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¡¡¡¡ Abstracts regarding Fibrate from Pubmed
1. Tolerability of statin-fibrate
and statin-niacin combination therapy in dyslipidemic patients at high
risk for cardiovascular events. Am J Cardiol. 2002 Feb 15;89(4):390-4.
Achieving recommended cholesterol and triglyceride targets for the prevention of cardiovascular events is difficult and frequently requires the use of >1 lipid-lowering medication. This study evaluated the tolerability and effectiveness of combination regimens in high-risk dyslipidemic patients resistant to monotherapy. A retrospective chart review of all patients referred to a cardiovascular risk reduction clinic over a 7.5-year period identified 136 patients who received combination therapy with a 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitor (statin) plus fibrate (n = 106) or a statin plus niacin (n = 30) regimen. During follow-up (mean 18.5 months), 28 patients (20.6%) discontinued combination therapy: 11 (8.1%) experienced myalgia with or without elevated creatine kinase, 3 had gastrointestinal upset, and 1 had asymptomatic creatine kinase elevation. No patient had combination therapy discontinued due to elevated liver enzymes. Medications were stopped in 8 patients for reasons other than reported adverse effects or biochemical abnormalities, and 5 patients were switched to alternate monotherapy. Mean percent change from baseline to treatment with combination therapy for total cholesterol (-35%), low-density lipoprotein cholesterol (-37%), high-density lipoprotein cholesterol (+23%), triglycerides (-62%), and total cholesterol/high-density lipoprotein cholesterol ratio (-41%) were all statistically significant (p <0.01). These results demonstrate that combination statin-fibrate and statin-niacin regimens are safe and effective in managing dyslipidemias in most patients at risk for cardiovascular events who are inadequately treated with one of these agents alone.
2. Statin-fibrate combination therapy Ann Pharmacother. 2001 Jul-Aug;35(7-8):908-17
BACKGROUND: Precautionary warnings for severe myopathy and rhabdomyolysis from the coadministration of statins and fibrates have been well publicized. However, a recent cerivastatin labeling change made the combined use with fibric acid derivatives a contraindication. Practical recommendations for clinicians who care for patients with refractory mixed hyperlipidemia are needed. OBJECTIVE: To provide recommendations for clinicians in the treatment of refractory mixed hyperlipidemia. DATA SOURCES: A comprehensive MEDLINE (1966-July 2000) and bibliographic search was performed. DATA SYNTHESIS: Thirty-six published clinical trials and 29 case reports involving combination therapy with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and fibric acid derivatives regarding the occurrence of rhabdomyolysis or myopathy were reviewed. The literature review demonstrated that combination therapy with a statin and fibrate increases the risk of muscle damage, with an incidence of 0.12%. Risk factors that predispose patients to myopathy caused by combination statin-fibrate therapy include increased age, female gender, renal or liver disease, diabetes, hypothyroidism, debilitated status, surgery, trauma, excessive alcohol intake, and heavy exercise. CONCLUSIONS: Combination therapy with a statin and fibrate offers significant therapeutic advantage for the treatment of severe or refractory mixed hyperlipidemia. Although such a combination does increase the risk of myopathy, with an incidence of approximately 0.12%, this small risk of myopathy rarely outweighs the established morbidity and mortality benefits of achieving lipid goals. Nevertheless, a higher incidence of myopathy has been reported with statin monotherapy. When monotherapy with a statin fails to control mixed hyperlipidemia, combination therapy may be considered. Niacin may be added before a fibrate is considered, as it appears to have less risk of myopathy. Statin-fibrate combination therapy must be undertaken cautiously and only after careful risk-benefit analysis. Patient counseling on the risks and warning signs of myopathy is extremely important.
3. Atorvastatin versus four
statin-fibrate combinations in patients with familial combined
hyperlipidaemia. J Cardiovasc Risk. 2002 Feb;9(1):33-9.
BACKGROUND: Statin-fibrate combinations are very effective in the treatment of familial combined hyperlipidaemia (FCHL). Nonetheless, they have not been extensively used because of the fear of side effects. Thus, a therapeutic alternative is required for this lipid disorder. OBJECTIVE: To compare the long-term (one-year) efficacy of atorvastatin monotherapy with those of four statin-fibrate combinations in 675 FCHL patients. METHODS: Patients were randomly assigned to atorvastatin monotherapy (A 20 mg/day) n = 134, or pravastatin (P 20 mg/day)+gemfibrozil (G 1200 mg/day) n = 135, simvastatin (S 20 mg/day)+G (1200 mg/day) n = 137, P (20 mg/day)+ciprofibrate (C 100 mg/day) n = 135, and S (20 mg/day)+C (100 mg/day) n = 134. RESULTS: Twelve patients on statin-fibrate combinations were withdrawn from the study because of side effects: three because of CK elevation, two because of myalgia and seven due to increase in serum transaminase levels. One patient on A was withdrawn because of persistent epigastric discomfort. Atorvastatin reduced low density lipoprotein cholesterol and apoprotein B more than all four combinations (-45% vs. maximum -40% of S+C, and -39% vs. maximum -32% of the same combination, respectively, P < 0.001 for both), but had a lesser effect on triglycerides (-38% vs. maximum -53% of S+C, P = 0.0002) and high density lipoprotein cholesterol (6% vs. maximum 21% of S+G, P = 0.0003). The effect of A on plasma fibrinogen was analogous to that of G combinations (-8% vs. -9% of P+G and -11% of S+G, P = NS vs. baseline and among each other) and inferior to that of the ciprofibrate combinations (-8% vs. -24% of P+C, P = 0.0002 and -26% S+C, P = 0.0001). A had a lower treatment cost and better patient compliance, P = 0.04 vs. C combinations and P = 0.02 vs. G combinations. CONCLUSIONS: The data suggest that statin-fibrate combinations have a beneficial effect on all lipid parameters. Atorvastatin monotherapy has a better effect on LDL-C and apoprotein B than statin-fibrate combinations, but a lesser effect on HDL-C, TG and in the case of ciprofibrate combinations, fibrinogen. The clinical significance of these findings should be tested in a large, long-term survival study.
