Effects Of Fibrates Research Articles

Effect of Fibrate Treatment on Circulating Adipokine Levels: A Systematic Review and Meta-analysis of Randomized Clinical Trials

Fibrates are widely used in the treatment of dyslipidemia and associated metabolic abnormalities; however, their effects on adipokines are unclear. This meta-analysis of clinical trials aimed to evaluate the effect of fibrates on circulating adipokine levels. Only randomized controlled trials investigating the impact/effect of fibrate treatment on circulating adipokine levels were included from searches in PubMed-Medline, SCOPUS, ClinicalTrials.gov, Web of Science, and Google Scholar databases. A random effects model and the generic inverse variance method were used for the meta-analysis. Sensitivity analysis was conducted using the leave-one-out method. This meta-analysis of 22 clinical trials showed a significant reduction on/in leptin (WMD: -1.58 ng/mL, 95% CI: -2.96, -0.20, p = 0.02, I2 = 0%), plasminogen activator inhibitor-1 (PAI-1) (WMD: -13.86 ng/mL, 95% CI: -26.70, -1.03, p = 0.03, I2 = 99%), and visfatin (WMD: -1.52 ng/mL, 95% CI: -2.49, -0.56, p = 0.002, I2 = 0%) after fibrate therapy; no significant effect was observed on adiponectin (WMD: -0.69 µg/ml, 95% CI: -1.40, 0.02, p = 0.06, I2 = 83%) and resistin (WMD: -2.27 ng/mL, 95% CI: -7.11, 2.57, p = 0.36, I2 = 0%). The sensitivity analysis was robust only for visfatin, while the effect size was sensitive to one arm for leptin, four for adiponectin, and two for PAI-1. This meta-analysis showed that fibrate treatment significantly improves adipokine levels with a decrease in leptin, PAI-1, and visfatin, suggesting potential additional clinical therapeutic benefits through/of fibrate treatment on adipose tissue.

Fibrates and the risk of cardiovascular outcomes in chronic kidney disease patients.

The high risk of major adverse cardiovascular events (MACE) in patients with chronic kidney disease (CKD) has been well described. However, the efficacy of fibrates on the risk of MACE in patients with CKD remains unclear. We conducted a nested case-control study using data from a large administrative database that included more than 1.5 million Japanese patients. We defined cases as CKD patients with incidences of MACE and matched them with controls based on age, sex, calendar year of cohort entry and CKD stage. Fibrate exposure timing was categorized as current, recent or past. A conditional logistic regression analysis was used to investigate the association between fibrate use and the risk of MACE. Our study included 47 490 patients with CKD, with 15 830 MACE identified during a median follow-up of 9.4 months. The numbers of fibrates used during the study period were 556 (3.5%) in the case group and 1109 (3.5%) in the control group. Fibrate use was significantly associated with a decreased risk of MACE [odds ratio (OR) 0.84; 95% confidence interval (CI) 0.75-0.94], particularly for current (OR 0.81; 95% CI 0.68-0.97) and recent use (OR 0.65; 95% CI 0.48-0.90). Regarding the class effect of fibrates, pemafibrate use, but not bezafibrate or fenofibrate use, was significantly associated with a decreased risk of MACE (OR 0.73; 95% CI 0.528-0.997). Recent and current fibrate use, especially pemafibrate use, was associated with a reduced risk of MACE in patients with CKD. This suggests the potential benefits of continuous fibrate therapy and the possible superiority of pemafibrate over other fibrates. However, further investigations in different populations are required to confirm the generalizability of these findings.

The Effect of Fibrates on Kidney Function: A Systematic Review and Meta-Analysis

The Effect of Fibrates on Kidney Function: A Systematic Review and Meta-Analysis

The effect of fibrates on lowering low-density lipoprotein cholesterol and cardiovascular risk reduction: a systemic review and meta-analysis.

