Nonstatin Therapies for Management of Dyslipidemia: A Review

National Center for Chronic Disease Prevention and Health Promotion. Heart Disease and Stroke Prevention: Addressing the National’s Leading Killers. At a Glance (2011). Centers for Disease Control. http://198.246.124.29/chronicdisease/resources/publications/aag/pdf/2011/heart-disease-and-stroke-aag-2011.pdf. Accessed April 20, 2015. Stone, 2014, 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines, J Am Coll Cardiol, 63, 2889, 10.1016/j.jacc.2013.11.002 Jacobson, 2014, National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 – Executive Summary, J Clin Lipidol, 8, 473, 10.1016/j.jacl.2014.07.007 2002, 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), Circulation, 106, 3143, 10.1161/circ.106.25.3143 2013, N–3 fatty acids in patients with multiple cardiovascular risk factors, N Engl J Med, 368, 1800, 10.1056/NEJMoa1205409 Parish, 2014, Effects of extended-release niacin with laropiprant in high-risk patients, N Engl J Med, 371, 203, 10.1056/NEJMoa1300955 Ginsberg, 2010, Effects of combination lipid therapy in type 2 diabetes mellitus, N Engl J Med, 362, 1563, 10.1056/NEJMoa1001282 Kamanna, 2008, Mechanism of action of niacin, Am J Cardiol, 101, 20B, 10.1016/j.amjcard.2008.02.029 1975, Clofibrate and niacin in coronary heart disease, JAMA, 231, 360, 10.1001/jama.1975.03240160024021 Canner, 1986, Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin, J Am Coll Cardiol, 8, 1245, 10.1016/S0735-1097(86)80293-5 Carlson, 1988, Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid, Acta Med Scand, 223, 405, 10.1111/j.0954-6820.1988.tb15891.x Blankenhorn, 1987, Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts, JAMA, 257, 3233, 10.1001/jama.1987.03390230069027 Cashin-Hemphill, 1990, Beneficial effects of colestipol-niacin on coronary atherosclerosis: a 4-year follow-up, JAMA, 264, 3013, 10.1001/jama.1990.03450230049028 Brown, 1991, 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, 325, 599 Brown, 2001, Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease, N Engl J Med, 345, 1583, 10.1056/NEJMoa011090 Taylor, 2004, Arterial Biology for the Investigation of the Treatment Effects of Reducing cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins, Circulation, 110, 3512, 10.1161/01.CIR.0000148955.19792.8D Taylor, 2009, Extended-release niacin or ezetimibe and carotid intima-media thickness, N Engl J Med, 361, 2113, 10.1056/NEJMoa0907569 Whitney, 2005, A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: effects on progression of coronary heart disease and clinical events, Ann Intern Med, 142, 95, 10.7326/0003-4819-142-2-200501180-00008 Boden, 2011, Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy, N Engl J Med, 365, 2255, 10.1056/NEJMoa1107579 Duggal, 2010, Effect of niacin therapy on cardiovascular outcomes in patients with coronary artery disease, J Cardiovasc Pharmacol Ther, 15, 158, 10.1177/1074248410361337 Teo, 2013, Extended-release niacin therapy and risk of ischemic stroke in patients with cardiovascular disease–the Atherothrombosis Intervention in Metabolic Syndrome with low HDL/high triglycerides: impact on global health outcome (AIM-HIGH) trial, Stroke, 44, 2688, 10.1161/STROKEAHA.113.001529 Lavigne, 2013, The current state of niacin in cardiovascular disease prevention: a systematic review and meta-regression, J Am Coll Cardiol, 61, 440, 10.1016/j.jacc.2012.10.030 Bays, 2008, Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications, Expert Rev Cardiovasc Ther, 6, 391, 10.1586/14779072.6.3.391 Bradberry, 2013, Overview of omega-3 fatty acid therapies, PT, 38, 681 Lavie, 2009, Omega-3 polyunsaturated fatty acids and cardiovascular diseases, J Am Coll Cardiol, 54, 585, 10.1016/j.jacc.2009.02.084 Grundy, 2004, Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines, Circulation, 110, 227, 10.1161/01.CIR.0000133317.49796.0E Berglund, 2012, Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab, 97, 2969, 10.1210/jc.2011-3213 Harper, 2005, Usefulness of omega-3 fatty acids and the prevention of coronary heart disease, Am J Cardiol, 96, 1521, 10.1016/j.amjcard.2005.07.071 Wang, 2006, n-3 Fatty acids from fish or fish-oil