Low density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors
- Robert S Rosenson, MD
Robert S Rosenson, MD
- Section Editor — Lipids
- Professor of Medicine
- Mount Sinai School of Medicine
- Director, Cardiometabolic Disorders
- Mount Sinai Heart
- John JP Kastelein, MD, PhD, FESC
John JP Kastelein, MD, PhD, FESC
- Professor of Medicine
- Academic Medical Center, University of Amsterdam
- Amsterdam, the Netherlands
Lipid (or lipoprotein) altering agents encompass several classes of drugs including statins, cholesterol absorbing inhibitors, fibric acid derivatives, bile acid sequestrants, PCSK9 inhibitors, nicotinic acid, and others. These drugs differ with respect to mechanism of action and to the degree and type of lipid altering.
Most patients for whom a prescription drug therapy is deemed advisable will have an elevation in their low density lipoprotein cholesterol (LDL-C) level and a statin is the established first line therapy. Other lipid lowering drugs are used to augment statin effects on LDL-C, substitute for statins when that class cannot be used, or to treat non-LDL-C disorders, primarily hypertriglyceridemia. The decision to use a non-statin drug can be influenced by clinical parameters other than the lipid values themselves.
The characteristics, efficacy, and safety of the lipid-lowering drugs other than the statins and PCSK9 inhibitors will be reviewed here. The efficacy of statins and PCSK9 inhibitors is discussed elsewhere. (See "Statins: Actions, side effects, and administration" and "PCSK9 inhibitors: Pharmacology, adverse effects, and use".)
Additionally, therapeutic decision making in patients with elevated lipid levels is discussed in detail separately:To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Sudhop T, Lütjohann D, Kodal A, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation 2002; 106:1943.
- Altmann SW, Davis HR Jr, Zhu LJ, et al. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science 2004; 303:1201.
- Klett EL, Patel SB. Biomedicine. Will the real cholesterol transporter please stand up. Science 2004; 303:1149.
- Temel RE, Tang W, Ma Y, et al. Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetimibe. J Clin Invest 2007; 117:1968.
- Myocardial Infarction Genetics Consortium Investigators, Stitziel NO, Won HH, et al. Inactivating mutations in NPC1L1 and protection from coronary heart disease. N Engl J Med 2014; 371:2072.
- Dujovne CA, Ettinger MP, McNeer JF, et al. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol 2002; 90:1092.
- Knopp RH, Gitter H, Truitt T, et al. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J 2003; 24:729.
- Gagné C, Gaudet D, Bruckert E, Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 2002; 105:2469.
- Gagné C, Bays HE, Weiss SR, et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol 2002; 90:1084.
- Davidson MH, McGarry T, Bettis R, et al. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002; 40:2125.
- Melani L, Mills R, Hassman D, et al. Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Eur Heart J 2003; 24:717.
- Goldberg AC, Sapre A, Liu J, et al. Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc 2004; 79:620.
- Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015; 372:2387.
- Baigent C, Landray MJ, 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.
- Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008; 359:1343.
- Peto R, Emberson J, Landray M, et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med 2008; 359:1357.
- Ballantyne CM, Houri J, Notarbartolo A, et al. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation 2003; 107:2409.
- Kosoglou T, Statkevich P, Fruchart JC, et al. Pharmacodynamic and pharmacokinetic interaction between fenofibrate and ezetimibe. Curr Med Res Opin 2004; 20:1197.
- Gustavson LE, Schweitzer SM, Burt DA, et al. Evaluation of the potential for pharmacokinetic interaction between fenofibrate and ezetimibe: A phase I, open-label, multiple-dose, three-period crossover study in healthy subjects. Clin Ther 2006; 28:373.
- Farnier M, Freeman MW, Macdonell G, et al. Efficacy and safety of the coadministration of ezetimibe with fenofibrate in patients with mixed hyperlipidaemia. Eur Heart J 2005; 26:897.
- McKenney JM, Farnier M, Lo KW, 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.
- Wang D, Liu B, Tao W, et al. Fibrates for secondary prevention of cardiovascular disease and stroke. Cochrane Database Syst Rev 2015; :CD009580.
- Saha SA, Kizhakepunnur LG, Bahekar A, Arora RR. The role of fibrates in the prevention of cardiovascular disease--a pooled meta-analysis of long-term randomized placebo-controlled clinical trials. Am Heart J 2007; 154:943.
- Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010; 375:1875.
- Frick MH, 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.
- Bezafibrate Infarction Prevention (BIP) study. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation 2000; 102:21.
- Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999; 341:410.
- Keech A, Simes RJ, Barter P, et al. 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.
- Rosenson RS, Wolff DA, Huskin AL, et al. Fenofibrate therapy ameliorates fasting and postprandial lipoproteinemia, oxidative stress, and the inflammatory response in subjects with hypertriglyceridemia and the metabolic syndrome. Diabetes Care 2007; 30:1945.
- Otvos JD, Collins D, Freedman DS, et al. Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation 2006; 113:1556.
- Rosenson RS. Fenofibrate: treatment of hyperlipidemia and beyond. Expert Rev Cardiovasc Ther 2008; 6:1319.
