Stein E.A.
        • Bays H.E.
        • et al.
        Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 4 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study.
        Clin Ther. 2007; 29: 1354-1367
        • Maki K.C.
        • Dicklin M.R.
        • Davidson M.H.
        • et al.
        • COMBination of prescription Omega-3 with Simvastatin (COMBOS) Investigators
        Baseline lipoprotein lipids and low-density lipoprotein cholesterol response to prescription omega-3 acid ethyl ester added to simvastatin therapy.
        Am J Cardiol. 2010; 105: 1409-1412
        • Burr M.L.
        • Fehily A.M.
        • Gilbert J.F.
        • et al.
        Effects of changes in fat, fish and fibre intakes on death and myocardial infarction: Diet And Reinfarction Trial (DART).
        Lancet. 1989; 2: 757-761
        • GISSI-Prevenzione
        Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: Results of the GISSI-Prevenzione trial: Gruppo Italiano per lo Studio della Sopravvivenza nell’ infarto miocardico.
        Lancet. 1999; 354: 447-455
        • Matsuzaki M.
        • Yokoyama M.
        • Saito Y.
        • et al.
        • for the JELIS Investigators, Japan
        Incremental effects of eicosapentaenoic acid on cardiovascular events in statin-treated patients with coronary artery disease: secondary prevention analysis from JELIS.
        Circ J. 2009; 73: 1283-1290
        • Jacobson T.A.
        • Glickstein S.B.
        • Rowe J.D.
        • et al.
        Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review.
        J Clin Lipidol. 2012; 6: 5-18
        • Bays H.
        • McElhattan J.
        • Bryzinski B.S.
        • Gallant 6 Study Group
        A double-blind, randomised trial of tesaglitazar versus pioglitazone in patients with type 2 diabetes mellitus.
        Diab Vasc Dis Res. 2007; 4: 181-193
        • Robins S.J.
        • Collins D.
        • Wittes J.T.
        • et al.
        • VA-HIT Study Group, Veterans Affairs High-Density Lipoprotein Intervention Trial
        Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial.
        JAMA. 2001; 285: 1585-1591
        • Tenkanen L.
        • Manttari M.
        • Manninen V.
        Some coronary risk factors related to the insulin resistance syndrome and treatment with gemfibrozil. Experience from the Helsinki Heart Study.
        Circulation. 1995; 92: 1779-1785
        • Sacks F.M.
        • Carey V.J.
        • Fruchart J.C.
        Combination lipid therapy in type 2 diabetes.
        N Engl J Med. 2010; 363: 692-695
        • Kamanna V.S.
        • Kashap M.L.
        Mechanism of action of niacin.
        Am J Cardiol. 2008; 101: 20B-26B
        • Elam M.B.
        • Hunninghake D.B.
        • Davis K.B.
        • et al.
        Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study, a randomized trial. Arterial Disease Multiple Intervention Trial.
        JAMA. 2000; 284: 1263-1270
        • Shepherd J.
        • Betteridge J.
        • Van Gaal L.
        Nicotinic acid in the management of dyslipidemia associated with diabetes and metabolic syndrome: a position paper developed by a European Consensus Panel.
        Curr Med Res Opin. 2005; 21: 665-682
        • Cheng K.
        • Wu T.J.
        • Wu K.K.
        • et al.
        Antagonism of the prostaglandin D2 receptor I suppresses nicotinic acid-induced vasodilation in mice and humans.
        Proc Natl Acad Sci U S A. 2006; 103: 6682-6687
        • Bays H.E.
        • Ballantyne C.
        What’s the deal with niacin development: is laropiprant add-on therapy a winning strategy to beat a straight flush?.
        Curr Opin Lipidol. 2009; 20: 467-476
        • Canner P.L.
        • Berge K.G.
        • Wenger N.K.
        • et al.
        Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin.
        J Am Coll Cardiol. 1986; 8: 1245-1255
        • Brown G.
        • Albers J.J.
        • Fisher L.D.
        • et al.
        Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B.
        N Engl J Med. 1990; 323: 1289-1298
        • Zhao X.Q.
        • Morse J.S.
        • Dowdy A.A.
        • et al.
        Safety and tolerability of simvastatin plus niacin in patients with coronary artery disease and low high-density lipoprotein cholesterol (The HDL Atherosclerosis Treatment Study).
        Am J Cardiol. 2004; 93: 307-312
        • Villines T.C.
        • Stanek E.J.
        • Devine P.J.
        • et al.
        The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol-6 HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration.
        J Am Coll Cardiol. 2010; 55: 2721-2726
        • Vasudevan A.R.
        • Jones P.H.
        Effective use of combination lipid therapy.
        Curr Atheroscler Rep. 2006; 8: 76-84
        • McKenney J.M.
        • Jones P.H.
        • Bays H.E.
        • et al.
        Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study).
        Atherosclerosis. 2007; 192: 432-437
        • Barter P.
        • Ginsberg H.N.
        Effectiveness of combined statin plus omega-3 fatty acid therapy for mixed dyslipidemia.
        Am J Cardiol. 2008; 102: 1040-1045
        • Moutzouri E.
        • Kei A.
        • Elisaf M.S.
        • Milionis H.J.
        Management of dyslipidemias with fibrates, alone or in combination with statins: role of delayed-release fenofibric acid.
        Vasc Health Risk Manag. 2010; 6: 525-539
        • Chapman M.J.
        • Ginsberg H.N.
        • Amarenco P.
        • et al.
        • European Atherosclerosis Society Consensus Panel
        Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management.
        Eur Heart J. 2011; 32: 1345-1361
        • McKenney J.M.
        • Farnier M.
        • Lo K.W.
        • et al.
        Safety and efficacy of long-term co-administration of fenofibrate and ezetimibe in patients with mixed hyperlipidemia.
        J Am Coll Cardiol. 2006; 47: 1584-1587
        • Roth E.M.
        • Bays H.E.
        • Forker A.D.
        • et al.
        Prescription omega-3 fatty acid as an adjunct to fenofibrate therapy in hypertriglyceridemic subjects.
        J Cardiovasc Pharmacol. 2009; 54: 196-203
        • Bays H.E.
        Statin safety: an overview and assessment of the data—2005.
        Am J Cardiol. 2006; 97: S6-S26