Fibrates, cholesterol-lowering effects

B. Clinical Use Gemfibrozil and other fibrates are used to treat hypertriglyceridemia (Table 35-2). Because these drugs ha"e only modest effects on LDL cholesterol, they often are combined with other cholesterol-lowering drugs for treatment of patients with elevated concentrations of both LDL and VLDL. 

The 3-thia, non-P-oxidable thia fatty acids (as exemplified by TTA (tetradecylth-ioacetic acid, HOOC-CH2-S-CH2(13)-CH3) decrease plasma triglycerides and cholesterol levels when administered to rats. At the same time TTA increased the hepatic fatty acid oxidation capacities. Recently we have demonstrated that stimulation of mitochondrial P-oxidation, but not peroxisomal fatty acid oxidation, decreases hepatic triglyceride formation. This has also been shown with co-3 fatty acids and fibrates in different animal models (rats, rabbits and dogs). Altogether the mitochondrion seems to be the principal target for the plasma triglycerid lowering effect. 

Combination drug therapy is an effective means to achieve greater reductions in LDL cholesterol (statin + ezetimibe or bile acid resin, bile acid resin + ezetimibe, or three-drug combinations) as well as raising HDL cholesterol and lowering serum triglycerides (statin + niacin or fibrate). 

Fibrates are the most effective triglyceride-lowering drugs and are used primarily in patients with elevated triglycerides and low HDL cholesterol. 

Fibrates are the most effective triglyceride-lowering agents and also raise HDL cholesterol levels. Combination therapy with a fibrate, particularly gemfibrozil, and a statin has been found to increase the risk for myopathy. Of the 31 rhabdomyolysis deaths reported with cerivastatin use, 12 involved concomitant gemfibrozil.25 Therefore, more frequent monitoring, thorough patient education, and consideration of factors that increase the risk as reviewed previously should be considered. 

A recently developed antihyperlipidemic is ezetimibe (Zetia, A.113) (Figure A.31). Ezetimibe inhibits the absorption of cholesterol across the intestinal wall. Like fibrates, ezetimibe is often prescribed with statins, although the effectiveness of ezetimibe has recently been called into question. A compound that may soon be approved for the treatment of high cholesterol is anacetrapib (A.114). Anacetrapib, a product of Merck, is currently in phase III trials. The compound inhibits cholesteryl ester transfer protein (CETP). The net effect of CETP inhibition is elevated HDL cholesterol and lower LDL cholesterol levels. 

The effects of the fibrates on lipoprotein levels differ widely, depending on the starting lipoprotein profile, the presence or absence of a genetic hyperlipoproteinemia, the associated environmental influences, and the specific fibrate used. Patients with type 111 hyperlipoproteinemia (dysbetalipoproteinemia) are among the most sensitive responders to fibrates. Elevated triglyceride and cholesterol levels are dramatically lowered, and xanthomas may regress completely. Angina and intermittent claudication also improve. 

Overall, fibrates decrease plasma triglyceride levels much more dramatically than they decrease plasma cholesterol levels. They significantly decrease VLDL levels, cause a moderate Increase In HDL levels, and have variable effects on LDL concentrations. As an example of this latter point, gemfibrozil will raise LDL levels In patients with hypertriglyceridemia but lower LDL levels in patients with normal triglyceride levels. The exact mechanisms for these actions have not been fully elucidated however, studies have shown that this class of compounds can produce a variety of beneficial effects on lipoprotein metabolism. Many of these effects have been proposed to be mediated through the activation of peroxisome proliferator-activated receptors (PPARs) and an alteration of gene expression. Specifically, fibrates bind to PPARa (7,15,27,44). 

Millions of people in the world suffer from cardiovascular disease, and it is a leading cause of death in both men and women. Elevation in plasma low-density lipoprotein (LDL) cholesterol levels is a major risk factor for myocardial infarction (heart attack) in these patients. Drugs to reduce dyslipidemia have included niacin and the fibrate class, but each of these has clinical limitations, such as low efficacy or toxic side effects. The development of HMG-CoA reductase inhibitors, or statins, has had an enormous clinical impact on the treatment of heart disease and prevention of heart attack, and these are taken by tens of millions of patients worldwide [1]. One of the first such drugs, lovastatin, was discovered in the 1970s as a fungal natural product [2] and lowered lipid levels in animals and healthy volunteers. Problems with the development of another early statin, compactin, halted advancement of lovastatin to regular clinical use until the late 1980s. Since then. 

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