- Bimmermann A, Boerschmann C, Schwartzkopff W, et al. Effective therapeutic measures for reducing lipoprotein(a) in patients with dyslipidemia. Lipoprotein(a) reduction with sustained-release bezafibrate. Curr Ther Res 1991; 49:635.
- Grundy SM, Mok HY, Zech L, Berman M. Influence of nicotinic acid on metabolism of cholesterol and triglycerides in man. J Lipid Res 1981; 22:24.
- Probstfield JL, Hunninghake DB. Nicotinic acid as a lipoprotein-altering agent. Therapy directed by the primary physician. Arch Intern Med 1994; 154:1557.
- Illingworth DR, Stein EA, Mitchel YB, et al. Comparative effects of lovastatin and niacin in primary hypercholesterolemia. A prospective trial. Arch Intern Med 1994; 154:1586.
- Stein EA, Raal F. Future Directions to Establish Lipoprotein(a) as a Treatment for Atherosclerotic Cardiovascular Disease. Cardiovasc Drugs Ther 2016; 30:101.
- AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011; 365:2255.
- HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014; 371:203.
- Anderson TJ, Boden WE, Desvigne-Nickens P, et al. Safety profile of extended-release niacin in the AIM-HIGH trial. N Engl J Med 2014; 371:288.
- Lloyd-Jones DM. Niacin and HDL cholesterol--time to face facts. N Engl J Med 2014; 371:271.
- Guyton JR, Goldberg AC, Kreisberg RA, et al. Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolemia. Am J Cardiol 1998; 82:737.
- Knopp RH, Alagona P, Davidson M, et al. Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia. Metabolism 1998; 47:1097.
- Cefali EA, Simmons PD, Stanek EJ, Shamp TR. Improved control of niacin-induced flushing using an optimized once-daily, extended-release niacin formulation. Int J Clin Pharmacol Ther 2006; 44:633.
- Maccubbin D, Koren MJ, Davidson M, et al. Flushing profile of extended-release niacin/laropiprant versus gradually titrated niacin extended-release in patients with dyslipidemia with and without ischemic cardiovascular disease. Am J Cardiol 2009; 104:74.
- Maccubbin D, Bays HE, Olsson AG, et al. Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia. Int J Clin Pract 2008; 62:1959.
- Etchason JA, Miller TD, Squires RW, et al. Niacin-induced hepatitis: a potential side effect with low-dose time-release niacin. Mayo Clin Proc 1991; 66:23.
- Goldberg A, Alagona P Jr, Capuzzi DM, et al. Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia. Am J Cardiol 2000; 85:1100.
- Garg A, Grundy SM. Nicotinic acid as therapy for dyslipidemia in non-insulin-dependent diabetes mellitus. JAMA 1990; 264:723.
- Rosenson RS. Measure for measure--sugar or fats? Reconciling cardiovascular and diabetes risk with niacin therapy. Nat Clin Pract Endocrinol Metab 2007; 3:72.
- Pasternak RC, Kolman BS. Unstable myocardial ischemia after the initiation of niacin therapy. Am J Cardiol 1991; 67:904.
- Garg R, Malinow M, Pettinger M, et al. Niacin treatment increases plasma homocyst(e)ine levels. Am Heart J 1999; 138:1082.
- Davidson MH, Dillon MA, Gordon B, et al. Colesevelam hydrochloride (cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects. Arch Intern Med 1999; 159:1893.
- Shepherd J, Packard CJ, Morgan HG, et al. The effects of cholestyramine on high density lipoprotein metabolism. Atherosclerosis 1979; 33:433.
- Insull W Jr, Toth P, Mullican W, et al. Effectiveness of colesevelam hydrochloride in decreasing LDL cholesterol in patients with primary hypercholesterolemia: a 24-week randomized controlled trial. Mayo Clin Proc 2001; 76:971.
- Brown G, Albers JJ, Fisher LD, 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.
- Comparative efficacy and safety of pravastatin and cholestyramine alone and combined in patients with hypercholesterolemia. Pravastatin Multicenter Study Group II. Arch Intern Med 1993; 153:1321.
- Knapp HH, 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.
- Gurakar A, Hoeg JM, Kostner G, et al. Levels of lipoprotein Lp(a) decline with neomycin and niacin treatment. Atherosclerosis 1985; 57:293.
- Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA 1995; 273:199.
- Kim CJ, Jang HC, Cho DH, Min YK. Effects of hormone replacement therapy on lipoprotein(a) and lipids in postmenopausal women. Arterioscler Thromb 1994; 14:275.
- Darling GM, Johns JA, McCloud PI, Davis SR. Estrogen and progestin compared with simvastatin for hypercholesterolemia in postmenopausal women. N Engl J Med 1997; 337:595.
- Binder EF, Williams DB, Schechtman KB, et al. Effects of hormone replacement therapy on serum lipids in elderly women. a randomized, placebo-controlled trial. Ann Intern Med 2001; 134:754.
- Ladenson PW, Kristensen JD, Ridgway EC, et al. Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med 2010; 362:906.