supplements, but not alpha-linolenic acid, benefit cardiovascular disease outcomes in primary- and secondary-prevention studies: a systematic review, Am J Clin Nutr, 84, 5, 10.1093/ajcn/84.1.5 Geleijnse, 2010, Alpha-linolenic acid: is it essential to cardiovascular health?, Curr Atheroscler Rep, 12, 359, 10.1007/s11883-010-0137-0 Zargar, 2011, Long chain omega-3 dietary supplements: a review of the National Library of Medicine Herbal Supplement Database, Metab Syndr Relat Disord, 9, 255, 10.1089/met.2011.0004 Weintraub, 2014, Overview of prescription omega-3 fatty acid products for hypertriglyceridemia, Postgrad Med, 126, 7, 10.3810/pgm.2014.11.2828 Burr, 1989, Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART), Lancet, 2, 757, 10.1016/S0140-6736(89)90828-3 1999, 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, 354, 447, 10.1016/S0140-6736(99)07072-5 Burr, 2003, Lack of benefit of dietary advice to men with angina: results of a controlled trial, Eur J Clin Nutr, 57, 193, 10.1038/sj.ejcn.1601539 Yokoyama, 2007, Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis, Lancet, 369, 1090, 10.1016/S0140-6736(07)60527-3 Tavazzi, 2008, Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial, Lancet, 372, 1223, 10.1016/S0140-6736(08)61239-8 Kromhout, 2010, N-3 fatty acids and cardiovascular events after myocardial infarction, N Engl J Med, 363, 2015, 10.1056/NEJMoa1003603 Rauch, 2010, OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction, Circulation, 122, 2152, 10.1161/CIRCULATIONAHA.110.948562 Galan, 2010, Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial, BMJ, 341, c6273, 10.1136/bmj.c6273 2012, The ORIGIN Trial Investigators. n–3 fatty acids and cardiovascular outcomes in patients with dysglycemia, N Engl J Med, 367, 309, 10.1056/NEJMoa1203859 Hu, 2002, Fish and omega-3 fatty acid intake and risk of coronary heart disease in women, JAMA, 287, 1815, 10.1001/jama.287.14.1815 Albert, 1998, Fish consumption and risk of sudden cardiac death, JAMA, 279, 23, 10.1001/jama.279.1.23 Wu, 2014, ω-3 Fatty acids, atherosclerosis progression and cardiovascular outcomes in recent trials: new pieces in a complex puzzle, Heart, 100, 530, 10.1136/heartjnl-2013-305257 Chen, 2011, Effects of omega-3 fatty acid for sudden cardiac death prevention in patients with cardiovascular disease: a contemporary meta-analysis of randomized, controlled trials, Cardiovasc Drugs Ther, 25, 259, 10.1007/s10557-011-6306-8 Hartweg, 2008, Omega-3 polyunsaturated fatty acids (PUFA) for type 2 diabetes mellitus, Cochrane Database Syst Rev, 10.1002/14651858.CD003205.pub2 Rizos, 2012, Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis, JAMA, 308, 1024, 10.1001/2012.jama.11374 Kwak, 2012, Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials, Arch Intern Med, 172, 686, 10.1001/archinternmed.2012.262 Kotwal, 2012, Omega 3 fatty acids and cardiovascular outcomes: systematic review and meta-analysis, Circ Cardiovasc Qual Outcomes, 5, 808, 10.1161/CIRCOUTCOMES.112.966168 Gupta, 2010, Systematic review on evidence of the effectiveness of cholesterol-lowering drugs, Adv Ther, 27, 348, 10.1007/s12325-010-0033-6 Filion, 2010, Omega-3 fatty acids in high-risk cardiovascular patients: a meta-analysis of randomized controlled trials, BMC Cardiovasc Disord, 10, 24, 10.1186/1471-2261-10-24 Enns, 2014, The impact of omega-3 polyunsaturated fatty acid supplementation on the incidence of cardiovascular events and complications in peripheral arterial disease: a systematic review and meta-analysis, BMC Cardiovasc Disord, 14, 70, 10.1186/1471-2261-14-70 Chowdhury, 2012, Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: systematic review and meta-analysis, BMJ, 345, e6698, 10.1136/bmj.e6698 Yzebe, 2004, Fish oils in the care of coronary heart disease patients: a meta-analysis of randomized controlled trials, Fundam Clin Pharmacol, 18, 581, 10.1111/j.1472-8206.2004.00268.x Hooper, 2004, Omega 3 fatty acids for prevention and treatment of cardiovascular disease, Cochrane Database Syst Rev, 10.1002/14651858.CD003177.pub2 Studer, 2005, Effect of different antilipidemic agents and diets on mortality: a systematic review, Arch Intern Med, 165, 725, 10.1001/archinte.165.7.725 