Effects Of Fibrates Research Articles

Circulating Levels of Proprotein Convertase Subtilisin Kexin Type 9 are Elevated by Fibrate Therapy

Proprotein convertase subtilisin kexin type 9 (PCSK9) affects lipid metabolism through modulation of low-density lipoprotein (LDL) receptor degradation. Circulating PCSK9 status is an important determinant of LDL-cholesterol levels and is thus implicated in atherogenesis. The present study aimed to resolve inconsistencies in clinical findings on the impact of fibrate therapy on circulating PCSK9 concentrations using a meta-analysis of all published studies. A comprehensive literature search in Medline and Scopus was carried out to identify clinical reports on the impact of treatment with fibrates on circulating concentrations of PCSK9. A meta-analysis of eligible studies was performed using a random-effects model. A weighed mean difference (WMD) with 95% confidence interval (CI) was used to assess the magnitude of fibrates' effect on PCSK9 concentrations. Six studies comprising 218 subjects fulfilled the eligibility criteria and were included for systematic review and quantitative data synthesis. A meta-analysis indicated a significant elevation of circulating PCSK9 concentrations following fibrate therapy (WMD: +60.37; 95% CI: 11.04-109.71; P = 0.02). The PCSK9-elevating effect of fibrates remained significant after comparison with a control group receiving either placebo or a statin (WMD: +23.97; 95% CI: 5.68-42.26; P = 0.01). Meta-regression analysis indicated that the effect size of fibrates in modulating circulating PCSK9 levels is not dependent on the duration of treatment (point estimate for slope = 0.59, SE = 4.56; 95% CI = -8.34 to 9.53; z = 0.130, P = 0.897). Fibrate therapy is associated with a significant increase in circulating PCSK9 concentrations. Such a PCSK9 elevation may partly explain the modest efficacy of fibrates on LDL-C.

Pharmacoepidemiologic and in vitro evaluation of potential drug–drug interactions of sulfonylureas with fibrates and statins

To examine whether initiation of fibrates or statins in sulfonylurea users is associated with hypoglycaemia, and examine in vitro inhibition of cytochrome P450 (CYP) enzymes by statins, fenofibrate and glipizide. We used healthcare data to conduct nested case-control studies of serious hypoglycaemia (i.e. resulting in hospital admission or emergency department treatment) in persons taking glipizide or glyburide, and calculated adjusted overall and time-stratified odds ratios (ORs) and 95% confidence intervals (CIs). We also characterized the in vitro inhibition of CYP enzymes by statins, fenofibrate and glipizide using fluorometric CYP450 inhibition assays, and estimated area under the concentration-time curve ratios (AUCRs) for the drug pairs. We found elevated adjusted overall ORs for glyburide-fenofibrate (OR 1.84, 95% CI 1.37, 2.47) and glyburide-gemfibrozil (OR 1.57, 95% CI 1.25, 1.96). The apparent risk did decline over time as might be expected from a pharmacokinetic mechanism. Fenofibrate was a potent in vitro inhibitor of CYP2C19 (IC50 = 0.2 μm) and CYP2B6 (IC50 = 0.7 μm) and a moderate inhibitor of CYP2C9 (IC50 = 9.7 μm). The predicted CYP-based AUCRs for fenofibrate-glyburide and gemfibrozil-glyburide interactions were only 1.09 and 1.04, suggesting that CYP inhibition is unlikely to explain such an interaction. Use of fenofibrate or gemfibrozil together with glyburide was associated with elevated overall risks of serious hypoglycaemia. CYP inhibition seems unlikely to explain this observation. We speculate that a pharmacodynamic effect of fibrates (e.g. activate peroxisome proliferator-activator receptor alpha) may contribute to these apparent interactions.

ABCD2 alters peroxisome proliferator-activated receptor α signaling in vitro, but does not impair responses to fenofibrate therapy in a mouse model of diet-induced obesity.

