View source for Fibrate

{{short description|Class of chemical compounds}}
{{Infobox drug class
| Name = Fibrates
| Image = File:Fenofibrate structure.svg
| ImageClass = skin-invert-image
| Alt = 
| Caption = [[Fenofibrate]], one of the most popular fibrates
| Use = [[hypertriglyceridemia]] and [[hypercholesterolaemia]]
| Biological_target = [[PPAR]]
| ATC_prefix = C10AB
| MeshID = D058607
| Drugs.com = <!-- N/A -->
| Consumer_Reports  = 
| medicinenet = Fibrates
| rxlist = 
}}

In [[pharmacology]], the '''fibrates''' are a class of [[Amphiphile|amphipathic]] [[carboxylic acid]]s and [[ester]]s. They are derivatives of [[fibric acid]] (phenoxyisobutyric acid). They are used for a range of [[metabolism|metabolic]] disorders, mainly [[hypercholesterolemia]] (high [[cholesterol]]), and are therefore [[hypolipidemic agent]]s.

==Medical uses==
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.<ref name="pmid15695129">{{cite journal | doi=10.1016/j.amjcard.2004.10.012| title=Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (The SAFARI trial)| year=2005| last1=Grundy| first1=Scott M.| last2=Vega| first2=Gloria L.| last3=Yuan| first3=Zhong| last4=Battisti| first4=Wendy P.| last5=Brady| first5=William E.| last6=Palmisano| first6=Joanne| journal=The American Journal of Cardiology| volume=95| issue=4| pages=462–468| pmid=15695129}}</ref> Fibrates are used in accessory therapy in many forms of [[hypercholesterolemia]], but the combination of some fibrates (e.g., gemfibrozil) with [[statin]]s is contraindicated due to an increased risk of [[rhabdomyolysis]].<ref name="pmid18158710">{{cite journal | vauthors = Steiner G | title = Atherosclerosis in type 2 diabetes: a role for fibrate therapy? | journal = Diabetes & Vascular Disease Research | volume = 4 | issue = 4 | pages = 368–74 | date = December 2007 | pmid = 18158710 | doi = 10.3132/dvdr.2007.067 | s2cid = 31624928 | doi-access = free }}</ref>

Fibrates stimulate peroxisome proliferator activated receptor (PPAR) alpha, which controls the expression of gene products that mediate the metabolism of [[triglycerides]] (TG) and [[high-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&nbsp;mmol/L (200&nbsp;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.<ref>{{cite journal | vauthors = Abourbih S, Filion KB, Joseph L, Schiffrin EL, Rinfret S, Poirier P, Pilote L, Genest J, Eisenberg MJ | display-authors = 6 | title = Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review | journal = The American Journal of Medicine | volume = 122 | issue = 10 | pages = 962.e1–8 | date = October 2009 | pmid = 19698935 | doi = 10.1016/j.amjmed.2009.03.030 }}</ref><ref>{{cite journal|title=Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis |vauthors=Jun M, Foote C, Lv J, etal |journal=Lancet|volume=375|issue=9729|pages=1875&ndash;1884|year=2010|doi=10.1016/S0140-6736(10)60656-3|pmid=20462635 |s2cid=15570639 }}</ref><ref>{{cite journal | vauthors = Jakob T, Nordmann AJ, Schandelmaier S, Ferreira-González I, Briel M | title = Fibrates for primary prevention of cardiovascular disease events | journal = The Cochrane Database of Systematic Reviews | volume = 11 | article-number = CD009753 | date = November 2016 | issue = 3 | pmid = 27849333 | pmc = 6464497 | doi = 10.1002/14651858.CD009753.pub2 | editor-last = Cochrane Heart Group }}</ref>

Although less effective in lowering [[Low-density lipoprotein|LDL]] levels, the ability of fibrates to increase HDL and lower [[triglyceride]] levels seems to reduce [[insulin resistance]] when the [[dyslipidemia]] is associated with other features of the [[metabolic syndrome]] ([[hypertension]] and [[diabetes mellitus type 2]]).<ref name="pmid15124979">{{cite journal | vauthors = Wysocki J, Belowski D, Kalina M, Kochanski L, Okopien B, Kalina Z | title = Effects of micronized fenofibrate on insulin resistance in patients with metabolic syndrome | journal = International Journal of Clinical Pharmacology and Therapeutics | volume = 42 | issue = 4 | pages = 212–7 | date = April 2004 | pmid = 15124979 | doi = 10.5414/cpp42212 }}</ref> They are therefore used in many [[hyperlipidemias]]. 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|date=July 2020}}

==Side effects==
Most fibrates can cause mild stomach upset and [[myopathy]] (muscle pain with [[creatine kinase|CPK]] elevations). Fibrates decrease the synthesis of bile acid by down-regulation of [[cholesterol 7 alpha-hydroxylase]] and [[sterol 27-hydroxylase]] expression, therefore making it easier for cholesterol to precipitate and increasing the risk for [[gallstone]]s.

