Combination Of Fenofibrate Research Articles

Study Design and Protocol for a Randomized Controlled Trial to Assess Long-Term Efficacy and Safety of a Triple Combination of Ezetimibe, Fenofibrate, and Moderate-Intensity Statin in Patients with Type 2 Diabetes and Modifiable Cardiovascular Risk Factors (ENSEMBLE).

Atherogenic dyslipidemia, which is frequently associated with type 2 diabetes (T2D) and insulin resistance, contributes to the development of vascular complications. Statin therapy is the primary approach to dyslipidemia management in T2D, however, the role of non-statin therapy remains unclear. Ezetimibe reduces cholesterol burden by inhibiting intestinal cholesterol absorption. Fibrates lower triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C) levels via peroxisome proliferator- activated receptor alpha agonism. Therefore, when combined, these drugs effectively lower non-HDL-C levels. Despite this, few clinical trials have specifically targeted non-HDL-C, and the efficacy of triple combination therapies, including statins, ezetimibe, and fibrates, has yet to be determined. This is a multicenter, prospective, randomized, open-label, active-comparator controlled trial involving 3,958 eligible participants with T2D, cardiovascular risk factors, and elevated non-HDL-C (≥100 mg/dL). Participants, already on moderate-intensity statins, will be randomly assigned to either Ezefeno (ezetimibe/fenofibrate) addition or statin dose-escalation. The primary end point is the development of a composite of major adverse cardiovascular and diabetic microvascular events over 48 months. This trial aims to assess whether combining statins, ezetimibe, and fenofibrate is as effective as, or possibly superior to, statin monotherapy intensification in lowering cardiovascular and microvascular disease risk for patients with T2D. This could propose a novel therapeutic approach for managing dyslipidemia in T2D.

Lipoprotein glomerulopathy with markedly increased arterial stiffness successfully treated with a combination of fenofibrate and losartan: a case report

BackgroundLipoprotein glomerulopathy (LPG) is a apolipoprotein E (ApoE)-related glomerular disease and has been associated with type III hyperlipidemia. Without appropriate treatment, chronic kidney disease (CKD) caused by LPG progresses, and approximately half of the patients develop end-stage kidney disease within 1–27 years of disease onset. However, few studies have highlighted the clinical course of cardiovascular diseases (CVDs) in patients with LPG. Herein, we report the first case of LPG in which the CVD risk was assessed using arterial stiffness.Case presentationA 32-year-old Japanese man was referred to our hospital due to persistent proteinuria. Kidney biopsy showed markedly dilated capillary lumens containing pale-stained thrombi, which stained positively with Oil Red O. Electron microscopy revealed the presence of thrombi in the capillary lumen with low electron density and vacuoles of various sizes in part of the thrombi. Toluidine blue and Sudan IV stains were used to stain the thin sections of Epon-embedded tissue samples for electron microscopy. Sudan IV-positive droplets were observed in the capillary lumens, vascular walls, and cytoplasm of tubular cells. Increased serum ApoE concentration was observed. Liquid chromatography-tandem mass spectrometry of laser-microdissected glomeruli from paraffin sections revealed an increase in ApoE. Direct deoxyribonucleic acid sequencing of ApoE revealed a heterozygous ApoE Sendai mutation (Arg145Pro). The patient was finally diagnosed with LPG with heterozygosity for ApoE-Sendai mutation (Arg145Pro). Notably, at the time of diagnosis, he had markedly increased arterial stiffness for his age. Arterial stiffness was measured using brachial-ankle pulse wave velocity (baPWV), which was equivalent to that of a 56-year-old man. After three months of treatment with fenofibrate and losartan, a significant reduction in proteinuria was achieved along with an improvement in baPWV. Furthermore, these effects were maintained despite the lack of decrease in serum ApoE levels.ConclusionHerein, we report the case of a patient with LPG with markedly increased arterial stiffness at the time of diagnosis, in whom combination therapy with fenofibrate and losartan successfully improved proteinuria and arterial stiffness. To the best of our knowledge, this is the first case report of LPG in which CVD risk was assessed using arterial stiffness.