Fenofibrate is a peroxisome proliferator-activated receptor (PPAR) α ligand that has been widely used as a lipid-lowering agent in the treatment of hypertriglyceridemia. ABCD2 (D2) is a peroxisomal long-chain acyl-CoA transporter that is highly induced by fenofibrate in the livers of mice. To determine whether D2 is a modifier of fibrate responses, wild-type and D2-deficient mice were treated with fenofibrate for 14 days. The absence of D2 altered expression of gene clusters associated with lipid metabolism, including PPARα signaling. Using 3T3-L1 adipocytes, which express high levels of D2, we confirmed that knockdown of D2 modified genomic responses to fibrate treatment. We next evaluated the impact of D2 on effects of fibrates in a mouse model of diet-induced obesity. Fenofibrate treatment opposed the development of obesity, hypertriglyceridemia, and insulin resistance. However, these effects were unaffected by D2 genotype. We concluded that D2 can modulate genomic responses to fibrates, but that these effects are not sufficiently robust to alter the effects of fibrates on diet-induced obesity phenotypes.

Chimeric mice with hepatocyte-humanized liver as an appropriate model to study human peroxisome proliferator-activated receptor-α.

Peroxisome proliferator (PP)-activated receptor-α (PPARα) agonists exhibit species-specific effects on livers of the rodent and human (h), which has been considered to reside in the difference of PPARα gene structures. However, the contribution of h-hepatocytes (heps) to the species-specificity remains to be clarified. In this study, the effects of fenofibrate were investigated using a hepatocyte-humanized chimeric mouse (m) model whose livers were replaced with h-heps at >70%. Fenofibrate induced hepatocellular hypertrophy, cell proliferation, and peroxisome proliferation in livers of severe combined immunodeficiency (SCID) mice, but not in the h-hep of chimeric mouse livers. Fenofibrate increased the expression of the enzymes of β- and ω-hydroxylation and deoxygenation of lipids at both gene and protein levels in SCID mouse livers, but not in the h-heps of chimeric mouse livers, supporting the studies with h-PPARα-transgenic mice, a hitherto reliable model for studying the regulation of h-PPARα in the h-liver in most respects, except the induction of the peroxisome proliferation. This study indicates the importance of not only h-PPARα gene but also h-heps themselves to correctly predict effects of fibrates on h-livers, and, therefore, suggests that the chimeric mouse is a currently available, consistent, and reliable model to obtain pharmaceutical data concerning the effects of fibrates on h-livers.

Old and novel therapies for primary biliary cirrhosis.

Despite the presumed immunological pathogenesis of primary biliary cirrhosis, no clear or even harmful consequences resulted from some specific treatments addressed to modify the immunological condition. However, ursodeoxycholic acid (UDCA; 13-16 mg/kg/d) has clear favorable effects not only by improving biochemical cholestasis, but also by delaying the histological progression. Long -term treatment with UDCA is associated with excellent survival, free of transplantation in cases showing biochemical response at one year. In the remaining patients, data on the effect of fibrates, budesonide, or obeticholic acid are encouraging. Pruritus is usually managed using resins; further steps are needed in resistant cases with the use of rifampicin, naltrexone, sertraline, or invasive procedures such as albumin dialysis. Osteoporosis, which is highly prevalent in patients with deep and prolonged cholestasis, improves with bisphosphonates; current data indicate that both weekly alendronate and monthly ibandronate increase bone mass in patients with osteoporosis. Nutritional and fat-vitamin supplementation is also mandatory in patients with severe cholestasis.

Peroxisome proliferator-activated receptor α activation induces hepatic steatosis, suggesting an adverse effect.

