Hyperlipidemias: Bots ML

Winters SM, Visser H, Steerneman AH, Thomas G, Bots ML, van der Heijden GJ. · Julius Center for Health Sciences and Primary Care, Str. 6.131, Heidelberglaan 100, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands. · Prim Care Diabetes. · Pubmed #18684421 No free full text.

Abstract: PURPOSE: To study the need for dietary measures to further reduce LDL cholesterol in patients with type 2 diabetes mellitus on statin therapy. METHODS: A Pubmed, Embase, CINAHL and Cochrane library search was performed to identify relevant articles. After critical appraisal six articles were ranked according to relevance, validation and level of evidence. RESULTS: There were no studies performed among type II diabetics. Among patients with hypercholesterolaemia, diet led to an additional LDL reduction from 0.20 to 0.88 mmol/l, translating into 23% reduction in vascular risk. CONCLUSION: We recommend a low-fat diet on top of statin therapy in patients with type 2 diabetes mellitus assuming that effects found in hypercholesterolaemic patients also apply to type 2 diabetics.

Bots ML, van der Bom JG, de Bruyne MC, Grobbee DE. · Universitair Medisch Centrum, Julius Centrum voor Gezondheidswetenschappen en Eerstelijns Geneeskunde, Postbus 80.035, 3508 GA Utrecht. · Ned Tijdschr Geneeskd. · Pubmed #12109307 No free full text.

Abstract: In recent years, an increasing amount of information has become available on new indicators of cardiovascular damage, their determinants and the value of these indicators in the prediction of the development of cardiovascular disease. These indicators include carotid intima-media thickness, ECG characteristics, endothelial function and the measurement of coronary calcium. These indicators are currently used predominantly in cardiovascular disease research. At present, only limited information is available as to whether these indicators are useful in clinical practice for estimating the absolute risk of cardiovascular disease in an individual. The relative value of these newer indicators compared to the routinely collected risk factor information such as medical history, lifestyle, anthropometric variables, blood pressure and lipids is also not yet well established. The recent Dutch guidelines for the initiation of treatment with blood pressure lowering and lipid lowering drugs as a function of the absolute risk of cardiovascular disease within 10 years for the individual patient point toward the urgent necessity for research in the area of new risk indicators of vascular damage.

van Venrooij FV, van de Ree MA, Bots ML, Stolk RP, Huisman MV, Banga JD, Anonymous00183. · Julius Center for General Practice and Patient Oriented Research and Department of Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. · Diabetes Care. · Pubmed #12087021 links to  free full text

Abstract: OBJECTIVE: Endothelial dysfunction is considered an important early marker of atherosclerosis and cardiovascular risk and is currently used as a surrogate end point for cardiovascular risk in clinical trials. Type 2 diabetic patients show a characteristic dyslipidemia. Aggressive lipid lowering might be an effective method to improve endothelial function in these patients. RESEARCH DESIGN AND METHODS: A randomized, double-blind, placebo-controlled trial was completed to study the effect of 30 weeks' administration of atorvastatin 10 mg and 80 mg on endothelial function, as assessed by B-mode ultrasound of the brachial artery, in 133 patients with type 2 diabetes without a history of cardiovascular disease. RESULTS: Patients with diabetes and diabetic dyslipidemia had considerable endothelium-dependent and endothelium-independent dysfunction; mean flow-mediated vasodilation (SD) was 3.16% (3.56), and mean response on sublingual nitroglycerin was 6.58% (6.04). Despite substantial lowering of all atherogenic lipid parameters, no improvement of endothelium-dependent vasodilatation was found (P > 0.8). CONCLUSIONS: We observed considerable baseline endothelium-dependent and endothelium-independent dysfunction in patients with diabetes and diabetic dyslipidemia without a history of cardiovascular disease. Aggressive lipid lowering by administration of atorvastatin, resulting in substantial improvement of the lipid profile, did not reverse endothelial dysfunction.

Bots ML, Palmer MK, Dogan S, Plantinga Y, Raichlen JS, Evans GW, O'Leary DH, Grobbee DE, Crouse JR, Anonymous00038. · Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands. · J Intern Med. · Pubmed #19298496 No free full text.

