Lipid lowering with fibric acid derivatives
- Robert S Rosenson, MD
Robert S Rosenson, MD
- Professor of Medicine
- Mount Sinai School of Medicine
- Director, Cardiometabolic Disorders
- Mount Sinai Heart
Lipid altering agents encompass several classes of drugs that include HMG CoA reductase inhibitors or statins, fibric acid derivatives, bile acid sequestrants, and nicotinic acid. These drugs differ with respect to mechanism of action and to the degree and type of lipid lowering. Thus, the indications for a particular drug are influenced by the underlying lipid abnormality. Conventional dosing regimens and common adverse reactions are described in a table (table 1), and the range of expected changes in the lipid profile are listed in another table (table 2).
Lipid lowering is beneficial in patients with dyslipidemias for both primary and secondary prevention of coronary heart disease (CHD). (See "Clinical trials of cholesterol lowering for primary prevention of coronary heart disease" and "Clinical trials of cholesterol lowering in patients with cardiovascular disease or diabetes".)
The mechanisms of benefit seen with lipid-lowering are incompletely understood. Regression of atherosclerosis occurs in only a minority of patients; furthermore, the benefit of lipid lowering is seen in as little as six months, before significant regression could occur. Thus, other factors must contribute; these include plaque stabilization, reversal of endothelial dysfunction, and decreased thrombogenicity. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".)
The characteristics and efficacy of the fibric acid derivatives will be reviewed here. Other lipid lowering drugs and dietary supplements are discussed separately. (See "Low density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors" and "Statins: Actions, side effects, and administration" and "Lipid lowering with diet or dietary supplements".)
Fibrates available in the United States include gemfibrozil and fenofibrate. Clofibrate, available in the past, should not be used since it has been associated with cholangiocarcinoma and other gastrointestinal cancers . Other fibrates that are available worldwide include bezafibrate and ciprofibrate.
- WHO cooperative trial on primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Report of the Committee of Principal Investigators. Lancet 1984; 2:600.
- Fruchart JC, Brewer HB Jr, Leitersdorf E. Consensus for the use of fibrates in the treatment of dyslipoproteinemia and coronary heart disease. Fibrate Consensus Group. Am J Cardiol 1998; 81:912.
- Staels B, Dallongeville J, Auwerx J, et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998; 98:2088.
- Birjmohun RS, Hutten BA, Kastelein JJ, Stroes ES. Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials. J Am Coll Cardiol 2005; 45:185.
- 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.
- Vu-Dac N, Schoonjans K, Kosykh V, et al. Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor. J Clin Invest 1995; 96:741.
- Berthou L, Duverger N, Emmanuel F, et al. Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice. J Clin Invest 1996; 97:2408.
- Jin FY, Kamanna VS, Chuang MY, et al. Gemfibrozil stimulates apolipoprotein A-I synthesis and secretion by stabilization of mRNA transcripts in human hepatoblastoma cell line (Hep G2). Arterioscler Thromb Vasc Biol 1996; 16:1052.
- 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.
- Jones PH, Pownall HJ, Patsch W, et al. Effect of gemfibrozil on levels of lipoprotein[a] in type II hyperlipoproteinemic subjects. J Lipid Res 1996; 37:1298.
- Avellone G, DiGarbo V, Cordova R, et al. Effects of gemfibrozil treatment on fibrinolytic system in patients with hypertriglyceridemia. Curr Ther Res 1992; 52:338.
- Nordt TK, Kornas K, Peter K, et al. Attenuation by gemfibrozil of expression of plasminogen activator inhibitor type 1 induced by insulin and its precursors. Circulation 1997; 95:677.
- Farnier M, Bonnefous F, Debbas N, Irvine A. Comparative efficacy and safety of micronized fenofibrate and simvastatin in patients with primary type IIa or IIb hyperlipidemia. Arch Intern Med 1994; 154:441.
