Statins fibrate drugs

Some investigators have concluded that rare drug-induced reversible hepatotoxicity calls for close monitoring of liver enzymes in long-term treatment with statin-fibrate combinations (75). 

The exact mechanism of these drugs is unclear, but they probably work by binding to a specific nuclear receptor known as the peroxisome proliferator activated receptor.52,141 This receptor, found primarily in the liver and adipose tissues, affects the transcription of genes that affect lipid metabolism.89 Fibrates activate this receptor, thereby mediating several changes at the nuclear level that ultimately cause a decrease in triglycerides and other beneficial changes in plasma lipid metabolism.30,52 In a manner similar to the statins, fibrates may also exert anti-inflammatory, antioxidant, and other beneficial effects in addition to their positive effects on plasma lipids.42,49... 

The fibrates are another class of antihyperlipidemic drug and are frequently coadministered with a statin. Fibrates act as agonists of the peroxisome proliferator-activated receptors (PPAR), particularly PPAR-a. PPARs are nuclear receptors that influence gene expression and lipid metabolism. Examples of fibrates include gemfibrozil (Lopid, A.110) and fenofibrate (Tricor, A.lll) (Figure A.30). Fenofibrate is hydrolyzed in the body to its active form, fenofibric acid (A.112). Fibrates do not decrease LDL levels as effectively as statins, but fibrates do elevate HDL cholesterol levels. 

Drugs which are highly protein bound (most statins, fibrates and ezetim-ibe) should be used with caution in hypoalbuminaemia and hyperbili-rubinaemia. 

Currently available treatments against atherosclerosis include cholesterol-lowering drugs such as statins, fibrates, nicotinic acid (NA) [8-13] and the cholesterol intestinal absorption inhibitor, ezetimibe (Fig. 1) [14]. 

Helsinki Heart Study (15) have all demonstrated the benefit of lipid lowering using various hypolipidemic agents for prevention of initial cardiac events. Secondary prevention trials have unequivocally shown that lipid lowering therapy not only reduces acute coronary events and other clinical endpoints, but also results in angiographic improvement. These studies have used different classes of drugs (statins, fibrates, niacin, bile acid resins—alone and in combination) in both hyper- and normo-cholesterolemic patients with established CAD. 

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). 

Rhabdomyolysis is the destruction of skeletal muscle tissues and may be associated with lipid-regulating drugs such as the fibrates and the statins. The risk of this side-effect is increased in patients with renal impairment and with hypothyroidism. Rhabdomyolysis may also occur with nicotinic acid, the antipsychotic aripiprazole, and the anaesthetic propofol. 

The fibrates potentiate the actions of the coumarin anticoagulants, such as warfarin, so care should be taken to reduce the dose of simultaneously administered anticoagulants, and plasma prothrombin should be frequently measured until the level stabilizes. As mentioned earlier, great care should be given to combining a statin with a fibrate, since this combination may increase the risk of myositis and perhaps rhabdomyolysis. Table 23.4 summarizes major interactions of drugs that lower cholesterol. 

Erectile dysfunction has been reported in 12% of 339 men treated with fibrate derivatives or statins, compared with 5.6% of similar patients not taking these drugs (60). The mechanism is unknown and should be confirmed in randomized studies. 

Although it is not exactly clear how much these agents can reduce the risk of a major cardiac event (e.g., infarction, stroke), these drugs will probably remain the first choice for people with certain hyper-lipidemias (e.g., increased triglycerides). These drugs are likewise advocated for mixed hyperlipidemias that are common in metabolic disorders such as type 2 diabetes mellitus (see Chapter 32).32,141 Certain fibrates can be used with other drugs, such as statins, to provide more comprehensive pharmacologic control of certain lipid disorders.30,147... 

Drugs used to increase HDL levels (fibrates, nicotinic acid, and statins) in otherwise normal people do not have the same effect in patients with Tangier disease. Therefore, it is necessary to identify and treat other risk factors associated with CAD. Exercise, weight reduction, dietary cholesterol and saturated fat reduction, and smoking cessation are the first line in management of low HDL cholesterol. Dietary management with low fat intake is beneficial in reducing the risk for CAD, as well... 

Prueksaritanont T, Tang C, Qiu Y, et al. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab. Dispos., 2002, 30, 1280-1287. 

Concomitant prescribing of drugs that increase the plasma statin concentration (e.g. fibrates) will increase the risk of muscle toxicity. 

In cirrhosis the first-pass effect is significantly reduced, and this may lead to greatly elevated concentrations of drug reaching the systemic circulation. Most statins and fibrates have a high first-pass extraction. 

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