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic triglyceride accumulation, ranging from steatosis to steatohepatitis and cirrhosis. NAFLD is a risk factor for cardiovascular diseases and is associated with metabolic syndrome. Antihyperlipidemic drugs are recommended as part of the treatment for NAFLD patients. Although fibrates activate peroxisome proliferator-activated receptor α (PPARα), leading to the reduction of serum triglyceride levels, the effects of these drugs on NAFLD remain controversial. Clinical studies have reported that PPARα activation does not improve hepatic steatosis. In the present study, we focused on exploring the effect and mechanism of PPARα activation on hepatic triglyceride accumulation and hepatic steatosis. Male C57BL/6J mice, Pparα-null mice and HepG2 cells were treated with fenofibrate, one of the most commonly used fibrate drugs. Both low and high doses of fenofibrate were administered. Hepatic steatosis was detected through oil red O staining and electron microscopy. Notably, in fenofibrate-treated mice, the serum triglyceride levels were reduced and the hepatic triglyceride content was increased in a dose-dependent manner. Oil red O staining of liver sections demonstrated that fenofibrate-fed mice accumulated abundant neutral lipids. Fenofibrate also increased the intracellular triglyceride content in HepG2 cells. The expression of sterol regulatory element-binding protein 1c (SREBP-1c) and the key genes associated with lipogenesis were increased in fenofibrate-treated mouse livers and HepG2 cells in a dose-dependent manner. However, the effect was strongly impaired in Pparα-null mice treated with fenofibrate. Fenofibrate treatment induced mature SREBP-1c expression via the direct binding of PPARα to the DR1 motif of the SREBP-1c gene. Taken together, these findings indicate the molecular mechanism by which PPARα activation increases liver triglyceride accumulation and suggest an adverse effect of fibrates on the pathogenesis of hepatic steatosis.

Fibrates ameliorate the course of bacterial sepsis by promoting neutrophil recruitment via CXCR2.

Bacterial sepsis results in high mortality rates, and new therapeutics to control infection are urgently needed. Here, we investigate the therapeutic potential of fibrates in the treatment of bacterial sepsis and examine their effects on innate immunity. Fibrates significantly improved the survival from sepsis in mice infected with Salmonella typhimurium, which was paralleled by markedly increased neutrophil influx to the site of infection resulting in rapid clearance of invading bacteria. As a consequence of fibrate-mediated early control of infection, the systemic inflammatory response was repressed in fibrate-treated mice. Mechanistically, we found that fibrates preserve chemotaxis of murine neutrophils by blocking LPS-induced phosphorylation of ERK. This results in a decrease of G protein-coupled receptor kinase-2 expression, thereby inhibiting the LPS-mediated downregulation of CXCR2, a chemokine receptor critical for neutrophil recruitment. Accordingly, application of a synthetic CXCR2 inhibitor completely abrogated the protective effects of fibrates in septicemia in vivo. Our results unravel a novel function of fibrates in innate immunity and host response to infection and suggest fibrates as a promising adjunct therapy in bacterial sepsis.

New therapeutics in primary biliary cirrhosis: will there ever be light?

New therapeutics in primary biliary cirrhosis: will there ever be light?

Lipoprotein glomerulopathy may provide a key to unlock the puzzles of renal lipidosis

Lipoprotein glomerulopathy is an inherited renal disease characterized by unique lipoprotein thrombi in the glomerulus and is associated with the APOE mutation. Hu and colleagues investigated the genetic and clinical features of a large group of patients with lipoprotein glomerulopathy who carried APOE Kyoto, a major APOE variant. Their findings suggest its descent through a founder effect. Fibrate therapy in this group showed favorable results in the patient and renal survival rates.

Head-to-head comparison of fibrates versus statins for elevation of circulating adiponectin concentrations: a systematic review and meta-analysis

