Advertisement

Nonstatin Therapies for Management of Dyslipidemia: A Review

Published:September 24, 2015DOI:https://doi.org/10.1016/j.clinthera.2015.09.001

      Abstract

      Purpose

      Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Recently published cholesterol treatment guidelines emphasize the use of statins as the preferred treatment strategy for both primary and secondary prevention of CVD. However, the optimal treatment strategy for patients who cannot tolerate statin therapy or those who need additional lipid-lowering therapy is unclear in light of recent evidence that demonstrates a lack of improved cardiovascular outcomes with combination therapy. The purpose of this review is to summarize and interpret evidence that evaluates nonstatin drug classes in reducing cardiovascular outcomes, to provide recommendations for use of nonstatin therapies in clinical practice, and to review emerging nonstatin therapies for management of dyslipidemia.

      Methods

      Relevant articles were identified through searches of PubMed, International Pharmaceutical Abstracts, and the Cochrane Database of Systematic Reviews by using the terms niacin, omega-3 fatty acids (FAs), clofibrate, fibrate, fenofibrate, fenofibric acid, gemfibrozil, cholestyramine, colestipol, colesevelam, ezetimibe, proprotein convertase subtilisin/kexin 9 (PCSK9), cholesteryl ester transfer protein (CETP), and cardiovascular outcomes. Only English language, human clinical trials, meta-analyses, and systematic reviews were included. Additional references were identified from citations of published articles.

      Findings

      Niacin may reduce cardiovascular events as monotherapy; however, recent trials in combination with statins have failed to show a benefit. Trials with omega-3 FAs have failed to demonstrate significant reductions in cardiovascular outcomes. Fibrates may improve cardiovascular outcomes as monotherapy; however, trials in combination with statins have failed to show a benefit, except in those with elevated triglycerides (>200 mg/dL) or low HDL-C (<40 mg/dL). There is a lack of data that evaluates bile acid sequestrant in combination with statin therapy on reducing cardiovascular events. Ezetimibe–statin combination therapy can reduce cardiovascular outcomes in those with chronic kidney disease and following vascular surgery or acute coronary syndrome. Long-term effects of emerging nonstatin therapies (CETP and PCSK9 inhibitors) are currently being evaluated in ongoing Phase III trials.

      Implications

      Nonstatin therapies have a limited role in reducing cardiovascular events in those maintained on guideline-directed statin therapy. In certain clinical situations, such as patients who are unable to tolerate statin therapy or recommended intensities of statin therapy, those with persistent severe elevations in triglycerides, or patients with high cardiovascular risk, some nonstatin therapies may be useful in reducing cardiovascular events. Future research is needed to evaluate the role of nonstatin therapies in those who are unable to tolerate guideline-directed statin doses.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

      1. 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 N.J.
        • Robinson J.G.
        • Lichtenstein A.H.
        • et al.
        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. 2014; 63: 2889-2934
        • Jacobson T.A.
        • Ito M.K.
        • Maki K.C.
        • et al.
        National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 – Executive Summary.
        J Clin Lipidol. 2014; 8: 473-488
        • National Cholesterol Education Program (NCEP) Expert Panel
        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. 2002; 106: 3143-3421
        • The Risk and Prevention Study Collaborative Group
        N–3 fatty acids in patients with multiple cardiovascular risk factors.
        N Engl J Med. 2013; 368: 1800-1808
        • Parish S.
        • Tomson J.
        • Wallendszus K.
        • et al.
        Effects of extended-release niacin with laropiprant in high-risk patients.
        N Engl J Med. 2014; 371: 203-212
        • Ginsberg H.N.
        • Elam M.B.
        • Lovato L.C.
        • et al.
        • The ACCORD Study Group
        Effects of combination lipid therapy in type 2 diabetes mellitus.
        N Engl J Med. 2010; 362: 1563-1574
        • Kamanna V.S.
        • Kashyap M.L.
        Mechanism of action of niacin.
