Role Of Fibrates Research Articles

Beyond LDL-C: unravelling the residual atherosclerotic cardiovascular disease risk landscape-focus on hypertriglyceridaemia.

Historically, atherosclerotic cardiovascular disease (ASCVD) risk profile mitigation has had a predominant focus on low density lipoprotein cholesterol (LDL-C). In this narrative review we explore the residual ASCVD risk profile beyond LDL-C with a focus on hypertriglyceridaemia, recent clinical trials of therapeutics targeting hypertriglyceridaemia and novel modalities addressing other residual ASCVD risk factors. Hypertriglyceridaemia remains a significant ASCVD risk despite low LDL-C in statin or proprotein convertase subtilisin/kexin type 9 inhibitor-treated patients. Large population-based observational studies have consistently demonstrated an association between hypertriglyceridaemia with ASCVD. This relationship is complicated by the co-existence of low high-density lipoprotein cholesterol. Despite significantly improving atherogenic dyslipidaemia, the most recent clinical trial outcome has cast doubt on the utility of pharmacologically lowering triglyceride concentrations using fibrates. On the other hand, purified eicosapentaenoic acid (EPA), but not in combination with docosahexaenoic acid (DHA), has produced favourable ASCVD outcomes. The outcome of these trials suggests alternate pathways involved in ASCVD risk modulation. Several other pharmacotherapies have been proposed to address other ASCVD risk factors targeting inflammation, thrombotic and metabolic factors. Hypertriglyceridaemia poses a significant residual ASCVD risk in patients already on LDL-C lowering therapy. Results from pharmacologically lowering triglyceride are conflicting. The role of fibrates and combination of EPA and DHA is under question but there is now convincing evidence of ASCVD risk reduction with pure EPA in a subgroup of patients with hypertriglyceridaemia. Clinical guidelines should be updated in line with recent clinical trials evidence. Novel agents targeting non-conventional ASCVD risks need further evaluation.

Effects of omega-3 fatty acids on coronary revascularization and cardiovascular events: is there a role for fibrates?

Effects of omega-3 fatty acids on coronary revascularization and cardiovascular events: is there a role for fibrates?

Effects of omega-3 fatty acids on coronary revascularization and cardiovascular events: is there a role for fibrates? A reply.

Effects of omega-3 fatty acids on coronary revascularization and cardiovascular events: is there a role for fibrates? A reply.

Can Concurrent Fibrate Use Reduce Cardiovascular Risks among Moderate Chronic Kidney Disease Patients Undergoing Statin Therapy? A Cohort Study.

The role of fibrates in treating hypertriglyceridemia in chronic kidney disease (CKD) patients to prevent cardiovascular disease (CVD) has been insufficiently investigated. Since statin is considered the first-line treatment for dyslipidemia in CKD patients, this study aims to evaluate the role of concurrent fibrate therapy with statins among moderate CKD patients. We recruited CKD3 patients from the Chang Gung Research Database who were receiving statin treatment but had not previously been administered ezetimibe or niacin. The participants were divided into two groups based on their use of fibrates (fibrate group) or those with triglyceride levels >200 mg/dL without fibrate treatment (non-fibrate group). The fibrate group (n = 954) only exhibited a significantly lower incidence of AMI (4.4% vs. 5.4%, HR: 0.77, 95% CI: 0.61 to 0.98). The risk of major adverse cardiovascular and cerebrovascular events (14.7% vs. 15.6%, HR: 0.91, 95% CI: 0.72 to 1.15) and all-cause mortality (5.7% vs. 6.1%, HR: 0.91, 95% CI: 0.63 to 1.30) did not significantly differ between the fibrate group and the non-fibrate group (n = 2358). In moderate CKD patients, combining fibrate therapy with statins may not offer additional cardiovascular protection compared to statin alone.