4. Effects of a lipid lowering fibrate and hormone
replacement therapy on serum lipids and lipoproteins in overweight
postmenopausal women with elevated triglycerides. Maturitas. 2002 May 20;42(1):55-62.
BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in women after menopause. In essence major risk factors for CVD are similar in women as for men inclusive of serum lipid perturbations. The effects of estrogens and hormone replacement therapy on lipid metabolism is widely discussed and warrant further evaluation especially when combined with other lipid lowering drugs. STUDY DESIGN: Postmenopausal women were studied by an open randomised study during 9 months. Subjects were recruited from outpatient clinics in a rural area of Sweden. Major inclusive criteria comprised body mass index (BMI) >28, serum triglycerides >1.5 mmol/l. Participants were at least 12 months postmenopause with a concomitant serum Follicle Stimulating Hormone (FSH) above 28 IU/l. After inclusion in the study patients were instructed to adhere to a low-fat and caloric diet for 3 months and after this period randomised into two groups of intervention; a lipidlowering fibrate (LLF) group and one hormone replacement therapy group (HRT). The LLF group was given gemfibrozil 600 mg orally twice daily and HRT group received 2 mg oestradiol in combination with 1 mg norethisterone acetate as a continuous combined therapy once daily. After 3 months, the LLF group added the HRT regimen and patients in the HRT group added gemfibrozil. Hence, all participants received the regimens combined for the last 6 months of the study. RESULTS: Serum s-cholesterol was markedly decreased in both groups during the first 3 months of single treatment (P<0.0001). This decrease reflected a reduction especially of calculated low density lipoprotein (LDL) s-cholesterol (P<0.001). High density lipoprotein (HDL) s-cholesterol was reduced in the HRT group (P<0.005) but increased (P<0.004) in the LLF group. Triglycerides were also decreased by both treatments but more marked in the LLF group (P<0.0001) than in the HRT group (P<0.02). After 9 months the reduction remained in both groups but no additive effects were encountered in any of the groups. CONCLUSION: The effects by gemfibrozil on s-cholesterol and triglycerides levels seem to be superior to continuous combined HRT in overweight women with elevated triglycerides. The combination of the two drugs did not seem to offer any additional benefit concerning the routine serum lipid or lipoprotein profile.
5 . Fibrate treatment does not modify the expression of
acyl coenzyme A oxidase in human liver. Clin Pharmacol Ther. 2002 Dec;72(6):692-701.
BACKGROUND AND OBJECTIVES: Fibrates induce hepatic peroxisome proliferation and carcinogenesis in rodents by activating peroxisome proliferator-activated receptor alpha (PPAR(alpha)). There is no conclusive evidence that humans are unresponsive to peroxisome proliferation, and concern exists about the long-term safety of fibrate treatment. METHODS: In a university hospital setting, 48 patients with uncomplicated gallstones and a serum level of low-density lipoprotein cholesterol greater than 130 mg/dL were randomly assigned to open-label treatment with bezafibrate (400 mg/d), fenofibrate (200 mg/d), gemfibrozil (900 mg/d), or placebo for 8 weeks before elective cholecystectomy. Serum samples for lipid determinations were obtained at baseline and before surgery. A liver specimen was obtained at operation, and the relative levels of messenger ribonucleic acid (mRNA) for the wild and truncated forms of PPAR(alpha), acyl coenzyme A oxidase, liver carnitine palmitoyltransferase I, apolipoprotein A-I, and stearoyl coenzyme A desaturase were determined. RESULTS: Fenofibrate, bezafibrate, and gemfibrozil reduced plasma low-density lipoprotein cholesterol levels by 22% (P =.009), 14% (P =.042), and 11% (not significant), respectively. Plasma triglyceride levels decreased significantly (24%-36%; P <.05), whereas high-density lipoprotein cholesterol levels rose nonsignificantly after treatment with the 3 fibrates. Except for a 35% increase of apolipoprotein A-I mRNA after fenofibrate administration (P <.05), none of the individual fibrates induced significant changes in the mRNAs tested, although as a group they increased the mRNA for liver carnitine palmitoyltransferase I by 40%(P =.08; marginally significant). CONCLUSIONS: Fibrate administration to humans at pharmacologic doses able to activate PPAR(alpha) and to induce a hypolipidemic effect does not increase the hepatic expression of acyl coenzyme A oxidase, a well-known marker of peroxisome proliferation in rodents.