Zhao, 2009, Prevention of sudden cardiac death with omega-3 fatty acids in patients with coronary heart disease: a meta-analysis of randomized controlled trials, Ann Med, 41, 301, 10.1080/07853890802698834 Delgado-Lista, 2012, Long chain omega-3 fatty acids and cardiovascular disease: a systematic review, Br J Nutr, 107, S201, 10.1017/S0007114512001596 Di Minno, 2010, Exploring newer cardioprotective strategies: n-3 fatty acids in perspective, Thromb Haemost, 104, 664, 10.1160/TH10-01-0008 Khoury, 2011, The use of fibric acid derivatives in cardiovascular prevention, Curr Treat Options Cardiovasc Med, 13, 335, 10.1007/s11936-011-0128-7 Goyal, 2014, Cardiometabolic impact of non-statin lipid lowering therapies, Curr Atheroscler Rep, 16, 390, 10.1007/s11883-013-0390-0 Reiner, 2010, Combined therapy in the treatment of dyslipidemia, Fundam Clin Pharmacol, 24, 19, 10.1111/j.1472-8206.2009.00764.x 2000, Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study, Circulation, 102, 21, 10.1161/01.CIR.102.1.21 Frick, 1987, Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia, N Engl J Med, 317, 1237, 10.1056/NEJM198711123172001 Rubins, 1999, Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol, N Engl J Med, 341, 410, 10.1056/NEJM199908053410604 Keech, 2005, Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomized controlled trial, Lancet, 366, 1849, 10.1016/S0140-6736(05)67667-2 Arthur, 1971, Trial of clofibrate in the treatment of ischaemic heart disease. Five-year study by a group of physicians of the Newcastle upon Tyne region, BMJ, 4, 767, 10.1136/bmj.4.5790.767 1971, Ischaemic heart disease: a secondary prevention trial using clofibrate. Report by a research committee of the Scottish Society of Physicians, BMJ, 4, 775, 10.1136/bmj.4.5790.775 Acheson, 1972, Controlled trial of clofibrate in cerebral vascular disease, Atherosclerosis, 15, 177, 10.1016/0021-9150(72)90067-6 1973, The treatment of cerebrovascular disease with clofibrate. Final report of the Veterans Administration Cooperative Study of Atherosclerosis, Neurology Section, Stroke, 4, 684, 10.1161/01.STR.4.4.684 1978, Cooperative trial committee of principal investigators. A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Report from the Committee of Principal Investigators, Br Heart J, 40, 1069, 10.1136/hrt.40.10.1069 Hanefeld, 1991, Diabetes Intervention Study. Multi-intervention trial in newly diagnosed NIDDM, Diabetes Care, 14, 308, 10.2337/diacare.14.4.308 Tenkanen, 1995, Some coronary risk factors related to the insulin resistance syndrome and treatment with gemfibrozil. Experience from the Helsinki Heart Study, Circulation, 92, 1779, 10.1161/01.CIR.92.7.1779 Jun, 2010, Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis, Lancet, 375, 1875, 10.1016/S0140-6736(10)60656-3 Birjmohun, 2005, Stroes ESG. Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials, J Am Coll Cardiol, 45, 185, 10.1016/j.jacc.2004.10.031 Allemann, 2006, Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus: meta-analysis of randomised controlled trials, Curr Med Res Opin, 22, 617, 10.1185/030079906X89865 Jun, 2012, Effects of fibrates in kidney disease: a systematic review and meta-analysis, J Am Coll Cardiol, 60, 2061, 10.1016/j.jacc.2012.07.049 Abourbih, 2009, Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review, Am J Med, 122, 962.e1, 10.1016/j.amjmed.2009.03.030 Keene, 2014, Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients, BMJ, 349, g4379, 10.1136/bmj.g4379 Gudzune, 2014, Effectiveness of combination therapy with statin and another lipid-modifying agent compared with intensified statin monotherapy, Ann Intern Med, 160, 468, 10.7326/M13-2526 Studer, 2005, Effect of different antilipidemic agents and diets on mortality: a systematic review, Arch Intern Med, 165, 725, 10.1001/archinte.165.7.725 Saha, 2010, Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus - a pooled meta-analysis of randomized placebo-controlled clinical trials, Int J Cardiol, 141, 157, 10.1016/j.ijcard.2008.11.211 Corvol, 2003, Differential effects of lipid-lowering therapies on stroke prevention: a meta-analysis of randomized trials, Arch Intern Med, 163, 669, 10.1001/archinte.163.6.669 