        Am J Cardiol. 2008; 101: 20B-26B
        • Coronary Drug Project Research Group
        Clofibrate and niacin in coronary heart disease.
        JAMA. 1975; 231: 360-381
        • 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
        • Carlson L.A.
        • Rosenhamer G.
        Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid.
        Acta Med Scand. 1988; 223: 405-418
        • Blankenhorn D.H.
        • Nessim S.A.
        • Johnson R.L.
        • et al.
        Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts.
        JAMA. 1987; 257: 3233-3240
        • Cashin-Hemphill L.
        • Mack W.J.
        • Pogoda J.M.
        • et al.
        Beneficial effects of colestipol-niacin on coronary atherosclerosis: a 4-year follow-up.
        JAMA. 1990; 264: 3013-3017
        • 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. 1991; 325: 599-605
        • Brown B.G.
        • Xue-Qiao Z.
        • Chait A.
        • et al.
        Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.
        N Engl J Med. 2001; 345: 1583-1592
        • Taylor A.J.
        • Sullenberger L.E.
        • Lee H.J.
        • et al.
        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. 2004; 110: 3512-3517
        • Taylor A.J.
        • Villines T.C.
        • Stanek E.J.
        • et al.
        Extended-release niacin or ezetimibe and carotid intima-media thickness.
        N Engl J Med. 2009; 361: 2113-2122
        • Whitney E.J.
        • Krasuski R.A.
        • Personius B.E.
        • et al.
        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. 2005; 142: 95-104
        • Boden W.
        • Probstfield J.
        • Anderson T.
        • et al.
        Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
        N Engl J Med. 2011; 365: 2255-2267
        • Duggal J.K.
        • Singh M.
        • Attri N.
        • et al.
        Effect of niacin therapy on cardiovascular outcomes in patients with coronary artery disease.
        J Cardiovasc Pharmacol Ther. 2010; 15: 158-166
        • Teo K.K.
        • Goldstein L.B.
        • Chaitman B.R.
        • et al.
        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. 2013; 44: 2688-2693
        • Lavigne P.M.
        • Karas R.H.
        The current state of niacin in cardiovascular disease prevention: a systematic review and meta-regression.
        J Am Coll Cardiol. 2013; 61: 440-446
        • Bays H.E.
        • Tighe A.P.
        • Sadovsky R.
        • Davidson M.H.
        Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications.
        Expert Rev Cardiovasc Ther. 2008; 6: 391-409
        • Bradberry J.C.
        • Hilleman D.E.
        Overview of omega-3 fatty acid therapies.
        PT. 2013; 38: 681-691
        • Lavie C.J.
        • Milani R.V.
        • Mehra M.R.
        • Ventura H.O.
        Omega-3 polyunsaturated fatty acids and cardiovascular diseases.
        J Am Coll Cardiol. 2009; 54: 585-594
        • Grundy S.M.
        • Cleeman J.I.
        • Bairey M.C.N.
        • et al.
        Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.
        Circulation. 2004; 110: 227-239
        • Berglund L.
        • Brunzell J.D.
        • Goldberg A.C.
        • et al.
        Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline.
        J Clin Endocrinol Metab. 2012; 97: 2969-2989
        • Harper C.R.
        • Jacobson T.A.
        Usefulness of omega-3 fatty acids and the prevention of coronary heart disease.
        Am J Cardiol. 2005; 96: 1521-1529
        • Wang C.
        • Harris W.S.
        • Chung M.
        • et al.
        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. 2006; 84: 5-17
        • Geleijnse J.M.
        • De Goede J.
        • Brouwer I.A.
        Alpha-linolenic acid: is it essential to cardiovascular health?.
        Curr Atheroscler Rep. 2010; 12: 359-367
        • Zargar A.
        • Ito M.K.
        Long chain omega-3 dietary supplements: a review of the National Library of Medicine Herbal Supplement Database.
        Metab Syndr Relat Disord. 2011; 9: 255-271
        • Weintraub H.S.
        Overview of prescription omega-3 fatty acid products for hypertriglyceridemia.
