Fibrate
| Fibrates | |
|---|---|
| Drug class | |
 Fenofibrate,one of the most popular fibrates | |
| Class identifiers | |
| Use | hypertriglyceridemiaandhypercholesterolaemia |
| ATC code | C10AB |
| Biological target | PPAR |
| Clinical data | |
| WebMD | MedicineNet |
| External links | |
| MeSH | D058607 |
| Legal status | |
| In Wikidata | |
Inpharmacology,thefibratesare a class ofamphipathiccarboxylic acidsandesters.They are derivatives offibric acid(phenoxyisobutyric acid). They are used for a range ofmetabolicdisorders, mainlyhypercholesterolemia(highcholesterol), and are thereforehypolipidemic agents.
Medical uses
[edit]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) withstatinsis 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 loweringLDLlevels, the ability of fibrates to increase HDL and lowertriglyceridelevels seems to reduceinsulin resistancewhen thedyslipidemiais associated with other features of themetabolic syndrome(hypertensionanddiabetes 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]
Side effects
[edit]Most fibrates can cause mild stomach upset andmyopathy(muscle pain withCPKelevations). Fibrates decrease the synthesis of bile acid by down-regulation ofcholesterol 7 alpha-hydroxylaseandsterol 27-hydroxylaseexpression, therefore making it easier for cholesterol to precipitate and increasing the risk forgallstones.
In combination withstatindrugs, fibrates cause an increased risk ofrhabdomyolysis,idiosyncratic destruction ofmuscletissue, leading tokidney failure.The lesslipophilicstatinsare less prone to cause this reaction, and are probably safer to be combined with fibrates than the more lipophilic statins are.
Drug toxicityincludesacute kidney injury.[7]
Pharmacology
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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 intracellularreceptorsthat modulatecarbohydrateandfat metabolismandadipose tissue differentiation.
Activating PPARs induces the transcription of a number ofgenesthat facilitatelipid metabolism.
Fibrates are pharmacologically related to thethiazolidinediones,a novel class ofanti-diabetic drugsthat 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]
Members
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See also
[edit]References
[edit]- ^Grundy, Scott M.; Vega, Gloria L.; Yuan, Zhong; Battisti, Wendy P.; Brady, William E.; Palmisano, Joanne (2005). "Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (The SAFARI trial)".The American Journal of Cardiology.95(4): 462–468.doi:10.1016/j.amjcard.2004.10.012.PMID15695129.
- ^Steiner G (December 2007)."Atherosclerosis in type 2 diabetes: a role for fibrate therapy?".Diabetes & Vascular Disease Research.4(4): 368–74.doi:10.3132/dvdr.2007.067.PMID18158710.S2CID31624928.
- ^Abourbih S, Filion KB, Joseph L, Schiffrin EL, Rinfret S, Poirier P, et al. (October 2009). "Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review".The American Journal of Medicine.122(10): 962.e1–8.doi:10.1016/j.amjmed.2009.03.030.PMID19698935.
- ^Jun M, Foote C, Lv J, et al. (2010). "Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis".Lancet.375(9729): 1875–1884.doi:10.1016/S0140-6736(10)60656-3.PMID20462635.S2CID15570639.
- ^Jakob T, Nordmann AJ, Schandelmaier S, Ferreira-González I, Briel M (November 2016). Cochrane Heart Group (ed.)."Fibrates for primary prevention of cardiovascular disease events".The Cochrane Database of Systematic Reviews.11(3): CD009753.doi:10.1002/14651858.CD009753.pub2.PMC6464497.PMID27849333.
- ^Wysocki J, Belowski D, Kalina M, Kochanski L, Okopien B, Kalina Z (April 2004). "Effects of micronized fenofibrate on insulin resistance in patients with metabolic syndrome".International Journal of Clinical Pharmacology and Therapeutics.42(4): 212–7.doi:10.5414/cpp42212.PMID15124979.
- ^Zhao YY, Weir MA, Manno M, Cordy P, Gomes T, Hackam DG, et al. (April 2012)."New fibrate use and acute renal outcomes in elderly adults: a population-based study".Annals of Internal Medicine.156(8): 560–9.doi:10.7326/0003-4819-156-8-201204170-00003.PMID22508733.S2CID207536477.
- ^abLee, T.K."Fibrates in Perspective: Answering an Age-Old Question"(PDF).Perspectives in Cardiology.20(6): 34–39.
- ^Brandstädt, Sven; Schmeisser, Kathrin; Zarse, Kim; Ristow, Michael (2013-04-08)."Lipid-lowering fibrates extendC. eleganslifespan in a NHR-49/PPARalpha-dependent manner ".Aging.5(4): 270–275.doi:10.18632/aging.100548.PMC3651519.PMID23603800.