Zhou, 2013, Lipid management in the prevention of stroke: a meta-analysis of fibrates for stroke prevention, BMC Neurol, 13, 1, 10.1186/1471-2377-13-1 Lee, 2011, Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis, Atherosclerosis, 217, 492, 10.1016/j.atherosclerosis.2011.04.020 Bruckert, 2011, Fibrates effect on cardiovascular risk is greater in patients with high triglyceride levels or atherogenic dyslipidemia profile: a systematic review and meta-analysis, J Cardiovasc Pharmacol, 57, 267, 10.1097/FJC.0b013e318202709f Nordmann, 2012, Fibrates for primary prevention of cardiovascular disease events, Cochrane Database Syst Rev, 10.1002/14651858.CD009753 Einarsson, 1991, Bile acid sequestrants: mechanisms of action on bile acid and cholesterol metabolism, Eur J Clin Pharmacol, 40, S53, 10.1007/BF03216291 Monroe AK, Gudzune KA, Sharma R, et al. Combination Therapy Versus Intensification of Statin Monotherapy: An Update, Comparative Effectiveness Review No 132. AHRQ Publication No. 14-EHC013-EF. Rockville, MD: Agency for Healthcare Research and Quality; February 2014. http://www.ncbi.nlm.nih.gov/books/NBK189822/. Accessed April 22, 2015. Kamal-Bahl, 2007, Discontinuation of lipid modifying drugs among commercially insured United States patients in recent clinical practice, Am J Cardiol, 99, 530, 10.1016/j.amjcard.2006.08.063 1984, The relationship of reduction in incidence of coronary heart disease to cholesterol lowering, JAMA, 251, 365, 10.1001/jama.1984.03340270043026 Dorr, 1978, Colestipol hydrochloride in hypercholesteroleamic patients- effect on serum cholesterol and mortality, J Chronic Dis, 31, 5, 10.1016/0021-9681(78)90076-0 Schrott, 1995, Enhanced low-density lipoprotein cholesterol reduction and cost-effectiveness by low-dose colestipol plus lovastatin combination therapy, Am J Cardiol, 75, 34, 10.1016/S0002-9149(99)80523-2 Knapp, 2001, Efficacy and safety of combination simvastatin and colesevelam in patients with primary hypercholesterolemia, Am J Med, 110, 352, 10.1016/S0002-9343(01)00638-6 Hunninghake, 2001, Coadministration of colesevelam hydrochloride with atorvastatin lowers LDL cholesterol additively, Atherosclerosis, 158, 407, 10.1016/S0021-9150(01)00437-3 1993, Comparative efficacy and safety of pravastatin and cholestyramine alone and combined in patients with hypercholesterolemia, Arch Intern Med, 153, 1321, 10.1001/archinte.1993.00410110029006 Ismail, 1990, Effects of pravastatin and cholestyramine on circulating levels of parathyroid hormone and vitamin D metabolites, Clin Ther, 12, 427 Barbi, 1992, Effect of pravastatin and cholestyramine on triglyceride-rich lipoprotein particles and Lp(a) in patients with type II hypercholesterolemia, Drug Development Res, 27, 297, 10.1002/ddr.430270309 Johansson, 1995, Low-dose combination therapy with colestipol and simvastatin in patients with moderate to severe hypercholesterolemia, Nutr Metab Cardiovasc Dis, 5, 39 Lioudaki, 2011, Ezetimibe; more than a low density lipoprotein cholesterol lowering drug? An update after 4 years, Curr Vasc Pharmacol, 9, 62, 10.2174/157016111793744760 Kouvelos, 2012, Effects of rosuvastatin with or without ezetimibe on clinical outcomes in patients undergoing elective vascular surgery: results of a pilot study, J Cardiovasc Pharmacol Ther, 18, 5, 10.1177/1074248412445506 Sharma, 2009, Systematic review: comparative effectiveness and harms of combination therapy and monotherapy for dyslipidemia, Ann Intern Med, 151, 622, 10.7326/0003-4819-151-9-200911030-00144 Luo, 2015, Safety and coadministration of ezetimibe and statins in patients with hypercholesterolemia: a meta-analysis, Intern Med J, 45, 546, 10.1111/imj.12706 Rossebo, 2007, Design and baseline characteristics of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, Am J Cardiol, 99, 970, 10.1016/j.amjcard.2006.10.064 Baigent, 2011, The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial, Lancet, 377, 2181, 10.1016/S0140-6736(11)60739-3 Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med, 372, 2387, 10.1056/NEJMoa1410489 Upadhyay, 2012, Lipid-lowering therapy in persons with chronic kidney disease, Ann Intern Med, 157, 251, 10.7326/0003-4819-157-4-201208210-00005 