        Postgrad Med. 2014; 126: 7-18
        • Burr M.L.
        • Fehily A.M.
        • Gilbert J.F.
        • et al.
        Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).
        Lancet. 1989; 2: 757-761
      2. 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
        • Burr M.L.
        • Ashfield-Watt P.A.
        • Dunstan F.D.
        • et al.
        Lack of benefit of dietary advice to men with angina: results of a controlled trial.
        Eur J Clin Nutr. 2003; 57: 193-200
        • Yokoyama M.
        • Origasa H.
        • Matsuzaki M.
        • et al.
        Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
        Lancet. 2007; 369: 1090-1098
        • Tavazzi L.
        • Maggioni A.P.
        • Marchioli R.
        • et al.
        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. 2008; 372: 1223-1230
        • Kromhout D.
        • Giltay E.J.
        • Geleijnse J.M.
        N-3 fatty acids and cardiovascular events after myocardial infarction.
        N Engl J Med. 2010; 363: 2015-2026
        • Rauch B.
        • Schiele R.
        • Schneider S.
        • et al.
        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. 2010; 122: 2152-2159
        • Galan P.
        • Kesse-Guyot E.
        • Czernichow S.
        • et al.
        Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial.
        BMJ. 2010; 341: c6273
      3. The ORIGIN Trial Investigators. n–3 fatty acids and cardiovascular outcomes in patients with dysglycemia.
        N Engl J Med. 2012; 367: 309-318
        • Hu F.B.
        • Bronner L.
        • Willett W.C.
        • et al.
        Fish and omega-3 fatty acid intake and risk of coronary heart disease in women.
        JAMA. 2002; 287: 1815-1821
        • Albert C.M.
        • Hennekens C.H.
        • O’Donnell C.J.
        • et al.
        Fish consumption and risk of sudden cardiac death.
        JAMA. 1998; 279: 23-28
        • Wu J.H.Y.
        • Mozaffarian D.
        ω-3 Fatty acids, atherosclerosis progression and cardiovascular outcomes in recent trials: new pieces in a complex puzzle.
        Heart. 2014; 100: 530-533
        • Chen Q.
        • Cheng L.-Q.
        • Xiao T.-H.
        • et al.
        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. 2011; 25: 259-265
        • Hartweg J.
        • Perera R.
        • Montori V.
        • et al.
        Omega-3 polyunsaturated fatty acids (PUFA) for type 2 diabetes mellitus.
        Cochrane Database Syst Rev. 2008; (Issue 1. Art No:D003205)
        • Rizos E.C.
        • Ntzani E.E.
        • Bika E.
        • et al.
        Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis.
        JAMA. 2012; 308: 1024-1033
        • Kwak S.M.
        • Myung S.-K.
        • Lee Y.J.
        • Seo H.G.
        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. 2012; 172: 686-694
        • Kotwal S.
        • Jun M.
        • Sullivan D.
        • et al.
        Omega 3 fatty acids and cardiovascular outcomes: systematic review and meta-analysis.
        Circ Cardiovasc Qual Outcomes. 2012; 5: 808-818
        • Gupta A.
        • Guyomard V.
        • Zaman M.J.S.
        • et al.
        Systematic review on evidence of the effectiveness of cholesterol-lowering drugs.
        Adv Ther. 2010; 27: 348-364
        • Filion K.B.
        • El Khoury F.
        • Bielinski M.
        • et al.
        Omega-3 fatty acids in high-risk cardiovascular patients: a meta-analysis of randomized controlled trials.
        BMC Cardiovasc Disord. 2010; 10: 24
        • Enns J.E.
        • Yeganeh A.
        • Zarychanski R.
        • et al.
        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. 2014; 14: 70
        • Chowdhury R.
        • Stevens S.
        • Gorman D.
        • et al.
        Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: systematic review and meta-analysis.
        BMJ. 2012; 345: e6698
        • Yzebe D.
        • Lievre M.
        Fish oils in the care of coronary heart disease patients: a meta-analysis of randomized controlled trials.
