Visseren, F.L.J.

Factor VIII deficiency does not protect against atherosclerosis (Article)

2012-01-01T00:00:00Z

Summary. Background: Hemophilia A patients have a lower cardiovascular mortality rate than the general population. Whether this protection is caused by hypocoagulability or decreased atherogenesis is unclear. Objectives: To evaluate atherosclerosis and endothelial function in hemophilia A patients with and without obesity as well as in matched, unaffected controls. Methods: Fifty-one obese (body mass index [BMI]≥30kgm-2) and 47 non-obese (BMI≤25kgm-2) hemophilia A patients, and 42 obese and 50 matched non-obese male controls were included. Carotid and femoral intima-media thickness [IMT] and brachial flow-mediated dilatation (FMD) were measured as markers of atherogenesis and endothelial function. Results: The overall population age was 50±13 years. Carotid IMT was increased in obese subjects (0.77±0.22mm) as compared with non-obese subjects (0.69±0.16mm) [mean difference 0.07mm (95% confidence interval [CI] 0.02-0.13, P=0.008)]. No differences in mean carotid and femoral IMT between obese hemophilic patients and obese controls were found (mean difference of 0.02mm [95% CI -0.07-0.11, P=0.67], and mean difference of 0.06mm [95% CI -0.13-0.25, P=0.55], respectively). Thirty-five per cent of the obese hemophilic patients and 29% of the obese controls had an atherosclerotic plaque (P=0.49), irrespective of the severity of hemophilia. Brachial FMD was comparable between obese hemophilic patients and obese controls (4.84%±3.24% and 5.32%±2.37%, P=0.45). Conclusion: Hemophilia A patients with obesity develop atherosclerosis to a similar extent as the general male population. Detection and treatment of cardiovascular risk factors in hemophilic patients is equally necessary.

The effects of the PPAR-γ agonist pioglitazone on plasma concentrations of circulating vasoactive factors in type II diabetes mellitus (Article)

2009-10-22T00:00:00Z

The effect of statin alone or in combination with ezetimibe on postprandial lipoprotein composition in obese metabolic syndrome patients (Article)

2009-01-01T00:00:00Z

Introduction: Fasting and postprandial hypertriglyceridemia are essential features of metabolic syndrome. Statins decrease fasting lipid levels but fail to reduce fat load induced hypertriglyceridemia. We established whether ezetimibe combined with simvastatin differently influences post fat load lipid levels and lipoprotein composition as compared to simvastatin 80 mg monotherapy in obese male metabolic syndrome patients. Methods: Prospective, randomized, double blind, crossover trial. Male obese metabolic syndrome (ATPIII) patients (n = 19) were treated with simvastatin 80 mg and simvastatin/ezetimibe 10 mg/10 mg for 6 weeks. At the start of the study and after each treatment period oral fat loading tests were performed. Lipoprotein fractions (triglyceride-rich lipoproteins (TRL), IDL, LDL, and HDL) were isolated by density gradient ultracentrifugation. Postprandial changes in lipid levels were integrated as areas under the curve (AUCs). Results: Fasting LDL-C, RLP-C and triglycerides were lowered equally by both simvastatin 80 mg and simvastatin/ezetimibe 10 mg/10 mg. Also postprandial plasma triglyceride levels (net AUC-TG) were equally lowered after both treatments (5.16 ± 0.50 mmol h/l after simvastatin/ezetimibe 10 mg/10 mg and 6.09 ± 0.71 mmol h/l after simvastatin 80 mg) compared to fat loading without treatment (6.64 ± 0.86 mmol h/l). In addition, triglyceride-content in lipoprotein fractions after fat load (net AUCs) were also equally reduced after both treatments. Similarly, TRL. IDL and LDL cholesterol and apoB concentrations were equally affected by both treatment regimens, leading to a reduced number of circulating particles, in both conditions. However the composition of these particles remained the same. Conclusion: Simvastatin 80 mg and simvastatin/ezetimibe 10 mg/10 mg were equally effective in reducing fasting and post fat load plasma lipid, and lipoprotein concentrations and lipoprotein composition in obese metabolic syndrome patients.

Cholesteryl ester transfer protein inhibitor torcetrapib and off-target toxicity: A pooled analysis of the rating atherosclerotic disease change by imaging with a new CETP inhibitor (RADIANCE) trials (Article)

