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.

Associations of omega-3 fatty acids vs. fenofibrate with adverse cardiovascular outcomes in people with metabolic syndrome: propensity matched cohort study.

AIMS: Omega-3 fatty acids and fenofibrates have shown some beneficial cardiovascular effects; however, their efficacy has not been compared. This study aimed to compare the effectiveness of currently available omega-3 fatty acids and fenofibrate for reducing major adverse cardiovascular events (MACE). METHODS AND RESULTS: From a nationwide population-based cohort in South Korea (2008-2019), individuals with metabolic syndrome (≥30 years) who received statin with omega-3 fatty acids and those receiving statin with fenofibrate were matched by propensity score (n = 39 165 in both groups). The primary outcome was MACE, including ischaemic heart disease (IHD), ischaemic stroke (IS), and death from cardiovascular causes. The risk of MACE was lower [hazard ratio (HR), 0.79; 95% confidence interval (CI), 0.74-0.83] in the fenofibrate group than in the omega-3 fatty acid group. Fenofibrate was associated with a lower incidence of IHD (HR, 0.72; 95% CI, 0.67-0.77) and hospitalization for heart failure (HR, 0.90; 95% CI, 0.82-0.97), but not IS (HR, 0.90; 95% CI, 0.81-1.00) nor death from cardiovascular causes (HR, 1.07; 95% CI, 0.97-1.17). The beneficial effect of fenofibrate compared to omega-3 fatty acids was prominent in patients with preexisting atherosclerotic cardiovascular disease and those receiving lower doses of omega-3 fatty acids (≤2 g per day). CONCLUSION: In a real-world setting, fenofibrate use was associated with a lower risk of MACE compared with low-dose omega-3 fatty acids when added to statins in people with metabolic syndrome.

Optimizing Lipid Pattern by Adding a Combined Nutraceutical or Pravastatin to Fenofibrate Treatment in Hypertriglyceridemic Subjects: Single Site, Randomized, Open-Label, Post-Market Clinical Investigation.

INTRODUCTION: Fenofibrate is an effective and safe treatment for hypertriglyceridemia. However, after TG reduction a residual dyslipidemia could appear and require further treatment. AIM: To comparatively evaluate the short-term tolerability and efficacy of a combined lipid-lowering nutraceutical and pravastatin 40 mg in fenofibrate treated patients. METHOD: We prospectively enrolled 40 patients well-tolerating treatment with micronized fenofibrate 145 mg/day and with residual dyslipidemia (LDL-C > 115 mg/dL and TG > 150 mg/dL). Exclusion criteria have been type 2 diabetes, Familial Hypercholesterolemia, previous cardiovascular diseases and severe chronic kidney disease. Then, we have randomly assigned the patients to treatment with pravastatin 40 mg or a combined lipid-lowering nutraceutical (Armolipid Plus®, containing monacolin 3 mg and berberine 500 mg). RESULTS: After 8 weeks of treatment, 80% of pravastatin treated patients (N. 16/20) and 75% of those treated with Armolipid Plus® (N. 15/20) reached the desired LDL-C target, while 50% of pravastatin treated patients (N. 10/20) and 80% of the Armolipid Plus® treated ones reached the desired TG target (N. 16/20). No one adverse event has been registered during Armolipid Plus®, while 1 patient claimed myalgia and 1 reported significant increase of CPK (> 3 ULN) during pravastatin treatment. Both patients were then treated with Armolipid Plus® with resolution of symptoms and CPK increase, respectively. CONCLUSION: In hypertriglyceridemic patients treated with fenofibrate, the association with a combined lipid lowering nutraceutical seem to be more effective in optimizing residual hypertriglyceridemia than pravastatin 40 mg, while being more tolerable and having similar effect on LDL-C plasma level.

Fenofibrate decreases the bone quality by down regulating Runx2 in high-fat-diet induced Type 2 diabetes mellitus mouse model.