BackgroundElevation of adiponectin levels is a potential therapeutic tool against cardiovascular and metabolic diseases. Clinical evidence suggests differences between fibrates and statins in improving circulating concentrations of adiponectin. AimTo compare the efficacy of fibrates vs. statins on circulating concentrations of adiponectin by meta-analysis of randomized head-to-head trials. MethodsA systematic literature search of Medline was conducted to identify randomized head-to-head comparative trials investigating the efficacy of fibrates vs. statins on circulating levels of adiponectin. Inverse variance-weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated for net changes in adiponectin concentrations using a random-effects model. Random-effects meta-regression was performed to assess the effect of putative moderators on adiponectin levels. ResultsSix trials with a total of 326 subjects (166 in the fibrate and 160 in the statin group) met the eligibility criteria and were selected for this meta-analysis. The estimated effect size for fibrate versus statin therapy was 0.42μg/mL (95% CI: −0.34–1.17). This effect size was robust in the leave-one-out sensitivity analysis and not sensitive to any single study. Meta-regression indicated a borderline significant association between duration of treatment and the effect of fibrates vs. statins on adiponectin concentrations (slope: −0.20; 95% CI: −0.41–0.01; p=0.06). However, baseline body mass index, glucose and lipid levels did not predict the effect of fibrate vs. statin therapy on circulating adiponectin concentrations (p>0.05). ConclusionsMonotherapy with either fibrates or statins has comparable effects on circulating concentrations of adiponectin. Thus, differential effects of statins and fibrates on the occurrence of cardiovascular events may not be attributed to the corresponding changes in adiponectin levels.

Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid

Ursodeoxycholic acid (UDCA) is the standard treatment for primary biliary cirrhosis (PBC) but excellent response is not observed in all cases. Since potential favourable effects of fibrates have been reported in short series with inconclusive results, we have carried out a pilot study to analyse the effects of bezafibrate in patients with suboptimal response to UDCA. Thirty women (age 52.3 ± 2.3 years) treated with UDCA and abnormal alkaline phosphatase (AP) levels received bezafibrate (400 mg/d) for 1 year. Changes were measured every 3 months during the study period of 12 months, 3 months after discontinuation and 3 months after resuming bezafibrate. Two patients discontinued the treatment after few days, three at 6 and one at 9 months. Bezafibrate treatment resulted in a significant decrease in AP as early as 3 months. Normalization or decrease of AP below 1.5 times normal levels was observed in 13 and 4 patients respectively. There was also a significant decrease in γ-glutamyl transferase and alanine aminotransferase, cholesterol and triglyceride levels. Bezafibrate treatment resulted in significant improvement of pruritus. A rebound in liver biochemistries and pruritus occurred upon drug discontinuation, changes which improved again after resuming bezafibrate. Response to bezafibrate was associated with lower liver stiffness and severity of cholestasis. No severe adverse effects were observed. Combination treatment of bezafibrate and UDCA is associated with marked decrease or normalization of alkaline phosphatase as early as 3 months in patients with PBC. Better biochemical response was observed in patients with early disease and lower cholestasis.

Monocyte-suppressing effect of high-dose metformin in fenofibrate-treated patients with impaired glucose tolerance

BackgroundFibrates were found to reduce cytokine release and low-grade inflammation in patients with impaired glucose tolerance. The aim of this study was to investigate whether these effects of fibrates may be potentiated by metformin treatment. MethodsThe study included 43 patients with isolated impaired glucose tolerance and normal plasma lipids who had been treated for at least 6 months with micronized fenofibrate (200mg daily). These subjects were randomly assigned to 12 weeks’treatment with either high dose metformin (3g daily in three divided doses) or placebo. Plasma lipids, glucose homeostasis markers, monocyte cytokine release and plasma C-reactive protein levels were determined before randomization and at the end of the treatment. ResultsMetformin treatment reduced plasma C-reactive protein levels and monocyte release of tumor necrosis factor-α and interleukin-6, as well as tended to reduce monocyte release of interleukin-1β and monocyte chemoattractant protein-1, which was accompanied by an improvement in insulin sensitivity. ConclusionsOur results show that high-dose metformin produces monocyte-suppressing and systemic anti-inflammatory effects in fibrate-treated patients with isolated impaired glucose tolerance. This suggests that fibrate-metformin combination therapy may bring clinical benefits to impaired glucose tolerance patients at high cardiovascular risk.

Fibrates as adjuvant therapy for chronic cholestatic liver disease: Its time has come

In 1993, the effects of fibrates in lowering serum alkaline phosphatase (ALP) was shown for bezafibrate (BF) to be the result of hepatic, rather than bone or intestinal, isoenzymes.1 These initial observations led to the suggestion that fibrates might be beneficial for patients with an elevated ALP and cholestatic liver disease. Since then, several dozen case reports and pilot studies have demonstrated the efficacy of fibrates in reducing serum biomarkers of cholestasis and liver function abnormalities in patients with primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) and incomplete responses to ursodeoxycholic acid (UDCA) monotherapy (Tables 1 and ​and22).