Abstract 4064: hetIL-15 and Fenofibrate combination alters the metabolic fitness of tumor-infiltrating CD8+T cells leading to TNBC tumor eradication in mice

Abstract Introduction: Tumor-infiltrating cytotoxic CD8+T cells frequently undergo an altered state of differentiation referred to as "exhaustion" and, as a result, they fail to control tumor growth. IL-15 is a cytokine which stimulates the generation, proliferation and cytotoxic function of tumor CD8+T and NK cells. We have produced the native heterodimeric form of IL-15 (hetIL-15) which has advanced in clinical trials. The aim of this study was to overcome the exhaustion of the tumor-infiltrating CD8+T cells and to increase their cytotoxicity, using Fenofibrate (FF), a PPAR-α agonist, in combination with hetIL-15. Experimental Procedures: We have evaluated the therapeutic efficacy of hetIL-15 immunotherapy as a monotherapy and in combination with FF in the murine EO771 orthotopic breast cancer model. The effects of hetIL-15 and/or FF on immune cells and on tumor microenvironment were analyzed by flow cytometry, transcriptomics, metabolomics and proteomics. The metabolic profile of tumor-infiltrating T cells was performed with Seahorse analysis. Results and Conclusions: hetIL-15 monotherapy resulted in tumor eradication in 40% of treated mice and increased survival. Seahorse analysis of tumor-infiltrating CD8+T cells confirmed a rise in oxygen consumption rate (OCR) with substantial increase of spare respiratory capacity. Upon hetIL-15 treatment, tumor-infiltrating CD8+T cells showed elevated extracellular acidification rate (ECAR), resulting in a pronounced shift in the OCR/ECAR ratio in comparison to control, confirming their increased proliferating status. These tumor-infiltrating CD8+T cells also showed increased mitochondrial potential and/or mass and fatty acid (FA) uptake, as evidenced by increased MitoTracker and Bodipy staining, respectively. Transcriptomic analysis revealed increased expression of genes involved in several metabolic pathways such as oxidative phosphorylation, FA oxidation and glycolysis. Monotherapy with FF had no effect on tumor growth delay, whereas the FF- hetIL-15 combination resulted in complete eradication of the tumors in 85%. Combination therapy reshaped the tumor microenvironment, resulting in higher IFN-γ and in differentially expressed metabolites as shown by tumor proteomics and metabolomics, respectively. The combination treatment increased the mitochondrial function, FA uptake and OCR, revealing a more metabolically active phenotype. We conclude that hetIL-15 supports a favorable metabolic profile of intratumoral effector lymphocytes, important for their function. Our data suggest that metabolic reprogramming of tumor specific CD8+T cells using FF is a promising strategy to overcome T cell exhaustion and to promote survival in a metabolically hostile tumor microenvironment. Citation Format: Dimitris Stellas, Sevasti Karaliota, Vasiliki Stravokefalou, Katherine C. Goldfarbmuren, Breana Myers, George N. Pavlakis, Barbara K. Felber. hetIL-15 and Fenofibrate combination alters the metabolic fitness of tumor-infiltrating CD8+T cells leading to TNBC tumor eradication in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4064.

Pharmacoeconomic analysis fenofibrate + rosuvastatin of fixed combination compare to loose-pill combination in patients with atherogenic dyslipidemia

