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Lp(a) (Lipoprotein(a)) Levels Predict Progression of Carotid Atherosclerosis in Subjects With Atherosclerotic Cardiovascular Disease on Intensive Lipid Therapy: An Analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) Carotid Magnetic Resonance Imaging Substudy-Brief Report.
Hippe, DS, Phan, BAP, Sun, J, Isquith, DA, O'Brien, KD, Crouse, JR, Anderson, T, Huston, J, Marcovina, SM, Hatsukami, TS, et al
Arteriosclerosis, thrombosis, and vascular biology. 2018;(3):673-678
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Abstract
OBJECTIVE To assess whether Lp(a) (lipoprotein(a)) levels and other lipid levels were predictive of progression of atherosclerosis burden as assessed by carotid magnetic resonance imaging in subjects who have been treated with LDL-C (low-density lipoprotein cholesterol)-lowering therapy and participated in the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes). APPROACH AND RESULTS AIM-HIGH was a randomized, double-blind study of subjects with established vascular disease, elevated triglycerides, and low HDL-C (high-density lipoprotein cholesterol). One hundred fifty-two AIM-HIGH subjects underwent both baseline and 2-year follow-up carotid artery magnetic resonance imaging. Plaque burden was measured by the percent wall volume (%WV) of the carotid artery. Associations between annualized change in %WV with baseline and on-study (1 year) lipid variables were evaluated using multivariate linear regression and the Bonferroni correction to account for multiple comparisons. Average %WV at baseline was 41.6±6.8% and annualized change in %WV over 2 years ranged from -3.2% to 3.7% per year (mean: 0.2±1.1% per year; P=0.032). Increases in %WV were significantly associated with higher baseline Lp(a) (β=0.34 per 1-SD increase of Lp(a); 95% confidence interval, 0.15-0.52; P<0.001) after adjusting for clinical risk factors and other lipid levels. On-study Lp(a) had a similar positive association with %WV progression (β=0.33; 95% confidence interval, 0.15-0.52; P<0.001). CONCLUSIONS Despite intensive lipid therapy, aimed at aggressively lowering LDL-C to <70 mg/dL, carotid atherosclerosis continued to progress as assessed by carotid magnetic resonance imaging and that elevated Lp(a) levels were independent predictors of increases in atherosclerosis burden.
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Effects of niacin and omega-3 fatty acids on the apolipoproteins in overweight patients with elevated triglycerides and reduced HDL cholesterol.
Savinova, OV, Fillaus, K, Harris, WS, Shearer, GC
Atherosclerosis. 2015;(2):520-5
Abstract
OBJECTIVE Prescription omega-3 acid ethyl esters (P-OM3) and extended release niacin (ERN) both have beneficial effects on plasma lipids and lipoproteins. The purpose of this study was to describe the effects of mono- and combination (Combo) therapy of these agents in patients with the metabolic syndrome. METHODS Very low density (VLDL), intermediate/low density (IDL/LDL, hereafter LDL), and high density lipoproteins (HDL) were isolated from 56 overweight patients with elevated triglyceride/HDL-C ratios at baseline and after 16 weeks of treatment with placebo, ERN (2g/day), P-OM3 (4g/day), or Combo and then analyzed by quantitative electrophoresis for apolipoproteins (apo) A1, A2, B, C2, C3 and E. Total plasma concentrations and the ratios of each apo with apoB (in VLDL and LDL) and with apoA1 (in HDL) were calculated. An apoC3 glycosylation index (a ratio between di- and mono-sialylated isoforms) was also determined in plasma and in each lipoprotein fraction. RESULTS ERN reduced plasma apoB (-11%, p < 0.05). Combo increased LDL apoE/apoB ratio (64%, p < 0.01) and LDL apoA1/apoB (91%, p < 0.05). ERN increased the apoC3 glycosylation index only in HDL (37%, p < 0.05), whereas P-OM3 and Combo increased the index in whole plasma (48% and 49%, respectively, p < 0.05 for both) and in every lipoprotein class (VLDL: 26%, p < 0.01 and 26%, p < 0.05; LDL: 55%, p < 0.01 and 61%, p < 0.01; HDL: 43%, p < 0.001 and 44%, p < 0.001, respectively). All findings were significant after adjustment for age, sex, body mass index (BMI), smoking, medications, and baseline apo value. CONCLUSIONS ERN produced a beneficial reduction in plasma apoB. The enrichment of LDL with apoE and apoA1 was unique to the Combo group and might be beneficial owing to the atheroprotective properties of apoE and HDL2 (a likely source of apoA1 in LDL fraction). The effect of therapies on the apoC3 glycosylation index is a novel finding, the implications of which will require further study.