The effect of fibrate treatment on cardiovascular risk is inconsistent. This meta-analysis aimed to assess the effect of fibrates on major adverse cardiovascular outcome (MACE) reduction. PubMed, Embase, and Cochrane library databases were searched up to February 2023 for randomized controlled trials comparing fibrate therapy against placebo and reporting cardiovascular outcomes and lipid profile changes. The primary outcome was the clinical outcomes of each trial that most closely corresponding to MACE, a composite of cardiovascular death, acute myocardial infarction, stroke, and coronary revascularization. A pre-specified meta-regression analysis to examine the relationship between the changes in lipid levels after fibrate treatment and the risk of MACE was also performed. Twelve trials were selected for final analysis, with 25 781 patients and 2741 MACEs in the fibrate group and 27 450 patients and 3754 MACEs in the control group. Overall, fibrate therapy was associated with decreased risk of MACE [RR 0.87, 95% confidence interval (CI) 0.81-0.94] with moderate heterogeneity (I2 = 47%). In meta-regression analysis, each 1 mmol/L reduction in low-density lipoprotein cholesterol (LDL-C) after fibrate treatment reduced MACE (RR 0.71, 95% CI 0.49-0.94, P = 0.01), while triglyceride level changes did not show a significant association (RR per 1mmol/L reduction 0.96, 95% CI 0.53-1.40, P = 0.86). A sensitivity analysis with the composite outcome of cardiovascular death or acute myocardial infarction produced similar results. Treatment with fibrates was associated with decreased risk of MACE. The reduction in MACE risk with fibrate therapy appears to be attributable to LDL-C reduction rather than a decrease in triglyceride levels.

Novel Selective PPARα Modulator Pemafibrate for Dyslipidemia, Nonalcoholic Fatty Liver Disease (NAFLD), and Atherosclerosis.

Statins, the intestinal cholesterol transporter inhibitor (ezetimibe), and PCSK9 inhibitors can reduce serum LDL-C levels, leading to a significant reduction in cardiovascular events. However, these events cannot be fully prevented even when maintaining very low LDL-C levels. Hypertriglyceridemia and reduced HDL-C are known as residual risk factors for ASCVD. Hypertriglyceridemia and/or low HDL-C can be treated with fibrates, nicotinic acids, and n-3 polyunsaturated fatty acids. Fibrates were demonstrated to be PPARα agonists and can markedly lower serum TG levels, yet were reported to cause some adverse effects, including an increase in the liver enzyme and creatinine levels. Recent megatrials of fibrates have shown negative findings on the prevention of ASCVD, which were supposed to be due to their low selectivity and potency for binding to PPAR α. To overcome the off-target effects of fibrates, the concept of a selective PPARα modulator (SPPARMα) was proposed. Kowa Company, Ltd. (Tokyo, Japan), has developed pemafibrate (K-877). Compared with fenofibrate, pemafibrate showed more favorable effects on the reduction of TG and an increase in HDL-C. Fibrates worsened liver and kidney function test values, although pemafibrate showed a favorable effect on liver function test values and little effect on serum creatinine levels and eGFR. Minimal drug-drug interactions of pemafibrate with statins were observed. While most of the fibrates are mainly excreted from the kidney, pemafibrate is metabolized in the liver and excreted into the bile. It can be used safely even in patients with CKD, without a significant increase in blood concentration. In the megatrial of pemafibrate, PROMINENT, for dyslipidemic patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL-C and LDL-C levels, the incidence of cardiovascular events did not decrease among those receiving pemafibrate compared to those receiving the placebo; however, the incidence of nonalcoholic fatty liver disease was lower. Pemafibrate may be superior to conventional fibrates and applicable to CKD patients. This current review summarizes the recent findings on pemafibrate.

Fibrates Affect Levels of Phosphorylated p38 in Intestinal Cells in a Differentiation-Dependent Manner.