Abstract: BACKGROUND: In several statin trials, vascular event rates for treatment groups begin to separate 1 year after commencement of treatment. For atherosclerosis progression, the temporal sequence of the effect has not been defined. We used data from the Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin (METEOR) trial to determine the earliest time point at which significant differences in atherosclerosis progression rates could be detected after initiation of statin therapy. METHODS: The METEOR trial was a double-blind, randomized placebo-controlled trial that studied the effect of LDL-C lowering with 40 mg rosuvastatin on the rate of change of carotid intima media thickness (CIMT) measured by B-mode ultrasound amongst 984 low risk subjects. Ultrasound assessments were made at baseline and every 6 months up to 2 years. RESULTS: Rosuvastatin treatment was associated with a 49% reduction in LDL-C-C, a 34% reduction in total cholesterol, an 8.0% increase in HDL-C and a 16% reduction in triglycerides (all P < 0.0001 compared with placebo). The difference in rate of mean maximum CIMT progression between the rosuvastatin and placebo groups (based on near and far wall measurements from both left and right common carotid and internal carotid segments and carotid bifurcation) was not statistically significant after 6 months (0.0023 mm year(-1) and 0.0106 mm year(-1), respectively P = 0.34). After 12 months, CIMT progression rates were significantly different between the groups: 0.0032 mm year(-1) and 0.0133 mm year(-1) in the rosuvastatin-treated and placebo-treated groups, respectively (P = 0.049). This divergence grew with further follow-up: -0.0009 mm year(-1) and 0.0131 mm year(-1) after 18 months (P < 0.001) and -0.0014 mm year(-1) and 0.0131 mm year(-1) after 24 months of treatment (P < 0.001). Results were stronger for the mean common CIMT progression (based on near and far wall measurements from both left and right common carotid segments). CONCLUSION: Aggressive LDL-C lowering seems to exert its beneficial effect on atherosclerosis progression during the first 12 months of treatment. This parallels the timing of event reduction seen in clinical trials and suggests that the efficacy of lipid lowering treatment on CIMT progression can be evaluated in trials with a duration of 1 year, given sufficient sample size, high precision of measurements and a treatment effect comparable to that seen in METEOR.

Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF, Visseren FL, Sijbrands EJ, Trip MD, Stein EA, Gaudet D, Duivenvoorden R, Veltri EP, Marais AD, de Groot E, Anonymous00010. · Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. · N Engl J Med. · Pubmed #18376000 links to  free full text

Abstract: 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 [ClinicalTrials.gov].).

Kastelein JJ, van Leuven SI, Evans GW, Riley WA, Revkin JH, Shear CL, Bots ML, Anonymous00891. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands. · Curr Med Res Opin. · Pubmed #17407645 No free full text.

Abstract: OBJECTIVE: The RADIANCE studies were designed to assess the effects of torcetrapib/atorvastatin (T/A) compared with atorvastatin alone on slowing atherosclerotic progression in patients with heterozygous familial hypercholesterolemia (RADIANCE 1) or mixed hyperlipidemia (RADIANCE 2), as measured by change in carotid intima-media thickness (CIMT). RESEARCH DESIGN AND METHODS: RADIANCE 1 and 2 were randomized, double-blind, controlled trials with a duration of 2 years. In both studies, eligible subjects began treatment with atorvastatin during a run-in period and were titrated to target LDL-C levels defined by NCEP ATP III guidelines. Subjects then proceeded to a double-blind randomized treatment period where they received one of two regimens: (i) fixed combination T/A (torcetrapib dose, 60 mg), or (ii) atorvastatin alone. In both regimens, the dose of atorvastatin was established during the run-in period (20-80 mg, RADIANCE 1; 10-80 mg RADIANCE 2). B-mode ultrasonography was performed in duplicate at baseline and at end of study, and every 6 months in between. MAIN OUTCOME MEASURES: The primary efficacy measure in both studies was the annualized rate of change in maximum CIMT of 12 pre-defined carotid segments. Further outcome measures included lipid and safety assessments. Current status: The number of subjects randomized was 904 in RADIANCE 1 and 752 in RADIANCE 2. Results are anticipated in 2007.