        Fundam Clin Pharmacol. 2004; 18: 581-592
        • Hooper L.
        • Harrison R.A.
        • Summerbell C.D.
        • et al.
        Omega 3 fatty acids for prevention and treatment of cardiovascular disease.
        Cochrane Database Syst Rev. 2004; (Issue 4. Art. No:CD003177)
        • Studer M.
        • Briel M.
        • Leimenstoll B.
        • et al.
        Effect of different antilipidemic agents and diets on mortality: a systematic review.
        Arch Intern Med. 2005; 165: 725-730
        • Zhao Y.-T.
        • Chen Q.
        • Sun Y.-X.
        • et al.
        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. 2009; 41: 301-310
        • Delgado-Lista J.
        • Perez-Martinez P.
        • Lopez-Miranda J.
        • Perez-Jimenez F.
        Long chain omega-3 fatty acids and cardiovascular disease: a systematic review.
        Br J Nutr. 2012; 107: S201-S213
        • Di Minno M.N.D.
        • Tremoli E.
        • Tufano A.
        • et al.
        Exploring newer cardioprotective strategies: n-3 fatty acids in perspective.
        Thromb Haemost. 2010; 104: 664-680
        • Khoury N.
        • Goldberg A.C.
        The use of fibric acid derivatives in cardiovascular prevention.
        Curr Treat Options Cardiovasc Med. 2011; 13: 335-342
        • Goyal P.
        • Igel L.I.
        • LaScalea K.
        • Borden W.B.
        Cardiometabolic impact of non-statin lipid lowering therapies.
        Curr Atheroscler Rep. 2014; 16: 390
        • Reiner Z.
        Combined therapy in the treatment of dyslipidemia.
        Fundam Clin Pharmacol. 2010; 24: 19-28
      4. 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
        • Frick M.H.
        • Elo O.
        • Haapa K.
        • et al.
        Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia.
        N Engl J Med. 1987; 317: 1237-1245
        • Rubins H.B.
        • Robins S.J.
        • Collins D.
        • et al.
        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.
        Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomized controlled trial.
        Lancet. 2005; 366: 1849-1861
        • Arthur J.B.
        • Raffle RB
        • Ashby WR
        • et al.
        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. 1971; 4: 767-775
        • Research Committee of the Scottish Society of Physicians
        Ischaemic heart disease: a secondary prevention trial using clofibrate. Report by a research committee of the Scottish Society of Physicians.
        BMJ. 1971; 4: 775-784
        • Acheson J.
        • Hutchinson E.C.
        Controlled trial of clofibrate in cerebral vascular disease.
        Atherosclerosis. 1972; 15: 177-183
        • The Veterans Administration Cooperative Study Group
        The treatment of cerebrovascular disease with clofibrate. Final report of the Veterans Administration Cooperative Study of Atherosclerosis, Neurology Section.
        Stroke. 1973; 4: 684-693
        • WHO
        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. 1978; 40: 1069-1118
        • Hanefeld M.
        • Fischer S.
        • Schmechel H.
        • et al.
        Diabetes Intervention Study. Multi-intervention trial in newly diagnosed NIDDM.
        Diabetes Care. 1991; 14: 308-317
        • 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
        • Jun M.
        • Foote C.
        • Lv J.
        • et al.
        Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis.
        Lancet. 2010; 375: 1875-1884
        • Birjmohun R.S.
        • Hutten B.A.
        • Kastelein J.J.P.
        Stroes ESG. Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials.
        J Am Coll Cardiol. 2005; 45: 185-197
        • Allemann S.
        • Diem P.
        • Egger M.
        • et al.
        Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus: meta-analysis of randomised controlled trials.
        Curr Med Res Opin. 2006; 22: 617-623
        • Jun M.
        • Zhu B.
        • Tonelli M.
        • et al.
        Effects of fibrates in kidney disease: a systematic review and meta-analysis.
        J Am Coll Cardiol. 2012; 60: 2061-2071
        • Abourbih S.