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Effect of rosuvastatin monotherapy or in combination with fenofibrate or ω-3 fatty acids on lipoprotein subfraction profile in patients with mixed dyslipidaemia and metabolic syndrome.
Agouridis, AP, Kostapanos, MS, Tsimihodimos, V, Kostara, C, Mikhailidis, DP, Bairaktari, ET, Tselepis, AD, Elisaf, MS
International journal of clinical practice. 2012;(9):843-53
Abstract
BACKGROUND Raised triglycerides (TG), decreased high-density lipoprotein cholesterol (HDL-C) levels and a predominance of small dense low density lipoproteins (sdLDL) are characteristics of the metabolic syndrome (MetS). OBJECTIVE To compare the effect of high-dose rosuvastatin monotherapy with moderate dosing combined with fenofibrate or ω-3 fatty acids on the lipoprotein subfraction profile in patients with mixed dyslipidaemia and MetS. METHODS We previously randomised patients with low-density lipoprotein cholesterol (LDL-C) > 160 and TG > 200 mg/dl to rosuvastatin monotherapy 40 mg/day (R group, n = 30) or rosuvastatin 10 mg/day combined with fenofibrate 200 mg/day (RF group, n = 30) or ω-3 fatty acids 2 g/day (Rω group, n = 30). In the present study, only patients with MetS were included (24, 23 and 24 in the R, RF and Rω groups respectively). At baseline and after 12 weeks of treatment, the lipoprotein subfraction profile was determined by polyacrylamide 3% gel electrophoresis. RESULTS The mean LDL size was significantly increased in all groups. This change was more prominent with RF than with other treatments in parallel with its greater hypotriglyceridemic capacity (p < 0.05 compared with R and Rω). A decrease in insulin resistance by RF was also noted. Only RF significantly raised HDL-C levels (by 7.7%, p < 0.05) by increasing the cholesterol of small HDL particles. The cholesterol of larger HDL subclasses was significantly increased by R and Rω. CONCLUSIONS All regimens increased mean LDL size; RF was the most effective. A differential effect of treatments was noted on the HDL subfraction profile.
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Effects of the new dual PPAR α/δ agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism.
Cariou, B, Zaïr, Y, Staels, B, Bruckert, E
Diabetes care. 2011;(9):2008-14
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Abstract
OBJECTIVE We evaluated the metabolic effects and tolerability of GFT505, a novel dual peroxisome proliferator-activated receptor α/δ agonist, in abdominally obese patients with either combined dyslipidemia or prediabetes. RESEARCH DESIGN AND METHODS The S1 study was conducted in 94 patients with combined dyslipidemia while the S2 study was conducted in 47 patients with prediabetes. Participants were randomly assigned in a double-blind manner to GFT505 at 80 mg/day or placebo for 28 (S1) or 35 (S2) days. Primary efficacy end points were changes from baseline at week 4 in both fasting plasma triglycerides and HDL cholesterol in the S1 group and 2-h glucose upon oral glucose tolerance test in the S2 group. RESULTS In comparison with placebo, GFT505 significantly reduced fasting plasma triglycerides (S1: least squares means -16.7% [95% one-sided CI -∞ to -5.3], P = 0.005; S2: -24.8% [-∞ to -10.5], P = 0.0003) and increased HDL cholesterol (S1: 7.8% [3.0 to ∞], P = 0.004; S2: 9.3% [1.7 to ∞], P = 0.009) in both studies, whereas LDL cholesterol only decreased in S2 (-11.0% [ -∞ to -3.5], P = 0.002). In S2, GFT505 did not reduce 2-h glucose (-0.52 mmol/L [-∞ to 0.61], P = 0.18) but led to a significant decrease of homeostasis model assessment of insulin resistance (-31.4% [-∞ to 12.5], P = 0.001), fasting plasma glucose (-0.37 mmol/L [-∞ to -0.10], P = 0.01) and fructosamine (-3.6% [-∞ to -0.20], P = 0.02). GFT505 also reduced γ glutamyl transferase levels in both studies (S1: -19.9% [-∞ to -12.8], P < 0.0001; S2: -15.1% [-∞ to -1.1], P = 0.004). No specific adverse safety signals were reported during the studies. CONCLUSIONS GFT505 may be considered a new drug candidate for the treatment of lipid and glucose disorders associated with the metabolic syndrome.
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Fenofibrate reduces systemic inflammation markers independent of its effects on lipid and glucose metabolism in patients with the metabolic syndrome.