BACKGROUND: This study is to investigate the effect of fenofibrate on the bone quality of Type 2 diabetes mellitus (T2DM) mouse model. METHODS: T2DM mouse model was induced by high-fat-diet, and the mice were treated with fenofibrate (100 mg/kg) (DIO-FENO) or PBS (DIO-PBS) for 4 weeks. The bone microstructure and biomechanical properties of femora were analyzed by micro-CT and 3-Point bending test. The protein expression was detected by immunohistochemical staining and Western blot. The cell apoptosis was evaluated by TUNEL staining. The Bcl2, caspase 3, and osteoblast marker genes were detected by RT-qPCR. RESULTS: The biomechanical properties of bones from DIO-FENO group were significantly lower than those in the control and DIO-PBS groups. Besides, the trabecular number was lower than those of the other groups, though the cortical porosity was decreased compared with that of DIO-PBS group because of the increase of apoptotic cells. The expression of osteocalcin and collagen I were decreased after treatment with fenofibrate in T2DM mice. Moreover, the cell viability was decreased after treated with different concentrations of fenofibrate, and the expression of Runx2 decreased after treated with high dose of fenofibrate. CONCLUSION: Fenofibrate decreases the bone quality of T2DM mice through decreasing the expression of collagen I and osteocalcin, which may be resulted from the down regulation of Runx2 expression.

Combination therapy with statins: who benefits?

Many lipid-lowering drugs improve cardiovascular (CV) outcomes. However, when therapies have been studied in addition to statins, it has been challenging to show an additional clinical benefit in terms of CV event reduction, although overall safety seems acceptable. This debate has been complicated by recent guidelines that emphasize treatment with high-potency statin monotherapy. Combination therapy allows more patients to successfully reach their ideal lipid targets. Further testing of novel therapies may introduce an era of potent low-density lipoprotein decrease without dependence on statins, but until then, they remain the mainstay of therapy.

Fenofibrate causes elevation of betaine excretion but not excretion of other osmolytes by healthy adults.

BACKGROUND: Cross-sectional data suggest that bezafibrate increases betaine excretion in dyslipidemic patients. OBJECTIVE: We aimed to demonstrate that fenofibrate induces increased betaine excretion in normal subjects and explore whether other 1-carbon metabolites and osmolytes are similarly affected. METHODS: Urine was collected from 26 healthy adults before and after treatment with fenofibrate (145 mg/day for 6 weeks). Excretions of betaine, N,N-dimethylglycine, free choline, myo-inositol, taurine, trimethylamine-N-oxide, carnitine, and acetylcarnitine were measured by liquid chromatography with mass spectrometric detection. RESULTS: Fenofibrate increased the median betaine excretion from 7.5 to 25.8 mmol/mole creatinine (median increase 3-fold), P < .001. The median increase in N,N-dimethylglycine excretion was 2-fold (P < .001). Median choline excretion increased 12% (significant, P = .029). Participants with higher initial excretions tended to have larger increases (P < .001 in all 3 cases). Fenofibrate did not significantly change the median excretions of myo-inositol, taurine, trimethylamine-N-oxide, and carnitine. The excretion of acetylcarnitine decreased 4-fold on treatment, with no correlation between the baseline and after-treatment excretions. Changes in all urine components tested, except trimethylamine-N-oxide, positively correlated with changes in betaine excretion even when the median excretions before and after were not significantly different. CONCLUSIONS: Fibrates increase betaine, and to a lesser extent N,N-dimethylglycine and choline, excretion. Other osmolytes are not elevated. Because the increase in betaine excretion depends on the baseline excretion, large increases in excretion in the metabolic syndrome and diabetes (where baseline excretions are high) could be expected. Replacement with betaine supplements may be considered.

Evaluation of the incidence and risk factors for development of fenofibrate-associated nephrotoxicity.

BACKGROUND: Fenofibrate-associated nephrotoxicity has been described in two randomized controlled trials and several observational studies. However, little is known regarding its incidence and the population(s) at risk. OBJECTIVE: This study aims to quantify the incidence and identify potential risk factors for development of nephrotoxicity in patients receiving fenofibrate. METHODS: A retrospective, observational study was conducted in the South Texas Veterans Health Care System. Data were collected regarding baseline demographics, concurrent medical conditions, medications, laboratory results, and fenofibrate use. RESULTS: Within 6 months after initiation of fenofibrate in 428 patients, 115 (27%) experienced an increase in serum creatinine of ≥ 0.3 mg/dL. Any renal disease (P = .001), chronic kidney disease (P = .01), and diabetes (P = .02) were significantly more prevalent in patients with fenofibrate-associated nephrotoxicity. Patients with nephrotoxicity had significantly greater serum creatinine (1.2 [SD 0.3] vs. 1.1 mg/dL [SD 0.3], P = .0002) and lower estimated glomerular filtration rate (72 [SD 20] vs 81 mL/min/1.73 m² [SD 20], P < .0001) at baseline. These patients also had greater use of calcium channel blockers (P = .0003), furosemide (P = .02), and angiotensin-converting enzyme inhibitors (P = .02). The incidence of nephrotoxicity was significantly greater in patients initiated on high-dose versus those on low-dose fenofibrate (P = .002). In a multivariable regression model, renal disease (P = .02), high-dose fenofibrate (P = .001), and dihydropyridine calcium channel blocker use (P = .02) were determined to be independent predictors of development of increased serum creatinine on fenofibrate. CONCLUSION: This observational study suggests fenofibrate-associated nephrotoxicity occurs more frequently than previously reported, particularly in patients with renal disease and in those receiving high-dose fenofibrate or concomitant calcium channel blockers.

