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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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Effects of Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) on Atherogenic Lipid/Lipoprotein, Apolipoprotein, and Inflammatory Parameters in Patients With Elevated High-Sensitivity C-Reactive Protein (from the ANCHOR Study).
Miller, M, Ballantyne, CM, Bays, HE, Granowitz, C, Doyle, RT, Juliano, RA, Philip, S
The American journal of cardiology. 2019;(5):696-701
Abstract
Icosapent ethyl is pure prescription eicosapentaenoic acid approved at 4 g/day as an adjunct to diet to reduce triglycerides (TG) in adults with TG ≥500 mg/dl. Elevated high-sensitivity C-reactive protein (hsCRP) is associated with increased cardiovascular risk. The 12-week ANCHOR study randomized 702 statin-treated patients at increased cardiovascular risk with TG 200 to 499 mg/dl despite low-density lipoprotein cholesterol (LDL-C) control (40 to 99 mg/dl). This post hoc analysis assessed 246 ANCHOR patients with baseline hsCRP ≥ 2.0 mg/L randomized to icosapent ethyl 4 g/day (n = 126; approved dose) or placebo (n = 120). Without increasing LDL-C, icosapent ethyl significantly reduced median TG (-20%; p < 0.0001), non-high-density lipoprotein cholesterol (-12.3%; p < 0.0001), total cholesterol (-11.1%; p < 0.0001), high-density lipoprotein cholesterol (-5.2%; p = 0.0042), very LDL-C (-21.0%; p < 0.0001), very low-density lipoprotein TG (-22.9%; p < 0.0001), remnant lipoprotein cholesterol (-23.0%; p = 0.0125), apolipoprotein B (-7.4%; p = 0.0021), apolipoprotein C-III (-16%; p < 0.0001), oxidized LDL (-13.7%; p = 0.0020), lipoprotein-associated phospholipase A2 (-19.6%; p < 0.0001), and hsCRP (-17.9%; p = 0.0213) versus placebo, while interleukin-6 and intercellular adhesion molecule-1 were not significantly changed. Eicosapentaenoic acid increased with icosapent ethyl 4 g/day +637% in plasma and +632% in red blood cells versus placebo (both p < 0.0001). Icosapent ethyl exhibited a safety profile similar to placebo. In conclusion, in statin-treated patients with hsCRP ≥ 2.0 mg/L and TG 200 to 499 mg/dl at baseline, icosapent ethyl 4 g/day significantly and safely reduced TG and other atherogenic and inflammatory parameters without increasing LDL-C versus placebo.
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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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Six-month adherence to Statin use and subsequent risk of major adverse cardiovascular events (MACE) in patients discharged with acute coronary syndromes.
Xie, G, Sun, Y, Myint, PK, Patel, A, Yang, X, Li, M, Li, X, Wu, T, Li, S, Gao, R, et al
Lipids in health and disease. 2017;(1):155
Abstract
BACKGROUND The evidence of adherence to statin decreasing risk of major adverse cardiovascular events (MACEs) is still lack among patients discharged with acute coronary syndrome (ACS). Our objective is to determine the relationship between six-month adherence to statins and subsequent risk of MACEs in patients discharged with ACS. METHODS Using two prospective registry cohorts (CPACS-1 and -2), we analyzed data from 12,516 consecutive patients with ACS who were prescribed statin at hospital discharge and survived beyond 6 months without recurrent myocardial infarction (MI) or stroke. Adherence to statin was defined as good (using statin at discharge and 6 months without declined dosage) and poor adherence groups (using statin at discharge but declining dosage or stopping at 6 months). We compared the hazard ratios of all-cause mortality and MACE in subsequent 6 months between groups, using Cox-regression models, adjusting for multiple potential confounders. RESULTS Seventy two percent of patients adhered to statin therapy at 6 months. The incident MACE in the poor adherence group was significantly higher than in good adherence group (2.7% vs. 1.8%, p = 0.002). Compared with poor adherence group, the good adherence group showed a 27% lower relative risk of MACE during the 6 month follow up (fully-adjusted hazard ratio (HR) = 0.73; 95%CI: 0.56-0.97). The protective effects of good adherence were similar in groups with different statin dose as well as groups by other baseline clinical characteristics and treatments (p > 0.05 for interaction). CONCLUSION Our study highlights the importance of adherence to statin therapy in prevention of MACE and clinicians should aim to achieve higher dosage if tolerable. CLINICAL TRIAL REGISTRATION CPACS2 was registered on URL: http://www.anzctr.org.au/default.aspx and unique identifier is ACTRN12609000491268 . CPACS1 was not a clinical trial and thus not registered.