This article presents the results of a pharmacoeconomic analysis of the use of a combination of rosuvastatin + fenofibrate in a single film-coated tablet (“Suprozafen”) and fenofibrate + rosuvastatin in the loose-pill combination of various trade names in the treatment of patients with atherogenic dyslip- idemia. In the pharmacoeconomic evaluation cost-effectiveness analysis and budget impact analysis were used. From the point of view of clinical efficacy, it was found that the fixed combination has an advantage compared to loose-pill combination, expressed in a decrease in the incidence of serious cardiovas- cular events when prescribing a fixed combination of drugs by 8.64%. The results of cost analysis calculations showed that annual cost of of treatment with the fixed combination drug Suprozafen is 11,184 rubles, while treatment with loose-pill combination of rosuvastatin and fenofibrate will be accompa- nied by costs of 10,775 rubles. Thus, the cost of a fixed combination is only 409 rubles. (per year per patient) or 3.7% more higher than when prescrib- ing rosuvastatin and fenofibrate separately, that reflects the comparability of this expenditures. Cost savings for the treatment of serious cardiovascular events when using the fixed combination drug (Suprozafen), which arose due to higher adherence to treatment and a decrease in the risk of these events, is 11,188.9 rubles. per patient per year. Taking into account the results of the cost analysis, the savings in the healthcare system budget for a time hori- zon of one year per 100 patients using a fixed combination of rosuvastatin + fenofibrate is 1,078,001 rubles. The results of the pharmacoeconomic study confirm and allow us to accept the hypothesis that the fixed combination of the drug rosuvastatin and fenofibrate (drug Suprozafen) has a pharmacoeco- nomic advantage compared to the appointment of loose-pill combination. At an almost comparable cost of treatment, the fixed combination, due to higher patient adherence, allows achieving better disease control, reducing the risk of developing serious cardiovascular events and the associated economic burden.

A novel mouse model of familial combined hyperlipidemia and atherosclerosis.

Within the context of residual cardiovascular risk in post-statin era, emerging evidence from epidemiologic and human genetic studies have demonstratedthattriglyceride (TG)-rich lipoproteinsand their remnants are causally related to cardiovascular risk. While,carriers of loss-of-function mutations of ApoC3 havelow TG levelsand are protected from cardiovascular disease (CVD). Of translational significance,siRNAs/antisense oligonucleotide (ASO) targeting ApoC3 is beneficial for patients with atheroscleroticCVD. Therefore, animal models of atherosclerosiswith bothhypercholesterolemia and hypertriglyceridemia are important for the discovery of novel therapeutic strategies targeting TG-lowering on top of traditional cholesterol-lowering.In this study, we constructed a novel mouse model of familial combined hyperlipidemia through inserting a human ApoC3 transgene(hApoC3-Tg) into C57BL/6 J mice and injecting a gain-of-function variant of adeno-associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-D377Y concurrently with high cholesterol diet (HCD) feeding for 16 weeks. In the last 10 weeks, hApoC3-Tg mice were orally treated with a combination of atorvastatin (10 mg·kg-1·d-1) and fenofibrate (100 mg·kg-1·d-1). HCD-treated hApoC3-Tg mice demonstrated elevated levels of serum TG, total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C). Oral administration of atorvastatin and fenofibrate significantly decreased the plaque sizes of en face aorta, aortic sinus and innominate artery accompanied by improved lipid profileand distribution. In summary,this novel mouse model is of considerable clinical relevance for evaluation of anti-atherosclerotic drugsby targeting both hypercholesterolemia and hypertriglyceridemia.

Is there still a place for fenofibrate-statin combination therapy?

Although low-density lipoprotein cholesterol (LDL-C) is the main target for the prevention of atherosclerotic cardiovascular disease (ASCVD), hypertriglyceridaemia (HTG), a common condition characterised by elevated blood triglyceride (TG) levels, contributes to residual cardiovascular risk independently of LDL-C levels. Elevated TG levels are a feature of atherogenic dyslipidaemia, which also includes low HDL-C levels and high levels of atherogenic small, dense LDL, together with accumulation of atherogenic remnant particles. Treatment of HTG includes lifestyle interventions, but these are not always sufficient to significantly reduce TG levels in people at high cardiovascular risk. Current guidelines for the treatment of dyslipidaemias recommend the use of statins as the first choice in people with HTG (TG >200 mg/dL) and high CV risk, and consideration of the use of specific TG-lowering drugs, such as fenofibrate, bezafibrate or icosapent ethyl if HTG persists. Fenofibrate acts by activating the peroxisome proliferator receptor alpha (PPARα), a nuclear receptor that plays an important role in lipid and lipoprotein metabolism, glucose homeostasis and inflammation. Several clinical trials have shown that fibrates may reduce the incidence of major cardiovascular events only in patients with high TG levels and low HDL-C levels, a finding that was also observed with fenofibrate in combination with a statin compared to statin therapy alone. The recent failure of the PROMINENT trial with pemafibrate in combination with a statin highlighted the notion that treatment with fibrates provides a clinical benefit only if they lower apoB levels.