Evaluating optimal lipid levels in patients with mixed dyslipidemia following short- and long-term treatment with fenofibric acid and statin combination therapy: a post hoc analysis.

OBJECTIVE: To evaluate the achievement of individual and combined lipid and lipoprotein/biomarker targets as specified by treatment guidelines with the combination of fenofibric acid and statin therapy in patients with mixed dyslipidemia. METHODS: Data for the post hoc analyses were derived from three 12-week controlled studies and a 52-week extension study. Patients were treated with fenofibric acid 135 mg; low-, moderate-, or high-dose statin (rosuvastatin 10, 20, or 40 mg; atorvastatin 20, 40, or 80 mg; or simvastatin 20, 40, or 80 mg); or fenofibric acid + low- or moderate-dose statin in the controlled studies; and with fenofibric acid + moderate-dose statin in the extension study. Achievement of risk-stratified low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (ApoB) targets; and optimal levels of ApoB <90 mg/dL, HDL-C >40/50 mg/dL in men/women, triglycerides (TG) < 150 mg/dL, and high-sensitivity C-reactive protein <2 mg/L were assessed. RESULTS: In the controlled studies, significantly lower percentage of high-risk patients treated with fenofibric acid + moderate-dose statin, and significantly higher percentage of high-risk patients treated with fenofibric acid + low-dose statin, compared with corresponding-dose statin monotherapies, achieved their LDL-C (51.3% vs. 72.9%, p < 0.001) and non-HDL-C targets (53% vs. 38%, p = 0.02), respectively. Among all patients, optimal levels of ApoB, HDL-C, TG, and the combined target of LDL-C + non-HDL-C + ApoB + HDL-C + TG were achieved by higher percentage of patients treated with fenofibric acid + low- and moderate-dose statin versus corresponding dose-statin monotherapies (p ≤ 0.04 for all comparisons). In the extension study, significantly (p < 0.001 for all comparisons) higher percentage of patients had achieved individual and combined targets at final visit, compared with baseline. CONCLUSIONS: In patients with mixed dyslipidemia, short-term treatment with the combination of fenofibric acid and low- or moderate-dose statin resulted in comparable or more patients achieving individual targets of non-HDL-C, ApoB, HDL-C, and TG, and combined targets for these parameters and LDL-C, compared with corresponding-dose statin monotherapy. In the long-term study, the proportion meeting these targets was significant, compared with baseline. Limitations include the post hoc nature of the analysis, and the fact that all patients had mixed dyslipidemia and majority were white, which limits generalization to other populations.

Fenofibrate, homocysteine and renal function.

