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Efficacy and Safety of Pemafibrate Versus Fenofibrate in Patients with High Triglyceride and Low HDL Cholesterol Levels: A Multicenter, Placebo-Controlled, Double-Blind, Randomized Trial.
Arai, H, Yamashita, S, Yokote, K, Araki, E, Suganami, H, Ishibashi, S, ,
Journal of atherosclerosis and thrombosis. 2018;(6):521-538
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Abstract
AIM: To verify the superiority of pemafibrate over placebo and the non-inferiority of pemafibrate to the maximum dose of fenofibrate for determining the percent change in fasting serum triglyceride (TG) levels and to investigate safety by assessing the incidence of adverse events (AEs) and adverse drug reactions (ADRs). METHODS This phase III, placebo/active drug-controlled, randomized, double-blind, parallel group comparison study enrolled patients with high TG and low high-density lipoprotein cholesterol levels. Patients were randomly assigned to receive placebo; pemafibrate 0.1 mg/day, 0.2 mg/day, or 0.4 mg/day; or fenofibrate 100 mg/day or 200 mg/day for 12 weeks. RESULTS Among 526 randomized patients, 489 completed the study, with drop-out rates of 0%, 6.7%, 5.5%, 5.9%, 8.2%, and 10.7% in the placebo; pemafibrate 0.1 mg/day, 0.2 mg/day, and 0.4 mg/day; and fenofibrate 100 mg/day and 200 mg/day groups. The study showed the non-inferiority of pemafibrate 0.4 mg/day and 0.2 mg/day to fenofibrate 200 mg/day as well the non-inferiority and superiority of all pemafibrate doses to fenofibrate 100 mg/day for reducing TG levels. No dose-dependent increase in the incidence of AEs or ADRs was observed among the pemafibrate dose groups. The incidence of AEs and ADRs for all pemafibrate doses was similar to that for placebo and fenofibrate 100 mg/day and significantly lower than that for fenofibrate 200 mg/day (P<0.05). CONCLUSIONS The favorable safety profile of pemafibrate, with fewer adverse effects on kidney/liver-related laboratory tests and fewer AEs/ADRs, including those leading to treatment discontinuation, over fenofibrate 200 mg/day may justify the use of this novel and potent treatment option for reducing TG levels in a broader range of patients.
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Efficacy and Safety of Alirocumab 150 mg Every 4 Weeks in Patients With Hypercholesterolemia Not on Statin Therapy: The ODYSSEY CHOICE II Study.
Stroes, E, Guyton, JR, Lepor, N, Civeira, F, Gaudet, D, Watts, GF, Baccara-Dinet, MT, Lecorps, G, Manvelian, G, Farnier, M, et al
Journal of the American Heart Association. 2016;(9)
Abstract
BACKGROUND The PCSK9 antibody alirocumab (75 mg every 2 weeks; Q2W) as monotherapy reduced low-density lipoprotein-cholesterol (LDL-C) levels by 47%. Because the option of a monthly dosing regimen is convenient, ODYSSEY CHOICE II evaluated alirocumab 150 mg Q4W in patients with inadequately controlled hypercholesterolemia and not on statin (majority with statin-associated muscle symptoms), receiving treatment with fenofibrate, ezetimibe, or diet alone. METHODS AND RESULTS Patients were randomly assigned to placebo, alirocumab 150 mg Q4W or 75 mg Q2W (calibrator arm), with dose adjustment to 150 mg Q2W at week (W) 12 if W8 predefined LDL-C target levels were not met. The primary efficacy endpoint was LDL-C percentage change from baseline to W24. Mean baseline LDL-C levels were 163.9 mg/dL (alirocumab 150 mg Q4W, n=59), 154.5 mg/dL (alirocumab 75 mg Q2W, n=116), and 158.5 mg/dL (placebo, n=58). In the alirocumab 150 mg Q4W and 75 mg Q2W groups (49.1% and 36.0% of patients received dose adjustment, respectively), least-squares mean LDL-C changes from baseline to W24 were -51.7% and -53.5%, respectively (placebo [+4.7%]; both groups P<0.0001 versus placebo). In total, 63.9% and 70.3% of alirocumab-treated patients achieved their LDL-C targets at W24. Treatment-emergent adverse events occurred in 77.6% (alirocumab 150 mg Q4W), 73.0% (alirocumab 75 mg Q2W), and 63.8% (placebo) of patients, with injection-site reactions among the most common treatment-emergent adverse events. CONCLUSIONS Alirocumab 150 mg Q4W can be considered in patients not on statin with inadequately controlled hypercholesterolemia as a convenient option for lowering LDL-C. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT02023879.
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The PPAR alpha gene is associated with triglyceride, low-density cholesterol and inflammation marker response to fenofibrate intervention: the GOLDN study.