Efficacy and safety of fenofibrate in combination with phototherapy for the treatment of neonatal hyperbilirubinemia: a systematic review and meta-analyses.

Phototherapy is the standard treatment for neonatal jaundice. We aimed to review the efficacy and safety of fenofibrate as an adjunct therapy. Twelve databases were searched and a systematic review and meta-analysis were conducted. Mean change (MC), mean difference (MD), and risk ratios (RR) with a 95% confidence interval (CI) were calculated using a random effects model. The GRADE approach was used to evaluate the evidence's certainty. Nine randomized trials were included. The MC of total serum bilirubin (mg/dL) was significant at 12, 24, 36, 48, and 72 h with respective MC (95% CI) values of -0.46 (-0.61, -0.310), -1.10 (-1.68, -0.52), -2.06 (-2.20, -1.91), -2.15 (-2.74, -1.56), and -1.13 (-1.71, -0.55). The FEN+PT group had a shorter duration of phototherapy (MD: -14.36 h; 95% CI: -23.67, -5.06) and a shorter hospital stay (MD: -1.40 days; 95% CI: -2.14, -0.66). There was no significant difference in the risk of complications (RR: 0.89; 95% CI: 0.54, 1.46) or the need for exchange transfusion (RR: 0.58; 95% CI: 0.12, 2.81). The certainty of the evidence was very low for all outcomes. In conclusion, fenofibrate might be a safe adjunct to neonatal phototherapy. Larger randomized controlled trials are needed for the confirmation of these results.

Evaluation of Drug Utilization and Dose Intensity Pattern in Dyslipidemic Patients with Type 2 Diabetes Mellitus

AbstractDyslipidemia can increase the risk of cardiovascular disease in individuals with metabolic diseases. Patients may have to take multiple medications simultaneously, leading to polypharmacy. A retrospective study was conducted to evaluate drug utilization and dose intensity patterns in dyslipidemic patients with type 2 diabetes mellitus over an 8-month period at a tertiary care hospital. The study included the case sheets of patients diagnosed with dyslipidemia and type 2 diabetes. The required data for the study were collected from the patient's case sheets from the Medical Records Department (from June 2015 to May 2020). The data were documented using MS Excel 2013 and analyzed descriptively using SPSS software version 20. Among the 384 study population, 53% were males and 47% were females, with an age group of 45 to 59 years. Metformin and glimepiride were the most commonly prescribed oral hypoglycemic agents, while glibenclamide was the least prescribed. Atorvastatin was the most prescribed hypolipidemic agent. The combination of atorvastatin and fenofibrate was the most preferred combination therapy. The most frequently prescribed hypoglycemic and hypolipidemic agents were metformin and atorvastatin, respectively. Dyslipidemic patients with diabetes mellitus require the administration of multiple medications. It is crucial to monitor medication adherence and medication-related problems among these populations.

Changing perceptions about the role of combination therapy with statin and fibrate in patients with hypertriglyceridemia

The article discusses the modern therapeutic approach to lowering blood triglyceride levels. The need to consider indications for the use of lipid-lowering therapy in patients with hypertriglyceridemia is caused by the emergence of new evidence-based information. The article describes how elevated blood TG levels are associated with the risk of developing cardiovascular (CV) complications, as well as pancreatitis. The mechanisms of TG metabolism that may regulate the relationship between elevated blood TG levels and the risk of developing CV complications are considered. The findings of large randomized clinical trials, including recent ones, which laid the foundation for the current clinical guidelines for the use of drugs to lower triglycerides levels, are discussed. Indications for fibrate therapy in patients with elevated blood TG levels in various clinical situations are considered. The article emphasizes that the icosapent ethyl ester drug is not currently available in the Russian Federation. According to the latest versions of international guidelines, it is considered a first-line drug to reduce the risk of developing CV complications in patients with an established diagnosis of CVD (i.e. for the purpose of secondary prevention). In this context, the significance of fenofibrate as a drug to lower blood triglyceride levels, specifically in secondary prevention of CV complications, can remain quite high in our country. The appearance of a rosuvastatin and fenofibrate combination drug on the pharmaceutical market of the Russian Federation will increase adherence to the therapy, if a fibrate is required to be added to statin therapy.

