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Fenofibrate increases circulating haematopoietic stem cells in people with diabetic retinopathy: a randomised, placebo-controlled trial.
Bonora, BM, Albiero, M, Morieri, ML, Cappellari, R, Amendolagine, FI, Mazzucato, M, Zambon, A, Iori, E, Avogaro, A, Fadini, GP
Diabetologia. 2021;(10):2334-2344
Abstract
AIM/HYPOTHESIS In two large RCTs, fenofibrate reduced the progression of diabetic retinopathy. We investigated whether fenofibrate increases circulating haematopoietic stem/progenitor cells (HSPCs), which have vascular properties and have been shown to protect from retinopathy. METHODS We conducted a 12 week parallel-group RCT comparing fenofibrate vs placebo. Patients with diabetic retinopathy and without other conditions that would affect HSPCs were enrolled at a tertiary diabetes outpatient clinic and randomised to receive fenofibrate or placebo based on a computer-generated sequence. Patients and study staff assessing the outcomes were blinded to group assignment. The primary endpoint was the change in the levels of circulating HSPCs, defined by expression of the stem cell markers CD34 and/or CD133. Secondary endpoints were the changes in endothelial progenitor cells, lipids, soluble mediators and gene expression. We used historical data on the association between HSPCs and retinopathy outcomes to estimate the effect of fenofibrate on retinopathy progression. RESULTS Forty-two participants with diabetic retinopathy were randomised and 41 completed treatment and were analysed (20 in the placebo group and 21 in the fenofibrate group). Mean age was 57.4 years, diabetes duration was 18.2 years and baseline HbA1c was 60 mmol/mol (7.6%). When compared with placebo, fenofibrate significantly increased levels of HSPCs expressing CD34 and/or CD133. CD34+ HSPCs non-significantly declined in the placebo group (mean ± SD -44.2 ± 31.6 cells/106) and significantly increased in the fenofibrate group (53.8 ± 31.1 cells/106). The placebo-subtracted increase in CD34+ HSPCs from baseline was 30% (99.3 ± 43.3 cells/106; p = 0.027) which, projected onto the relationship between HSPC levels and retinopathy outcomes, yielded an OR of retinopathy progression of 0.67 for fenofibrate vs placebo. Endothelial differentiation of CD34+ cells, estimated by the %KDR (kinase insert domain receptor) expression, was significantly reduced by fenofibrate. Fenofibrate decreased serum triacylglycerols, but the change in triacylglycerols was unrelated to the change in HSPCs. No effect was observed for endothelial progenitor cells, cytokines/chemokines (stromal-cell derived factor-1, vascular endothelial growth factor, monocyte chemoattractant protein-1) and gene expression in peripheral blood mononuclear cells. CONCLUSIONS/INTERPRETATION Fenofibrate increased HSPC levels in participants with diabetic retinopathy and this mechanism may explain why fenofibrate reduced retinopathy progression in previous studies. TRIAL REGISTRATION ClinicalTrials.gov NCT01927315.
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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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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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Serum preadipocyte factor-1 concentrations in females with obesity and type 2 diabetes mellitus: the influence of very low calorie diet, acute hyperinsulinemia, and fenofibrate treatment.
Kavalkova, P, Touskova, V, Roubicek, T, Trachta, P, Urbanova, M, Drapalova, J, Haluzikova, D, Mraz, M, Novak, D, Matoulek, M, et al
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2013;(11):820-6
Abstract
Appropriate differentiation capacity of adipose tissue significantly affects its ability to store lipids and to protect nonadipose tissues against lipid spillover and development of insulin resistance. Preadipocyte factor-1 (Pref-1) is an important negative regulator of preadipocyte differentiation. The aim of our study was to explore the changes in circulating Pref-1 concentrations in female subjects with obesity (OB) (n=19), females with obesity and type 2 diabetes mellitus (T2DM) (n=22), and sex- and age-matched healthy control subjects (C) (n=22), and to study its modulation by very low calorie diet (VLCD), acute hyperinsulinemia during isoglycemic-hyperinsulinemic clamp, and 3 months' treatment with PPAR-α agonist fenofibrate. At baseline, serum Pref-1 concentrations were significantly higher in patients with T2DM compared to control group, while only nonsignificant trend towards higher levels was observed in OB group. 3 weeks of VLCD decreased Pref-1 levels in both OB and T2DM group, whereas 3 months of fenofibrate treatment had no significant effect. Hyperinsulinemia during the clamp significantly suppressed Pref-1 levels in both C and T2DM subjects and this suppression was unaffected by fenofibrate treatment. In a combined population of all groups, circulating Pref-1 levels correlated positively with insulin, leptin and glucose levels and HOMA (homeostasis model assessment) index. We conclude that elevated Pref-1 concentrations in T2DM subjects may contribute to impaired adipose tissue differentiation capacity associated with insulin resistance in obese patients with T2DM. The decrease of Pref-1 levels after VLCD may be involved in the improvement of metabolic status and the amelioration of insulin resistance in T2DM patients.