        • Filion K.B.
        • Joseph L.
        • et al.
        Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review.
        Am J Med. 2009; 122: 962.e1-962.e8
        • Keene D.
        • Price C.
        • Shun-Shin M.J.
        • Francis D.P.
        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. 2014; 349: g4379
        • Gudzune Kimberly A
        • Monroe Anne K.
        • Sharma R.
        • et al.
        Effectiveness of combination therapy with statin and another lipid-modifying agent compared with intensified statin monotherapy.
        Ann Intern Med. 2014; 160: 468-476
        • Studer M.
        • Briel M.
        • Leimenstoll B.
        • et al.
        Effect of different antilipidemic agents and diets on mortality: a systematic review.
        Arch Intern Med. 2005; 165: 725-730
        • Saha S.A.
        • Arora R.R.
        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. 2010; 141: 157-166
        • Corvol J.-C.
        • Bouzamondo A.
        • Sirol M.
        • et al.
        Differential effects of lipid-lowering therapies on stroke prevention: a meta-analysis of randomized trials.
        Arch Intern Med. 2003; 163: 669-676
        • Zhou Y.H.
        • Ye X.F.
        • Yu F.F.
        • et al.
        Lipid management in the prevention of stroke: a meta-analysis of fibrates for stroke prevention.
        BMC Neurol. 2013; 13: 1
        • Lee M.
        • Saver J.L.
        • Towfighi A.
        • et al.
        Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis.
        Atherosclerosis. 2011; 217: 492-498
        • Bruckert E.
        • Labreuche J.
        • Deplanque D.
        • et al.
        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. 2011; 57: 267-272
        • Nordmann A.J.
        • Ferreira-González I.
        • Kasenda B.
        • et al.
        Fibrates for primary prevention of cardiovascular disease events.
        Cochrane Database Syst Rev. 2012; (Issue 3. Art No:CD009753)
        • Einarsson K.
        • Ericsson S.
        • Ewerth S.
        • et al.
        Bile acid sequestrants: mechanisms of action on bile acid and cholesterol metabolism.
        Eur J Clin Pharmacol. 1991; 40: S53-S58
      5. 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 S.J.
        • Burke T.
        • Watson D.
        • Wentworth C.
        Discontinuation of lipid modifying drugs among commercially insured United States patients in recent clinical practice.
        Am J Cardiol. 2007; 99: 530-534
        • The Lipid Research Clinics Coronary Primary Prevention Trial Results. II
        The relationship of reduction in incidence of coronary heart disease to cholesterol lowering.
        JAMA. 1984; 251: 365-374
        • Dorr A.E.
        • Gundersen K.
        • Schneider J.
        • et al.
        Colestipol hydrochloride in hypercholesteroleamic patients- effect on serum cholesterol and mortality.
        J Chronic Dis. 1978; 31: 5-14
        • Schrott H.G.
        • Stein E.A.
        • Du C.A.
        • et al.
        Enhanced low-density lipoprotein cholesterol reduction and cost-effectiveness by low-dose colestipol plus lovastatin combination therapy.
        Am J Cardiol. 1995; 75: 34-39
        • Knapp H.H.
        • Schrott H.
        • Ma P.
        • et al.
        Efficacy and safety of combination simvastatin and colesevelam in patients with primary hypercholesterolemia.
        Am J Med. 2001; 110: 352-360
        • Hunninghake D.
        • Insull W.
        • Toth P.
        • et al.
        Coadministration of colesevelam hydrochloride with atorvastatin lowers LDL cholesterol additively.
        Atherosclerosis. 2001; 158: 407-416
        • Pravastatin Multicenter Group II
        Comparative efficacy and safety of pravastatin and cholestyramine alone and combined in patients with hypercholesterolemia.
        Arch Intern Med. 1993; 153: 1321-1329
        • Ismail F.
        • Corder C.N.
        • Epstein S.
        • et al.
        Effects of pravastatin and cholestyramine on circulating levels of parathyroid hormone and vitamin D metabolites.