6. Influence of fibrate treatment
on malondialdehyde-modified LDL concentration. Clin Chim Acta. 2004 Jan;339(1-2):97-103.
BACKGROUND: Drug therapy is considered essential to the clinical prevention of atherosclerotic lesions in patients with diabetes mellitus (DM). METHODS: To confirm the effects of fibrate therapy, we determined low-density lipoprotein (LDL) size by gradient gel electrophoresis and malondialdehyde-modified LDL (MDA-LDL) concentrations by enzyme-linked immunosolvent assay (ELISA) and clarified the association between apolipoprotein B (apo B) and MDA-LDL during the fibrate therapy. RESULTS: Mean MDA-LDL concentrations were higher in healthy men than in healthy women. There were no significant differences in mean MDA-LDL concentrations between age groups for males or females. According to the regression equation (y = 0.063x + 10.9) obtained for apo B and MDA-LDL concentrations with fibrate treatment, the apo B concentration in those may need to be decreased to 1260 mg/l to restore the MDA-LDL concentration to the control concentration (65 +/- 25 units/l). This slope of the apoB/MDA-LDL regression line was approximately half of that with no-drug treatment (y = 0.109x - 10.8). CONCLUSIONS: Fibrate therapy had an effect on reducing serum MDA-LDL concentration in diabetic patients
7. Fibrate treatment and prevalence
risk of mild hyperhomocystein- aemia in clinical coronary heart disease
patients. Eur J Cardiovasc Prev Rehabil. 2004 Jun;11(3):244-9.
BACKGROUND: Several prospective studies reported that fibrates might increase blood total homocysteine (tHcy). In this study we aimed to establish whether the reported fibrate treatment was associated with an increased risk of mild hyperhomocysteinaemia in patients with clinical coronary heart disease, and to establish whether confounding variables may influence this effect. DESIGN: A retrospective, case-control analysis. METHODS: A total of 410 patients, 301 males and 109 females, mean age 59.2 were examined in a Czech sample from the EUROASPIRE II survey. In addition to examinations and measurements, defined by the protocol, we estimated serum total homocysteine (tHcy), folate, B12 vitamin and methylenetetrahydrofolate reductase (MTHFR) genotypes. RESULTS: We found significantly higher tHcy concentrations in patients with reported treatment with fibrate (16.6 +.- 0.66 micromol/l) compared with no lipid-lowering treatment (13.5 +/- 0.64 micromol/l, P<0.001) or to statin (12.4 +/- 0.39 micromol/l, P<0.001). Concentrations of tHcy > or =15 mmol/l (i.e. mild hyperhomocysteinaemia) as a dependent variable were positively associated with age (OR 1.18, P<0.0003), serum vitamin B12 (OR 0.87, P<0.003), serum creatinine (OR 1.35, P<0.0001 and treatment with fibrates (OR 1.30, P<0.0001), using multiple regression. Using unifactorial or multifactorial analyses, association between fibrate and tHcy is independent from conventional confounders such as age, gender, smoking, folate or B12 concentration, serum creatinine and MTHFR genotypes, however interference of low folate or B12 and fibrate treatment resulted in concentrations of tHcy more than 20 micromol/l. CONCLUSIONS: Fibrate treatment was associated with a significant increase in prevalence of the risk of mild hyperhomocysteinaemia in coronary patients, independently from conventional confounders.
8. Comparison of combined
statin-fibrate treatment to monotherapy in patients with mixed
hyperlipidemia. Kardiol Pol. 2004 Jun;60(6):567-77.
BACKGROUND: Statins are the preferred drugs for the treatment of hypercholesterolemia, and fibrates for hypertriglyceridemia. In patients with mixed hyperlipidemia, monotherapy with one of these agents may not be effective and combined treatment may be preferable. AIM: To compare retrospectively the efficacy and safety of combined statin-fibrate treatment in patients with mixed hyperlipidemia in whom previous monotherapy with one of these agents occurred ineffective. METHODS AND RESULTS: The initial study group consisted of 327 patients who received micronised fenofibrate and 93 patients who received simvastatin for 12 months. Both agents caused significant changes in lipid profile. Following fibrate therapy, total cholesterol (TC), LDL-cholesterol (LDL-C) and triglyceride (TG) levels decreased by 27.9%, 28.2% and 58%, respectively, and following simvastatin therapy by 33.6%, 42.8% and 37.5%, respectively. The HDL-cholesterol (HDL-C) level increased after fenofibrate by 14.8% and remained unchanged following simvastatin therapy. The TC/HDL-C ratio decreased following fenofibrate by 35.6%, and following simvastatin by 35.3%. In some patients the required reduction in lipid parameters was not achieved fenofibrate or simvastatin. Subsequently, 93 patients underwent combined therapy by adding a second agent (simvastatin in a dose of 20 mg/day or fenofibrate in a dose of 200 mg per day) which was continued for another 12 months. The addition of simvastatin to fenofibrate decreased TC, LDL-C and TG levels by 35.5%, 42.1% and 59.6%, respectively in comparison to before treatment volumes. HDL-C level was increased by 11.1%, and TC/HDL-C ratio decreased by 45.3%. The addition of fenofibrate to simvastatin decreased TC, LDL-C and TG levels by 39.3%, 48.9% and 51,6%, respectively. HDL-C level was increased by 13.4%, and TC/HDL-C ratio decreased by 49.3%. No clinical side effects nor an increase in the transaminase levels, requiring termination of the treatment, were observed. CONCLUSIONS: Combined therapy with 20 mg of simvastatin and 200 mg of micronised fenofibrate is highly effective and safe in patients with mixed hyperlipidemia.