Fibrates or PPAR alpha agonists, in particular fenofibrate, are known to increase homocysteine levels (Hcy). A 3 to 5 micromol/L increase in Hcy is commonly observed within the first few weeks of fenofibrate treatment; it then persists in plateau when treatment is continued and is reversible upon its cessation. Since its description in 1999, this pharmacological effect attracted a great deal of attention as epidemiological studies in most populations have shown that elevated Hcy levels i.e.Hcy> or =15 micromol/L are associated with an increased risk of cardiovascular events (CVD), venous thromboembolic events (VTE) and possibly cognitive disorders and bone fractures. Chronic kidney disease is also associated with elevated Hcy levels and since fenofibrate increases creatinine levels by about 10-12 micromol/L, a relationship between Hcy and creatinine was postulated. Animal studies have shown that the Hcy increase is PPARalpha dependent but to date animal or human studies have not provided a clear mechanism. In particular, fenofibrate treatment does not change vitamin B levels; however, vitamin B supplements reduce fenofibrate-induced Hcy elevation but not the concomitant cysteine elevation. Similarly, the increase in creatinine with fenofibrate only partially accounted for by a reduction in glomerular filtration rate (GFR) since creatinine production is also increased by 5-10%. In the FIELD study, a placebo-controlled study in 9795 patients with type 2 diabetes, fenofibrate over 5 years reduced non-fatal cardiovascular events and microvascular events such as albuminuria, the need for laser treatment for proliferative retinopathy or maculopathy and amputations but did not reduce fatal events. The increase in Hcy was indeed much larger that what would be explained by creatinine elevation and independent from baseline kidney function. Although baseline Hcy and creatinine levels were associated with subsequent risk of CVD, as suggested by epidemiology, their respective elevation was not. Of interest, after withdrawal of fenofibrate, a potential renoprotective effect was unmasked, as estimated GFR was 5 ml/min/1.73 m2 higher in previous fenofibrate-allocated patients than in previous placebo-allocated patients. There was no suggestion that Hcy elevation was associated with VTE (which were increased by an unknown mechanism) or bone disorders. In conclusion, the discrepancy between the role of baseline Hcy levels in epidemiology and the absence of effect when altering its levels by either decreasing them with vitamin B supplements or increasing them with fenofibrate, suggests that the risk factor(s) behind homocysteine should be found. Nevertheless, other studies are also needed to understand the mechanism and the implications of the moderate homocysteine and creatinine elevations with fenofibrate and other PPARalpha agonists.

Efficacy and safety of fenofibric acid co-administered with low- or moderate-dose statin in patients with mixed dyslipidemia and type 2 diabetes mellitus: results of a pooled subgroup analysis from three randomized, controlled, double-blind trials.

BACKGROUND: Monotherapy with lipid-modifying medication is frequently insufficient to normalize lipid abnormalities in patients with mixed dyslipidemia and type 2 diabetes mellitus. OBJECTIVE: To evaluate the efficacy and safety of fenofibric acid + statin combination therapy in this population. STUDY DESIGN: A pooled, subgroup analysis of three randomized, controlled, double-blind, 12-week trials. SETTING: Multiple clinical research facilities in the US and Canada. PATIENTS: Patients with mixed dyslipidemia and type 2 diabetes (n = 586). INTERVENTION: Fenofibric acid (Trilipix) 135 mg monotherapy; low-, moderate-, or high-dose statin monotherapy (rosuvastatin [Crestor] 10, 20, or 40 mg; simvastatin [Zocor] 20, 40, or 80 mg; or atorvastatin [Lipitor] 20, 40, or 80 mg); or fenofibric acid + low- or moderate-dose statin. MAIN OUTCOME MEASURE: Mean percentage changes in lipid parameters, percentages of patients achieving optimal serum lipid/apolipoprotein levels, and incidence of adverse events. RESULTS: Fenofibric acid + low-dose statin resulted in significantly (p < 0.001) greater mean percentage changes in high-density lipoprotein cholesterol (HDL-C) [16.8%] and triglycerides (-43.9%) than low-dose statin monotherapy (4.7% and -18.1%, respectively) and significantly (p < 0.001) greater reductions in low-density lipoprotein cholesterol (LDL-C) [-34.0%] than fenofibric acid monotherapy (-5.3%). Similarly, fenofibric acid + moderate-dose statin resulted in significantly (p < or = 0.011) greater mean percentage changes in HDL-C (16.3%) and triglycerides (-43.4%) than moderate-dose statin monotherapy (8.7% and -24.2%, respectively) and significantly (p < 0.001) greater reductions in LDL-C (-32.6%) than fenofibric acid monotherapy (-5.3%). Compared with low- or moderate-dose statin, fenofibric acid + low- or moderate-dose statin resulted in over 5-fold higher percentages of patients achieving optimal levels of LDL-C, non-HDL-C, apolipoprotein B, HDL-C, and triglycerides simultaneously. Incidence of adverse events was generally similar among treatments. CONCLUSION: Fenofibric acid + statin combination therapy in patients with mixed dyslipidemia and type 2 diabetes was well tolerated and resulted in more comprehensive improvement in the lipid/apolipoprotein profile than either monotherapy. [Clinical trials are registered at www.clinicaltrials.gov: NCT00300482, NCT00300456, and NCT00300469].