Fibrates are widely used hypolipidaemic agents that act as ligands of the peroxisome proliferator-activated receptor α (PPARα). p38 is a protein kinase that is mainly activated by environmental and genotoxic stress. We investigated the effect of the PPARα activators fenofibrate and WY-14643 and the PPARα inhibitor GW6471 on the levels of activated p38 (p-p38) in the colorectal cancer cell lines HT-29 and Caco2 in relation to their differentiation status. Fibrates increased p-p38 in undifferentiated HT-29 cells, whereas in other cases p-p38 expression was decreased. HT-29 cells showed p-p38 predominantly in the cytoplasm, whereas Caco2 cells showed higher nuclear positivity. The effect of fibrates may depend on the differentiation status of the cell, as differentiated HT-29 and undifferentiated Caco2 cells share similar characteristics in terms of villin, CYP2J2, and soluble epoxide hydrolase (sEH) expression. In human colorectal carcinoma, higher levels of p-p38 were detected in the cytoplasm, whereas in normal colonic surface epithelium, p-p38 showed nuclear positivity. The decrease in p-p38 positivity was associated with a decrease in sEH, consistent with in vitro results. In conclusion, fibrates affect the level of p-p38, but its exact role in the process of carcinogenesis remains unclear and further research is needed in this area.

Use of fibrates is not associated with reduced risks of mortality or cardiovascular events among ESRD patients: A national cohort study.

Although a recent study reported that fibrates are associated with a low risk of cardiovascular (CV) death and can postpone the need for long-term hemodialysis in patients with advanced chronic kidney disease (CKD), little is known regarding whether the CV protective effects of fibrates extend to patients with end-stage renal disease (ESRD). The present study compared CV outcomes and mortality among patients with ESRD treated with fibrates, statins, neither, or their combination. This cohort study extracted data from Taiwan's National Health Insurance Research Database (NHIRD). Adult patients with ESRD and hyperlipidemia were identified and categorized into four groups (fibrate, statin, combination, and non-user groups) according to their use of different lipid-lowering therapies within 3 months prior to the commencement of permanent dialysis. Inverse probability of treatment weighting was used to balance the baseline characteristics of the groups. The follow-up outcomes were all-cause mortality, CV death, and major adverse cardiac and cerebrovascular events (MACCEs). Compared with the non-user and statin groups, the fibrate group did not exhibit significantly lower risks of all-cause mortality [fibrate vs. non-user: hazard ratio (HR), 0.97; 95% confidence interval (CI), 0.92-1.03; statin vs. fibrate: HR, 0.95; 95% CI, 0.90-1.01], CV death (fibrate vs. non-user: HR, 0.97; 95% CI, 0.90-1.05; statin vs. fibrate: HR, 0.97; 95% CI, 0.90-1.06), and MACCEs (fibrate vs. non-user: HR, 1.03; 95% CI, 0.96-1.10; statin vs. fibrate: HR, 0.94; 95% CI, 0.87-1.004). The combination of fibrates and statins (specifically moderate- to high-potency statins) did not result in lower risks of all-cause mortality, CV death, or MACCEs compared with statins alone. In patients with ESRD, the use of fibrates might be not associated with reduced mortality or CV risks, regardless of whether they are used alone or in combination with statins.

Lipids, hyperreflective crystalline deposits and diabetic retinopathy: potential systemic and retinal-specific effect of lipid-lowering therapies.

The metabolically active retina obtains essential lipids by endogenous biosynthesis and from the systemic circulation. Clinical studies provide limited and sometimes conflicting evidence as to the relationships between circulating lipid levels and the development and progression of diabetic retinopathy in people with diabetes. Cardiovascular-system-focused clinical trials that also evaluated some retinal outcomes demonstrate the potential protective power of lipid-lowering therapies in diabetic retinopathy and some trials with ocular primary endpoints are in progress. Although triacylglycerol-lowering therapies with fibrates afforded some protection against diabetic retinopathy, the effect was independent of changes in traditional blood lipid classes. While systemic LDL-cholesterol lowering with statins did not afford protection against diabetic retinopathy in most clinical trials, and none of the trials focused on retinopathy as the main outcome, data from very large database studies suggest the possible effectiveness of statins. Potential challenges in these studies are discussed, including lipid-independent effects of fibrates and statins, modified lipoproteins and retinal-specific effects of lipid-lowering drugs. Dysregulation of retinal-specific cholesterol metabolism leading to retinal cholesterol accumulation and potential formation of cholesterol crystals are also addressed.

The Effect of Fibrates on Kidney Function and Chronic Kidney Disease Progression: A Systematic Review and Meta-Analysis of Randomised Studies.