Kastelein JJ, van Leuven SI, Burgess L, Evans GW, Kuivenhoven JA, Barter PJ, Revkin JH, Grobbee DE, Riley WA, Shear CL, Duggan WT, Bots ML, Anonymous00340. · Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · N Engl J Med. · Pubmed #17387131 links to  free full text

Abstract: BACKGROUND: Torcetrapib, an inhibitor of cholesteryl ester transfer protein, may reduce atherosclerotic vascular disease by increasing levels of high-density lipoprotein (HDL) cholesterol. METHODS: A total of 850 patients with heterozygous familial hypercholesterolemia underwent B-mode ultrasonography at baseline and at follow-up to measure changes in carotid intima-media thickness. The patients completed an atorvastatin run-in period and were subsequently randomly assigned to receive either atorvastatin monotherapy or atorvastatin combined with 60 mg of torcetrapib for 2 years. RESULTS: After 24 months, in the atorvastatin-only group, the mean (+/-SD) HDL cholesterol level was 52.4+/-13.5 mg per deciliter and the mean low-density lipoprotein (LDL) cholesterol level was 143.2+/-42.2 mg per deciliter, as compared with 81.5+/-22.6 mg per deciliter and 115.1+/-48.5 mg per deciliter, respectively, in the torcetrapib-atorvastatin group. During the study, average systolic blood pressure increased by 2.8 mm Hg in the torcetrapib-atorvastatin group, as compared with the atorvastatin-only group. The increase in maximum carotid intima-media thickness, the primary measure of efficacy, was 0.0053+/-0.0028 mm per year in the atorvastatin-only group and 0.0047+/-0.0028 mm per year in the torcetrapib-atorvastatin group (P=0.87). The secondary efficacy measure, annualized change in mean carotid intima-media thickness for the common carotid artery, indicated a decrease of 0.0014 mm per year in the atorvastatin-only group, as compared with an increase of 0.0038 mm per year in the torcetrapib-atorvastatin group (P=0.005). CONCLUSIONS: In patients with familial hypercholesterolemia, the use of torcetrapib with atorvastatin, as compared with atorvastatin alone, did not result in further reduction of progression of atherosclerosis, as assessed by a combined measure of carotid arterial-wall thickness, and was associated with progression of disease in the common carotid segment. These effects occurred despite a large increase in HDL cholesterol levels and a substantial decrease in levels of LDL cholesterol and triglycerides. (ClinicalTrials.gov number, NCT00136981 [ClinicalTrials.gov].).

Oren A, Vos LE, Uiterwaal CS, Bak AA, Gorissen WH, Grobbee DE, Bots ML. · Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands. · Eur J Epidemiol. · Pubmed #12952149 No free full text.

Abstract: INTRODUCTION: Despite recent advances in treatment, cardiovascular disease (CVD) is still health problem number one in western societies. Aiming at specific prevention strategies for high-risk individuals and shifting the available prevention programs towards younger age groups might increase the success of primary prevention. However, before addressing age-specific prevention programs, more insight in the determinants of early vascular damage and increased cardiovascular risk is warranted as well as insight in determinants increased cardiovascular risk, including vascular damage, at an early age. The Atherosclerosis Risk in Young Adults (ARYA) study was specifically designed to address this issue. OBJECTIVES: The ARYA study started off with studies evaluating (1) whether it is possible to predict cardiovascular risk at young adulthood by routinely measured adolescent data, and (2) evaluating the role of birth characteristics and adolescent characteristics to the development of vascular damage at young adulthood. METHODS: The ARYA study comprises of two cohorts of young adults. The Utrecht cohort includes 750 young adults, aged 27-30 years. The Hague-cohort includes 261 young adults born between 1963 and 1968. Data on birth characteristics, growth in early infancy as well as adolescent anthropometry, blood pressure, lipids, body mass index were obtained from the original medical records of the Municipal Health Service. In 1999/2001, the extent of subclinical vascular damage was measured using carotid wall thickness and aortic stiffness. Also, data on adult cardiovascular risk profile, bone density and central blood pressure were assessed, fasting blood was drawn and timed overnight urine samples were collected. CONCLUSION: The ARYA study is aimed to provide data on early determinants of cardiovascular risk, including vascular damage, at an early age. This knowledge enhances the understanding of atherosclerosis development and CVD risk and is needed to improve the available primary prevention programs.

