| Fibrates | |
|---|---|
| Drug class | |
 Fenofibrate, one of the most popular fibrates | |
| Class identifiers | |
| Use | hypertriglyceridemia andhypercholesterolaemia |
| ATC code | C10AB |
| Biological target | PPAR |
| Clinical data | |
| WebMD | MedicineNet |
| External links | |
| MeSH | D058607 |
| Legal status | |
| In Wikidata | |
Inpharmacology, thefibrates are a class ofamphipathiccarboxylic acids andesters. They are derivatives offibric acid (phenoxyisobutyric acid). They are used for a range ofmetabolic disorders, mainlyhypercholesterolemia (highcholesterol), and are thereforehypolipidemic agents.
Fibrates improve atherogenic dyslipidemia characterized by high triglyceride and/or low HDL-C levels and elevated concentrations of small dense LDL particles, with or without high LDL-C levels. Fibrates may be compared to statin drugs, which reduce LDL-cholesterol (LDL-C) and have only limited effects on other lipid parameters. Clinical trials have shown that the combination of statins and fibrates results in a significantly greater reduction in LDL-C and triglyceride levels and greater increases in high-density lipoprotein cholesterol (HDL-C) compared with monotherapy with either drug.[1] Fibrates are used in accessory therapy in many forms ofhypercholesterolemia, but the combination of some fibrates (e.g., gemfibrozil) withstatins is contraindicated due to an increased risk ofrhabdomyolysis.[2]
Fibrates stimulate peroxisome proliferator activated receptor (PPAR) alpha, which controls the expression of gene products that mediate the metabolism oftriglycerides (TG) andhigh-density lipoprotein (HDL). As a result, synthesis of fatty acids, TG and VLDL is reduced, whilst that of lipoprotein lipase, which catabolises TG, is enhanced. In addition, production of Apo A1 and ATP binding cassette A1 is up-regulated, leading to increased reverse cholesterol transport via HDL. Consequently, fibrates reduce TG by up to 50% and increase HDL-C by up to 20%, but LDL-C changes are variable.Fewer large-scale trials have been conducted with fibrates than with statins and the results are less conclusive, but reduced rates of cardiovascular disease have been reported with fibrate therapy in the subgroup of patients with low HDL-C levels and elevated TG (e.g. TG > 2.3 mmol/L (200 mg/dL)). Fibrates are usually well tolerated but share a similar side-effect profile to statins. In addition, they may increase the risk of cholelithiasis and prolong the action of anticoagulants. Accumulating evidence suggests that they may also have a protective effect against diabetic microvascular complications.
Clinical trials do support their use as monotherapy agents. Fibrates reduce the number of non-fatal heart attacks, but do not improve all-cause mortality and are therefore indicated only in those not tolerant to statins.[3][4][5]
Although less effective in loweringLDL levels, the ability of fibrates to increase HDL and lowertriglyceride levels seems to reduceinsulin resistance when thedyslipidemia is associated with other features of themetabolic syndrome (hypertension anddiabetes mellitus type 2).[6] They are therefore used in manyhyperlipidemias. Due to a rare paradoxical decrease in HDL-C seen in some patients on fenofibrate, as per US FDA label change, it is recommended that the HDL-C levels be checked within the first few months after initiation of fibrate therapy. If a severely depressed HDL-C level is detected, fibrate therapy should be withdrawn, and the HDL-C level monitored until it has returned to baseline.[citation needed]
Most fibrates can cause mild stomach upset andmyopathy (muscle pain withCPK elevations). Fibrates decrease the synthesis of bile acid by down-regulation ofcholesterol 7 alpha-hydroxylase andsterol 27-hydroxylase expression, therefore making it easier for cholesterol to precipitate and increasing the risk forgallstones.
In combination withstatin drugs, fibrates cause an increased risk ofrhabdomyolysis, idiosyncratic destruction ofmuscle tissue, leading tokidney failure. The lesslipophilicstatins are less prone to cause this reaction, and are probably safer to be combined with fibrates than the more lipophilic statins are.
Drug toxicity includesacute kidney injury.[7]
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Although used clinically since at least 1962, the mechanism of action of fibrates remained unelucidated until the 1990s, when it was discovered that fibrates activateperoxisome proliferator-activated receptors (PPARs), especiallyPPARα.[8] The PPARs are a class of intracellularreceptors that modulatecarbohydrate andfat metabolism andadipose tissue differentiation.
Activating PPARs induces the transcription of a number ofgenes that facilitatelipid metabolism.
Fibrates are pharmacologically related to thethiazolidinediones, a novel class ofanti-diabetic drugs that also act onPPARs (more specificallyPPARγ)[citation needed]
Fibrates are a substrate of (metabolized by)CYP3A4.[8]
Fibrates have been shown to extend lifespan in the roundwormC. elegans.[9]