Solvent electrospinning amorphous solid dispersions with high itraconazole, celecoxib, mebendazole and fenofibrate drug loading and release potential

In this work, the feasibility of ultra-high drug loaded amorphous solid dispersions (ASDs) for the poorly soluble itraconazole, mebendazole and celecoxib via solvent electrospinning in combination with poly(2-ethyl-2-oxazoline) and fenofibrate in combination with polyvinylpyrrolidone is demonstrated. By lowering the polymer concentration in the electrospinning solution below its individual spinnable limit, ASDs with a drug content of up to 80 wt% are obtained. This is attributed to drug-polymer interactions not being limited by default to hydrogen bonds, as also Van der Waals interactions can result in high drug loadings. The theoretically predicted miscibility by the Flory-Huggins theory is corroborated by the experimental findings based on (modulated) differential scanning calorimetry and x-ray diffraction. Globally, the maximally obtained amorphous drug loadings are higher compared to the loadings found in literature. Additionally, non-sink dissolution tests demonstrate an increase in solubility of up to 50 times compared to their crystalline counterparts. Moreover, due to the lack of precipitation biocompatible PEtOx succeeds in stabilizing the dissolved drug and inhibiting its instant precipitation. The current work thus demonstrates the broader applicability of the electrospinning technique for the production of physically stable ASDs with ultra-high drug loadings, a result which has been validated for several Biopharmaceutics Classification System class II drugs.

Flow-mediated dilation after treatments of fixed dose combination of simvastatin and fenofibrate versus high dose rosuvastatin in hypertriglyceridemia

Flow-mediated dilation after treatments of fixed dose combination of simvastatin and fenofibrate versus high dose rosuvastatin in hypertriglyceridemia

Is fixed dose combination of rosuvastatin with fenofibrate more effective than high dose Rosuvastatin inpatients with stable coronary artery disease with mixed dyslipidemia? A study

: We aimed to compare lipid lowering efficacy and safety of fixed dose combination (FDC) of rosuvastatin and fenofibrate with high dose rosuvastatin (HDR) in patients of stable coronary artery disease (CAD) with mixed dyslipidemia.: 165 patients with stable CAD with mixed dyslipidaemia were randomly assigned to HDR group, 40mg per day (n=79) and FDC group; fenofibrate with rosuvastatin, 145 mg and 20 mg per day respectively (n=88). The lipid profile was measured at baseline and at 12 weeks. The safety profile was measured by recording self-reported adverse reactions during follow up visits and by measuring serum levels of transaminases, creatinine phosphokinase (CPK) at 4 weeks. The lipid lowering efficacy was compared by estimating differences in percentage mean change from baseline values of the lipid fractions and percentage of patients achieving target goals between study groups using unpaired t test and Xtest respectively. : The FDC achieved greater reduction compared to HDR in LDL-C, -11.0% 95% C.I. (-17.7% to -4.3%) p<0.001, NHDL-C levels, -10.1% (-16.0% to -4.2%) p<0.001, triglyceride, -18.4% (-32.0% to -4.7%) p<0.0001. The increase in HDL-C was significantly higher in FDC arm, 14.9% (8.3% to 21.4%) p<0.001.The percentage of patients achieving LDL-C and Non HDL-C target goals were higher in FDC arm but difference was statistically not significant. The FDC was tolerated well than HDR regimen. : The combination of moderate dose rosuvastatin and fenofibrate is more effective in reducing atherogenic lipid fractions and increasing the HDL-C level compared to high dose rosuvastatin and had better safety profile.

