Fibrates with statins

Fibrates are being combined with statins to expand their potential in the dyslipidemia market. A recent clinical study examined the effects of rosuvastatin (10) and fenofibrate as mono and combination therapy in hyperlipidemic diabetic patients [43]. In late 2006, large scale Phase III clinical trials of rosuvastatin in combination with a next-generation fibrate, ABT 335, were initiated for evaluation of safety and efficacy in patients with mixed dyslipidemia. 

It has been suspected that low concentrations of serum cholesterol might be associated with an increased risk of cancer or overall mortality. All fibrates and statins cause cancer in rodents, but the relevance of this finding to man has been questioned (68). In an epidemiological study these risks were almost non-existent after adjusting for confounding factors. 

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). 

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. 

Ballantine CM, Davidson MH. Possible differences between fibrates in pharmacokinetic interactions with statins. Arch. Intern. Med., 2003, 163, 2394. 

The British National Formulary (BNF) recommends that fibrates or nicotinic acid should not be combined with statins because of the potential for myopathy and rhabdomyolysis with this combination [54]. This is widely discussed in the medical literature. Numerous deaths have been reported and the high mortality associated with concurrent use of cerivastatin and gemfibrozil was partly instrumental in the decision to withdraw cerivastatin from the market in 2001 [34]. It appears that the high mortality in patients using concurrent gemfibrozil and cerivastatin was due to interactions at the level of glucuronidation, CYP2C8 inhibition and OATP inhibition [17, 55]. 

The fibrates act at the level of the liver to decrease VLDL-TG substantially and to increase HDLc secretion. Nicotinic acid also decreases TG and is considered to the most potent agent to increase HDL. The effects of fibrates and nicotinic acid on TG and HDL are generally greater than those observed with statins, which are generally the most effective LDLc-lowering agents. 

The increased risk of myopathy observed during concomitant treatment with statins and fibrates may be partly pharmacokinetic in origin. In interactions between fibrates and statins there may be differences between... 

For now, in patients with established CHD it is recommended to initiate diet and lifestyle changes along with statin therapy to target an LDL of 70 mg/dL or less and then, if the HDL is <40 mg/dL, to consider adding a fibrate or niacin to raise the HDL cholesterol level. Of note, no specific level of HDL was set in the recent ATP III guidelines, further adding to the uncertainty of how to optimally treat low HDL cholesterol levels. 

Treatment targets for drcnlating levels of LDL-cholesterol and triglycerides can in most cases rather easily be achieved with statins, ezemtibine, fibrates and omega-3 fatty acids. In contrast, it is much more difficult to improve the low serum level of HDL-cholesterol as a prominent CVD risk factor in type 2 diabetes. Some hope is given to several novel drug candidates [39]. 

As described above, the outcome data with fibrates is mixed. Gemfibrozil is the fibrate with the best outcome data but should not be combined with a statin as it can increase plasma levels of all statins and therefore the risk of severe side effects. If the major abnormality is a high LDL-cholesterol, gemfibrozil will have little impact. Bezafibrate has a better impact on LDL as well as increasing HDL-cholesterol and decreasing triglyceride but the clinical benefits from RCTs relate only to post hoc analyses. 

The administration of niacin in combination with statin or fibrate has shown significant reduction in cardiovascular mortality. For instance, the Stockholm Ischaemic Heart Disease secondary prevention study showed that combined treatment of clofibrate and niacin for five years was assodated with marked decrease in ischaemic heart disease (Carlson and Rosenhamer 1988). 

Key randomized clinical trials employing niacin with cardiovascular and clinical endpoints are summarized in Table 39.2. Most of the trials used niacin in combination with other agents—bile acid sequestrants, fibrates or statins. 

LC-ESI-MS/MS has been used to determine lipid-regulating agents, including the fibrates and statins classes in water. For the fibrates, N1 mode was generally employed with deprotonated molecules [M — H] at m/z 213 for clofibric acid, m/z 249 for gemfibrozil, and m/z 360 for bezafibrate [85,87,140,147]. However, PI mode was also used for fenofibrate and bezafibrate [86]. In ESI(—) tandem MS mode, the deprotonated molecule of clofibric... 

Fenofibric acid+a statin Fenqftbric acid (Trilipix ), the choline salt of fenofibrate, is designed to overcome the drawbacks of older fibrates, particularly in terms of pharmacokinetic properties. It is well absorbed and is not subject to first-pass hepatic metabolism. The combination of fenofibric acid with statins is used to improve the lipid profile compared with the corresponding statin dose. The use of combination of fenofibric acid with statins has been reviewed [12]. 

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