Frank L.J. Visseren

Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia

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].).

Adipose tissue dysfunction in obesity, diabetes, and vascular diseases

The classical perception of adipose tissue as a storage place of fatty acids has been replaced over the last years by the notion that adipose tissue has a central role in lipid and glucose metabolism and produces a large number of hormones and cytokines, e.g. tumour necrosis factor-alpha, interleukin-6, adiponectin, leptin, and plasminogen activator inhibitor-1. The increased prevalence of excessive visceral obesity and obesity-related cardiovascular risk factors is closely associated with the rising incidence of cardiovascular diseases and type 2 diabetes mellitus. This clustering of vascular risk factors in (visceral) obesity is often referred to as metabolic syndrome. The close relationship between an increased quantity of visceral fat, metabolic disturbances, including low-grade inflammation, and cardiovascular diseases and the unique anatomical relation to the hepatic portal circulation has led to an intense endeavour to unravel the specific endocrine functions of this visceral fat depot. The objective of this paper is to describe adipose tissue dysfunction, delineate the relation between adipose tissue dysfunction and obesity and to describe how adipose tissue dysfunction is involved in the development of diabetes mellitus type 2 and atherosclerotic vascular diseases. First, normal physiology of adipocytes and adipose tissue will be described.

Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial

BACKGROUND Patients with mixed dyslipidaemia have raised triglycerides, low high-density lipoprotein (HDL) cholesterol, and high low-density lipoprotein (LDL) cholesterol. Augmentation of HDL cholesterol by inhibition of the cholesteryl ester transfer protein (CETP) could benefit these patients. We aimed to investigate the effect of the CETP inhibitor, torcetrapib, on carotid atherosclerosis progression in patients with mixed dyslipidaemia. METHODS We did a randomised double-blind trial at 64 centres in North America and Europe. 752 eligible participants completed an atorvastatin-only run-in period for dose titration, after which they all continued to receive atorvastatin at the titrated dose. 377 of these patients were randomly assigned to receive 60 mg of torcetrapib per day and 375 to placebo. We made carotid ultrasound images at baseline and at 6-month intervals for 24 months. The primary endpoint was the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Analysis was restricted to 683 patients who had at least one dose of treatment and had at least one follow-up carotid intima-media measurement; they were analysed as randomised. Mean follow-up for these patients was 22 (SD 4.8) months. This trial is registered with ClinicalTrials.gov, number NCT00134238. FINDINGS The change in maximum carotid intima-media thickness was 0.025 (SD 0.005) mm per year in patients given torcetrapib with atorvastatin and 0.030 (0.005) mm per year in those given atorvastatin alone (difference -0.005 mm per year, 95% CI -0.018 to 0.008, p=0.46). Patients in the combined-treatment group had a 63.4% relative increase in HDL cholesterol (p<0.0001) and an 17.7% relative decrease in LDL cholesterol (p<0.0001), compared with controls. Systolic blood pressure increased by 6.6 mm Hg in the combined-treatment group and 1.5 mm Hg in the atorvastatin-only group (difference 5.4 mm Hg, 95% CI 4.3-6.4, p<0.0001). INTERPRETATION Although torcetrapib substantially raised HDL cholesterol and lowered LDL cholesterol, it also increased systolic blood pressure, and did not affect the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further.

Obesity and Cancer: The Role of Dysfunctional Adipose Tissue

Overweight and obesity are health problems of epidemic proportions, increasing the risk not only of cardiovascular disease and type 2 diabetes mellitus but also of various types of cancer. Obesity is strongly associated with changes in the physiological function of adipose tissue, leading to insulin resistance, chronic inflammation, and altered secretion of adipokines. Several of these factors, such as insulin resistance, increased levels of leptin, plasminogen activator inhibitor-1, and endogenous sex steroids, decreased levels of adiponectin, and chronic inflammation, are involved in carcinogenesis and cancer progression. This article reviews these mechanisms, focusing on adipose tissue dysfunction as a unifying causal factor. Although understanding of the link between obesity and cancer might provide therapeutic targets, preventing overweight and obesity still remains number one priority. (Cancer Epidemiol Biomarkers Prev 2009;18(10):2569–78)