Simons PC, Algra A, Bots ML, Grobbee DE, van der Graaf Y. · Julius Center for Patient Oriented Research, University Medical Center, Utrecht, the Netherlands. · Circulation. · Pubmed #10468526 links to  free full text

Abstract: BACKGROUND: Common carotid intima-media thickness (IMT) and distensibility are markers of structural and functional vessel wall properties. Both parameters have been found in population-based studies to be associated with cardiovascular risk factors and prevalent cardiovascular disease. We investigated cross-sectionally whether IMT and distensibility are associated with cardiovascular risk in patients who already have vascular disease or atherosclerotic risk factors and evaluated the diagnostic ability of IMT and distensibility to discriminate between low- and high-risk patients. METHODS AND RESULTS: IMT and distensibility (change of diameter) of the left and right common carotid arteries were measured in the first 570 patients (537 for distensibility) enrolled in the Second Manifestations of ARTerial disease (SMART) study, a cohort study among patients with a manifestation of vascular disease or cardiovascular risk factors. Three risk scores were used to classify each patient's vascular risk. Areas under the curve (AUCs) of receiver-operating characteristic curves were calculated for IMT and distensibility after the patients were dichotomized on the median of the risk scores as the outcome. Risk scores increased nearly linearly with increasing IMT and decreasing distensibility. The AUCs for IMT predicting high-risk patients were 0.77, 0.73, and 0.77 based on the 3 risk scores. The AUCs for distensibility were 0. 65, 0.62, and 0.66. CONCLUSIONS: Common carotid IMT and distensibility are clear markers of cardiovascular risk in patients who already have vascular disease or atherosclerotic risk factors. IMT appears to discriminate between low- and high-risk patients better than distensibility.

van der Bom JG, Bots ML, Haverkate F, Meyer P, Hofman A, Grobbee DE, Kluft C. · Department of Epidemiology & Biostatistics, and The Netherlands Institute for Health Sciences, Erasmus University Medical School, Rotterdam. · Thromb Haemost. · Pubmed #10064006 No free full text.

Abstract: Increased concentrations of plasminogen activator inhibitor type 1 (PAI-1) and of D-dimer have jointly been found in subjects with cardiovascular disease. To understand this apparent paradox of increased inhibition of fibrinolysis (high PAI-1) combined with increased fibrinolytic activity (high D-dimer), we examined the relation between D-dimer, PAI-1 and the activator of fibrinolysis, tissue type plasminogen activator (t-PA) in subjects with varying severity of peripheral atherosclerosis. In 325 subjects selected from the Rotterdam Study, a cohort of 7983 men and women aged 55 years and over, the ankle to brachial systolic blood pressure ratio, t-PA antigen and activity, PAI-1 antigen and D-dimer were measured. T-PA antigen and t-PA activity were, independent from each other, increased with degree of atherosclerosis; t-PA antigen increased with 3.5 ng/ml (SE 1.7, p = 0.04) and t-PA activity with 0.46 IU/ml (0.20, p = 0.02) per unit decrease in ankle to brachial pressure ratio (i.e. increase in atherosclerosis). PAI-1 antigen was not related to atherosclerosis. More marked atherosclerosis was associated with increased D-dimer, mainly in subgroups with PAI-1 antigen below 50 ng/ml, t-PA antigen below 10 ng/ml, or t-PA activity above 1.5 IU/ml. In contrast to current beliefs, we found that only a fraction of the variation of t-PA antigen was due to the variation in circulating PAI-1 antigen. A slight positive association was observed between t-PA antigen and D-dimer. PAI-1 and t-PA activity were not associated with D-dimer concentration. In conclusion, in subjects with peripheral atherosclerosis PAI-1 antigen is not increased, but low PAI-1 levels (and possibly also low levels of t-PA antigen and high levels of t-PA activity) appear to be required to increase circulating D-dimer. This suggests that increased D-dimer levels in subjects with atherosclerosis do not reflect increased inhibition, but rather reflect increased fibrinolysis.