Role of fibrates in attenuated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat heart

The present study has been designed to investigate the beneficial role of Fenofibrate in attenuated the cardioprotective effect of ischemic preconditioning (IPC) in hyperlipidemic (Hpl) rat heart. Experimental Hpl was produced by feeding high fat diet to rats for a period of 28 days. Isolated langendorff's perfused normal and Hpl rat hearts were subjected to global ischemia for 30 min followed by reperfusion for 120 min. The myocardial infarct size was assessed macroscopically using triphenyltetrazolium chloride staining. Coronary effluent was analyzed for lactate dehydrogenase (LDH) and creatine kinase-MB release to assess the extent of cardiac injury. Moreover, the oxidative stress in heart was assessed by measuring thiobarbituric acid reactive substance, superoxide anion generation and reduced form of glutathione. Moreover, I/R produced myocardial injury, which was assessed in terms of increase in myocardial infarct size, LDH and CK-MB release in coronary effluent and decrease in coronary flow rate. Four episodes of IPC (5 min each) afforded cardioprotection against I/R-induced myocardial injury in normal rat heart. On the other hand, IPC mediated myocardial protection against I/R-injury was abolished in Hpl rat heart. However, Treatment with Fenofibrate (100 mg/kg/day, i.p.) as agonists of PPAR-α have not affected the cardioprotective effect of IPC in normal rat heart, but its treatment markedly restored the cardioprotective potentials of IPC in Hpl rat heart. It is noted that the high degree of oxidative stress produced in Hpl rat heart during reperfusion and consequent down regulation of PPAR-α may be responsible to abolish the cardioprotectivepotentials of IPC.

Lipid Lowering and Incidence of Cataract, a Role for Fibrates

Lipid Lowering and Incidence of Cataract, a Role for Fibrates

Fenofibrate, HDL, and cardiovascular disease in Type-2 diabetes: The DAIS trial

BackgroundThere are conflicting reports on the role of fibrates in CVD-risk. Several studies indicate beneficial effects of fibrates on CVD risk in type-2 diabetic patients. We tested how fenofibrate changes lipoprotein subfractions and glucose homeostasis in type-2 diabetic patients. Study designSelected markers of lipid and glucose homeostasis and inflammation were measured in 204 diabetic patients who participated in the Diabetes Atherosclerosis Intervention Study (DAIS) and were randomly assigned to 200 mg fenofibrate or placebo. Percent changes from baseline until a minimum of 3 years (average 39.6 months) on therapy (end of study) were calculated for all study parameters. ResultsThe concentrations of total LDL-C and small dense LDL-C (sdLDL-C) did not change on fenofibrate compared to placebo. Compared to placebo, fenofibrate significantly decreased concentrations of triglyceride and remnant-like particle cholesterol (RLP-C) and activity of lipoprotein-associated phospholipase A2 (Lp-PLA2), while significantly increased concentrations of HDL-C. In contrast to other lipid-modifying drugs (e.g. statins) which increase HDL-C by increasing large (α-1) HDL particles, fenofibrate increased HDL-C by increasing the smaller, less antiatherogenic HDL-C particles, α-3 and α-4. Furthermore, despite lowering TG levels by 20%, fenofibrate failed to decrease pre-β1 levels. On fenofibrate, glycated serum-protein levels increased moderately, while insulin and adiponectin levels did not change. ConclusionOn fenofibrate, lipid homeostasis improved and Lp-PLA2 activity decreased while there was no improvement in glucose homeostasis. Despite increasing HDL-C and decreasing triglyceride levels, fenofibrate failed to improve the antiatherogenic properties of the HDL subpopulation profile.

PPARα-dependent exacerbation of experimental colitis by the hypolipidemic drug fenofibrate.