9. Comparative effects of statin and fibrate on nitric
oxide bioactivity and matrix metalloproteinase in hyperlipidemia. Int J Cardiol. 2004 Nov;97(2):239-44.
OBJECTIVE: Because the lipoprotein effects of statin and fibric acid derivatives therapies differ, we studied the effects of these therapies in patients with hyperlipidemia on lipoproteins, vasomotor function, and plaque stability. METHODS: We administered simvastatin, 20 mg daily, to 27 patients with hypercholesterolemia and coronary artery disease, or fenofibrate, 200 mg daily, to 27 patients with pure hypertriglyceridemia during 8 weeks. RESULTS: As expected, simvastatin significantly lowered total cholesterol and low-density lipoprotein cholesterol (LDL-C) more, and fenofibrate decreased triglyceride and increased high-density lipoprotein cholesterol (HDL-C) more than either therapy. Simvastatin and fenofibrate significantly improved the percent flow-mediated dilator response to hyperemia by 183+/-41% and by 30+/-7%, respectively (each P<0.001); however, simvastatin significantly improved more (P<0.001). Simvastatin and fenofibrate significantly lowered plasma levels of tumor necrosis factor alpha (TNF-alpha) by 13+/-4% and by 10+/-4%, respectively (P=0.009 and P=0.006, respectively) with a similar degree (P=0.614). Simvastatin significantly reduced plasma levels of total MMP-9 and TIMP-1 more (P=0.005 and P=0.036, respectively), compared with fenofibrate showing no reduction. There were significant correlations between the degree of changes in TNF-alpha and the degree of changes in MMP-9 activity (r=0.376, P=0.053). CONCLUSIONS: Simvastatin and fenofibrate demonstrated antiatherosclerotic effects via different mechanisms.
10. Anti-inflammatory effect of fibrate protects from
cisplatin-induced ARF. Am J Physiol Renal Physiol. 2005 Aug;289(2):F469-80.
receptor-alpha (PPARalpha) ligand ameliorates cisplatin-induced acute renal failure (ARF) by preventing inhibition of substrate oxidation, and also by preventing apoptosis and necrosis of the proximal tubule (Li S, Bhatt R, Megyesi J, Gokden N, Shah SV, and Portilla D. Am J Physiol Renal Physiol 287: F990-F998, 2004). In the following studies, we examined the protective effect of PPARalpha ligand on cisplatin-induced inflammatory responses during ARF. Mice subjected to a single intraperitoneal injection of cisplatin developed ARF at day 3. Cisplatin increased mRNA and protein expression of TNF-alpha, RANTES, and also upregulated endothelial adhesion molecules ICAM-1/VCAM-1 and chemokine receptors CCR1/CCR5. Cisplatin also led to neutrophil infiltration in the corticomedullary region. Pretreatment of wild-type mice with WY-14,643, a fibrate class of PPARalpha ligands, before cisplatin significantly suppressed cisplatin-induced upregulation of cytokine/chemokine expression, prevented neutrophil accumulation, and ameliorated renal dysfunction. In contrast, treatment with PPARalpha ligand before cisplatin did not prevent cytokine/chemokine production, neutrophil accumulation, and did not protect kidney function in PPARalpha null mice. In addition, we observed that cisplatin-induced NF-kappaB binding activity in nuclear extracts from wild-type mice was markedly reduced by treatment with PPARalpha ligand. These results demonstrate that PPARalpha exerts an anti-inflammatory effect in kidney tissue by a mechanism that includes inhibition of NF-kappaB DNA binding activity, and this effect results in inhibition of neutrophil infiltration, cytokine/chemokine release, and amelioration of cisplatin-induced ARF.
11. Differential associations of
statin and fibrate treatment with carotid arterial remodeling. Am J Hypertens. 2005 Nov;18(11):1476-81.
BACKGROUND: The effects of statins on intima-media thickness (IMT) are well documented, whereas those of fibrates are unknown. Therefore we compared IMT under treatment with each class of drugs. METHODS: We studied a cohort of consecutive dyslipidemic subjects treated with statin (n = 291) or fibrate (n = 82) drugs. Fibrate-treated subjects were matched with the same number of statin-treated subjects to obtain two subgroups of similar demographic and risk factors including LDL cholesterol. Common carotid far wall IMT and lumen diameter were measured by ultrasonography. RESULTS: In the entire study population, IMT was greater in the fibrate group than in the statin group (P < .001), even after adjustment for LDL cholesterol and other covariates (P < .05). In the matched groups, IMT was greater in fibrate group than in the statin group (P < .01), even after adjustment for LDL cholesterol and other covariates including treatment duration (P < .01). The IMT correlated positively with treatment duration in the fibrate group (P < 0.05) but not in the statin group. In addition, IMT correlated positively with carotid lumen diameter in both the fibrate and statin groups (P < .05, P < .01) but with a lower slope in the former (P < .05). CONCLUSIONS: In this study fibrate treatment was associated with greater IMT, steeper IMT-time relationship, and lower compensatory carotid enlargement than was statin treatment. These differences were not explained by differences in LDL cholesterol.