        Clin Ther. 1990; 12: 427-430
        • Barbi G.
        • Corder C.N.
        • Koren E.
        • et al.
        Effect of pravastatin and cholestyramine on triglyceride-rich lipoprotein particles and Lp(a) in patients with type II hypercholesterolemia.
        Drug Development Res. 1992; 27: 297-306
        • Johansson J.
        Low-dose combination therapy with colestipol and simvastatin in patients with moderate to severe hypercholesterolemia.
        Nutr Metab Cardiovasc Dis. 1995; 5: 39-44
        • Lioudaki E.
        • Ganotakis E.
        • Mikhailidis D.
        Ezetimibe; more than a low density lipoprotein cholesterol lowering drug? An update after 4 years.
        Curr Vasc Pharmacol. 2011; 9: 62-86
        • Kouvelos G.N.
        • Arnaoutoglou E.M.
        • Matsagkas M.I.
        • et al.
        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. 2012; 18: 5-12
        • Sharma M.
        • Ansari M.T.
        • Abou-setta A.M.
        • Soares-weiser K.
        Systematic review: comparative effectiveness and harms of combination therapy and monotherapy for dyslipidemia.
        Ann Intern Med. 2009; 151: 622-630
        • Luo L.
        • Yuan X.
        • Huang W.
        • et al.
        Safety and coadministration of ezetimibe and statins in patients with hypercholesterolemia: a meta-analysis.
        Intern Med J. 2015; 45: 546-557
        • Rossebo A.B.
        • Pedersen T.R.
        • Allen C.
        • et al.
        Design and baseline characteristics of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study.
        Am J Cardiol. 2007; 99: 970-973
        • Baigent C.
        • Landray M.J.
        • Reith C.
        • et al.
        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. 2011; 377: 2181-2192
        • Cannon C.P.
        • Blazing M.A.
        • Giugliano R.P.
        • et al.
        Ezetimibe added to statin therapy after acute coronary syndromes.
        N Engl J Med. 2015; 372: 2387-2397
        • Upadhyay A.
        • Earley A.
        • Lamont J.
        • et al.
        Lipid-lowering therapy in persons with chronic kidney disease.
        Ann Intern Med. 2012; 157: 251-262
        • Gordon D.J.
        • Probstfield J.L.
        • Garrison R.J.
        • et al.
        High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies.
        Circulation. 1989; 79: 8-15
        • Rensen P.C.N.
        • Havekes L.M.
        Cholesteryl ester transfer protein inhibition: effect on reverse cholesterol transport?.
        Arterioscler Thromb Vasc Biol. 2006; 26: 681-684
        • Kastelein J.J.P.
        • van Leuven S.I.
        • Burgess L.
        • et al.
        Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia.
        N Engl J Med. 2007; 356: 1620-1630
        • Bots M.L.
        • Visseren F.L.
        • Evans G.W.
        • et al.
        Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial.
        Lancet. 2007; 370: 153-160
        • Nissen S.E.
        • Tardif J.C.
        • Nicholls S.J.
        • et al.
        Effect of torcetrapib on the progression of coronary atherosclerosis.
        N Engl J Med. 2007; 356: 1304-1316
        • Barter P.J.
        • Caulfield M.
        • Eriksson M.
        • et al.
        Effects of torcetrapib in patients at high risk for coronary events.
        N Engl J Med. 2007; 357: 2109-2122
        • Fayad Z.A.
        • Mani V.
        • Woodward M.
        • et al.
        Safety and efficacy of dalcetrapib on atherosclerotic disease using non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial.
        Lancet. 2011; 378: 1547-1559
        • Lüscher T.F.
        • Taddei S.
        • Kaski J.-C.
        • et al.
        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. 2012; 33: 857-865
        • Schwartz G.G.
        • Olsson A.G.
        • Abt M.
        • et al.
        Effects of dalcetrapib in patients with a recent acute coronary syndrome.
        N Engl J Med. 2012; 367: 2089-2099
        • Cannon C.P.
        • Shah S.