Fibrates, such as fenofibrate, are peroxisome proliferator-activated receptor-α (PPARα) agonists and have been used for several decades as hypolipidemic agents in the clinic. However, contradictory observations exist on the role of fibrates in host response to acute inflammation, with unclear mechanisms. The role of PPARα in colitis was assessed using fenofibrate and Ppara-null mice. Wild-type or Ppara-null mice were subjected to acute colitis under three distinct protocols, dextran sulfate sodium, trinitrobenzenesulfonic acid, and Salmonella Typhi. Serum and colon lipidomics were analyzed to characterize the metabolic profiles by ultra-performance liquid chromatography-coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. Messenger RNAs of PPARα target genes and genes involved in inflammation were determined by qunatitative PCR analysis. Fenofibrate treatment exacerbated inflammation and tissue injury in acute colitis, and this was dependent on PPARα activation. Lipidomics analysis revealed that bioactive sphingolipids, including sphingomyelins (SM) and ceramides, were significantly increased in the colitis group compared with the control group; this was further potentiated following fenofibrate treatment. In the colon, fenofibrate did not reduce the markedly increased expression of mRNA encoding TNFα found in the acute colitis model, while it decreased hydrolysis and increased synthesis of SM, upregulated RIPK3-dependent necrosis, and elevated mitochondrial fatty acid β-oxidation, which were possibly related to the exacerbated colitis.

Confronting the Residual Cardiovascular Risk Beyond Statins: The Role of Fibrates, Omega-3 Fatty Acids, or Niacin, in Diabetic Patients

Diabetics are regarded a special category of patients known to experience higher rates of cardiovascular complications as compared to the non-diabetic ones. Despite substantial efforts to minimize these risks, with aggressive antiplatelet and lipid lowering therapy, some of the diabetic patients still have a considerable residual risk for cardiovascular adverse events. Important preclinical data with potent lipid-lowering agents, like fibrates, omega-3-fatty acids, and niacin, have shown that they can provide sufficient help in reducing rates of cardiovascular events. In the present review, we are aim to explain their basic mechanisms of action, to present all the available clinical data regarding the efficacy of those agents, and to identify specific diabetic patients' subsets, in whom supplementary therapy with those agents could provide substantial benefit in terms of clinical outcome and not only lipid profile improvement.

The role of fibrates in chronic kidney disease and diabetes mellitus

The role of fibrates in chronic kidney disease and diabetes mellitus

Role of fibrates in cardiovascular disease prevention, the ACCORD-Lipid perspective.

To examine the results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD)-Lipid trial, particularly the subgroup analyses. It is important, when a study fails to meet its overall primary endpoint, to ensure that interpretation of the results include analyses of subgroups that might benefit from the treatment tested. The goal of this review, therefore, is to provide insight and advice to physicians and healthcare workers treating patients similar to those enrolled in ACCORD. The recently published results of ACCORD-Lipid trial will be presented upon the background of previous trials that have tested the ability of fibrates to lower cardiovascular risk. Although ACCORD-Lipid trial did not provide support for the general addition of fenofibrate to statin-treated patients with type 2 diabetes mellitus (T2DM), it added significantly to the results from fibrate monotherapy trials indicative of benefit from such treatment in subgroups of patients who present with significant dyslipidemia. In particular, ACCORD-Lipid trial, in our view, supports the addition of fenofibrate to statin therapy in patients with T2DM and optimal low-density lipoprotein cholesterol levels but persistent, significant hypertriglyceridemia (>200 mg/dl) and low high-density lipoprotein cholesterol levels (<35-40 mg/dl).