12. Fenofibrate reverses the
decline in HDL cholesterol in mice overexpressing human phospholipid
transfer protein. Biochim Biophys Acta. 2005 Dec 30;1738(1-3):48-53.
In humans, fibrates are used to treat dyslipidemia, because these drugs lower plasma triglycerides and raise HDL cholesterol. Treatment with fibrates lowers plasma phospholipid transfer protein (PLTP) activity in humans, but increases PLTP activity in mice, without a consistent effect on HDL-cholesterol concentration. Earlier, we found that PLTP overexpression in transgenic mice results in decreased plasma HDL levels and increased diet-induced atherosclerosis. So it seems that the interplay between fibrates, PLTP and HDL is different in mice and man, which may be important for atherosclerosis development. In the present study, we measured the effects of fibrates on PLTP expression in cultured human hepatocytes and effects of fibrate treatment on human PLTP expression, plasma PLTP activity and HDL levels in human PLTP transgenic mice. Fibrate treatment did not influence PLTP mRNA levels in human hepatocytes. Hepatic human PLTP mRNA levels and PLTP activity were both moderately elevated by fenofibrate treatment in human PLTP transgenic mice. In wild-type mice, however, feeding fenofibrate resulted in a strong induction of PLTP mRNA in the liver and a more than 4-fold increase of plasma PLTP activity. Plasma triglycerides were reduced in all mice by 48% or more by fenofibrate treatment. HDL-cholesterol concentrations were substantially increased by fenofibrate in PLTP overexpressing mice (+72%), but unaffected in wild-type mice. We conclude that fenofibrate treatment reverses the HDL-lowering effect of PLTP overexpression in human PLTP transgenic mice.
13. Effects of long-term
fenofibrate therapy on cardiovascular events in 9795 people with type 2
diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005 Nov 26;366(9500):1849-61.
BACKGROUND: Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease, partly owing to dyslipidaemia, which can be amenable to fibrate therapy. We designed the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study to assess the effect of fenofibrate on cardiovascular disease events in these patients. METHODS: We did a multinational, randomised controlled trial with 9795 participants aged 50-75 years, with type 2 diabetes mellitus, and not taking statin therapy at study entry. After a placebo and a fenofibrate run-in phase, we randomly assigned patients (2131 with previous cardiovascular disease and 7664 without) with a total-cholesterol concentration of 3.0-6.5 mmol/L and a total-cholesterol/HDL-cholesterol ratio of 4.0 or more or plasma triglyceride of 1.0-5.0 mmol/L to micronised fenofibrate 200 mg daily (n=4895) or matching placebo (n=4900). Our primary outcome was coronary events (coronary heart disease death or non-fatal myocardial infarction); the outcome for prespecified subgroup analyses was total cardiovascular events (the composite of cardiovascular death, myocardial infarction, stroke, and coronary and carotid revascularisation). Analysis was by intention to treat. The study was prospectively registered (number ISRCTN 64783481). FINDINGS: Vital status was confirmed on all but 22 patients. Averaged over the 5 years' study duration, similar proportions in each group discontinued study medication (10% placebo vs 11% fenofibrate) and more patients allocated placebo (17%) than fenofibrate (8%; p<0.0001) commenced other lipid treatments, predominantly statins. 5.9% (n=288) of patients on placebo and 5.2% (n=256) of those on fenofibrate had a coronary event (relative reduction of 11%; hazard ratio [HR] 0.89, 95% CI 0.75-1.05; p=0.16). This finding corresponds to a significant 24% reduction in non-fatal myocardial infarction (0.76, 0.62-0.94; p=0.010) and a non-significant increase in coronary heart disease mortality (1.19, 0.90-1.57; p=0.22). Total cardiovascular disease events were significantly reduced from 13.9% to 12.5% (0.89, 0.80-0.99; p=0.035). This finding included a 21% reduction in coronary revascularisation (0.79, 0.68-0.93; p=0.003). Total mortality was 6.6% in the placebo group and 7.3% in the fenofibrate group (p=0.18). Fenofibrate was associated with less albuminuria progression (p=0.002), and less retinopathy needing laser treatment (5.2%vs 3.6%, p=0.0003). There was a slight increase in pancreatitis (0.5%vs 0.8%, p=0.031) and pulmonary embolism (0.7%vs 1.1%, p=0.022), but no other significant adverse effects. INTERPRETATION: Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reduce total cardiovascular events, mainly due to fewer non-fatal myocardial infarctions and revascularisations. The higher rate of starting statin therapy in patients allocated placebo might have masked a moderately larger treatment benefit.
14. An open-label, crossover study of the pharmacokinetics of Insoluble Drug Delivery-MicroParticle fenofibrate in combination with atorvastatin, simvastatin, and extended-release niacin in healthy volunteers. Penn R, Williams RX 3rd, Guha-Ray DK, et al. Clin Ther. 2006 Jan;28(1):45-54.