Prescription omega-3 fatty acid as an adjunct to fenofibrate therapy in hypertriglyceridemic subjects.

BACKGROUND/RATIONALE: Treatment of severe hypertriglyceridemia is indicated to reduce the risk of pancreatitis in patients with triglyceride (TG) levels > or =500 mg/dL. Hypertriglyceridemia is also a risk factor for atherosclerotic coronary heart disease. Prescription omega-3 fatty acids (P-OM3) and fenofibrate (FENO) are among the most effective lipid-altering agents that reduce TG levels. Given that some patients may not achieve optimal TG levels with a single agent, we hypothesized that concomitant use of P-OM3 or addition of P-OM3 to FENO would result in a TG reduction greater than that with FENO alone. METHODS: This randomized, 8-week, double-blind, placebo-controlled study was designed to compare the safety and efficacy of P-OM3 4 g QD plus concomitant FENO 130 mg with FENO 130 mg QD plus placebo in subjects with very high TG levels (> or =500 mg/dL). Subjects who completed the double-blind study were given the option to continue into an open-label, 8-week extension study, wherein they all received P-OM3 4 g plus FENO 130 mg QD. On completion of the first extension study, subjects were eligible to continue into an open-label 24-month extension of the treatment with P-OM3 4 g plus FENO 130 mg QD. RESULTS: Concomitant P-OM3 + FENO (n = 81) and FENO monotherapy (n = 82) reduced median TG values from 649.5 to 267.5 mg/dL (60.8%) and from 669.3 to 310 mg/dL (53.8%), respectively (P = 0.059). When subjects who had received 8 weeks of stable FENO monotherapy were given P-OM3 during the 8-week, open-label extension study (n = 58), TG levels were reduced 17.5% (P = 0.003) over the course of the extension. The second extension phase was terminated early (n = 93)-not because of a safety signal but because of the lack of a substantial incremental change in the primary endpoint lipid values above that reached in either the original study or the first extension in subjects receiving the combination of fenofibrate and P-OM3. CONCLUSIONS: Both FENO monotherapy and P-OM3 + FENO significantly reduced TGs in subjects with very high TGs, with a trend to greater reduction in the P-OM3 + FENO group. The addition of P-OM3 to stable FENO therapy in the same subjects in an open-label extension study resulted in a statistically significant reduction in TG levels. Subjects who received P-OM3 + FENO for 16 weeks and subjects in which P-OM3 was added to FENO monotherapy during the open-label phase of the study did not differ in their final lipid responses. In the second open-label extension, within the combined group taking P-OM3 and FENO, analysis of change from the second extension baseline to end of treatment revealed no clinically important change.

Efficacy and tolerability of atorvastatin/fenofibrate fixed-dose combination tablet compared with atorvastatin and fenofibrate monotherapies in patients with dyslipidemia: a 12-week, multicenter, double-blind, randomized, parallel-group study.