        • Dansky H.M.
        • et al.
        Safety of anacetrapib in patients with or at high risk for coronary heart disease.
        N Engl J Med. 2010; 363: 2406-2415
        • Ranalletta M.
        • Bierilo K.K.
        • Chen Y.
        • et al.
        Biochemical characterization of cholesteryl ester transfer protein inhibitors.
        J Lipid Res. 2010; 51: 2739-2752
        • Krishna R.
        • Anderson M.S.
        • Bergman A.J.
        • et al.
        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. 2007; 370: 1907-1914
        • Bloomfield D.
        • Carlson G.L.
        • Sapre A.
        • et al.
        Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients.
        Am Heart J. 2009; 157: 352-360
        • Cao G.
        • Beyer T.P.
        • Zhang Y.
        • et al.
        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. 2011; 52: 2169-2176
        • Nicholls S.J.
        • Brewer H.B.
        • Kastelein J.J.P.
        • et al.
        Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial.
        JAMA. 2011; 306: 2099-2109
        • Seidah N.G.
        • Benjannet S.
        • Wickham L.
        • et al.
        The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation.
        Proc Natl Acad Sci USA. 2003; 100: 928-933
        • Stawowy P.
        • Just I.A.
        • Kaschina E.
        Inhibition of PCSK9: a novel approach for the treatment of dyslipidemia.
        Coron Artery Dis. 2014; 25: 353-359
        • Werner C.
        • Hoffmann M.M.
        • Winkler K.
        • et al.
        Risk prediction with proprotein convertase subtilisin/kexin type 9 (PCSK9) in patients with stable coronary disease on statin treatment.
        Vascul Pharmacol. 2014; 62: 94-102
        • Khera A.V.
        • Qamar A.
        • Reilly M.P.
        • et al.
        Effects of niacin, statin, and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 levels in patients with dyslipidemia.
        Am J Cardiol. 2015; 115: 178-182
        • Farnier M.
        PCSK9: From discovery to therapeutic applications.
        Arch Cardiovasc Dis. 2014; 107: 58-66
        • Catapano A.L.
        • Papadopoulos N.
        The safety of therapeutic monoclonal antibodies: implications for cardiovascular disease and targeting the PCSK9 pathway.
        Atherosclerosis. 2013; 228: 18-28
        • Stein E.A.
        • Gipe D.
        • Bergeron J.
        • et al.
        Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial.
        Lancet. 2012; 380: 29-36
        • Roth E.M.
        • McKenney J.M.
        • Hanotin C.
        • et al.
        Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia.
        N Engl J Med. 2012; 367: 1891-1900
        • McKenney J.M.
        • Koren M.J.
        • Kereiakes D.J.
        • et al.
        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. 2012; 59: 2344-2353
        • Giugliano R.P.
        • Desai N.
        • Kohli P.
        • et al.
        Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study.
        Lancet. 2012; 380: 2007-2017
        • Koren M.J.
        • Scott R.
        • Kim J.B.
        • et al.
        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. 2012; 380: 1995-2006
        • Sullivan D.
        • Olsson A.G.
        • Scott R.
        • et al.
        Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial.
        JAMA. 2012; 308: 2497-2506
        • Raal F.
        • Scott R.
        • Somaratne R.
        • et al.
        Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the reduction of LDL-C with PCSK9 inhibition in heterozygous familial hypercholesterolemia disorder (RUTHERFORD) randomized trial.
        Circulation. 2012; 126: 2408-2417
        • Ballantyne C.M.
        • Neutel J.
        • Cropp A.
        • et al.
        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. 2015; 115: 1212-1221
        • Robinson J.G.
        • Farnier M.
        • Krempf M.
        • et al.
        Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.
        N Engl J Med. 2015; 372: 1489-1499
        • Sabatine M.S.
        • Giugliano R.P.
        • Wiviott S.D.
        • et al.
        Efficacy and safety of evolocumab in reducing lipids and cardiovascular events.
        N Engl J Med. 2015; 372: 1500-1509