BACKGROUND: Fenofibrate has been prescribed concomitantly with other lipid-lowering agents as a treatment for dyslipidemia. However, combination therapy, particularly a statin-fibrate combination, may be associated with an increased risk of myopathy, although this risk appears to be less with fenofibrate than with other fibrates. OBJECTIVE: The objective of this study was to determine the effect of administering a single dose of atorvastatin, simvastatin, or extended-release (ER) niacin on the pharmacokinetics and safety of a single dose of fenofibrate Insoluble Drug Delivery-MicroParticle (IDD-P). METHODS: This was an open-label, single-center,randomized, 4-treatment, 4-period crossover study in healthy adult volunteers. Subjects were randomized to 1 of 4 treatment sequences, administered 1 week apart, that included all 4 of the following treatments: 1 IDD-P fenofibrate 160-mg tablet alone; 1 IDD-P fenofibrate 160-mg tablet plus 1 atorvastatin 10-mg tablet; 1 IDD-P fenofibrate 160-mg tablet plus 1 simvastatin 10-mg tablet; and 1 IDD-P fenofibrate 160-mg tablet plus 1 ER niacin 500-mg tablet. Blood samples for pharmacokinetic analysis were obtained immediately before and up to 72 hours after administration during each of the 4 treatment periods. If the 90% CI for the log-transformed parameter was between 0.80 and 1.25, and the 90% CI for the nontransformed parameter was between 0.80 and 1.20, then the absence of a clinically significant drug interaction was assumed. However, the absence of a drug interaction was not to be ruled out if one or more of the CIs exceeded the boundary, provided the CI included 1.00. RESULTS: Twenty healthy subjects were enrolled.Sixteen (80%) of the subjects were male and 17 (85%) were black; mean (SD) age was 35 (9.3) years. The mean C(max), AUC from the time of administration to the last quantifiable concentration (AUC(0-t)), and AUC from the time of administration to infinity (AUC(0-infinity)) were 5%, 6%, and 2% lower, respectively, with IDD-P fenofibrate plus atorvastatin than with IDD-P fenofibrate alone; the mean C(max), AUC(0-t), and AUC(0-infinity) were 6% lower, and 10% and 9% higher, respectively, with IDD-P fenofibrate plus simvastatin than with IDD-P fenofibrate alone; and the mean C(max), AUC(0-t), and AUC(0-infinity) were 12%, 6%, and 5% lower, respectively, with IDD-P fenofibrate plus ER niacin than with IDD-P fenofibrate alone. The 90% CIs surrounding the mean ratios for AUC(0-infinity) and AUC(0-infinity) for all 3 comparisons were between 0.80 and 1.25, suggesting the absence of a drug interaction for these parameters. For C(max), an absence of a drug interaction was observed between concomitantly administered IDD-P fenofibrate and both atorvastatin and simvastatin; absence of drug interaction was not found for IDD-P fenofibrate plus ER niacin. All treatments were well tolerated; headache was the most common adverse event (AE) (10%). One subject with creatinine kinase levels of 1300 IU/L (>6 times the upper limit of normal) at baseline experienced a seizure approximately 12 to approximately 13 hours after administration of IDD-P fenofibrate plus atorvastatin; this serious AE was deemed to be possibly related to study drug. CONCLUSIONS: Concomitant administration of a single dose of either atorvastatin or simvastatin had no significant effect on the pharmacokinetics of a single dose of IDD-P fenofibrate. A drug interaction between concomitantly administered single doses of IDD-P fenofibrate and ER niacin could not be ruled out.
15. PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice. Park CW, Zhang Y, Zhang X, et al. Kidney Int. 2006 May;69(9):1511-7.
Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the ligand-activated nuclear receptor superfamily, and plays an important role in lipid metabolism and glucose homeostasis. The purpose of this study is to determine whether the activation of PPARalpha by fenofbrate would improve diabetes and its renal complications in type II diabetes mellitus. Male C57 BLKS db/db mice and db/m controls at 8 weeks of age were divided to receive either a regular diet chow (db/db, n=8; db/m, n=6) or a diet containing fenofibrate (db/db, n=8; db/m, n=7). Mice were followed for 8 weeks. Fenofibrate treatment dramatically reduced fasting blood glucose (P<0.001) and HbA1c levels (P<0.001), and was associated with decreased food intake (P<0.01) and slightly reduced body weight. Fenofibrate also ameliorated insulin resistance (P<0.001) and reduced plasma insulin levels (P<0.05) in db/db mice. Hypertrophy of pancreatic islets was decreased and insulin content markedly increased (P<0.05) in fenofibrate-treated diabetic animals. In addition, fenofibrate treatment significantly reduced urinary albumin excretion (P<0.001). This was accompanied by dramatically reduced glomerular hypertrophy and mesangial matrix expansion. Furthermore, the addition of fenofibrate to cultured mesangial cells, which possess functional active PPARalpha, decreased type I collagen production. Taken together, the PPARalpha agonist fenofibrate dramatically improves hyperglycemia, insulin resistance, albuminuria, and glomerular lesions in db/db mice. The activation of PPARalpha by fenofibrate in mesangial cells may partially contribute to its renal protection. Thus, fenofibrate may serve as a therapeutic agent for type II diabetes and diabetic nephropathy.
