Fibric acid compounds usually are well tolerated. Side effects, most often Gl-related, may occur in 5-10% of patients but most often are not sufficient to cause drug discontinuation. Other infrequent side effects include rash, urticaria, hair loss, myalgias, fatigue, headache, impotence, and anemia. Minor increases in liver transaminases and alkaline phosphatase have been reported. Clofibrate, bezafibrate, and fenofibrate reportedly can potentiate the action of oral anticoagulants by displacing them from their binding sites on albumin; thus, monitoring of the prothrombin time and reduction in anticoagulant dosage may be appropriate.
Myopathy occasionally occurs in subjects taking clofibrate, gemfibrozil, or fenofibrate, and may occur in up to 5% of patients treated with a combination of gemfibrozil and higher doses of statins. Statin doses therefore should be reduced when a statin plus a fibrate are combined. Several drug interactions may contribute to this adverse response. Gemfibrozil inhibits hepatic uptake of statins by OATP2 and also competes for the same glucuronosyl transferases that metabolize most statins. Thus, levels of both drugs may increase with coadministation. Patients taking this combination should be told about potential symptoms and followed at 3-month intervals with careful history and determination of CK values until a stable pattern is established. Until there is more experience, patients taking fibrates with rosuvastatin should be followed especially closely even at low doses (5-10 mg) of rosuvastatin. Fenofibrate is glucuronidated by enzymes that are not involved in statin glucuronidation; thus, fenofibrate-statin combinations are less likely to cause myopathy than combination therapy with gemfibrozil and statins.
All fibrates increase the lithogenicity of bile. Clofibrate has been associated with increased risk of gallstone formation; gemfibrozil and fenofibrate reportedly do not increase biliary tract disease. Renal failure and hepatic dysfunction are relative contraindications to fibrate therapy. Combined statin-fibrate therapy should be avoided in patients with impaired renal function. Gem-fibrozil should be used with caution and at a reduced dosage to treat the hyperlipidemia of renal failure. Fibrates should not be used by children or pregnant women.
THERAPEUTIC USES Clofibrate is available for oral administration and may be useful in patients who do not tolerate gemfibrozil or fenofibrate. The usual dose is 2 g/day in divided doses. Gemfibrozil (lopid) is usually administered as a 600-mg dose taken twice a day, 30 minutes before the morning and evening meals. The tricor brand of fenofibrate is available in tablets of 48 and 145 mg. The usual daily dose is 145 mg. Generic fenofibrate (lofibra) is available in capsules containing 67, 134, and 200 mg. tricor, 145 mg, and lofibra, 200 mg, are equivalent doses.
Fibrates are the drugs of choice for treating hyperlipidemic subjects with type III hyperlipoproteinemia and for subjects with severe hypertriglyceridemia (triglycerides >1000 mg/dL) who are at risk for pancreatitis. Fibrates appear to have an important role in subjects with high triglycerides and low HDL-C levels associated with the metabolic syndrome or type 2 diabetes mellitus. In these settings, the LDL levels should be monitored; if LDL levels rise, the addition of a low dose of a statin may be needed. Many experts now treat such patients first with a statin, and then add a fibrate, based on the reported benefit of gemfibrozil therapy. If this combination is used, there should be careful monitoring for myopathy.
Ezetimibe and the Inhibition of Dietary Cholesterol Uptake
Ezetimibe is the first compound approved for lowering total and LDL-C levels that inhibits cholesterol absorption by enterocytes in the small intestine. It lowers LDL-C levels by 15-20% and is used primarily as adjunctive therapy with statins. Ezetimibe does not affect intestinal triglyceride absorption. In human subjects, ezetimibe reduced cholesterol absorption by 54%, precipitating a compensatory increase in cholesterol synthesis, which can be inhibited with a cholesterol synthesis inhibitor such as a statin. The consequence of inhibiting intestinal cholesterol absorption is a reduction in the incorporation of cholesterol into chylomicrons. The reduced cholesterol content of chylomicrons diminishes the delivery of cholesterol to the liver by chylomicron remnants. The diminished remnant cholesterol content may decrease atherogenesis directly, as chylomicron remnants are very atherogenic lipoproteins.
Reduced delivery of intestinal cholesterol to the liver by chylomicron remnants stimulates expression of the hepatic genes regulating LDL receptor expression and cholesterol biosynthesis. The greater expression of hepatic LDL receptors enhances LDL-C clearance from the plasma.
As monotherapy, ezetimibe is limited to the small group of statin-intolerant patients. The actions of ezetimibe, which inhibits intestinal cholesterol absorption and enhances cholesterol biosynthesis, are complementary to those of statins, and there is a further reduction of 15—20% in LDL-C when ezetimibe is combined with any statin at any dose. Increasing statin dosages from the usual starting dose of20-80 mg normally yields only an additional 12% reduction in LDL-C, whereas adding ezetimibe, 10 mg daily, to 20 mg of a statin will reduce LDL-C by an additional 18-20%. A combination tablet containing ezetimibe, 10 mg, and various doses of simvastatin (10, 20, 40, and 80 mg) is available (vytorin). At the highest simvastatin dose (80 mg), plus ezetimibe (10 mg), average LDL-C reduction was 60%, exceeding that attained with any statin as monotherapy.
ABSORPTION, FATE, AND EXCRETION
Ezetimibe is highly water insoluble. After ingestion, it is glucuronidated in the intestinal epithelium, absorbed, and enters an enterohepatic recirculation. Pharmacokinetic studies indicate that ~70%o is excreted in the feces and ~10% in the urine (as a glucuronide conjugate). Bile acid sequestrants inhibit absorption of ezetimibe, and the two agents should not be coadministered. otherwise, no significant drug interactions have been reported.
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