Fibrates are an essential part of modern anti-dyslipidemic arsenal: spotlight on atherogenic dyslipidemia and residual risk reduction

Abstract

Currently the world faces epidemic of several closely related conditions: obesity, metabolic syndrome and type 2 diabetes (T2DM). The lipid profile of these patients and those with metabolic syndrome is characterized by the concurrent presence of qualitative as well as quantitative lipoprotein abnormalities: low levels of HDL, increased triglycerides, and prevalence of LDL particles that are smaller and denser than normal. This lipid phenotype has been defined as atherogenic dyslipidemia. Overwhelming evidences demonstrate that all components of the atherogenic dyslipidemia are important risk-factors for cardiovascular diseases. Optimal reduction of cardiovascular risk through comprehensive management of atherogenic dyslipidemias basically depends of the presence of efficacious lipid-modulating agents (beyond statin-based reduction of LDL-C). The most important class of medications which can be effectively used nowadays to combat atherogenic dyslipidemias is the fibrates. From a clinical point of view, in all available 5 randomized control trials beneficial effects of major fibrates (gemfibrozil, fenofibrate, bezafibrate) were clearly demonstrated and were highly significant in patients with atherogenic dyslipidemia. In these circumstances, the main determinant of the overall results of the trial is mainly dependent of the number of the included appropriate patients with atherogenic dyslipidemia. In a meta-analysis of dyslipidemic subgroups totaling 4726 patients a significant 35% relative risk reduction in cardiovascular events was observed compared with a non significant 6% reduction in those without dyslipidemia. However, different fibrates may have a somewhat different spectrum of effects. Currently only fenofibrate was investigated and proved to be effective in reducing microvascular complications of diabetes. Bezafibrate reduced the severity of intermittent claudication. Cardinal differences between bezafibrate and other fibrates are related to the effects on glucose metabolism and insulin resistance. Bezafibrate is the only clinically available pan - (alpha, beta, gamma) PPAR balanced activator. Bezafibrate decreases blood glucose level, HbA1C, insulin resistance and reduces the incidence of T2DM compared to placebo or other fibrates. Among major fibrates, bezafibrate appears to have the strongest and fenofibrate the weakest effect on HDL-C. Current therapeutic use of statins as monotherapy is still leaving many patients with atherogenic dyslipidemia at high risk for coronary events because even intensive statin therapy does not eliminate the residual cardiovascular risk associated with low HDL and/or high triglycerides. As compared with statin monotherapy (effective mainly on LDL-C levels and plaque stabilization), the association of a statin with a fibrate will also have a major impact on triglycerides, HDL and LDL particle size. Moreover, in the specific case of bezafibrate one could expect neutralizing of the adverse pro-diabetic effect of statins. Though muscle pain and myositis is an issue in statin/...

Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor

“…Therefore, in patients with high triglycerides, fibrates -either as monotherapy or combined with statins -are consistently associated with reduced risk of cardiovascular events [171,172]. Therefore, if the primary goal is to lower TG levels, fibrates (bezafibrate and fenofibrate for monotherapy and combination with statin; gemfibrozil only for monotherapy) now are the preferable drugs [173,174].…”

Agoniści receptorów aktywowanych proliferatorami eroksysomów w farmakoterapii. Obecne znaczenie i perspektywy zastosowania

“…małych, gęstych LDL do postaci prawidłowych [13]. Z uwagi na wywoływaną normalizację lipidogramu, fi braty są zalecane u pacjentów z aterogenną hiperlipidemią, obserwowaną u osób z cukrzycą, zwłaszcza skorelowaną z otyłością brzuszną i nadciśnieniem tętniczym w zespole metabolicznym [12][13][14]. Opisane hipolipemiczne efekty fibratów są również wynikiem ich agonistycznego wpływu na receptory PPAR-α, co prowadzi do zmian aktywności genów kontrolujących przemiany lipidów.…”

“…Zmiany aktywności genów indukowane przez fi braty za pośrednictwem PPAR-α są plejotropowe i obejmują również pozahipolipemiczne efekty, związane ze stabilizacją blaszki miażdżycowej. Efekt ten uwarunkowany jest działaniem przeciwzapalnym (wskutek zahamowania migracji makrofagów i syntezy wielu prozapalnych mediatorów, jak NF-κB, MCP-1 -głównego białka chemoatraktantowego dla monocytów, CRP lub TNF-α), zmniejszeniem stężenia i wykrzepiania fi brynogenu i nasilaniem fi brynolizy [12][13][14][15].…”

Diabeteses dyslipidaemia és atherosclerosis

“…Ennek az összehasonlításnak a szignifikanciaszintje 0,057. A közismerten szigorú amerikai gyógyszerügyi hatóság, az FDA (Food and Drug Administ ration) honlapjáról letölthető elemzésben [33] összehasonlításra kerül a dyslipidaemiás és a nem dyslipidaemiás alcsoportokban külön is a statinnal és a statin + fenofibráttal kezeltek szignifikanciaszintje, amely statisztikailag szignifikánsnak bizonyult (p = 0,03) [33,34]. Ez konzisztens a korábbi fibrátvizsgálatok (Helsinki Heart Study, VA-HIT, BIP és FIELD) atherogen dyslipidaemiás (magas TG-és alacsony HDL-C-szintű) alcsoportjainak eredményeivel (5. ábra) [35].…”