Effects of fibrates on duodenal contractions

Fibrates (e.g. gemfibrozil) are a class of lipid‐lowering drugs that have been used clinically for over 80 years. But fibrates cause adverse gastrointestinal (GI) side effects, which occur with them all but more frequently with gemfibrozil. Our recent work showed that gemfibrozil could inhibit spontaneous contractility of intact duodenal tissues isolated from female rats. If this occurs in vivo in the form of decreased motility, it would help explain such side effects. In the present work, we found that gemfibrozil can also inhibit spontaneous contractions in duodenum from male rats. Secondly, we found that bezafibrate and fenofibrate can also inhibit spontaneous duodenal contractions but gemfibrozil does so to a greater extent. Thirdly, we found that pretreatment with tetrodotoxin did not affect gemfibrozil's ability to inhibit such contractions. Thus, that ability is not due to an action of gemfibrozil on enteric neuronal activity. Finally, we found that contractions induced by acetylcholine and 5‐hydroxytryptamine can be inhibited by gemfibrozil. Thus, gemfibrozil appears to nonspecifically inhibit duodenal smooth muscle contractions induced by at least two known intestinal contractile substances, an action which if present in vivo may help explain its GI side effects and likely those of other fibrates. Support: MWU Masters Program.

The Role of Fibrate Treatment in Dyslipidemia: An Overview

Dyslipidemia, and especially atherogenic dyslipidemia, a combination of small low-density lipoproteins cholesterol (LDL-C), decreased high-density lipoprotein cholesterol (HDL-C) and increased triglyceride (TG) concentrations, represents a major cardiovascular (CV) risk factor. Nuclear receptor peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of lipid metabolism; PPAR ligands are used to treat dyslipidemias. Fibrates have a major impact on TG metabolism as well as on modulating LDL size and subclasses. Fibrates target atherogenic dyslipidemia by increasing plasma HDL-C concentrations and decreasing small dense LDL (sdLDL) particles and TGs, thus contributing to dyslipidemia management, particularly in patients with diabetes (DM) or the metabolic syndrome (MetS). Furthermore, fibrates exert beneficial effects on adipokines, inflammation and oxidative stress as well as neuroprotective properties. However, further studies are needed to define the role of fibrates in the prevention of CV events. We review the effects of fibrates on atherogenic dyslipidemia and CV risk reduction.

Fibrate treatment induced quantitative and qualitative HDL changes associated with an increase of SR-BI cholesterol efflux capacities in rabbits

Fibrates are widely used as lipid lowering drugs acting as peroxisome proliferator-activated receptors α (PPARα) agonists and modulating the expression of several genes involved in lipid and lipoprotein metabolism. Much less is known on the effect of fibrates in HDL structure and composition. Therefore, we examined whether fenofibrate induces quantitative and/or qualitative modifications in HDL metabolism in the rabbit, an animal that, contrary to rodents and similar to humans, is less sensitive to peroxisome proliferators. We first demonstrated that 3-week treatment with fenofibrate (250 mg/kg/day) induced an important increase in serum apolipoprotein A-I, HDL-cholesterol and HDL-phospholipids concentrations and a relative enrichment in HDL cholesteryl ester content. Moreover, the fatty acid profiles from fenofibrate-treated rabbits displayed a dramatic increase in the serum or HDL C18:3 ω6 to C18:2 ω6 ratio suggesting higher Δ6 desaturase activity. In addition, HDL from fenofibrate-treated animals exhibited higher relative proportions of sphingomyelin, phosphatidylinositol and phosphatidylethanolamine. We then reported that fenofibrate induced major changes in the physical characteristics of HDL, mainly a higher size and a faster mobility on agarose gel electrophoresis. Finally, serum or HDL from treated rabbits exhibited higher capacity to promote cholesterol efflux from Scavenger receptor class B type I (SR-BI)-rich Fu5AH cells compared to controls. Our findings demonstrate that fenofibrate has beneficial effects in rabbits by increasing the mass of the circulating HDL pool and by modifying their composition transforming them as better acceptors of cellular cholesterol through SR-BI pathway. These effects of fenofibrate might contribute to its benefits on the prevention and treatment of atherosclerosis.