Aim: Fibrates have proven efficacy in cardiovascular risk reduction and are commonly used, in addition to statins, to control hypertriglyceridaemia. Their use is often limited due to reduction in glomerular filtration rate at treatment initiation. However, recent studies suggest benign changes in kidney function and improvement of proteinuria, an established early marker of microvascular disease and kidney disease progression. We summarize the evidence from existing trials and provide a summary of effects of fibrates, alone or in combination, on kidney disease progression and proteinuria. Methods and Results: Systematic review and meta-analysis of randomized, controlled trials (PROSPERO CRD42020187764). Out of 12,243 potentially eligible studies, 29 were included in qualitative and quantitative analysis, with a total of 20,176 patients. Mean creatinine increased by 1.05 (95% CI (0.63 to 1.46)) units in patients receiving fibrates vs. comparator, and this was similar in all other subgroups. eGFR showed a bigger decrease in the fibrates arm (SMD −1.99; 95% CI (−3.49 to −0.48)) when all studies were pooled together. Notably, short-term serum creatinine and eGFR changes remained constant in the long-term. Pooled estimates show that fibrates improve albuminuria progression, RR 0.86; 95% CI (0.76 to 0.98); albuminuria regression, RR 1.19; 95% CI (1.08 to 1.310). Conclusions: Fibrates improve albuminuria in patients with and without diabetes when used to treat hyperlipidaemia. The modest creatinine increase should not be a limiting factor for fibrate initiation in people with preserved renal function or mild CKD. The long-term effects on kidney disease progression warrant further study.

The Effect of Fibrates on Kidney Function and CKD Progression: A Systematic Review and Meta-Analysis of Randomised Studies

The Effect of Fibrates on Kidney Function and CKD Progression: A Systematic Review and Meta-Analysis of Randomised Studies

Fibrates for the treatment of pruritus in primary biliary cholangitis: a systematic review and meta-analysis.

This meta-analysis aimed to evaluate the effectiveness of fibrates in the treatment of pruritus in patients with primary biliary cholangitis (PBC), so as to guide the clinical treatment of such cases. Searches of the PubMed, Google Scholar, and Cochrane Library databases were performed to identify randomized controlled trials (RCTs) and prospective studies published up to December 2020 that used bezafibrate and fenofibrate as treatments for pruritus in patients with PBC. Data extraction and quality evaluation of the included literature were performed. Review Manager 5.3 software was employed for statistical analysis of the data. This meta-analysis included 7 studies, comprising 382 patients with PBC, which assessed the efficacy of bezafibrate and fenofibrate for treating pruritus. The results showed that treatment with fibrates significantly improved pruritus symptoms in patients with PBC [relative risk (RR) =6.52, 95% confidence interval (CI): 3.26-13.06, P<0.00001]. Subgroup analysis revealed that in comparison with fenofibrate (RR =5.34, 95% CI: 0.88-32.62, P=0.07), bezafibrate (RR =25.87, 95% CI: 7.93-84.42, P<0.00001) was more effective in improving pruritic symptoms in patients with PBC. Bezafibrate was also superior to fenofibrate in reducing the degree of pruritus in patients (mean difference =3.36, 95% CI: 2.62-4.09, P=0.05, I2=73%). Fibrates can significantly improve pruritus symptoms in patients with PBC but only in a subset of patients. Further studies are needed to elucidate the pathophysiological mechanisms underlying the effect of fibrates on pruritus in PBC, and thus guide future treatment regimens.

Effects of Fibrates on Risk of Development of Diabetic Retinopathy in Japanese Working Age Patients with Type 2 Diabetes and Dyslipidemia: a Retrospective Cohort Study