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Effect of physician characteristics and knowledge on the quality of dyslipidemia management and LDL-C target goal achievement in China: Subgroup analysis of the Dyslipidemia International Study.
Ding, R, Ye, P, Zhao, S, Zhao, D, Yan, X, Dong, Y, Li, J, Ran, Y, Hu, D, ,
Journal of global health. 2017;(2):020702
Abstract
OBJECTIVE This study aimed to investigate the effect of physicians' characteristics and knowledge of LDL-C target goals on the quality of lipid management in China. METHODS A total of 25 317 dyslipidemia patients who had taken lipid-lowering medication for >3 months were enrolled in our study. Patients' demographic data, medical history, lipid profile, their physician's specialty and professional title and their hospital level as well as their LDL-C goal opinions were recorded. RESULTS Questionnaires were completed by 926 physicians with 6 different specialties and 4 professional statuses, in 3 different-level hospitals. Most (74.5%) of the physicians recognized the importance of considering LDL-C serum concentration for treating dyslipidemia, and set target LDL-C goals according to the 2007 Chinese guidelines for 83.4% of their patients. The LDL-C goal achievement rate was significantly higher for patients whose physicians' knowledge of LDL-C target goals was consistent with guideline recommendations, compared with those whose physicians' knowledge was inconsistent with the guidelines (60.4% vs 31.1%, P < 0.0001). Physicians working in tier 1 (odds ration (OR) = 2.95; 95% CI 2.37-3.67), (OR = 1.56; 95% CI 1.34-1.81) and tier 2 (OR = 2.53; 95% CI 2.22-2.88), (OR = 1.16; 95% CI 1.06-1.27) hospitals, specialized in neurology (OR = 1.13; 95% CI 0.93-1.36), (OR = 1.57; 95% CI 1.40-1.77), internal medicine (OR = 1.07; 95% CI 0.90-1.27), (OR = 1.58; 95% CI 1.39-1.80), endocrinology (OR = 1.02; 95% CI 0.87-1.21), (OR = 1.63; 95% CI 1.47-1.82) and being a resident vs attending physician (OR = 1.05; 95% CI 0.92-1.20), (OR = 1.00; 95% CI 1.00-1.19) were independent risk factors for low knowledge of LDL-C target goals and low LDL-C goal achievement. CONCLUSION Chinese physicians' characteristics and knowledge of LDL-C target goals were associated with patients' LDL-C goal achievement.
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Design and rationale of the EBBINGHAUS trial: A phase 3, double-blind, placebo-controlled, multicenter study to assess the effect of evolocumab on cognitive function in patients with clinically evident cardiovascular disease and receiving statin background lipid-lowering therapy-A cognitive study of patients enrolled in the FOURIER trial.
Giugliano, RP, Mach, F, Zavitz, K, Kurtz, C, Schneider, J, Wang, H, Keech, A, Pedersen, TR, Sabatine, MS, Sever, PS, et al
Clinical cardiology. 2017;(2):59-65
Abstract
Some observational studies raised concern that statins may cause memory impairment, leading to a US Food and Drug Administration warning. Similar questions were raised regarding proprotein convertase subtilisin/kexin-type 9 inhibitors (PCSK9i) and neurocognitive function. No prospectively designed study has evaluated the relationship between long-term PCSK9i use and cognition changes. Patients with prior cardiovascular disease treated with maximally tolerated statin enrolled in FOURIER (the randomized, double-blind, placebo-controlled cardiovascular outcome study of the PCSK9i evolocumab) could participate in this prospective assessment of cognitive function (EBBINGHAUS). Key additional exclusion criteria for EBBINGHAUS were dementia, cognitive impairment, or other significant mental or neurological disorder. Cognitive testing was performed using the Cambridge Neuropsychological Test Automated Battery, a tablet-based tool assessing executive function, working memory, memory function, and psychomotor speed at baseline, weeks 24 and 48, every 48 weeks thereafter, and study end. The primary endpoint was spatial working memory strategy index of executive function (SWMSI). The primary hypothesis was that evolocumab would be noninferior to placebo in the mean change from baseline over time in SWMSI. Fifteen hundred cognitively normal patients completing the assessments provided approximately 97% power to demonstrate that the upper 95% confidence interval for the treatment difference in mean change from baseline in SWMSI over time is <20% of the SD of the mean change in the placebo group. An exploratory analysis will compare neurocognitive function in patients with post-baseline low-density lipoprotein cholesterol <25 mg/dL. EBBINGHAUS will evaluate whether the addition of evolocumab to statin therapy affects cognitive function over time in patients with stable cardiovascular disease.