2008-12-09T00:00:00Z

Background - Torcetrapib, an inhibitor of cholesteryl ester transfer protein, has been shown to increase the cardiovascular event rate despite conferring a significant high-density lipoprotein cholesterol increase. Using data from the Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor (RADIANCE) trials, which assessed the impact of torcetrapib on carotid intima-media thickness (cIMT), we sought to explore potential mechanisms underlying this adverse outcome. Methods and Results - Data from the RADIANCE 1 and 2 studies, which examined cIMT in 904 subjects with familial hypercholesterolemia and in 752 subjects with mixed dyslipidemia, were pooled. Subjects were randomized to either atorvastatin or torcetrapib combined with atorvastatin. Mean common cIMT progression was increased in subjects receiving torcetrapib plus atorvastatin compared with subjects receiving atorvastatin alone (0.0076±0.0011 versus 0.0025±0.0011 mm/y; P=0.0014). Subjects treated with torcetrapib plus atorvastatin displayed higher postrandomization systolic blood pressure and plasma sodium and bicarbonate levels in conjunction with lower potassium levels. The decrease in potassium levels was associated with the blood pressure increase. Markedly, the use of renin-angiotensin-aldosterone system inhibitors tended to aggravate the blood pressure increase. Subjects receiving torcetrapib plus atorvastatin with the strongest low-density lipoprotein cholesterol reduction showed the smallest cIMT progression, whereas subjects with the highest systolic blood pressure increase showed the largest cIMT progression. High-density lipoprotein cholesterol increase was not associated with cIMT change. Conclusions - These analyses support mineralocorticoid-mediated off-target toxicity in patients receiving torcetrapib as a contributing factor to an adverse outcome. The absence of an inverse relationship between high-density lipoprotein cholesterol change and cIMT progression suggests that torcetrapib-induced high-density lipoprotein cholesterol increase does not mediate atheroprotection. Future studies with cholesteryl ester transfer protein inhibitors without off-target toxicity are needed to settle this issue.

Lipid-lowering therapy does not affect the postprandial drop in high density lipoprotein-cholesterol (HDL-c) plasma levels in obese men with metabolic syndrome: A randomized double blind crossover trial (Article)

2008-12-01T00:00:00Z

Introduction: The postprandial lipid metabolism in metabolic syndrome patients is disturbed and may add to the increased cardiovascular risk in these patients. It is not known whether postprandial high density lipoprotein- cholesterol (HDL-c) metabolism is also affected and whether this can be influenced by statin and/or ezetimibe treatment. Methods: Prospective, randomized, double blind, crossover trial comparing simvastatin 80 mg with simvastatin/ezetimibe 10 mg/10 mg treatment for 6 weeks on postprandial HDL-c metabolism in 15, nonsmoking, male, obese metabolic syndrome patients (Adult Treatment Panel III, ATPIII). Only study medication was allowed. HDL-c concentrations, cholesteryl ester transfer (CET), CET protein (CETP) mass and adiponectin were measured before and after oral fat loading. ClinicalTrials.gov NCT00189085. Results: Plasma HDL-c levels remained stable during continuous fasting following an overnight fast. Pre-fat load HDL-c concentrations without treatment, after simvastatin and simvastatin/ezetimibe treatment were 1.15 ± 0.04, 1.16 ± 0.05 and 1.11 ± 0.04 mmol/l. Fat load induced a 11% drop in HDL-c plasma levels; 1.02 ± 0.05 mmol/l (P < 0.001) which was not affected by either therapy. Triglyceride levels during fat load were similar after both treatments. Total CET increased from 9.73 ± 0.70 to 12.20 ± 0.67 nmol/ml/h (P = 0.004). Four hours after fat loading CETP mass was increased while adiponectin levels were decreased, irrespective of treatment. Discussion: HDL-c levels decrease as CET increases after fat loading in obese metabolic syndrome patients. This is not influenced by either simvastatin or simvastatin/ezetimibe treatment. After fat loading, CETP mass and CET increased, and adiponectin decreased pointing towards a potential role for intra-abdominal fat. Decreased postprandial HDL-c levels may contribute to the increased cardiovascular risk in metabolic syndrome patients on top of already low HDL-c levels.

Simvastatin with or without ezetimibe in familial hypercholesterolemia (Article)

2008-04-03T00:00:00Z

Background: Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprotein (LDL) cholesterol when added to statin treatment. However, the effect of ezetimibe on the progression of atherosclerosis remains unknown. Methods: We conducted a double-blind, randomized, 24-month trial comparing the effects of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia. Patients underwent B-mode ultrasonography to assess the intima-media thickness of the walls of the carotid and femoral arteries. The primary outcome measure was the change in the mean carotid-artery intima-media thickness, which was defined as the average of the means of the far-wall intima-media thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries. Results: The primary outcome, the mean (±SE) change in the carotid-artery intima-media thickness, was 0.0058±0.0037 mm in the simvastatin-only group and 0.0111±0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P = 0.29). Secondary outcomes (consisting of other variables regarding the intima-media thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (±SD) LDL cholesterol level was 192.7±60.3 mg per deciliter (4.98±1.56 mmol per liter) in the simvastatin group and 141.3±52.6 mg per deciliter (3.65±1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P<0.01). The differences between the two groups in reductions in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined-therapy group (P<0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups. Conclusions: In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097.) Copyright