- Giral P, Bruckert E, Jacob N, et al. Homocysteine and lipid lowering agents. A comparison between atorvastatin and fenofibrate in patients with mixed hyperlipidemia. Atherosclerosis 2001; 154:421.
- Insua A, Massari F, Rodríguez Moncalvo JJ, et al. Fenofibrate of gemfibrozil for treatment of types IIa and IIb primary hyperlipoproteinemia: a randomized, double-blind, crossover study. Endocr Pract 2002; 8:96.
- Dierkes J, Westphal S, Luley C. Serum homocysteine increases after therapy with fenofibrate or bezafibrate. Lancet 1999; 354:219.
- Westphal S, Dierkes J, Luley C. Effects of fenofibrate and gemfibrozil on plasma homocysteine. Lancet 2001; 358:39.
- 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.
- 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.
- Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. JAMA 1997; 278:313.
- Muldoon MF, Manuck SB, Mendelsohn AB, et al. Cholesterol reduction and non-illness mortality: meta-analysis of randomised clinical trials. BMJ 2001; 322:11.
- Adkins JC, Faulds D. Micronised fenofibrate: a review of its pharmacodynamic properties and clinical efficacy in the management of dyslipidaemia. Drugs 1997; 54:615.
- Ooi TC, Heinonen T, Alaupovic P, et al. Efficacy and safety of a new hydroxymethylglutaryl-coenzyme A reductase inhibitor, atorvastatin, in patients with combined hyperlipidemia: comparison with fenofibrate. Arterioscler Thromb Vasc Biol 1997; 17:1793.
- Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 2001; 357:905.
- Vakkilainen J, Steiner G, Ansquer JC, et al. Relationships between low-density lipoprotein particle size, plasma lipoproteins, and progression of coronary artery disease: the Diabetes Atherosclerosis Intervention Study (DAIS). Circulation 2003; 107:1733.
- Rajamani K, Colman PG, Li LP, et al. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet 2009; 373:1780.
- Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007; 370:1687.
- ACCORD Study Group, ACCORD Eye Study Group, Chew EY, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010; 363:233.
- Boissonnat P, Salen P, Guidollet J, et al. The long-term effects of the lipid-lowering agent fenofibrate in hyperlipidemic heart transplant recipients. Transplantation 1994; 58:245.
- Monk JP, Todd PA. Bezafibrate. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hyperlipidaemia. Drugs 1987; 33:539.
- Magarian GJ, Lucas LM, Colley C. Gemfibrozil-induced myopathy. Arch Intern Med 1991; 151:1873.
- Miller DB, Spence JD. Clinical pharmacokinetics of fibric acid derivatives (fibrates). Clin Pharmacokinet 1998; 34:155.
- Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA 1990; 264:71.
- Athyros VG, Papageorgiou AA, Hatzikonstandinou HA, et al. Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia. Am J Cardiol 1997; 80:608.
- Ballantyne CM, Davidson MH. Possible differences between fibrates in pharmacokinetic interactions with statins. Arch Intern Med 2003; 163:2394.
- Rosenson RS. Current overview of statin-induced myopathy. Am J Med 2004; 116:408.
- Goldberg AC, Bays HE, Ballantyne CM, et al. Efficacy and safety of ABT-335 (fenofibric acid) in combination with atorvastatin in patients with mixed dyslipidemia. Am J Cardiol 2009; 103:515.
- Zhao YY, Weir MA, Manno M, et al. New fibrate use and acute renal outcomes in elderly adults: a population-based study. Ann Intern Med 2012; 156:560.
- Davis TM, Ting R, Best JD, et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia 2011; 54:280.
- Nissen SE, Nicholls SJ, Wolski K, et al. Effects of a potent and selective PPAR-alpha agonist in patients with atherogenic dyslipidemia or hypercholesterolemia: two randomized controlled trials. JAMA 2007; 297:1362.
- Preiss D, Tikkanen MJ, Welsh P, et al. Lipid-modifying therapies and risk of pancreatitis: a meta-analysis. JAMA 2012; 308:804.