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Effect of niacin on triglyceride-rich lipoprotein apolipoprotein B-48 kinetics in statin-treated patients with type 2 diabetes.
Pang, J, Chan, DC, Hamilton, SJ, Tenneti, VS, Watts, GF, Barrett, PH
Diabetes, obesity & metabolism. 2016;(4):384-91
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Abstract
AIM: To investigate the effects of extended-release (ER) niacin on apolipoprotein B-48 (apoB-48) kinetics in statin-treated patients with type 2 diabetes (T2DM). METHODS A total of 12 men with T2DM were randomized to rosuvastatin or rosuvastatin plus ER niacin for 12 weeks and then crossed to the alternate therapy. Postprandial metabolic studies were performed at the end of each treatment period. D3-leucine tracer was administered as subjects consumed a high-fat liquid meal. ApoB-48 kinetics were determined using stable isotope tracer kinetics with fractional catabolic rates (FCRs) and secretion rates derived using a non-steady-state compartmental model. Area-under-the-curve (AUC) and incremental AUC (iAUC) for plasma triglyceride and apoB-48 were also calculated over the 10-h period after ingestion of the fat meal. RESULTS In statin-treated patients with T2DM, apoB-48 concentration was lower with ER niacin (8.24 ± 1.98 vs 5.48 ± 1.14 mg/l, p = 0.03) compared with statin alone. Postprandial triglyceride and apoB-48 AUC were also significantly lower on ER niacin treatment (-15 and -26%, respectively; p < 0.05), without any change to triglyceride and apoB-48 iAUC. ApoB-48 secretion rate in the basal state (3.21 ± 0.34 vs 2.50 ± 0.31 mg/kg/day; p = 0.04) and number of apoB-48-containing particles secreted in response to the fat load (1.35 ± 0.19 vs 0.84 ± 0.12 mg/kg; p = 0.02) were lower on ER niacin. ApoB-48 FCR was not altered with ER niacin (8.78 ± 1.04 vs 9.17 ± 1.26 pools/day; p = 0.79). CONCLUSIONS ER niacin reduces apoB-48 concentration by lowering fasting and postprandial apoB-48 secretion rate. This effect may be beneficial for lowering atherogenic postprandial lipoproteins and may provide cardiovascular disease risk benefit in patients with T2DM.
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Lowering of lipoprotein(a) level under niacin treatment is dependent on apolipoprotein(a) phenotype.