The aims of the present study were to investigate the effects of fenofibrate and bezafibrate on the risk of development of diabetic retinopathy (DR) in patients with type 2 diabetes and dyslipidemia. Japanese working age patients with type 2 diabetes and dyslipidemia were extracted from the Nihon University School of Medicine Clinical Data Warehouse. These patients were divided into three groups: control group (n=2549), fenofibrate group (n=40), and bezafibrate group (n=135). Multivariate logistic regression analysis was performed to assess the association between fibrates and the development of DR. After adjustment for covariates, fenofibrate showed no association with the risk of DR [adjusted odds ratio (OR), 0.160; 95% CI, 0.021-1.209; p=0.0758]. Bezafibrate also showed no association with the risk of DR (adjusted OR, 0.731; 95% CI, 0.411-1.299; p=0.2855). However, poor control of hemoglobin A1c (HbA1c ≥8.0%; adjusted OR, 3.623; 95% CI, 2.649-4.956; p<0.0001) and high low-density lipoprotein cholesterol (LDL-C ≥140 mg/dL; adjusted OR, 1.399; 95% CI, 1.013-1.932; p=0.0415) within the follow-up period of type 2 diabetes and dyslipidemia increased the risk of DR. Our results suggested that to prevent development of DR in patients with type 2 diabetes and dyslipidemia, controlling LDL-C levels as well as HbA1c levels under coexistence type 2 diabetes and dyslipidemia is more important than the selection of fibrate.

Fenofibrate (a PPAR-α Agonist) Administered During Ethanol Withdrawal Reverts Ethanol-Induced Astrogliosis and Restores the Levels of Glutamate Transporter in Ethanol-Administered Adolescent Rats.

High-ethanol intake induces a neuroinflammatory response, which has been proposed as responsible for the maintenance of chronic ethanol consumption. Neuroinflammation decreases glutamate transporter (GLT-1) expression, increasing levels of glutamate that trigger dopamine release at the corticolimbic reward areas, driving long-term drinking behavior. The activation of peroxisome proliferator-activated receptor alpha (PPARα) by fibrates inhibits neuroinflammation, in models other than ethanol consumption. However, the effect of fibrates on ethanol-induced neuroinflammation has not yet been studied. We previously reported that the administration of fenofibrate to ethanol-drinking rats decreased ethanol consumption. Here, we studied whether fenofibrate effects are related to a decrease in ethanol-induced neuroinflammation and to the normalization of the levels of GLT-1. Rats were administered ethanol on alternate days for 4 weeks (2 g/kg/day). After ethanol withdrawal, fenofibrate was administered for 14 days (50 mg/kg/day) and the levels of glial fibrillary acidic protein (GFAP), phosphorylated NF-κB-inhibitory protein (pIκBα) and GLT-1, were quantified in the prefrontal cortex, hippocampus, and hypothalamus. Ethanol treatment increased the levels of GFAP in the hippocampus and hypothalamus, indicating a clear astrocytic activation. Similarly, ethanol increased the levels of pIκBα in the three areas. The administration of fenofibrate decreased the expression of GFAP and pIκBα in the three areas. These results indicate that fenofibrate reverts both astrogliosis and NF-κB activation. Finally, ethanol decreased GLT-1 expression in the prefrontal cortex and hippocampus. Fenofibrate normalized the levels of GLT-1 in both areas, suggesting that its effect in reducing ethanol consumption could be due to the normalization of glutamatergic tone.

The impact of vitamin D status on cardiometabolic effects of fenofibrate in women with atherogenic dyslipidemia.

Vitamin D deficiency is a risk factor for cardiometabolic disease. The aim of this study was to determine the role of vitamin D status in the impact of fenofibrate on plasma levels of cardiometabolic risk factors. The study population (n=61) consisted of three matched groups of women with atherogenic dyslipidaemia: vitamin D-naïve women withvitamin Dinsufficiency (group A), women receiving vitamin D preparations because ofvitamin Ddeficiency (group B), as well as vitamin D-naïve women with normalvitamin Dstatus (group C), who were treated with micronized fenofibrate (200mg daily). Glucose homeostasis markers, plasma lipids, as well as plasma levels of 25-hydroxyvitamin D, uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen and homocysteine were determined at the beginning of the study and 6months later. At entry, group A was characterized by lower levels of 25-hydroxyvitamin D, reduced insulin sensitivity and higher concentrations of uric acid, hsCRP, fibrinogen and homocysteine. Apart from a weaker effect on HDL-cholesterol and triglycerides in group A, there were no differences between the treatment arms in the effect of fenofibrate on plasma lipids. However, only in groups B and C the drug improved insulin sensitivity and reduced circulating levels of uric acid and hsCRP, as well as increased levels of 25-hydroxyvitamin D and these effects correlated with the degree of improvement in insulin sensitivity. Treatment-induced increase in homocysteine was observed only in group A. The results of the study indicate that cardiometabolic effects offibrates may depend on thevitamin Dstatus of patients.