Frazier-Wood, AC, Ordovas, JM, Straka, RJ, Hixson, JE, Borecki, IB, Tiwari, HK, Arnett, DK
The pharmacogenomics journal. 2013;(4):312-7
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As a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fenofibrate favorably modulates dyslipidemia and inflammation markers, which are associated with cardiovascular risk. To determine whether variation in the PPARα receptor gene was associated with lipid and inflammatory marker response, we conducted a 3-week trial of fenofibrate in 861 men and women. Mixed linear models that controlled for age and sex, as well as family pedigree and study center, were constructed using single-nucleotide polymorphisms (SNPs) in the PPARα gene as predictors and changes in fasting triglycerides (TGs), cholesterol and inflammatory markers as outcomes. Significant associations with low-density cholesterol and interleukin-2 (P<0.001) responses to fenofibrate were found. Although there were suggestive associations with tumor necrosis factor-alpha and TG responses (P<0.05), these did not survive the correction for multiple testing. We conclude that variants in the PPARα gene may contribute to future pharmacogenomic paradigms seeking to predict fenofibrate responders from both an anti-dyslipidemic and anti-inflammatory perspective.
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Variants in the APOA5 gene region and the response to combination therapy with statins and fenofibric acid in a randomized clinical trial of individuals with mixed dyslipidemia.
Brautbar, A, Covarrubias, D, Belmont, J, Lara-Garduno, F, Virani, SS, Jones, PH, Leal, SM, Ballantyne, CM
Atherosclerosis. 2011;(2):737-42
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OBJECTIVE Atherogenic dyslipidemia is highly associated with coronary heart disease and is characterized by elevated triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), and elevated low-density lipoprotein cholesterol (LDL-C). The combination of statins and fibrates is a common modality to treat individuals with atherogenic dyslipidemia. We sought to identify single nucleotide polymorphisms (SNPs) associated with HDL-C, TG, and apolipoprotein A1 (ApoA-I) response to combination therapy with statins and fenofibric acid (FA) in individuals with atherogenic dyslipidemia. METHODS 2228 individuals with mixed dyslipidemia who were participating in a multicenter, randomized, double-blind, active-controlled study comparing FA alone, in combination with a statin, or statin alone for a 12-week period, were genotyped for 304 candidate SNPs. A multivariate linear regression analysis for percent change in HDL-C, ApoA-I and TG levels was performed. RESULTS SNPs in the apolipoprotein (APO) A5-ZNF259 region rs3741298 (P = 1.8 × 10(-7)), rs964184 (P = 3.6 × 10(-6)), rs651821 (P = 4.5 × 10(-5)), and rs10750097 (P = 1 × 10(-4)), were significantly associated with HDL-C response to combination therapy with statins and FA, with a similar association identified for ApoA-I. A haplotype composed of the minor alleles of SNPs rs3741298, rs964184, and rs10750097, was associated with a positive response to statins and FA (P = 8.7 × 10(-7)) and had a frequency of 18% in the study population. CONCLUSION In a population with atherogenic dyslipidemia, common SNPs and haplotypes within the APOA5-ZNF259 region are highly associated with HDL-C and ApoA-I response to combination therapy with statins and FA.
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[Effects of micronized fenofibrate on lipid and uric acid metabolism in patients with hyperlipidemia].
Li, LJ, Chen, H, Ren, JY, Wang, L, Luo, Y
Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences. 2009;(5):541-4
Abstract
OBJECTIVE To evaluate the efficacy and safety of micronised fenofibrate on lipid and uric acid metabolism in patients with hyperlipidemia. METHODS A total of 116 patients with hypertriglyceridemia and hyperuricemia received 200 mg micronised fenofibrate for 4 weeks. Physical and laboratory investigations of lipid profiles, serum uric acid, and 24 h urine uric acid, for adverse effects were assessed. RESULTS (1) Serum triglyceride (TG) was significantly reduced by 51%, whilst high density lipoprotein cholesterol (HDL-C) increased 24% after 4-week fenofibrate treatment. Moreover, serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) were reduced by 10% and 12%, respectively. (2) Serum uric acid levels were significantly reduced by 28.3% [from (462.8+/-73.5) micromol/L to (320.1+/-83.0) micromol/L] after fenofibrate treatment, independent of baseline uric acid levels. There was no difference in serum uric acid changes between male gender and female gender(29.8% and 25.1%, respectively). (3) Urine uric acid levels were increased by 36.0% [from (2 874.2+/-503.4) micromol/L to (3 604.2+/-769.7) micromol/L]. The urine uric acid changes were 41.1% in male gender group and 33.4% in female gender group. The uric acid clearance/creatinin clearance ratio was increased in all cases after treatment. CONCLUSION Micronised fenofibrate treatment could significantly improve lipid and uric acid metabolism in patients with hypertriglyceridemia and hyperuricemia, and is generally safe and well tolerated. The anti-hyperuricemic effect of fenofibrate is a result of increasing the urinary excertion of uric acid, independent of baseline level and gender.
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Fenofibrate effectively reduces remnants, and small dense LDL, and increases HDL particle number in hypertriglyceridemic men - a nuclear magnetic resonance study.