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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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Efficacy of fenofibrate in Chinese patients with primary biliary cirrhosis partially responding to ursodeoxycholic acid therapy.
Han, XF, Wang, QX, Liu, Y, You, ZR, Bian, ZL, Qiu, DK, Ma, X
Journal of digestive diseases. 2012;(4):219-24
Abstract
OBJECTIVE To investigate the efficacy of fenofibrate combination therapy in Chinese patients with primary biliary cirrhosis (PBC) who had a partial response to standard dose of ursodeoxycholic acid (UDCA) for at least one year. METHODS PBC patients were treated with UDCA (13-15 mg/kg/day) for more than one year. The biochemical response to UDCA treatment was evaluated after treatment. Fenofibrate (200 mg/day) was added to 22 patients with partial response to UDCA. RESULTS In patients with partial response to UDCA, serum alkaline phosphatase (ALP) and γ-glutamyl transpeptidase levels significantly decreased after 3-month combination therapy of UDCA and fenofibrate, 68% of these patients even reached normal ALP level. Serum triglyceride (TG) and cholesterol levels were improved, and alanine transaminase (ALT) and aspartate transaminase (AST) were also decreased during the combination therapy. However, fenofibrate had no significant effect on serum bilirubin levels. The improvement of liver biochemical tests was maintained in some patients with long-term therapy (at least 6 months). No obvious adverse effects were observed in patients taking fenofibrate. CONCLUSIONS Fenofibrate is effective for improving liver biochemical tests in patients who have partial response to UDCA monotherapy. It is worth exploring the efficacy of fenofibrate on histological changes in PBC patients.
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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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A comparative study of anti-inflammatory and antidyslipidemic effects of fenofibrate and statins on rheumatoid arthritis.
Goto, M
Modern rheumatology. 2010;(3):238-43
Abstract
We prospectively compared the anti-inflammatory and antidyslipidemic effects of fenofibrate and statins in rheumatoid arthritis (RA) patients. Forty-four RA patients [male (M) = 7, female (F) = 37] with dyslipidemia were enrolled in this 6-month study and randomly allocated to the fenofibrate (2 M + 21 F = 23) or statins (5 M + 16 F = 21) group. We measured blood chemistry (serum lipid profile, sugar, urate, and gamma-glutamyl transpeptidase) and blood pressure 2 h after breakfast. Visual analog scale (VAS), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and prednisolone (PSL) dosage were also recorded immediately before and after the study. Fenofibrate, but not statins, significantly decreased serum levels of total cholesterol, low-density lipoprotein-cholesterol, and triglycerides (all p < 0.05). A significant improvement in VAS was observed in both the fenofibrate group (49.1 +/- 24.7 --> 14.7 +/- 11.2; p < 0.0001) and the statins group (47.4 +/- 29.7 --> 20.2 +/- 16.5; p < 0.001). PSL dosage significantly decreased only in the fenofibrate group (3.58 +/- 2.68 --> 2.00 +/- 2.22 mg/day; p < 0.01). Significant correlation was observed between VAS and CRP in the fenofibrate group (p < 0.05). Fenofibrate showed more anti-inflammatory and antidyslipidemic activity than statins in RA.
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Heterogeneous postprandial lipoprotein responses in the metabolic syndrome, and response to fenofibrate therapy.
Rosenson, RS, Helenowski, IB, Tangney, CC
Cardiovascular drugs and therapy. 2010;(5-6):439-47
Abstract
BACKGROUND Hypertriglyceridemia subjects with metabolic syndrome exhibit variable postprandial triglyceride responses. We investigate the effects of fenofibrate therapy on postprandial triglyceride-containing lipoproteins in subjects with early (3.5 h) versus late (8 h) postprandial triglyceride responses. METHODS Fifty-five subjects with fasting hypertriglyceridemia (≥1.7 mmol/L (150 mg/ dL) and <5.8 mmol/L (500 mg/dL)) and ≥2 Adult Treatment Panel III criteria of the metabolic syndrome were randomized to daily fenofibrate (160 mg/d) or placebo for 12 weeks in a double-blind controlled clinical trial. A standardized fat load (50 g/m(2)) was given orally after a 12 h fast. Blood specimens were obtained at 0 h (fasting), 3.5 h, and 8 h after the test meal. Analysis is confined to the 53 subjects with clearly identifiable early or late triglyceride peaks prior to therapy. RESULTS Fenofibrate was more effective in late peakers (n = 8) when compared to early peakers (n = 15) with respect to reducing postprandial triglyceride concentrations (-67% vs. -34%, p = 0.0024) and large VLDL (-76% vs. -31%, p = 0.0016), and increasing total HDL particles (20% vs. 11%, p = 0.008) and large HDL particles (185% vs. 88%, p = 0.003). On fenofibrate therapy, 100% of those initially designated as late peakers were reclassified as early peakers; 47% of late peakers assigned to placebo were reclassified as early peakers. CONCLUSIONS Late postprandial triglyceride responders have attenuated clearance of large VLDL particles, but they were more responsive to fenofibrate.
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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.