Gordon, 1989, High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies, Circulation, 79, 8, 10.1161/01.CIR.79.1.8 Rensen, 2006, Cholesteryl ester transfer protein inhibition: effect on reverse cholesterol transport?, Arterioscler Thromb Vasc Biol, 26, 681, 10.1161/01.ATV.0000214979.24518.95 Kastelein, 2007, Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia, N Engl J Med, 356, 1620, 10.1056/NEJMoa071359 Bots, 2007, Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial, Lancet, 370, 153, 10.1016/S0140-6736(07)61088-5 Nissen, 2007, Effect of torcetrapib on the progression of coronary atherosclerosis, N Engl J Med, 356, 1304, 10.1056/NEJMoa070635 Barter, 2007, Effects of torcetrapib in patients at high risk for coronary events, N Engl J Med, 357, 2109, 10.1056/NEJMoa0706628 Fayad, 2011, Safety and efficacy of dalcetrapib on atherosclerotic disease using non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial, Lancet, 378, 1547, 10.1016/S0140-6736(11)61383-4 Lüscher, 2012, Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial, Eur Heart J, 33, 857, 10.1093/eurheartj/ehs019 Schwartz, 2012, Effects of dalcetrapib in patients with a recent acute coronary syndrome, N Engl J Med, 367, 2089, 10.1056/NEJMoa1206797 Cannon, 2010, Safety of anacetrapib in patients with or at high risk for coronary heart disease, N Engl J Med, 363, 2406, 10.1056/NEJMoa1009744 Ranalletta, 2010, Biochemical characterization of cholesteryl ester transfer protein inhibitors, J Lipid Res, 51, 2739, 10.1194/jlr.M007468 Krishna, 2007, Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies, Lancet, 370, 1907, 10.1016/S0140-6736(07)61813-3 Bloomfield, 2009, Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients, Am Heart J, 157, 352, 10.1016/j.ahj.2008.09.022 Cao, 2011, Evacetrapib is a novel, potent, and selective inhibitor of cholesteryl ester transfer protein that elevates HDL cholesterol without inducing aldosterone or increasing blood pressure, J Lipid Res, 52, 2169, 10.1194/jlr.M018069 Nicholls, 2011, Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial, JAMA, 306, 2099, 10.1001/jama.2011.1649 Seidah, 2003, The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation, Proc Natl Acad Sci USA, 100, 928, 10.1073/pnas.0335507100 Stawowy, 2014, Inhibition of PCSK9: a novel approach for the treatment of dyslipidemia, Coron Artery Dis, 25, 353, 10.1097/MCA.0000000000000113 Werner, 2014, Risk prediction with proprotein convertase subtilisin/kexin type 9 (PCSK9) in patients with stable coronary disease on statin treatment, Vascul Pharmacol, 62, 94, 10.1016/j.vph.2014.03.004 Khera, 2015, Effects of niacin, statin, and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 levels in patients with dyslipidemia, Am J Cardiol, 115, 178, 10.1016/j.amjcard.2014.10.018 Farnier, 2014, PCSK9: From discovery to therapeutic applications, Arch Cardiovasc Dis, 107, 58, 10.1016/j.acvd.2013.10.007 Catapano, 2013, The safety of therapeutic monoclonal antibodies: implications for cardiovascular disease and targeting the PCSK9 pathway, Atherosclerosis, 228, 18, 10.1016/j.atherosclerosis.2013.01.044 Stein, 2012, Lancet, 380, 29, 10.1016/S0140-6736(12)60771-5 Roth, 2012, Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia, N Engl J Med, 367, 1891, 10.1056/NEJMoa1201832 McKenney, 2012, Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy, J Am Coll Cardiol, 59, 2344, 10.1016/j.jacc.2012.03.007 Giugliano, 2012, Lancet, 380, 2007, 10.1016/S0140-6736(12)61770-X Koren, 2012, Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study, Lancet, 380, 1995, 10.1016/S0140-6736(12)61771-1 Sullivan, 2012, Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial, JAMA, 308, 2497, 10.1001/jama.2012.25790 Raal, 2012, Circulation, 126, 2408, 10.1161/CIRCULATIONAHA.112.144055 Ballantyne, 2015, Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia, Am J Cardiol, 115, 1212, 10.1016/j.amjcard.2015.02.006 Robinson, 2015, Efficacy and safety of alirocumab in reducing lipids and cardiovascular events, N Engl J Med, 372, 1489, 10.1056/NEJMoa1501031 Sabatine, 2015, Efficacy and safety of evolocumab in reducing lipids and cardiovascular events, N Engl J Med, 372, 1500, 10.1056/NEJMoa1500858