Effects of omega-3 on lipid profile and inflammation markers in peritoneal dialysis patients

Introduction: Cardiovascular complications are the main cause of mortality in patients with end-stage renal disease (ESRD). Peritoneal dialysis (PD) patients generally have a more atherogenic serum lipid profile. Although statins are the cornerstone of lipid-lowering therapy, there is an important role of fibrates in the treatment of hypertriglyceridemia. Fibrates increased the risk of rhabdomyolysis. ESRD patients are at risk for inadequate omega-3 intake as a result of renal dietary recommendations. In the general population omega-3 fatty acids play an important modulatory role in lipid regulation, immune and inflammatory responses, progression of arteriosclerosis, and cardiovascular disease. Aim: To evaluate the effect of oral omega-3 administration on plasma lipid levels and inflammatory markers in PD patients. Patients and methods: Fifteen adult and stable PD patients who did not receive omega-3 or fibrates treatment before were included in the study. All subjects followed the usual dialysis diet and regimen and continued with the same cholesterol-lowering statins. The patients were treated with daily oral 2.4 g docosahexaenoic acid and 1 g eicosapentaenoic acid supplementation in three divided doses with meals for 8 weeks. Triglycerides, LDL-C, HDL-C, and inflammation markers were evaluated before the administration of omega-3 and at 8 weeks. Results: Triglyceride levels were decreased significantly (p = 0.001). Total, HDL and LDL cholesterol levels were not affected. ESR, CRP, IL-6, TNF-α, 4-hydroxynonenal, and malondialdehyde levels reduced insignificantly. Conclusions: This short-term pilot study demonstrated the efficacy, safety, and well tolerability of omega-3 in the treatment of hypertriglyceridemia in PD patients.

Fibrates: no ACCORD on their use in the treatment of dyslipidaemia

New data have emerged over the last few years about the role of fibrates in treatment of microvascular and macrovascular disease. Endpoint studies have been conducted with fibrates in coronary heart disease since 1971 and results have been contradictory. Fibrates have shown benefits in patients with low HDL-cholesterol and low LDL-cholesterol. Fibrates remain topical, given their actions on the lipid triad present in the metabolic syndrome and in diabetes. In the Fenofibrate Intervention in Endpoint Lowering in Diabetes study of mixed primary and secondary prevention cohorts, fenofibrate therapy resulted in an 11% reduction in coronary or cardiovascular events in monotherapy. Despite frequent use, there was little endpoint data on fibrate-statin combination therapy until recently. The Action to Control Cardiovascular Risk in Diabetes trial of fenofibrate added to baseline simvastatin therapy in diabetes showed a nonsignificant 8% reduction in cardiovascular events. The benefits were concentrated in men, and women did slightly worse with fibrate therapy. In post-hoc analysis, slight beneficial effects of fenofibrate were seen in patients with moderate hypertriglyceridaemia (>2.3 mmol/l) and low HDL-cholesterol (<0.88 mmol/l). The safety profile of fibrate-simvastatin combination was good. Fenofibrate and bezafibrate are reasonable second-line therapies for dyslipidaemia and in diabetes. They are safe in combination therapy with statins but add little endpoint benefit except possibly in patients with a significant degree of atherogenic dyslipidaemia (high triglycerides and low HDL-cholesterol). The benefits of fibrates on microvascular disease remain to be fully explored.

Fibrates in the treatment of cardiovascular risk and atherogenic dyslipidaemia

New data have emerged over the last few years about the role of fibrates in treatment of microvascular and macrovascular disease. Endpoint studies have been conducted with fibrates in coronary heart disease (CHD) since 1971 and initial results were contradictory. Fibrates later showed benefits in patients with low HDL-C and low LDL-C. The prominence ascribed to the lipid triad of the metabolic syndrome and the increasing prevalence of diabetes has increased the topicality of fibrates given their main action of converting small dense to light buoyant LDL. The Fenofibrate Intervention in Endpoint Lowering in Diabetes (FIELD) study has carried on the tradition. Fenofibrate therapy in 9795 patients comprising a mixed low-risk primary and a medium-risk secondary prevention cohort resulted in an 11% reduction in coronary events (P = 0.16), a similar but significant reduction in cardiovascular events (P = 0.04; number-needed-to-treat = 70). The benefits were concentrated in primary prevention and on nonfatal myocardial events, and post-hoc greater effects were seen in patients with moderate hypertriglyceridaemia (>2.3 mmol/l) and low HDL-C, as had previously been noted in a trial with bezafibrate. Safety was generally good, including in combination with statins, but old concerns about sudden death, pancreatitis and venous thrombosis returned. Unexpected benefits were seen with fenofibrate for microvascular endpoints including microalbuminuria and retinopathy. Fenofibrate and bezafibrate are reasonable second-line therapies for dyslipidaemia and in diabetes, and well tolerated in combination therapy. The benefits of fenofibrate for microvascular disease and its potential role in combination therapy require further confirmation.

