Fenofibrate 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. 

Fenofibrate appears to be complementary with certain statins in the treatment of familial combined hyperlipoproteinemia and other conditions involving elevations of both LDL and VLDL. The combination of fenofibrate with rosuvastatin is particularly effective. Some other statins may interact unfavorably owing to effects on cytochrome P450 metabolism. 

It has been an attractive option to use combination therapy of statin and fibrate when HDL remains low but there is no data from RCTs to support this approach. It is ironic that gemfibrozil with the best outcome data should not be used in this context given drug interactions. The results of the FIELD trial with fenofibrate as sole therapy were disappointing [59] however, a combination trial with fenofibrate and statin in type 2 diabetes, the ACCORD study, is in progress. 

Bays HE, Jones PH, Mohiuddin SM, Kelly MT, Sun H, Seize CM, Buttler SM, Sleep DJ, Stolzenbach JC. Long-term safety and efficacy of fenofibric acid in combination with statin therapy for the treatment of patients with mixed dyslipidemia. J Clin Lipidol 2008 2(6) 426-35. 

Fenofibrate + a statin Raised triglycerides (TG), decreased HDL-C levels and a predominance of small LDL are characteristics of the metabolic syndrome. In patients with mixed hyperlipidemia and metabolic syndrome, high-dose rosuvastatin (40 mg/d, n = 30) was more effective in decreasing LDL-C and non-HDL-C levels... 

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]. 

Filippatos TD. A review of time courses and predictors of hpid changes with fenofibric acid-statin combination. Cardiovasc Drugs Ther... 

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. 

Clinically important, potentially hazardous interactions with cyclosporine, fenofibrate, gemfibrozil, HMG-CoA inhibitors (statins), ritonavir... 

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. Gemfibrozil 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. 

Interest in fenofibrate has re-emerged with the near demise of gemfibrozil in some countries, once it became apparent that a statin+fenofibrate combination was highly likely to be safe. It is currently by far the preferred fibrate for the management of hypertriglyceridemia or in combination with a statin for treating combined hyperlipidemia. Different studies with a variety of statins have uniformly found no greater incidence of serious adverse reactions when fenofibrate is added compared with placebo. 

The authors of a major review of rosuvastatin concluded that its adverse reaction profile resembles that of other commonly used statins [34 ]. Increments in fiver enzymes are in most cases minor and of minimal concern, renal dysfunction is quite uncommon, myopathy is unusual, and rhab-domyolysis is rare. Interactions with other drugs are fisted but no new information given. Combinations with fenofibrate, omega-3 fatty acids, ezetimibe, rifampicin, and clopidogrel appear to be safe. 

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... 

Stolzenbach JC. Efficacy and safety of fenofibric acid in combination with a statin in patients with mixed dyslipidemia pooled analysis of three phase 3,12-week randomized, controlled studies. J Clin Lipidol 2009 3(2) 125-37. 

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