BACKGROUND: Coadministration of statin and fenofibrate monotherapies is frequently used to treat patients with dyslipidemia; however, a fixed-dose combination (FDC) tablet is not currently marketed. OBJECTIVE: This study evaluates a new FDC tablet of atorvastatin 40 mg and fenofibrate 100 mg. METHODS: This was a 12-week, multicenter, double-blind, randomized, parallel-group Phase IIb study. Adults with dyslipidemia (non-HDL-C >130 mg/dL and triglycerides [TG] > or =150 but < or =500 mg/dL) were randomly assigned in a 1:1:1 ratio to receive the FDC, atorvastatin 40 mg, or fenofibrate 145 mg for 12 weeks. Study medication was taken once daily in the evening, without regard to meals. Patients attended follow-up visits after 4, 8, and 12 weeks of the double-blind treatment. The primary efficacy end points were the mean percentage changes from baseline to the final visit (week 12) in non-HDL-C, HDL-C, and TG. Secondary variables were LDL-C, VLDL-C particle concentration, total cholesterol, apolipoprotein B, lipoprotein (a), high-sensitivity C-reactive protein, fibrinogen, homocysteine, creatinine, myeloperoxidase, and lipoprotein-associated phospholipase A2. Tolerability was assessed by adverse events, laboratory parameters, vital signs, physical examinations, and ECGs. RESULTS: Patients (n = 220) were aged 26 to 87 years; 115 (52.3%) were men and 105 (47.7%) were women; 189 (85.9%) were white, 17 (7.7%) were black, and 15 (6.8%) were Hispanic or Latino; and mean (SD) weight was 200.5 (40.85) lb (range, 103.5-367.4 lb). Previous treatments were statins (25.9% [57/220]), fibrates (1.8% [4/220]), and dietary supplements (25.5% [56/220]); 57.7% (127/220) of patients were treatment naive. Use of the FDC was associated with an improvement in non-HDL-C (-44.8%) that was significantly greater than with fenofibrate monotherapy (-16.1%; P < 0.001) but was not significantly different from that with atorvastatin monotherapy (-40.2%; P = NS). HDL-C increased significantly more in the FDC group (19.7%) than with atorvastatin (6.5%; P < 0.001) but was not significantly different from fenofibrate (18.2%; P = NS). TG lowering in the FDC group (-49.1%) was significantly greater than with both atorvastatin (-28.9%; P < 0.001) and fenofibrate (-27.8%; P = 0.001). LDL-C lowering in the FDC group (-42.3%) was significantly greater than with fenofibrate (-13.9%; P < 0.001) but not significantly different from atorvastatin (-43.1%; P = NS). The FDC had either comparable or significantly greater improvements in other lipid variables and multiple secondary variables. The FDC was generally well tolerated; the tolerability profile was consistent with those of atorvastatin and fenofibrate monotherapies. Treatment-emergent adverse events (ie, those occurring after the first dose of study medication) were recorded in 43 of 73 patients (58.9%) for the FDC, 49 of 74 (66.2%) for atorvastatin, and 48 of 73 (65.8%) for fenofibrate. CONCLUSIONS: In this 12-week study, patients with dyslipidemia treated with the 40/100-mg atorvastatin/ fenofibrate FDC had a significantly greater reduction in TG than those treated with atorvastatin 40 mg or higher-dose fenofibrate 145 mg. Treatment with the FDC was also associated with a significantly greater reduction in non-HDL-C compared with fenofibrate alone and a greater increase in HDL-C compared with atorvastatin alone. All treatments were generally well tolerated.

ABT-335, the choline salt of fenofibric acid, does not have a clinically significant pharmacokinetic interaction with rosuvastatin in humans.

ABT-335 is the choline salt of fenofibric acid under clinical development as a combination therapy with rosuvastatin for the management of dyslipidemia. ABT-335 and rosuvastatin have different mechanisms of actions and exert complementary pharmacodynamic effects on lipids. The current study assessed the pharmacokinetic interaction between the 2 drugs following a multiple-dose, open-label, 3-period, randomized, crossover design. Eighteen healthy men and women received 40 mg rosuvastatin alone, 135 mg ABT-335 alone, and the 2 drugs in combination once daily for 10 days. Blood samples were collected prior to dosing on multiple days and up to 120 hours after day 10 dosing for the measurements of fenofibric acid and rosuvastatin plasma concentrations. Coadministering 40 mg rosuvastatin had no significant effect on the steady-state Cmax, Cmin, or AUC24 of fenofibric acid (P > .05). Coadministering ABT-335 had no significant effect on the steady-state Cmin or AUC24 of rosuvastatin (P > .05) but increased Cmax by 20% (90% confidence interval: 12%-28%). All 3 regimens were generally well tolerated with no clinically significant changes in clinical laboratory values, vital signs, or electrocardiograms during the study. Results from this study demonstrate no clinically significant pharmacokinetic interaction between ABT-335 at the full clinical dose and rosuvastatin at the highest approved dose.

Effects of fenofibrate and xuezhikang on high-fat diet-induced non-alcoholic fatty liver disease.