Neonatal administration of fenofibrate had no developmental programming effect on the lipid profile and relative leucocyte telomere lengths of adolescent rats fed a high-fructose diet postnatally.

Telomere length, a marker of ageing, is susceptible to developmental programming that may cause its accelerated attrition. Metabolic syndrome triggers telomere attrition. Fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, is protective against telomere attrition. We investigated the impact of fenofibrate administered during suckling on the lipid profile and leucocyte telomere lengths of rats fed a high-fructose diet post-weaning. Suckling Sprague-Dawley pups (n=119) were allocated to four groups and gavaged with either 10mL·kg-1 body mass 0.5% dimethyl sulfoxide, 100mg·kg-1 body mass fenofibrate, fructose (20%, w / v), or a combination of fenofibrate and fructose for 15 days. Upon weaning, each of the initial groups was split into two subgroups: one had plain water while the other had fructose solution (20%, w / v) to drink for 6 weeks. Blood was collected for DNA extraction and relative leucocyte telomere length determination by real-time PCR. Plasma triglycerides and cholesterol were also quantified. The treatments had no effect (p>0.05) on body mass, cholesterol concentration, and relative leucocyte telomere lengths in both sexes. Post-weaning fructose increased triglyceride concentrations (p<0.05) in female rats. Fenofibrate administered during suckling did not affect ageing nor did it prevent high fructose-induced hypertriglyceridaemia in female rats.

Dyslipidemia Correction by Combination of Statin and Choline Fenofibrate in Diabetic Patients with Multifocal Atherosclerosis

Dyslipidemia Correction by Combination of Statin and Choline Fenofibrate in Diabetic Patients with Multifocal Atherosclerosis

Effectiveness of fenofibrate in treatment-naïve patients with primary biliary cholangitis: A Randomized Clinical Trial.

Primary biliary cholangitis (PBC) is a progressive autoimmune liver disease, and patients with inadequate response to ursodeoxycholic acid (UDCA) treatment show reduced long-term survival. Recent studies have shown that fenofibrate is an effective off-label therapy for PBC. However, prospective studies on biochemical response including timing of fenofibrate administration are lacking. This study is aimed to evaluate the efficacy and safety of fenofibrate in UDCA treatment- naïve patients with PBC. A total of 117 treatment-naïve patients with PBC were recruited from the Xijing Hospital for a 12-month randomized, parallel and open-label clinical trial. Study participants were assigned to receive either UDCA standard dose (UDCA-only group) or fenofibrate at a daily dose of 200 mg in addition to UDCA (UDCA-Fenofibrate group). Primary outcome was biochemical response percentage in patients according to the Barcelona criterion at 12 month. In the UDCA-Fenofibrate group, 81.4% [69.9-92.9%] of the patients achieved the primary outcome and 64.3% [51.9-76.8%] in the UDCA-only group achieved (p = 0.048). There was no difference between two groups in noninvasive measures of liver fibrosis and biochemical markers other than alkaline phosphatase at 12 months. Creatinine and transaminases levels in the UDCA-Fenofibrate group increased within the first month, then returned to normal, and remained stable thereafter until the end of the study, even in patients with cirrhosis. In this randomized clinical trial in treatment-naïve patients with PBC, the combination of fenofibrate and UDCA resulted in a significantly higher biochemical response rate. Fenofibrate seemed to be well-tolerated in patients.

비알코올성 지방간에서 지질대사와 간 염증에 대한 fenofibrate와 수영운동 조합의 유익한 효과

The study analyzed the effects of combination of fenofibrate and swimming exercise on the improvement of fatty liver and hepatic inflammation in mice with non-alcoholic fatty liver by consuming a high-fat diet. High-fat diet fed male mice were divided into high-fat diet (H), high-fat diet+fenofibrate (H/F), high-fat diet+swimming exercise (H/Ex), and high-fat diet+ fenofibrate+swimming exercise (H/F/Ex) and raised for 8 weeks. Compared to H, H/F and H/Ex decreased body weight, adipose tissue weight, hepatic lipid accumulation, and serum ALT and AST. H/F/Ex reduced these factors more effectively than H/F. The expression of the fatty acid β-oxidation and inflammatory cytokine genes in liver was decreased in both H/F and H/Ex compared to H. In particular, the expression of these genes in H/F/Ex was further decreased compared to H/F. Thus, this suggests that the combination of fenofibrate and swimming exercise is more effective lipid metabolism and liver inflammation improvement than fenofibrate alone in non-alcoholic fatty liver.