Fibrates in Chronic Kidney Disease Patients: A Controversial Issue

Background: Fenofibrates were not previously known to affect renal function tests until some reports indicated that these drugs may lead to a decrease in renal function. Likewise, the nephrotoxic effect of fibrates remains to be vague and unclear. Guidelines regarding fenofibrate dosing in renal impairment vary internationally. Patients and methods: A prospective cohort study over 6 months with a total of 80 patients on fibrates divided into 2 groups, 40 of which received statins, and the other 40 continued on fibrates. All patients were subjected to full history, clinical examination, and complete baseline labs. The KFTs including serum creatinine and eGFR were measured at 0, 1, 2, and 6-months intervals and lipid profile at 0,3,6 months serially in both groups. Results: Out of the baseline values of KFTs, the statin group showed a significant decrease in all kidney function values including mean serum creatinine by (0.9mg/dL, P=0.001) and an increase in eGFR (8.9 mL/min/1.73 m2, P<0.001). Whilst in patients who continued to receive fibrates the KFTs continued to rise as serum creatinine showed a significant increase in their mean serum Cr levels (by 0.9 mg/dL or 20%, P=0.001), and a significant decrease in their mean eGFR values (by 8.2 mL/min/1.73 m2 or 20.55%, P<0.001). On the other hand, total and LDL Cholesterol were significantly lower in the statin group at all follow-up intervals. Also, triglycerides were significantly higher in the Statin group at the end of month-6 from baseline. Conclusion: In our study fibrates administration showed a short-term state of renal insufficiency. The long-term effects of fibrates versus variable renal derangement are yet to be identified.

Fibrates in Chronic Kidney Disease Patients: A Controversial Issue

Fenofibrates were not previously known to affect renal function tests until some reports indicated that these drugs may lead to a decrease in renal function. Likewise, the nephrotoxic effect of fibrates remains to be vague and unclear. Guidelines regarding fenofibrate dosing in renal impairment vary internationally.

What are the effects of fibrates used for prevention of melanoma?

What are the effects of fibrates used for prevention of melanoma?

Legacy effect of fibrate add-on therapy in diabetic patients with dyslipidemia: a secondary analysis of the ACCORDION study

BackgroundThe Action to Control Cardiovascular Risk in Diabetes (ACCORD)-Lipid study found no evidence of a beneficial effect of statin-fibrate combined treatment, compared to statins alone, on cardiovascular outcomes and mortality in type 2 diabetes mellitus after 5 years of active treatment. However, a beneficial reduction in major CVD events was shown in a pre-specified sub-group of participants with dyslipidemia. The extended follow-up of this trial provides the opportunity to further investigate possible beneficial effects of fibrates in this group of patients. We aimed to evaluate possible “legacy effects” of fibrate add-on therapy on mortality and major cardiovascular outcomes in patients with dyslipidemia.MethodsThe ACCORD-lipid study was a randomized controlled trial of 5518 participants assigned to receive simvastatin plus fenofibrate vs simvastatin plus placebo. After randomized treatment allocation had finished at the end of the trial, all surviving participants were invited to attend an extended follow-up study (ACCORDION) to continue prospective collection of clinical outcomes. We undertook a secondary analysis of trial and post-trial data in patients who had dyslipidemia. The primary outcome was all-cause and cardiovascular mortality, and secondary outcomes were nonfatal myocardial infarction, stroke, congestive heart failure and major coronary heart disease. We used an intention-to-treat approach to analysis to make comparisons between the original randomized treatment groups.Results853 participants with dyslipidemia had survived at the end of the trial. Most participants continued to use statins, but few used fibrates in either group during the post-trial period. The incidence rates in the fenofibrate group were lower with respect to all-cause mortality, CVD mortality, nonfatal myocardial infarction, congestive heart failure and major coronary heart disease than those in the placebo group over a post-trial follow-up. Allocation to the combined fibrate-statin treatment arm during the trial period had a beneficial legacy effect on all-cause mortality (adjusted HR = 0.65, 95% CI 0.45–0.94; P = 0.02).ConclusionsFibrate treatment during the initial trial period was associated with a legacy benefit of improved survival over a post-trial follow-up. These findings support re-evaluation of fibrates as an add-on strategy to statins in order to reduce cardiovascular risk in diabetic patients with dyslipidemia.Trial registration clinicaltrials.gov, Identifier: NCT00000620