Effect of combination therapy with fenofibrate and simvastatin on postprandial lipemia in the ACCORD lipid trial.

OBJECTIVEThe Action to Control Cardiovascular Risk in Diabetes lipid study (ACCORD Lipid), which compared the effects of simvastatin plus fenofibrate (FENO-S) versus simvastatin plus placebo (PL-S) on cardiovascular disease outcomes, measured only fasting triglyceride (TG) levels. We examined the effects of FENO-S on postprandial (PP) lipid and lipoprotein levels in a subgroup of ACCORD Lipid subjects.RESEARCH DESIGN AND METHODSWe studied 139 subjects (mean age of 61 years, 40% female, and 76% Hispanic or black) in ACCORD Lipid, from a total 529 ACCORD Lipid subjects in the Northeast Clinical Network. PP plasma TG, apolipoprotein (apo)B48, and apoCIII were measured over 10 h after an oral fat load.RESULTSThe PP TG incremental area under the curve (IAUC) above fasting (median and interquartile range [mg/dL/h]) was 572 (352–907) in the FENO-S group versus 770 (429–1,420) in the PL-S group (P = 0.008). The PP apoB48 IAUC (mean ± SD [μg/mL/h]) was also reduced in the FENO-S versus the PL-S group (23.2 ± 16.3 vs. 35.2 ± 28.6; P = 0.008). Fasting TG levels on the day of study were correlated with PP TG IAUC (r = 0.73 for FENO-S and r = 0.62 for PL-S; each P < 0.001). However, the fibrate effect on PP TG IAUC was a constant percentage across the entire range of fasting TG levels, whereas PP apoB48 IAUC was only reduced when fasting TG levels were increased.CONCLUSIONSFENO-S lowered PP TG similarly in all participants compared with PL-S. However, levels of atherogenic apoB48 particles were reduced only in individuals with increased fasting levels of TG. These results may have implications for interpretation of the overall ACCORD Lipid trial, which suggested benefit from FENO-S only in dyslipidemic individuals.

Lipid management in the prevention of stroke: a meta-analysis of fibrates for stroke prevention

BackgroundFibrates has been extensively used to improve plasma lipid levels and prevent adverse cardiovascular outcomes. However, the effect of fibrates on stroke is unclear at the present time. We therefore carried out a comprehensive systematic review and meta-analysis to evaluate the effects of fibrates on stroke.MethodsWe systematically searched Medline, Embase, the Cochrane Central Register of Controlled Trials, reference lists of articles, and proceedings of major meetings to identify studies for our analysis. We included randomized placebo controlled trials which reported the effects of fibrates on stroke. Relative risk (RR) was used to measure the effect of fibrates on the risk of stroke under random effect model. The analysis was further stratified by factors that could affect the treatment effects.ResultsOverall, fibrate therapy was not associated with a significant reduction on the risk of stroke (RR, 1.02, 95% CI, 0.90 to 1.16, P = 0.78). In the subgroup analyses, we observed that gemfibrozil therapy showed a beneficial effect on stroke (RR, 0.72, 95% CI, 0.53 to 0.98, P = 0.04). Similarly, fibrate therapy comparing to placebo had no effect on the incidence of fatal stroke. Subgroup analysis suggested that fibrate therapy showed an effect on fatal stroke when the Jadad score more than 3 (RR, 0.41, 95% CI, 0.17 to 1.00, P = 0.049). Furthermore, a sensitivity analysis indicated that fibrate therapy may play a role in fatal stroke (RR, 0.49, 95% CI, 0.26 to 0.93, P = 0.03) for patients with previous diabetes, cardiovascular disease or stroke.ConclusionsOur study indicated that fibrate therapy might play an important role in reducing the risk of fatal stroke in patients with previous diabetes, cardiovascular disease or stroke. However, it did not have an effect on the incidence of stroke.