1. Fenofibrate and xuezhikang are two types of drugs widely used in the treatment of dyslipidaemia in China. The main purpose of present study was to test the efficacies and explore the potential mechanisms of action of the two lipid-lowering agents on high-fat diet-induced non-alcoholic fatty liver disease (NAFLD). 2. Rats were randomly divided into four groups, with eight rats per group. One group was given normal diet, whereas the other three groups were fed a high-fat diet. Forty-two days later, two of the high-fat diet-fed groups were administered fenofibrate (100 mg/kg, p.o.) and xuezhikang (300 mg/kg, p.o.) for another 42 consecutive days. The other two groups were administered placebo (saline) by gavage. 3. Typical pathological symptoms of NAFLD occurred in the high-fat diet groups. Fenofibrate and xuezhikang treatment markedly improved NAFLD, ameliorating dyslipidaemia and fat accumulation in the liver, improving insulin resistance and ameliorating oxidative stress. Hepatic steatosis, necro-inflammation and collagen deposition were lessened in the drug-treated groups. However, both xuezhikang and fenofibrate failed to reverse hepatomegaly and fenofibrate even aggravated it. Xuezhikang reversed aminotransferase abnormalities, but fenofibrate had less of an effect. 4. The common therapeutic mechanism of action of fenofibate and xuezhikang likely involves inhibition of the hepatic expression of tumour necrosis factor-alpha. Fenofibrate upregulated mRNA levels of peroxisome proliferator-activated receptor (PPAR) alpha in the liver, whereas xuezhikang had no effect on the hepatic expression of PPARalpha and this may explain, in part, their different effects on the NAFLD rats. 5. The results suggest that fenofibrate and xuezhikang may have potential clinical application in the treatment of NAFLD. However, the side-effects of fenofibrate and the underlying constituents of xuezhikang need to be determined and investigated further.

Fenofibrate-induced hyperhomocysteinaemia: clinical implications and management.

Fenofibrate is among the drugs of choice for treatment of hypertriglyceridaemia and low levels of high-density lipoprotein (HDL)-cholesterol, both recognised as risk factors for cardiovascular disease. Recently, a number of studies have shown an elevation of homocysteine levels with fenofibrate or bezafibrate therapy. Homocysteine is an atherogenic amino acid derived from the methionine cycle. At present, the underlying mechanism for this elevation has not been elucidated. While deterioration of vitamin status does not seem to be involved, impairment of renal function or changes in creatine metabolism are regarded as probable mechanisms. In patients not receiving lipid-lowering drugs, vitamin supplementation with folic acid and vitamin B12 effectively reduces the plasma homocysteine level. Two studies have shown that addition of folic acid or a vitamin combination to fenofibrate prevented most of the homocysteine increase associated with fenofibrate. Although the consequence of increasing homocysteine levels for cardiovascular risk has not been proven at present, it has to be considered that fenofibrate will be given for long-term treatment. Therefore, addition of folic acid and vitamin B12 to fenofibrate can be recommended to prevent the increase of homocysteine associated with fenofibrate, or treatment could be changed to gemfibrozil, which does not increase plasma homocysteine levels.

Folate supplementation prevents plasma homocysteine increase after fenofibrate therapy.

BACKGROUND: Homocysteine is associated with an increased risk of atherosclerosis. The administration of fibrates has been reported to significantly increase plasma homocysteine levels, a potentially adverse effect of fibrates. We investigated the hypothesis that concomitant treatment with fenofibrate and folic acid leads to a smaller increase in plasma total homocysteine levels than treatment with fenofibrate alone. METHODS: A randomized, open-label study compared the effect of micronized fenofibrate (200 mg daily) alone versus fenofibrate plus folic acid (10 mg every other day) on plasma homocysteine levels. Twenty-two patients with mixed hyperlipidemia participated. The 9-wk treatment period was preceded by a 4-wk wash-out period without hypolipidemic drugs. RESULTS: In patients treated with fenofibrate only, plasma homocysteine levels increased by 6.85 +/- 5.23 micromol/L (from 12.27 +/- 3.15 to 19.13 +/- 7.20 micromol/L); in patients treated with fenofibrate and folic acid, plasma homocysteine levels increased by 2.01 +/- 2.88 micromol/L (from 10.14 +/- 2.32 to 12.15 +/- 3.08 micromol/L). The difference in the homocysteine increase between the two groups was statistically significant at P = 0.014. CONCLUSIONS: Folic acid supplementation in patients treated with fenofibrate significantly reduced the increase in plasma homocysteine levels. More studies are needed to clarify whether amelioration of this side effect increases the clinical benefit of fibrates.

Vitamin supplementation can markedly reduce the homocysteine elevation induced by fenofibrate.