A novel therapy for hepatic cholestasis treatment—the combination of rosiglitazone and fenofibrate

Hepatic cholestasis can develop into liver fibrosis and eventually liver failure. Currently, ursodeoxycholic acid (UDCA) or UDCA combined with fenofibrate is used for cholestasis treatment. Rosiglitazone inhibited α-naphthyl isothiocyanate (ANIT)-induced cholestasis in mice. In this study, we compared the effect of rosiglitazone, UDCA, fenofibrate, combined rosiglitazone and fenofibrate or UDCA and fenofibrate on ANIT-induced cholestasis. C57BL/6J mice were induced cholestasis by ANIT while treated with rosiglitazone, UDCA, fenofibrate, combination of rosiglitazone and fenofibrate, or combination of UDCA and fenofibrate. Liver and serum samples were collected to determine liver necrosis and serum biochemical parameters. Rosiglitazone alone or combined with fenofibrate demonstrated better effects than UDCA alone or UDCA combined with fenofibrate in reduction of cholestasis-induced serum biochemical parameters and liver necrosis. Surprisingly, UDCA combined with fenofibrate, but not rosiglitazone combined with fenofibrate, potently increased accumulation of free fatty acids (FFAs) in the liver. Mechanistically, the protection of combination of rosiglitazone and fenofibrate against cholestasis was attributed to activated adiponectin pathway to enhance FXR and mitochondrial functions and reduce apoptosis in the liver. The accumulation of FFAs in the liver by combination of UDCA and fenofibrate was caused by activation of fatty acid biosynthesis and uptake, and triglyceride hydrolysis. Taken together, our study not only demonstrates the adverse effect of combination therapy of UDCA and fenofibrate, but also suggests the combination of rosiglitazone and fenofibrate can be another option for cholestasis treatment.

Efficacy and safety of fenofibrate add-on therapy in patients with primary biliary cholangitis refractory to ursodeoxycholic acid: A retrospective study and updated meta-analysis.

Background: Ursodeoxycholic acid (UDCA) is currently used for the treatment of primary biliary cholangitis (PBC), but some people do not respond well to UDCA. It reported that the combination of fenofibrate and UDCA can improve the clinical indices in these patients. However, more high-quality evidence is needed to improve guideline recommendations. Methods: Through an updated meta-analysis, studies included were valued by the Cochrane Evaluation Manual and Robins-I. Biochemical and clinical indicator changes in UDCA-refractory PBC patients receiving combination therapy were analyzed by Revman 5.42. Then, we explored the influence of fenofibrate dose and the effectiveness and safety of long-term application by retrospective cohort study. Results: Our meta-analysis included nine publications with a total of 389 patients, including 216 treated with UDCA alone and 173 who received combination therapy. The meta-analysis showed that combination therapy was more effective than UDCA monotherapy in decreasing biochemical parameters, such as ALP, GGT, IgM, and TG. However, the occurrence of pruritus and adverse events was slightly higher with combination therapy than with UDCA monotherapy. A total of 156 patients were included in our cohort study: 68 patients underwent UDCA monotherapy, and 88 patients underwent combination therapy. Among UDCA-refractory patients, fenofibrate add-on therapy significantly improved the ALP normalization rate. Conclusion: The combination of fenofibrate and UDCA can decrease biochemical parameters, of UDCA-refractory PBC patient. Furthermore, the efficacy and safety of long-term combination therapy were also confirmed in our cohort study.