Reply

We thank Walker and colleagues for their comments on our article showing that the extent of the biochemical response to ursodeoxycholic acid (UDCA) has a major impact on the prognosis of primary biliary cirrhosis (PBC), thus confirming previous data indicating that not only the fall in bilirubin levels but also in liver enzymes may have prognostic values in patients treated for PBC.1, 2 In this context, Walker and colleagues highlight the possible role of fibrates as new therapeutic agents for PBC. Indeed, they found in their cohort from Northeast England that the combination of fenofibrate and UDCA was able to markedly decrease both alkaline phosphatase and immunoglobulin M levels in patients with PBC with an incomplete response to UDCA, thus confirming recently published results from Iwasaki et al. in Japan.3 First, Iwasaki and colleagues showed that bezafibrate (400 mg/day) was as effective as UDCA (600 mg/day) in reducing liver enzymes. Second, they showed that the combination of bezafibrate and UDCA produces a higher reduction in alkaline phosphatase levels than does UDCA (600 mg/day) alone, but there were no significant differences in other biochemistries between the two therapeutic regimens. Fibrates derivatives have a 40-year history in the management of dyslipidemia. Their use led to the discovery of peroxisome proliferator-activated receptor (PPAR) genes. This class of drugs is generally well-tolerated; however, safety issues have arisen from their use. Their parsimonious use in Europe for the treatment of PBC came initially from the reports of Schaffner4 and Summerfield et al.,5 who showed that clofibrate could induce paradoxical hypercholesterolemia, intrahepatic, and choledocolithiasis in patients with PBC. There were further reports of cases of acute and chronic liver injuries described under the forms of acute cholestatic, autoimmune, chronic liver diseases and biliary tract diseases as well as acute pancreatitis mostly associated with gallstones.6-8 At the same time, occurrence of severe photosensitivity, cutaneous rash, rhabdomyolysis, polymyositis, and renal failure, in addition to the suspected possible role in human liver carcinogenesis, which was demonstrated in rodents, discouraged hepatologists from prescribing fibrates even in the case of dyslipidemia in their patients with PBC. We have a little experience of the use of fibrates for dyslipidemia in PBC. Following the reports from Japan, the review of these cases indeed suggests that fibrates may potentiate the effects of UDCA given at a daily dose of more than 13 mg/kg body weight on alkaline phosphatase and immunoglobulin M levels. We did not find the side-effects mentioned above with the combined therapy. Fibrates are PPAR alpha receptor activators, which are known to exert an array of effects on a myriad of genes including those involved in hepatic lipid metabolism, suppression of bile acid synthesis, increased biliary secretion of phospholipids and cholesterol, inflammation, and defense against oxidative stress, all of these being processes which possibly act in the pathobiology of PBC. As for UDCA over the last 20 years, it remains to be demonstrated that the effects of fibrates will not only be “cosmetic” but really effective in terms of progression toward end-stage disease. Lessons from the UDCA story will certainly be useful to achieve this goal. Raoul Poupon M.D.*, Olivier Chazouilleres M.D.*, Christophe Corpechot M.D.*, * UPMC Liver Center, INSERM, UMRS 893, Centre de Référence des Maladies Inflammatoires des Voies Biliaires, Service d'Hépatologie, Hôpital Saint-Antoine, Assistance Publique–Hôpitaux de Paris, Paris.