Elevated homocysteine concentrations are a risk factor for atherosclerotic disease. Recently it was reported that lipid lowering with fibrates increases homocysteine by up to 40%. Since elevated homocysteine concentrations can readily be lowered by vitamin supplementation, a randomized, double-blind crossover study was performed to investigate the effect of fenofibrate plus folic acid, vitamin B6 and B12 versus fenofibrate plus placebo in hyperlipidemic men. The crossover study comprised a run-in period of 6 weeks, a first treatment phase of 6 weeks, a washout phase of 8 weeks and a second treatment phase of 6 weeks. Vitamins were given at doses of 650 microg folic acid, 50 microg vitamin B12 and 5 mg vitamin B6 per day for a period of 6 weeks. After fenofibrate plus placebo the increase in homocysteine concentration was 44+/-47%. After fenofibrate plus vitamins it was 13+/-25%, being significantly lower than without vitamins. The increase in homocysteine in response to fenofibrate may counteract the cardioprotective effect of lipid lowering. The addition of vitamins involved in homocysteine metabolism can prevent most of the homocysteine increase seen after fenofibrate plus placebo. Addition of these vitamins to fenofibrate may therefore be warranted for routine use.

Evaluation of the phototoxic properties of some hypolipidemics in vitro: fenofibrate exhibits a prominent phototoxic potential in the UVA and UVB region.

As some fibric acid derivatives have been reported to exhibit photosensitizing effects in vivo, the antilipemic drugs fenofibrate, bezafibrate, clofibrate, and gemfibrozil were tested for their phototoxic potential in vitro by a photohemolysis test using human erythrocytes and different irradiation sources. In this system only fenofibrate revealed strong phototoxic properties, which were dependent both on the drug concentration and the irradiation doses. Above a surface dose of 40 J/cm2 UVA of an UVA (320-400 nm)-rich irradiation source or 1.6 J/cm2 UVB/0.8 J/cm2 UVA of an UVB (280-320 nm)-rich irradiation source human red blood cells were completely photohemolysed in the presence of fenofibrate. Bezafibrate- and gemfibrozil-induced photohemolysis remained beneath 10%, and clofibrate showed no phototoxicity at all. As the phototoxic potential of fenofibrate lies in the UVB and UVA range, this might be of relevance with regard to clinical photosensitivity.

Comparative toxicity and safety profile of fenofibrate and other fibric acid derivatives.

It is estimated that there are approximately six million patient-years of clinical experience with fenofibrate among physicians outside of the United States. A review of the European literature and unpublished studies supplied by the manufacturer (Laboratoires Fournier, Dijon, France) has been compiled with the data recently reported from a double-blind, placebo-controlled study completed in the United States. In general, fenofibrate has been found to reduce serum triglyceride levels by 30 to 60 percent in patients with type II B and IV hyperlipoproteinemia. Serum cholesterol levels were also reduced by 20 to 25 percent in this group of hypertriglyceridemic patients. A similar reduction in serum cholesterol levels was also found in type II A patients (normal triglyceride levels). Low-density lipoprotein levels were usually reduced in those patients with elevated levels and high-density lipoprotein levels increased when baseline levels were low. Fenofibrate also produced a 10 to 28 percent reduction in uric acid that was sustained for years. The incidence of unwanted effects ranged from 2 to 15 percent in the open trials lasting from a few months up to six years. Gastrointestinal problems (abdominal discomfort, diarrhea, and constipation) are most common, occurring in approximately 5 percent of patients. Reports including fatigue, headache, loss of libido, impotence, dizziness, and insomnia were grouped as neurologic and occurred with a total incidence of 3 to 4 percent. In about 1 percent of patients, muscle tenderness developed, often accompanied by elevated creatine phosphokinase levels. These and the gastrointestinal problems occurred with a similar frequency in the placebo-treated cohort in controlled studies. In approximately 2 percent of patients, a skin rash developed, an incidence that appears significantly higher than that of placebo control groups. Liver changes in rodents have included marked peroxisome proliferation and increased hepatic carcinomas with very high doses. In humans, only a small increase in incidence of elevated levels of serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase seems to be present and is not clearly different from that of the control groups. Alkaline phosphatase, gamma-glutamyl transferase, and bilirubin levels are often decreased with no known undesirable effects. Investigations into the lithogenicity of bile indicated a significant increase in five studies. However, there has been no evidence of a significant rise in the incidence of cholelithiasis in the clinical trials completed to date.