Cost-Effectiveness of Icosapent Ethyl, Evolocumab, Alirocumab, Ezetimibe, or Fenofibrate in Combination with Statins Compared to Statin Monotherapy.

BackgroundDespite treatment with statins, dyslipidaemia patients with elevated cholesterol- and triglyceride-levels remain at high residual risk for major adverse cardiovascular events (MACE). New lipid-lowering drugs must prevent the occurrence of MACE and exhibit cost-effectiveness for their successful adoption to clinical practice.ObjectiveTo assess the cost effectiveness of icosapent ethyl, fenofibrate, ezetimibe, evolocumab, and alirocumab in combination with statins compared to statin monotherapy for cardiovascular prevention from the perspective of UK’s National Health Service.MethodsA Markov model simulated the progression of cardiovascular disease and MACE, including myocardial infarction, stroke, angina pectoris, and coronary revascularisation, in dyslipidaemia patients. The model was populated with cardiovascular outcome trial data for each drug. Cost and utility data were extracted from peer-reviewed literature. The incremental cost-effectiveness ratio (ICER) is reported per quality-adjusted life years (QALY) gained in 2021 Great Britain Pounds (£).ResultsFor primary cardiovascular prevention, icosapent ethyl increased QALYs by 0.79 and costs by £15,421 compared to statin monotherapy (ICER = £19,485/QALY). Fenofibrate yielded 0.62 additional QALYs at cost-savings of − £6127 (ICER = − £9932/QALY). For secondary prevention, the omega-3 fatty acid icosapent ethyl extended QALYs by 0.98 at costs of £12,981 compared to statin monotherapy (ICER = £13,285/QALY). Fenofibrate added 0.85 QALYs whilst saving − £637 (ICER = − £7472/QALY). Ezetimibe increased QALYs by 0.60 at cost reductions of − £2529 (ICER = − £4231/QALY). PCSK9 inhibitors provided QALYs of 0.53 and 0.86 at costs of £45,279 and £46,375 for evolocumab (ICER = £85,193/QALY) and alirocumab (ICER = £54,211/QALY), respectively. At a willingness-to-pay threshold of £25,000/QALY, there is a probability of 100% for icosapent ethyl (98% in primary prevention) and 0% for PCSK9 inhibitors to be cost effective in secondary prevention.ConclusionsIcosapent ethyl is cost effective for primary and secondary cardiovascular prevention at an annual price of £2064 in the UK. For PCSK9 inhibitors, price discounts or prescription restrictions are necessary to achieve cost effectiveness.Graphical abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s40261-022-01173-3.

Beneficial Effect of Fenofibrate and Silymarin on Hepatic Steatosis and Gene Expression of Lipogenic and Cytochrome P450 Enzymes in Non-Obese Hereditary Hypertriglyceridemic Rats.

The efficacy of fenofibrate in the treatment of hepatic steatosis has not been clearly demonstrated. In this study, we investigated the effects of fenofibrate and silymarin, administered as monotherapy and in combination to existing hepatic steatosis in a unique strain of hereditary hypertriglyceridemic rats (HHTg), a non-obese model of metabolic syndrome. HHTg rats were fed a standard diet without or with fenofibrate (100 mg/kg b.wt./day) or with silymarin (1%) or with a combination of fenofibrate with silymarin for four weeks. Fenofibrate alone and in combination with silymarin decreased serum and liver triglycerides and cholesterol and increased HDL cholesterol. These effects were associated with the decreased gene expression of enzymes involved in lipid synthesis and transport, while enzymes of lipid conversion were upregulated. The combination treatment had a beneficial effect on the gene expression of hepatic cytochrome P450 (CYP) enzymes. The expression of the CYP2E1 enzyme, which is source of hepatic reactive oxygen species, was reduced. In addition, fenofibrate-induced increased CYP4A1 expression was decreased, suggesting a reduction in the pro-inflammatory effects of fenofibrate. These results show high efficacy and mechanisms of action of the combination of fenofibrate with silymarin in treating hepatic steatosis and indicate the possibility of protection against disorders in which oxidative stress and inflammation are involved.