Effect of bezafibrate on office, home and ambulatory blood pressure in hypertensive patients with dyslipidemia

It has been suggested that fibrates, lipid-lowering agents with a peroxisome proliferator-activated receptor-α agonistic property, lower blood pressure (BP) in some experimental models of hypertension. However, the effect of fibrates on BP in humans has been inconsistent, and there are few studies using home or ambulatory BP monitoring. We investigated the effects of bezafibrate on office, home and ambulatory BP in hypertensive patients with dyslipidemia. Thirty-two essential hypertensive patients with dyslipidemia (6 men and 26 women, mean age 65±8 years old) were assigned to a control period and a bezafibrate period (200 mg twice daily) for 8 weeks each in a randomized crossover manner. Bezafibrate significantly reduced serum triglyceride, total and low-density lipoprotein-cholesterol, blood glucose, plasma insulin, the homeostasis model assessment ratio and increased high-density lipoprotein-cholesterol. Compared with the control period, changes in office, home and 24-h BP with bezafibrate were -0.7±2.1/-1.6±1.2 mm Hg, +0.9±1.0/-0.5±0.6 and +0.8±1.4/-0.6±0.9 mm Hg, respectively. None of these differences in BP was significant. In conclusion, bezafibrate improved lipid metabolism and insulin sensitivity but did not affect office, home or ambulatory BP in hypertensive patients with dyslipidemia. Fibrates do not appear to lower BP in patients with essential hypertension.

Effects of Fibrates in Kidney Disease: A Systematic Review and Meta-Analysis

The purpose of this systematic review and meta-analysis was to determine the efficacy and safety of fibrate therapy in the chronic kidney disease (CKD) population. Fibrate therapy produces modest cardiovascular benefits in people at elevated cardiovascular risk. There is limited evidence about the clinical benefits and safety of fibrate therapy in the CKD population. MEDLINE, EMBASE, and the Cochrane Library were systematically searched (1950 to January 2012) for prospective randomized controlled trials assessing the effects of fibrate therapy compared with placebo in people with CKD or on kidney-related outcomes were included. Ten studies including 16,869 participants were identified. In patients with mild-to-moderate CKD (estimated glomerular filtration rate [eGFR] ≤60 ml/min/1.73 m(2)), fibrates improved lipid profiles (lowered total cholesterol [-0.32 mmol/l, p = 0.05] and triglyceride levels [-0.56 mmol/l, p = 0.03] but not low-density lipoprotein cholesterol [-0.01 mmol/l, p = 0.83]; increased high-density lipoprotein cholesterol [0.06 mmol/l, p = 0.001]). In people with diabetes, fibrates reduced the risk of albuminuria progression (relative risk [RR]: 0.86; 95% confidence interval [CI]: 0.76 to 0.98; p = 0.02). Serum creatinine was elevated by fibrate therapy (33 μmol/l, p < 0.001), calculated GFR was reduced (-2.67 ml/min/1.73 m(2), p = 0.01) but there was no detectable effect on the risk of end-stage kidney disease (RR: 0.85; 95% CI: 0.49 to 1.49; p = 0.575). In patients with eGFR of 30 to 59.9 ml/min/1.73 m(2), fibrates reduced the risk of major cardiovascular events (RR: 0.70; 95% CI: 0.54 to 0.89; p = 0.004) and cardiovascular death (RR: 0.60; 95% CI: 0.38 to 0.96; p = 0.03) but not all-cause mortality. There were no clear safety concerns specific to people with CKD but available data were limited. Fibrates improve lipid profiles and prevent cardiovascular events in people with CKD. They reduce albuminuria and reversibly increase serum creatinine but the effects on major kidney outcomes remain unknown. These results suggest that fibrates have a place in reducing cardiovascular risk in people with mild-to-moderate CKD.