PPAR‐alpha: therapeutic role in diabetes‐related cardiovascular disease

Among individuals with diabetes mellitus, cardiovascular disease remains the leading cause of death, despite the many treatment modalities that have been developed over time. The PPAR family, including PPAR-alpha, play important roles in glucose and lipid metabolism and atherosclerosis and thus are potential therapeutic targets. Fibrates act upon PPAR-alpha and appear to target the typical dyslipidaemia of diabetes. Several large prospective clinical trials have shown both primary prevention and secondary prevention benefit with fibrates, although they only had small subgroups of patients with diabetes. The first large outcome study to exclusively study those with diabetes was the FIELD study, which showed no reduction in the primary cardiovascular end-point and only some benefit in the secondary end-point. There are many potential explanations for these results; however, it would appear that at present, there is no role for fibrates as monotherapy for the reduction of cardiovascular risk among those with diabetes. However, their potential role in combination with statin therapy remains to be further elucidated with ongoing studies.

Statins limit the role for fibrates

Statins limit the role for fibrates

Statins limit the role for fibrates

Statins limit the role for fibrates

The role of fibrates in the prevention of cardiovascular disease—a pooled meta-analysis of long-term randomized placebo-controlled clinical trials

Fibrates are effective antilipidemic agents with peroxisome proliferator-activated receptor agonist activity, but clinical trial data on their role in cardiovascular prevention are conflicting. We conducted a systematic review and meta-analysis of randomized clinical trials to evaluate their role in prevention of cardiovascular events. A total of 36,489 patients from 10 published randomized placebo-controlled trials were analyzed using the Mantel-Haenszel fixed-effects model. Odds ratios were computed for cardiovascular outcomes from data pooled from the selected trials, and statistical significance was tested using the z-test statistic (2-sided alpha error <.05). Fibrates significantly reduced plasma total cholesterol and triglyceride levels by about 8% and 30%, respectively, and raised high-density lipoprotein cholesterol levels by about 9% compared with placebo. The odds of all-cause mortality tended to be higher (P = .08), and the odds of noncardiovascular mortality were significantly higher (P = .004) with the use of fibrates. However, these significant differences did not persist after exclusion of trials using clofibrate as the study drug. Fibrates did not significantly reduce the odds of cardiovascular mortality (P = .68), fatal myocardial infarction (MI) (P = .76), or stroke (P = .56). On the other hand, fibrates significantly reduced the odds of nonfatal MI by about 22% (P < .00001). The odds of developing cancer were not significantly higher with the use of fibrates (P = .98), nor were the odds of cancer-related death (P = .17). In conclusion, our meta-analysis revealed that the long-term use of fibrates significantly reduces the occurrence of nonfatal MI but has no significant effect on other adverse cardiovascular outcomes.

Is There a Role for Fibrates in the Management of Dyslipidemia in the Metabolic Syndrome?

The outcomes of fibrate trials have varied: positive with gemfibrozil in the primary prevention Helsinki Heart Study and the secondary prevention VA-HIT trial; positive with reservations in the primary prevention WHO trial (clofibrate); and mixed with bezafibrate in the secondary prevention BIP study and with fenofibrate in the combined primary and secondary prevention FIELD study. Overall, the mixed results, combined with potential for adverse effects when given in combination with statins, have limited the use of these fibrates as cardioprotective agents. However, post hoc analyses of several of the fibrate studies have shown that people with features of the metabolic syndrome, particularly overweight people with high plasma triglyceride levels and low levels of HDL cholesterol, derive a disproportionately large reduction in cardiovascular events when treated with these agents. Thus, there is a strong case for the use of a fibrate to reduce the cardiovascular risk in overweight people with high triglyceride and low HDL-C. However, it should be noted that such people also have their cardiovascular risk reduced by statin therapy. It remains to be determined whether the combination of a fibrate plus statin reduces the risk beyond that achieved with a statin alone.