Belfort, R, Berria, R, Cornell, J, Cusi, K
The Journal of clinical endocrinology and metabolism. 2010;(2):829-36
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Abstract
CONTEXT Fenofibrate is a peroxisome proliferator-activated receptor alpha agonist widely used in clinical practice, but its mechanism of action is incompletely understood. OBJECTIVE The aim of the study was to assess whether improvement in subclinical inflammation or glucose metabolism contributes to its antiatherogenic effects in insulin-resistant subjects with the metabolic syndrome (MetS). DESIGN AND SETTING We conducted a randomized, double-blind, placebo-controlled study in the research unit at an academic center. PATIENTS We studied 25 nondiabetic insulin-resistant MetS subjects. INTERVENTION(S): We administered fenofibrate (200 mg/d) and placebo for 12 wk. MAIN OUTCOME MEASURES Before and after treatment, we measured plasma lipids/apolipoproteins, inflammatory markers (high-sensitivity C-reactive protein, IL-6, intercellular adhesion molecule/vascular cell adhesion molecule), adipocytokines (adiponectin, TNFalpha, leptin), and insulin secretion (oral glucose tolerance test). We also assessed adipose tissue, hepatic and peripheral (muscle) insulin resistance fasting and during a euglycemic insulin clamp with (3)H glucose and (14)C palmitate infusion combined with indirect calorimetry. RESULTS Subjects displayed severe insulin resistance and systemic inflammation. Fenofibrate significantly reduced plasma triglyceride, apolipoprotein (apo) CII, apo CIII, and apo E (all P < 0.01), with a modest increase in high-density lipoprotein-cholesterol (+12%; P = 0.06). Fenofibrate markedly decreased plasma high-sensitivity C-reactive protein by 49.5 +/- 8% (P = 0.005) and IL-6 by 29.8 +/- 7% (P = 0.03) vs. placebo. However, neither insulin secretion nor adipose tissue, hepatic or muscle insulin sensitivity or glucose/lipid oxidation improved with treatment. Adiponectin and TNF-alpha levels were also unchanged. Improvement in plasma markers of vascular/systemic inflammation was dissociated from changes in triglyceride/high-density lipoprotein-cholesterol, apo CII/CIII, or free fatty acid concentrations or insulin secretion/insulin sensitivity. CONCLUSIONS In subjects with the MetS, fenofibrate reduces systemic inflammation independent of improvements in lipoprotein metabolism and without changing insulin sensitivity. This suggests a direct peroxisome proliferator-activated receptor alpha-mediated effect of fenofibrate on inflammatory pathways, which may be important for the prevention of CVD in high-risk patients.
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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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ALLHAT findings revisited in the context of subsequent analyses, other trials, and meta-analyses.
Wright, JT, Probstfield, JL, Cushman, WC, Pressel, SL, Cutler, JA, Davis, BR, Einhorn, PT, Rahman, M, Whelton, PK, Ford, CE, et al
Archives of internal medicine. 2009;(9):832-42
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Abstract
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is reevaluated considering information from new clinical trials, meta-analyses, and recent subgroup and explanatory analyses from ALLHAT, especially those regarding heart failure (HF) and the association of drug treatment with new-onset diabetes mellitus (DM) and its cardiovascular disease (CVD) consequences. Chlorthalidone was superior to (1) doxazosin mesylate in preventing combined CVD (CCVD) (risk ratio [RR], 1.20; 95% confidence interval [CI], 1.13-1.27), especially HF (RR, 1.80; 95% CI, 1.40-2.22) and stroke (RR, 1.26; 95% CI, 1.10-1.46); (2) lisinopril in preventing CCVD (RR, 1.10; 95% CI, 1.05-1.16), including stroke (in black persons only) and HF (RR, 1.20; 95% CI, 1.09-1.34); and (3) amlodipine besylate in preventing HF, overall (by 28%) and in hospitalized or fatal cases (by 26%). Central independent blinded reassessment of HF hospitalizations confirmed each comparison. Results were consistent by age, sex, race (except for stroke and CCVD), DM status, metabolic syndrome status, and renal function level. Neither amlodipine nor lisinopril was superior to chlorthalidone in preventing end-stage renal disease overall, by DM status, or by renal function level. In the chlorthalidone arm, new-onset DM was not significantly associated with CCVD (RR, 0.96; 95% CI, 0.88-2.42). Evidence from subsequent analyses of ALLHAT and other clinical outcome trials confirm that neither alpha-blockers, angiotensin-converting enzyme inhibitors, nor calcium channel blockers surpass thiazide-type diuretics (at appropriate dosage) as initial therapy for reduction of cardiovascular or renal risk. Thiazides are superior in preventing HF, and new-onset DM associated with thiazides does not increase CVD outcomes.
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Preferential increase in high-molecular weight adiponectin after niacin.