In combination with [[statin]] drugs, fibrates cause an increased risk of [[rhabdomyolysis]], idiosyncratic destruction of [[muscle]] tissue, leading to [[kidney failure]]. The less [[lipophilic]] [[statin]]s are less prone to cause this reaction, and are probably safer to be combined with fibrates than the more lipophilic statins are.

[[Drug toxicity]] includes [[acute kidney injury]].<ref name="pmid22508733">{{cite journal | vauthors = Zhao YY, Weir MA, Manno M, Cordy P, Gomes T, Hackam DG, Juurlink DN, Mamdani M, Moist L, Parikh CR, Paterson JM, Wald R, Yao Z, Garg AX | display-authors = 6 | title = New fibrate use and acute renal outcomes in elderly adults: a population-based study | journal = Annals of Internal Medicine | volume = 156 | issue = 8 | pages = 560–9 | date = April 2012 | pmid = 22508733 | doi = 10.7326/0003-4819-156-8-201204170-00003 | s2cid = 207536477 }}</ref>

==Pharmacology==
[[Image:PPAR-diagram.png|thumb|class=skin-invert-image|[[peroxisome proliferator-activated receptor|PPAR]]]]
{{cite check|date=February 2019}}
Although used clinically since at least 1962, the mechanism of action of fibrates remained unelucidated until the 1990s, when it was discovered that fibrates activate [[peroxisome proliferator-activated receptor|peroxisome proliferator-activated receptors (PPARs)]], especially [[PPARα]].<ref name=LeeHandbook>{{cite journal|url=http://www.stacommunications.com/journals/cardiology/2004/June/Pdf/034.pdf|title=Fibrates in Perspective: Answering an Age-Old Question|journal=Perspectives in Cardiology|volume=20|number=6|pages=34–39|first=T.K.|last=Lee}}</ref> The PPARs are a class of intracellular [[receptor (proteomics)|receptors]] that modulate [[carbohydrate metabolism|carbohydrate]] and [[lipid metabolism|fat metabolism]] and [[adipose tissue|adipose tissue differentiation]].

Activating PPARs induces the transcription of a number of [[gene]]s that facilitate [[lipid metabolism]].

Fibrates are pharmacologically related to the [[thiazolidinedione]]s, a novel class of [[anti-diabetic drug]]s that also act on [[peroxisome proliferator-activated receptor|PPARs]] (more specifically [[PPARγ]]){{Citation needed|date=February 2019}}

Fibrates are a substrate of (metabolized by) [[CYP3A4]].<ref name=LeeHandbook/>

Fibrates have been shown to extend lifespan in the roundworm ''C. elegans''.<ref>{{cite journal | last1=Brandstädt | first1=Sven | last2=Schmeisser | first2=Kathrin | last3=Zarse | first3=Kim | last4=Ristow | first4=Michael | title=Lipid-lowering fibrates extend ''C. elegans'' lifespan in a NHR-49/PPARalpha-dependent manner | journal=[[Aging (journal)|Aging]] | volume=5 | issue=4 | date=2013-04-08 | pmid=23603800 | doi=10.18632/aging.100548 | doi-access=free | pages=270–275 | pmc=3651519 }}</ref>

== Members ==
<div class="skin-invert-image">
<gallery class="center" widths="170px">
File:Aluminium clofibrate.svg|[[Aluminium clofibrate]]
File:Bezafibrate.svg|[[Bezafibrate]]
File:Ciprofibrate.svg|[[Ciprofibrate]]
File:Choline fenofibrate.svg|[[Choline fenofibrate]]
File:Clinofibrate.svg|[[Clinofibrate]]
File:Clofibrate.svg|[[Clofibrate]]
File:Clofibride.svg|[[Clofibride]]
File:Fenofibrate structure.svg|[[Fenofibrate]]
File:Gemfibrozil.svg|[[Gemfibrozil]]
File:Nafenopin.svg|[[Nafenopin]]
File:Ronifibrate.svg|[[Ronifibrate]]
File:Simfibrate.svg|[[Simfibrate]]
</gallery>
</div>
== See also ==
* [[Statin]]
* [[Hypertriglyceridemia]]

== References ==
{{reflist|30em}}

{{Major drug groups}}
{{Lipid modifying agents}}
{{PPAR modulators}}

[[Category:Fibrates| ]]
[[Category:4-Chlorophenyl compounds]]