Ikewaki, K, Tohyama, J, Nakata, Y, Wakikawa, T, Kido, T, Mochizuki, S
Journal of atherosclerosis and thrombosis. 2004;(5):278-85
Abstract
Hypertriglyceridemia is often associated with small dense low density lipoprotein (LDL), elevated remnants, and decreased high density lipoprotein (HDL)-cholesterol (C), which comprise the dyslipidemic triad. The objective of this study was to investigate the effect of fenofibrate on the lipoprotein subfraction profile and inflammation markers in hypertriglyceridemic men. Twenty hypertriglyceridemic men were administered fenofibrate, 200 mg daily, for 8 weeks. Lipoprotein subclasses were measured by nuclear magnetic resonance (NMR) spectroscopy. Inflammation markers including C-reactive protein (CRP), interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1) were also determined. Fenofibrate lowered triglyceride (TG) by 58% and increased HDL-C by 18%. NMR analysis revealed that very low density lipoprotein (VLDL), particularly large VLDL, intermediate density lipoprotein (IDL), and small LDL, were significantly decreased, and LDL distribution shifted towards the larger particles. HDL distribution was altered; there was an increase in small HDL and a decrease in large HDL, resulting in a significant decrease in HDL particle size, from 9.1 to 8.9 nm, as well as a 27% increase in HDL particle number. Among inflammation markers, CRP was significantly decreased by 42%. In conclusion, fenofibrate effectively improves atherogenic dyslipidemia by reducing remnants and small LDL, as well as by increasing HDL particles. These effects, together with the favorable effect on inflammation, might provide a clinical benefit in hypertriglyceridemic subjects.
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Effect of fenofibrate on uric acid metabolism in Japanese hyperlipidemic patients.
Noguchi, Y, Tatsuno, I, Suyama, K, Shibata, T, Yoshida, T, Otsuka, Y, Fuse, M, Takeo, C, Saito, Y
Journal of atherosclerosis and thrombosis. 2004;(6):335-40
Abstract
Forty Type IIb or IV hyperlipidemic patients (serum triglyceride concentrations were higher than 150 mg/dl) were treated with fenofibrate (300 mg/day) for 12 weeks. Lipid profile and uric acid metabolism were evaluated before and after the treatment; the serum concentrations of total cholesterol and triglyceride respectively decreased from 224 +/- 41.9 mg/dl to 199 +/- 35.2 mg/dl and from 205 +/- 71.7 mg/dl to 134 +/- 67.5 mg/dl (p < 0.001). The uric acid concentrations in the serum also significantly decreased from 7.0 +/- 1.58 mg/dl to 5.2 +/- 1.57 mg/dl (p < 0.001). Fenofibrate treatment did not cause any change in the serum xanthine and hypoxanthine concentrations. Instead the urinary concentrations of uric acid decreased from 7.0 +/- 1.58 mg/dl to 5.2 +/- 1.57 mg/dl (p < 0.01), while the clearance ratio of uric acid and creatinin increased from 6.1 +/- 2.56 to 9.9 +/- 3.87 (p = 0.02) by the fenofibrate treatment. Fenofibrate decreases uric acid concentrations in the serum not as a result of inhibition of uric acid production but by increasing the urinary excretion of uric acid.
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Effects of micronized fenofibrate versus atorvastatin in the treatment of dyslipidaemic patients with low plasma HDL-cholesterol levels: a 12-week randomized trial.
Després, JP, Lemieux, I, Salomon, H, Delaval, D
Journal of internal medicine. 2002;(6):490-9
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BACKGROUND Studies have suggested that raising low levels of high-density lipoprotein cholesterol (HDL-C) may be an important target for the prevention of coronary heart disease. OBJECTIVE To compare the ability of micronized fenofibrate and atorvastatin to increase plasma HDL-C levels. DESIGN Multicentre, randomized open-label study. Settings. The study was conducted in 19 centres across the UK and Canada. SUBJECT One hundred and eighty-one patients were randomized and the full analysis set included 165 nondiabetic patients with low HDL-C (women <46 mg dL-1, i.e. 1.2 mmol L-1 and men <43 mg dL-1, i.e. 1.1 mmol L-1): 86 patients in the atorvastatin group and 79 patients in the micronized fenofibrate group. Interventions. Micronized fenofibrate (200 mg day-1, 87 patients) or atorvastatin (10 mg day-1, 94 patients) for a period of 12 weeks. Main outcome measures. Percent change in HDL-C levels. RESULT After 12 weeks of treatment, the mean percent change from baseline in HDL-C was significantly higher in the micronized fenofibrate group (13.3%) compared with the atorvastatin group (5.3%, P=0.0003). The magnitude of such relative change was inversely related to the baseline HDL-C levels only in the micronized fenofibrate group. Furthermore, in the fenofibrate treatment group, 50.9% of the patients (29 of 57 patients) with a baseline HDL-C <40 mg dL-1 achieved a plasma HDL-C level above 40 mg dL-1 after 12 weeks of treatment versus 27.9% of the patients (19 of 68 patients) in the atorvastatin group (P=0.01). CONCLUSIONS On the basis of (1) the greater impact of fenofibrate than atorvastatin on HDL-C levels and (2) the greater proportion of dyslipidemic patients achieving HDL-C levels above 40 mg dL-1 with fenofibrate than atorvastatin, it is suggested that micronized fenofibrate should be considered as a good therapeutic option to treat dyslipidemic patients with low HDL-C and moderately elevated LDL-C concentrations.