Westphal, S, Luley, C
Atherosclerosis. 2008;(1):179-83
Abstract
OBJECTIVE Recently we have demonstrated that treatment with niacin raises adiponectin between 52% and 95% in patients with the metabolic syndrome. In this study we investigated whether all three adiponectin fractions are increased equally, and, secondly, whether the increase in the biologically most active high-molecular weight (HMW) fraction can prevent the deterioration of insulin sensitivity that was also observed after niacin. METHODS AND RESULTS We used sera frozen at -80 degrees C from a randomized double-blind placebo-controlled treatment study in which 20 men with the metabolic syndrome received 1500 mg niacin for 6 weeks. Low- and medium-molecular weight adiponectin increased by 35% and 33%, respectively, but HMW adiponectin by 88% (all p<0.05). The increase in HMW adiponectin was almost two times as large in patients with lower BMI and better insulin sensitivity. However, treatment with niacin induced a deterioration of insulin sensitivity, as assessed by the HOMA-IR, independently of the increase in HMW adiponectin. CONCLUSION HMW adiponectin is the fraction most affected by treatment with niacin. The niacin-associated deterioration of insulin sensitivity, however, occurs even in subgroups with the greatest increase of HMW adiponectin.
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Atorvastatin and fenofibrate have comparable effects on VLDL-apolipoprotein C-III kinetics in men with the metabolic syndrome.
Chan, DC, Watts, GF, Ooi, EM, Ji, J, Johnson, AG, Barrett, PH
Arteriosclerosis, thrombosis, and vascular biology. 2008;(10):1831-7
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Abstract
OBJECTIVE The metabolic syndrome (MetS) is characterized by insulin resistance and dyslipidemia that may accelerate atherosclerosis. Disturbed apolipoprotein (apo) C-III metabolism may account for dyslipidemia in these subjects. Atorvastatin and fenofibrate decrease plasma apoC-III, but the underlying mechanisms are not fully understood. METHODS AND RESULTS The effects of atorvastatin (40 mg/d) and fenofibrate (200 mg/d) on the kinetics of very-low density lipoprotein (VLDL)-apoC-III were investigated in a crossover trial of 11 MetS men. VLDL-apoC-III kinetics were studied, after intravenous d(3)-leucine administration using gas chromatography-mass spectrometry and compartmental modeling. Compared with placebo, both atorvastatin and fenofibrate significantly decreased (P<0.001) plasma concentrations of triglyceride, apoB, apoB-48, and total apoC-III. Atorvastatin, not fenofibrate, significantly decreased plasma apoA-V concentrations (P<0.05). Both agents significantly increased the fractional catabolic rate (+32% and +30%, respectively) and reduced the production rate of VLDL-apoC-III (-20% and -24%, respectively), accounting for a significant reduction in VLDL-apoC-III concentrations (-41% and -39%, respectively). Total plasma apoC-III production rates were not significantly altered by the 2 agents. Neither treatment altered insulin resistance and body weight. CONCLUSIONS Both atorvastatin and fenofibrate have dual regulatory effects on VLDL-apoC-III kinetics in MetS; reduced production and increased fractional catabolism of VLDL-apoC-III may explain the triglyceride-lowering effect of these agents.
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Postprandial triglyceride responses to aerobic exercise and extended-release niacin.
Plaisance, EP, Mestek, ML, Mahurin, AJ, Taylor, JK, Moncada-Jimenez, J, Grandjean, PW
The American journal of clinical nutrition. 2008;(1):30-7
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BACKGROUND Aerobic exercise and niacin are frequently used strategies for reducing serum triglycerides, and, yet, there is no information regarding the combined effects of these strategies on postprandial triglycerides. OBJECTIVE We compared the effects of aerobic exercise and 6 wk of extended-release niacin on postprandial triglycerides in men with the metabolic syndrome. DESIGN Fifteen participants underwent each of 4 conditions: control--high-fat meal only (100 g fat); exercise--aerobic exercise performed 1 h before a high-fat meal; niacin--high-fat meal consumed after 6 wk of niacin; and niacin + exercise--high-fat meal consumed after 6 wk of niacin and 1 h after aerobic exercise. Temporal responses for triglyceride and insulin concentrations were measured and total (AUC(T)) and incremental (AUC(I)) areas under the curve were calculated. Differences were determined by using a 2-factor repeated-measures analysis of variance (P < 0.05 for all). RESULTS Exercise lowered the triglyceride AUC(I) by 32% compared with control (724 +/- 118 and 1058 +/- 137, respectively). Niacin had no influence on the triglyceride AUC(I) and attenuated the triglyceride-lowering effect of exercise when combined. Niacin + exercise had no effect on the triglyceride AUC(I) but decreased the insulin AUC(I) after niacin administration. CONCLUSIONS Aerobic exercise lowers the postprandial triglyceride response to a high-fat meal. Niacin lowers fasting but not postprandial triglycerides and appears to influence the triglyceride-lowering effect of aerobic exercise when combined. However, exercise decreases postprandial insulin concentrations after niacin administration, which illustrates the potential metabolic benefits of exercise in persons taking niacin.