Additive beneficial effects of Fibrates combined with Obeticholic acid in the treatment of patients with Primary Biliary Cholangitis and inadequate response to second-line therapy: data from the Italian PBC Study Group

Obeticholic acid (OCA) and fibrates are the only therapies, which have shown biochemical benefit in PBC patients with inadequate response to ursodeoxycholic acid (UDCA). However, the efficacy of their combination is unknown. Aim of our study was to investigate the efficacy of a combined therapy with OCA and fibrateson the liver biochemistry in high-risk PBC patients, i.e. those with inadequate response to UDCA. This is a proof-of-concept retrospective cohort study. Patients with PBC treated with at least 12 weeks with combination therapy of UDCA (13-15 mg/kg/day), OCA (5-10 mg/daily) and fibrates (bezafibrate 400 mg/daily or fenofibrate 200 mg/daily) were included. Demographical, clinical and biochemical data were collected and analysed before starting the second line therapy, before starting the third line therapy and after 3-6 months of triple therapy. Eleven PBC patients from three liver centres in Italy were included. Median ALP level at the start of the second line therapy was 273U/L (interquartile range, IQR 203,311) with a median reduction of 22%[-0.9,35]. The median ALP level at the start of the third line therapy was 232U/L[199,293] with a median reduction of 29%[22,48] (Figure 1). Eight patients experienced any reduction in ALP levels during triple therapy.The median bilirubin level at the start of the second line therapy was of 0.72 mg/dL[0.6,1] with a median reduction of 13%[-36,20]. The median bilirubin level at the start of the third line therapy was 0.80 mg/dL[0.7,0.9] with a median reduction of 3%[-5,18]. One patient dropped out for persistently abnormal transaminases secondary to introduction of bezafibrates. Triple therapy with UDCA, OCA and fibrates improves liver biochemistry and increases the rate of ALP normalization in patients with PBC and an inadequate response to OCA/UDCA or fibrates/UDCA dual therapy. A randomized clinical trial to assess the efficacy and safety of triple therapy in high-risk PBC patients is warranted.

Additional fibrate treatment in UDCA-refractory PBC patients.

There is no proven treatment for ursodeoxycholic acid (UDCA)-refractory primary biliary cholangitis (PBC) other than obeticholic acid. Although fibrates have been reported to improve biochemical parameters, the long-term effects remain unclear. This study evaluated the effect of fibrate on clinical outcomes of UDCA-refractory PBC. Patients whose alkaline phosphatase (ALP) was not normalized with at least 13mg/kg of UDCA treatment for >1year were included from two tertiary referral centres. The primary outcome was ALP normalization. Secondary outcomes included the development of cirrhosis and hepatic deterioration. Immortal time bias was adjusted using the Mantel-Byar method. A total of 100 UDCA-refractory PBC patients were included: 71 patients received UDCA alone (the UDCA group) and 29 patients received UDCA plus additional fibrate treatment of 160mg/d fenofibrate or 400mg/d bezafibrate (the fibrate/UDCA group). During the follow-up period, the probability of ALP normalization was significantly higher in the fibrate/UDCA group (hazard ratio [HR]=5.00, 95% confidence interval=2.87-8.27, P<0.001). Among 58 non-cirrhotic patients (43 in the UDCA group and 15 in the fibrate/UDCA group), 19 patients (44.1%) in the UDCA group and none in the fibrate/UDCA group developed cirrhosis (HR=0.12, P=0.04). Hepatic deterioration (Child-Pugh score increase or signs of decompensated cirrhosis) occurred in 17 patients (23.9%) of the UDCA group and none in the fibrate/UDCA group in which the difference was significant (HR=0.12, P=0.04). In patients with UDCA-refractory PBC, additional fibrate treatment is associated with a higher probability of ALP normalization and a lower risk of cirrhosis development and hepatic deterioration.