16. Effects of fenofibrate and simvastatin on HDL-related biomarkers in low-HDL patients. Franceschini G, Calabresi L, Colombo C, et al. Atherosclerosis. 2006 Nov 14; [Epub ahead of print]
The objective of the present study was to compare the effects of fenofibrate versus simvastatin on various HDL-related biomarkers in dyslipidemic patients with low HDL-C, in whom it is as yet unclear whether a statin or a fibrate is the most appropriate treatment. Fifty-two patients received either fenofibrate (160mg/day) or simvastatin (40mg/day) for 8 weeks in a randomized, double-blind, parallel group trial. Simvastatin effectively lowered plasma LDL-C and apoB levels, but did not change plasma HDL levels and HDL-related biomarkers, except for a small, significant increase in the capacity of plasma to promote SR-BI mediated cholesterol efflux. Fenofibrate did not affect plasma LDL-C levels but lowered triglycerides, and exerted a remarkable HDL-C raising activity (+22%), with patients in the lowest range of HDL-C getting the maximal benefit. The HDL-C raise was associated with a shift of HDL from large to small particles, and from LpA-I to LpA-I:A-II, which might explain the observed increase in the plasma capacity to promote ABCA1 mediated efflux with no changes in SR-BI efflux. The distinct and complementary effects of fenofibrate and simvastatin on lipid parameters and HDL-related biomarkers suggest that a combination therapy with the two drugs in dyslipidemic patients with low HDL would be fully justified.
17. The reduction of inflammatory biomarkers by statin, fibrate, and combination therapy among diabetic patients with mixed dyslipidemia: the DIACOR (Diabetes and Combined Lipid Therapy Regimen) study. Muhlestein JB, May HT, Jensen JR, et al. J Am Coll Cardiol. 2006 Jul 18;48(2):396-401.
OBJECTIVES: The primary objective was to determine the effect of statin-fibrate combination therapy on inflammatory biomarkers in patients with diabetes. BACKGROUND: Atherosclerosis is a long-term, chronic inflammatory disease that is exacerbated in patients with diabetes. METHODS: Patients (n = 300) with type II diabetes, mixed dyslipidemia (2 or more of low-density lipoprotein > or =100 mg/dl, triglycerides > or =200 mg/dl, or high-density lipoprotein <40 mg/dl), and no history of coronary heart disease were randomly assigned to receive simvastatin 20 mg, fenofibrate 160 mg, or a combination of simvastatin 20 mg and fenofibrate 160 mg daily. At 12 weeks after randomization, we measured levels of high-sensitivity C-reactive protein (hsCRP) and lipoprotein-associated phospholipase A2 (Lp-PLA(2)). RESULTS: At 12 weeks, median hsCRP was significantly reduced (-14.6%, p = 0.004) from baseline, but the effect did not differ between treatments. The effect was greatest among patients with baseline hsCRP levels >2.0 mg/l (fenofibrate = -18.9%, p = 0.002 vs. baseline; simvastatin = -24.8%, p < 0.0001; combination = -27.3%, p = 0.002). Likewise, median Lp-PLA(2) levels in the overall study population were significantly reduced (-16.8%, p < 0.0001), and the effect did not differ among treatments. This effect also was greatest among patients with increased baseline levels of Lp-PLA(2) greater than the median of 320.9 ng/ml (fenofibrate = -41.3%, p < 0.0001; simvastatin = -47.5%, p < 0.0001; combination = -46.8%, p < 0.0001). CONCLUSIONS: Simvastatin, fenofibrate, and combination therapy each lowered hsCRP and Lp-PLA(2). These anti-inflammatory effects were most pronounced among patients with increased baseline levels. Combination therapy was no more effective than either form of monotherapy.
18. The association between fibrate use, change in high-density lipoprotein cholesterol, and the risk of cardiovascular disease: a retrospective chart review involving up to 8 years of follow-up. Nichols GA, Koro CE, Chan W, et al. Clin Ther. 2006 Feb;28(2):243-50.
BACKGROUND: Clinical trials have indicated that the use of fibric acid derivatives confers a benefit against cardiovascular disease (CVD) in selected populations. However, whether fibrates provide a CVD risk reduction independent of changes in the traditional lipoprotein fractions and other known CVD risk factors is not clear. OBJECTIVE: This study examined whether the use of fibrate therapy in a general clinical setting provided cardiovascular benefits independent of changes in the traditional lipoprotein fractions. METHODS: This was a matched, retrospective cohort study. From the electronic records of a large health maintenance organization in the northwestern United States, we identified a population that had newly initiated fibrate pharmacotherapy between January 1, 1996, and December 31, 2000. We then identified a comparator group of patients not using fibrates, matching them to fibrate users based on high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels, age, sex, and year of HDL-C and TG measurement. Subjects were followed until a CVD hospitalization, termination from the health plan, or December 31, 2003, whichever came first. We then used multivariate analysis accounting for differences in followup to identify predictors of CVD incidence. RESULTS: The study population included 1722 matched pairs (56.6% male; mean [SD] age, 57.3 [11.1] years). The patients who had newly initiated fibrate pharmacotherapy had low baseline HDL-C levels (mean, 37.4 mg/dL) and very high TG levels (617 mg/dL). The 2 groups were similar overall, with the only significant differences between fibrate users and nonfibrate controls being a greater prevalence of diabetes (37.7% vs 34.3%, respectively; P=0.040) and greater use of angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (56.6% vs 51.6%, respectively; P=0.003), beta-blockers (53.7% vs 49.0%; P=0.006), calcium channel blockers (25.1% vs 20.9%; P=0.004), and niacin (11.7% vs 7.4%; P<0.001). Overall, CVD risk was 26% lower for every 5-mg/dL increment in HDL-C. After adjustment for age, sex, smoking history, diabetes, existing diagnosis of CVD, weight, systolic blood pressure, baseline HDL-C, change in HDL-C, total cholesterol, TG, and use of statins, niacin, and other CVD drugs, fibrate use did not confer an additional CVD risk reduction. CONCLUSIONS: In this cohort with low baseline HDL-C levels and very high TG levels, fibrate use did not confer an independent CVD risk reduction after adjustment for CVD risk factors. Given the current obesity epidemic in the United States and the corresponding rise in the number of patients with the metabolic syndrome, the apparent risk reduction observed in association with higher HDL-C levels should not be ignored.