Metabolic and Additional Vascular Effects of Thiazolidinediones

Several cardiovascular risk factors (dyslipidaemia, hypertension, glucose intolerance, hypercoagulability, obesity, hyperinsulinaemia and low-grade inflammation) cluster in the insulin resistance syndrome. Treatment of these individual risk factors reduces cardiovascular complications. However, targeting the underlying pathophysiological mechanisms of the insulin resistance syndrome is a more rational treatment strategy to further improve cardiovascular outcome.Our understanding of the so-called cardiovascular dysmetabolic syndrome has been improved by the discovery of nuclear peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated transcription factors belonging to the nuclear receptor superfamily. As transcription factors, PPARs regulate the expression of numerous genes and affect glycaemic control, lipid metabolism, vascular tone and inflammation. Activation of the subtype PPAR-γ improves insulin sensitivity. Expression of PPAR-γ is present in several cell types involved in the process of atherosclerosis. Thus, modulation of PPAR-γ activity is an interesting therapeutic approach to reduce cardiovascular events.Thiazolidinediones are PPAR-γ agonists and constitute a new class of pharmacological agents for the treatment of type 2 (non-insulin-dependent) diabetes mellitus. Two such compounds are currently available for clinical use: rosiglitazone and pioglitazone. Thiazolidinediones improve insulin sensitivity and glycaemic control in patients with type 2 diabetes. In addition, improvement in endothelial function, a decrease in inflammatory conditions, a decrease in plasma levels of free fatty acids and lower blood pressure have been observed, which may have important beneficial effects on the vasculature.Several questions remain to be answered about PPAR-γ agonists, particularly with respect to the role of PPAR-γ in vascular pathophysiology. More needs to be known about the adverse effects of thiazolidinediones, such as hepatotoxicity, increased low-density lipoprotein cholesterol levels and increased oedema. The paradox of adipocyte differentiation with weight gain concurring with the insulin-sensitising effect of thiazolidinediones is not completely understood. The decrease in blood pressure induced by thiazolidinedione treatment seems incompatible with an increase in the plasma volume, and the discrepancy between the stimulation of the expression of CD36 and the antiatherogenic effects of the thiazolidinediones also needs further explanation. Long-term clinical trials of thiazolidinediones with cardiovascular endpoints are currently in progress.In conclusion, studying the effects of thiazolidinediones may shed more light on the mechanisms involved in the insulin resistance syndrome. Furthermore, thiazolidinediones could have specific, direct effects on processes involved in the development of vascular abnormalities.

Relation of epicardial and pericoronary fat to coronary atherosclerosis and coronary artery calcium in patients undergoing coronary angiography.

Fat surrounding coronary arteries might aggravate coronary artery disease (CAD). We investigated the relation between epicardial adipose tissue (EAT) and pericoronary fat and coronary atherosclerosis and coronary artery calcium (CAC) in patients with suspected CAD and whether this relation is modified by total body weight. This was a cross-sectional study of 128 patients with angina pectoris (61 +/- 6 years of age) undergoing coronary angiography. EAT volume and pericoronary fat thickness were measured with cardiac computed tomography. Severity of coronary atherosclerosis was assessed by the number of stenotic (> or =50%) coronary vessels; extent of CAC was determined by the Agatston score. Patients were stratified for median total body weight (body mass index [BMI] 27 kg/m(2)). Overall, EAT and pericoronary fat were not associated with severity of coronary atherosclerosis and extent of CAC. In patients with low BMI, those with multivessel disease had increased EAT volume (100 vs 67 cm(3), p = 0.04) and pericoronary fat thickness (9.8 vs 8.4 mm, p = 0.06) compared with those without CAD. Also, patients with severe CAC had increased EAT volume (108.0 vs 69 cm(3), p = 0.02) and pericoronary fat thickness (10.0 vs 8.2 mm, p value = 0.01) compared with those with minimal/absent CAC. In conclusion, EAT and pericoronary fat were not associated with severity of coronary atherosclerosis and CAC in patients with suspected CAD. However, in those with low BMI, increased EAT and pericoronary fat were related to more severe coronary atherosclerosis and CAC. Fat surrounding coronary arteries may be involved in the process of coronary atherosclerosis, although this is different for patients with low and high BMIs.

Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands

BACKGROUND Heterozygous familial hypercholesterolemia (heFH) is a common autosomal dominant hereditary disorder caused by mutations in the LDL-receptor gene that lead to elevated plasma levels of low-density lipoprotein-cholesterol (LDL-c). Robust lowering of LDL-c levels is essential for risk reduction of premature cardiovascular diseases and early death. European and Dutch guidelines recommend to treat LDL-c to plasma levels <2.5mmol/l. In the present study we evaluated the treatment of heFH patients in The Netherlands. METHODS A cross-sectional study was conducted in outpatient lipid clinics of three Academic Centers and two regional hospitals. Patient records of known heFH patients were retrieved and data were reviewed on the use of lipid-lowering medication, plasma lipids and lipoproteins, safety laboratory results and reasons for not achieving treatment goals. RESULTS The data of 1249 patients with heFH were available. Nearly all patients (96%) were on statin treatment. The treatment goal for LDL-c <2.5mmol/l was achieved in 261 (21%) patients. Among those who did not reach LDL-c goals, 261 (27%) were on combination therapy of maximum statin dose and ezetimibe. Main reason (32%) why patients did not use maximum therapy despite an LDL-c >or=2.5mmol/l, was acceptance of a higher target LDL-c level by the treating physician. An alternative treatment goal of >50% LDL-c reduction, as recommended in the NICE guidelines, was achieved in 47% of patients with an LDL-c >or=2.5mmol/l and not using maximum therapy. CONCLUSION Only a small proportion of patients with heFH reaches the LDL-c treatment target of <2.5mmol/l. These results emphasize the need for better monitoring, better utilization of available medication and for new treatment options in heFH to further decrease LDL-c levels.

Asymptomatic carotid artery stenosis and the risk of new vascular events in patients with manifest arterial disease: the SMART study.

Background and Purpose— The frequency of asymptomatic carotid artery stenosis (CAS) increases with age from 0.5% in individuals below 50 years of age to 5% to 10% in individuals over 65 years of age in the general population. Its prognostic value has been examined in the general population but less often in patients with clinical manifestations of arterial disease other than retinal or cerebral ischemia. We examined the relationship between asymptomatic CAS and the risk of subsequent events in this specific group of patients. Methods— This study involved 2684 consecutive patients with clinical manifestations of arterial disease or type 2 diabetes mellitus, but without a history of cerebral ischemia, enrolled in the SMART study (Second Manifestations of ARTerial disease). The degree of asymptomatic CAS was assessed with Duplex scanning and defined on the basis of the blood flow velocity patterns at baseline in both carotid arteries. None of the patients underwent carotid endarterectomy or endovascular intervention. During the follow-up period, vascular events (vascular death, ischemic stroke, and myocardial infarction) were documented in detail. Data were analyzed with Cox proportional hazards regression and adjusted for age, gender, and classic vascular risk factors. Results— Asymptomatic CAS of 50% or greater was present in 221 (8%) patients. During a mean follow up of 3.6 years (SD=2.3), a first vascular event occurred in 253 patients (9%). The cumulative incidence rate for the composite of subsequent vascular events after 5 years was 12.3% (95% CI=10.7 to 13.9), for cerebral infarction 2.2% (95% CI=1.4 to 2.8), and for myocardial infarction 8.0% (95% CI=6.6 to 9.4). Adjusted for age and gender, asymptomatic CAS of 50% or greater was related to a higher risk of subsequent vascular events (hazard ratio=1.5, 95% CI=1.1 to 2.1), in particular of vascular death (hazard ratio=1.8, 95% CI=1.2 to 2.6). After additional adjustment for vascular risk factors, the hazard ratios remained essentially the same. Conclusion— Asymptomatic carotid artery stenosis is an independent predictor of vascular events, especially vascular death, in patients with clinical manifestations of arterial disease or type 2 diabetes but without a history of cerebral ischemia.

Dementia and cognitive decline in type 2 diabetes and prediabetic stages: towards targeted interventions

Type 2 diabetes is associated with dementia, and also with more slight cognitive decrements. In this Review we discuss trajectories from normal cognition to dementia in people with type 2 diabetes, and explore opportunities for treatment. Slight diabetes-associated cognitive decrements and dementia affect different age groups and show a different evolution. These cognitive entities should therefore not be regarded as a continuum, although their effects might be additive. Vascular damage is a key underlying process in both entities. Glucose-mediated processes and other metabolic disturbances might also have a role. No treatment has been established, but management of vascular risk factors and optimisation of glycaemic control could have therapeutic benefit. We identify possible opportunities for intervention to improve cognitive outcomes in people with type 2 diabetes, and suggest how treatment can be tailored to individual risk profiles and comorbidities.

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

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. Received February 11, 2008; accepted September 19, 2008. # CLINICAL PERSPECTIVE {#article-title-2}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.