Artemeva, NV, Safarova, MS, Ezhov, MV, Afanasieva, OI, Dmitrieva, OA, Pokrovsky, SN
Atherosclerosis. Supplements. 2015;:53-8
Abstract
BACKGROUND Lipoprotein(a) [Lp(a)] is a cardiovascular risk factor; in addition to being a low-density lipoprotein (LDL)-like particle, it contains highly heterogeneous apolipoprotein(a) [apo(a)]. No prior studies have evaluated extended-release (ER) niacin effect on Lp(a) level depending on apo(a) phenotype. METHODS For this 24-week, prospective, open-label clinical trial we recruited 30 men (mean age 46.2 ± 7.5 years) with Lp(a) levels >20 mg/dL. No participant had previously received lipid lowering therapy, and started ER niacin 500 mg with stepwise dose increasing up to 1.5-2.0 g. Subjects were evaluated for Lp(a), lipids, high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2 (Lp-PLA2), and fibrinolytic markers (plasminogen activator inhibitor-1, tissue plasminogen activator/plasminogen activator inhibitor-1 complex, plasmin-antiplasmin complex). Patients were divided into two groups with major low- (LMW) or high-molecular weight (HMW) apo(a) isoforms determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of plasma under reducing conditions followed by immunoblotting. RESULTS At baseline, groups were comparable in age, lipid, inflammatory and fibrinolytic biomarkers levels. There was a significant difference in baseline Lp(a) concentrations: 92 ± 29 mg/dL versus 54 ± 46 mg/dL in LMW and HMW apo(a) groups, respectively, p < 0.01. During the course of niacin treatment Lp(a) decreased by 28% (p < 0.003), Lp-PLA2 by 22% (p < 0.001), C-reactive protein by 24% (p = 0.07) in LMW apo(a) group, whereas no changes in Lp(a) and biomarkers levels were obtained in HMW apo(a) group. CONCLUSION High-dose ER niacin declines elevated Lp(a) level in male subjects with low- but not high-molecular weight apo(a) phenotype.
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Anagliptin decreases serum lathosterol level in patients with type 2 diabetes: a pilot study.
Aoki, K, Ijima, T, Kamiyama, H, Kamiko, K, Terauchi, Y
Expert opinion on pharmacotherapy. 2015;(12):1749-54
Abstract
OBJECTIVE The mechanism responsible for the lipid-lowering effect of dipeptidyl peptidase-4 (DPP-4) inhibitors remains unknown in humans. We evaluated the effect of anagliptin on serum lipid profiles, including cholesterol synthesis and absorption markers, in Japanese patients with type 2 diabetes. METHODS Thirty patients with type 2 diabetes (20 - 70 years old, low-density lipoprotein cholesterol (LDL-C) level over 120 mg/dl, and no history of treatment with antidiabetic or antihyperlipidemic drugs) were enrolled. One hundred milligrams of anagliptin were administered twice a day for a month. RESULTS After treatment of anagliptin, the LDL-C and total cholesterol (TC) levels did not decrease overall, but the TC level decreased significantly in 28 patients whose HbA1c levels decreased. Lathosterol decreased significantly, whereas no changes in campesterol, sitosterol or cholestanol were observed. CONCLUSION These results of our study show no significant change in LDL-C, a tendency of decrease in TC and non-high-density lipoprotein cholesterol (non-HDL-C) after treatment of anagliptin for 1 month. Anagliptin therapy decreased the cholesterol synthesis marker lathosterol without changing cholesterol absorption markers.
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Effect of Extended-Release Niacin/Laropiprant Combination on Plasma Adiponectin and Insulin Resistance in Chinese Patients with Dyslipidaemia.
Hu, M, Yang, YL, Masuda, D, Yamashita, S, Tomlinson, B
Disease markers. 2015;:154014
Abstract
OBJECTIVES This study examined whether the increase of adiponectin associated with extended-release (ER) niacin/laropiprant combination attenuates the adverse effect of niacin on glucose and insulin resistance in Hong Kong Chinese patients with dyslipidaemia. METHODS Patients (N = 121) were treated with ER niacin/laropiprant 1 g/20 mg for 4 weeks and then the dose was doubled for an additional 8 weeks. Measurements of fasting lipids, glucose, insulin, and adiponectin were performed at baseline and during the study. RESULTS There were significant (P < 0.001) increases in glucose (9.4 ± 13.1%), insulin (70.2 ± 91.0%), HOMA-IR (87.8 ± 103.9%), and adiponectin (169.3 ± 111.6%). The increase in adiponectin was significantly associated with increase in glucose (r = 0.221, P < 0.05), insulin (r = 0.184, P < 0.05), and HOMA-IR (r = 0.237, P < 0.01) and the association remained significant after adjustment for changes in body weight or body fat mass. CONCLUSION Treatment with ER niacin/laropiprant led to a significant increase in adiponectin levels but worsening of glucose levels and insulin resistance, and the increase in adiponectin and insulin resistance were correlated suggesting the increase in adiponectin did not ameliorate the deterioration in insulin resistance. Clinical trial is registered with number on WHO-ICTRP ChiCTR-ONC-10001038.