19. Differential effects of peroxisome proliferator-activated receptor ligands and sulfonylurea plus statin treatment on plasma concentrations of adipokines in type 2 diabetes with dyslipidemia. Yin WH, Jen HL, Chen JW, et al. Diabetes Metab. 2006 Jun;32(3):229-35.
OBJECTIVES: Peroxisome proliferator-activated receptor gamma is the master regulator of adipocyte differentiation and controls many adipocyte genes in response to anti-diabetic thiazolidinediones (TZDs) and lipid-lowering fibrates. We hypothesized that the combination of TZD+fibrate may be better than the sulfonylurea + statin approach regarding modifying the adipokine profile in diabetic patients with dyslipidemia. METHODS: We measured the lipid profiles and circulating levels of adiponectin, resistin, and inflammatory markers before and after treatment in 24 type 2 diabetic patients with dyslipidemia (aged 64+/-9 years; M/F=5/19). The study patients were randomly assigned to receive an 8-week treatment of either rosiglitazone 4 mg daily and fenofibrate 160 mg daily (PPAR group) or glibenclamide 5 mg daily and atorvastatin 10 mg daily (non-PPAR group). RESULTS: Even though the administration of sulfonylurea+statin can achieve a greater reduction of total cholesterol and LDL-cholesterol levels and a comparable glucose control compared to PPAR treatment, their administration did not change the plasma adipokine levels significantly. In contrast, a significant greater increase of the plasma concentrations of adiponectin (P<0.0001), a trend to a greater decrease of the plasma resistin levels (P=0.061), a significantly greater increase of HDL-cholesterol (P=0.002), and a significantly greater reduction of triglyceride levels (P=0.018) were seen in the PPAR group. CONCLUSIONS: Considering the clinical significance of the adipokine-endothelial interaction in the progression and long-term prognosis of atherosclerosis, the differential effects of PPAR ligands and sulfonylurea+statin on plasma adipokine concentrations demonstrated in this study are interesting foci of investigation in the future.
20. Extralipid effects of micronized fenofibrate in dyslipidemic patients. Okopien B, Haberka M, Madej A, et al. Pharmacol Rep. 2006 Sep-Oct;58(5):729-35.
The aim of this study was to evaluate the levels of lipid and extralipid parameters in patients with atherogenic dyslipidemia. We investigated the lipid-lowering therapeutic efficacy of fenofibrate and its extralipid influence on oxidized low-density lipoprotein (oxLDL), C-reactive protein (CRP), Fibrinogen, factor VII and plasminogen activator type 1 (PAI-1) during 1-month treatment. Fourteen individuals with HLPIIb were treated with micronized fenofibrate (267 mg/d) for 1 month. The control group included twelve volunteers. Lipidograms were determined with enzymatic kits. ELISA method was used to measure oxLDL and PAI-1. Plasma CRP levels were measured spectrophotometrically. Fibrinogen and factor VII serum levels were evaluated with automatic coagulometer. After 1-month therapy with micronized fenofibrate, we observed a significant reduction of total cholesterol (TC) (277.2 to 217.8 mg/dl, p < 0.05), LDL (183.6 to 129.4 mg/dl, p < 0.05), trigliceryde (TG) (316.7 to 220.6 mg/dl, p < 0.05), oxLDL (68.7 +/- 5.5 to 39.7 +/- 3.7 U/l, p < 0.001) and increase in high-density lipoprotein (HDL) (35.1 to 41.9 mg/dl, p < 0.05). Fibrate treatment also decreased CRP(5.81 +/- 0.26 to 5.08 +/- 0.06 mg/l, p < 0.001), PAI-1 (120.4 +/- 9.7 to 84.7 +/- 5.9 ng/ml; p < 0.05), fibrinogen (3.65 +/- 0.17 to 3.44 +/- 0.16 g/l, ns) and factor VII (159.7% +/- 56.7 to 141% +/- 42.4, ns). The micronized fenofibrate at a daily dose of 267 mg demonstrated a highly beneficial effect on all lipid parameters and advantageous influence on inflammatory and thrombogenic plasma risk factors in patients with dyslipidemia HLPIIb.
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