Patterns and predictors of statin prescription in patients with type 2 diabetes

<p>Abstract</p> <p>Background</p> <p>The benefit of statins for prevention of cardiovascular events in type 2 diabetes is established, but a gap exists between guideline recommendations and clinical practice. The aim of the study was to identify patient-related factors predicting statin prescription.</p> <p>Methods</p> <p>We assessed the quality of care in 51,640 patients with type 2 diabetes in a German diabetes registry. Patients were stratified according to primary and secondary prevention. Five-year risk for cardiovascular events was calculated in primary prevention patients. A multivariate adjusted logistic regression model was constructed to determine which parameters influenced statin prescription.</p> <p>Results</p> <p>34% had established atherosclerotic disease and 25.5% received a statin. Prescription was significantly higher in the secondary compared to the primary prevention group (38.1% [95% CI 37.4–38.9%] vs. 18.5% [95% CI 18.0–19.0%], respectively). In primary prevention the odds for statin prescription increased with estimated cardiovascular risk (OR 1.17 per 5% increase in 5-year risk, 95% CI 1.11–1.22). Positive predictors for statin prescription were secondary prevention, hypertension, former smoking, baseline LDL-cholesterol, and microalbuminuria. The odds of receiving a statin had an inverted U-shaped relation with age (nadir, 66 years), age at first diagnosis of diabetes (nadir, 56 years), and body mass index (nadir, 32 kg/m²). The model predicted prescription in 70% of the patients correctly.</p> <p>Conclusion</p> <p>The majority of patients with type 2 diabetes are not receiving statins. The predominant factors determining statin prescription are the patient's prevention status and, in primary prevention, estimated cardiovascular risk. The results suggest that although physicians are aware of the general concept of cardiovascular risk, they fail to consistently implement guidelines.</p

Ezetimibe alone or in combination with simvastatin increases small dense low-density lipoproteins in healthy men: a randomized trial

Aims The predominance of small dense low-density lipoproteins (sdLDLs) has been associated with increased cardiovascular risk. The effect of ezetimibe on LDL subfraction distribution has not been fully elucidated. This study assessed by gradient gel electrophoresis the effects of ezetimibe alone, simvastatin alone, and their combination on sdLDL subfraction distribution. Methods and results A single-centre, randomized, parallel three-group open-label study was performed in 72 healthy men with a baseline LDL-cholesterol (LDL-C) concentration of 111 ± 30 mg/dL (2.9 ± 0.8 mmol/L). They were treated with ezetimibe (10 mg/day, n = 24), simvastatin (40 mg/day, n = 24), or their combination (n = 24) for 14 days. Blood was drawn before and after the treatment period. Generalized estimating equations were used to assess the influence of drug therapy on LDL subfraction distribution, controlling for within-subject patterns (clustering). We adjusted for age, body mass index, and baseline concentrations of LDL-C and triglycerides. Ezetimibe alone changed LDL subfraction distribution towards a more atherogenic profile by significantly increasing sdLDL subfractions (LDL-IVA +14.2%, P = 0.0216 and LDL-IVB +16.7%, P = 0.039; fully adjusted Wald χ2 test). In contrast, simvastatin alone significantly decreased the LDL-IVB subfraction (−16.7%, P = 0.002). This effect was offset when simvastatin was combined with ezetimibe (LDL-IVB +14.3%, P = 0.44). All three treatments decreased the large, more buoyant LDL-I subfraction, the effects of ezetimibe being the most pronounced (ezetimibe -13.9%, P < 0.0001; combination therapy −7.3%, P = 0.0743; simvastatin −4.6%, P < 0.0001). Conclusion In healthy men, treatment with ezetimibe alone is associated with the development of a pro-atherogenic LDL subfraction profile. Potentially atheroprotective effects of simvastatin are offset by ezetimibe. This study is registered with ClinicalTrials.gov, identifier no. NCT0031799

Effects of Lipid-Lowering Drugs on Irisin in Human Subjects In Vivo and in Human Skeletal Muscle Cells Ex Vivo

Context and Objective The myokine irisin has been proposed to regulate energy homeostasis. Little is known about its association with metabolic parameters and especially with parameters influencing pathways of lipid metabolism. In the context of a clinical trial, an exploratory post hoc analysis has been performed in healthy subjects to determine whether simvastatin and/or ezetimibe influence serum irisin levels. The direct effects of simvastatin on irisin were also examined in primary human skeletal muscle cells (HSKMCs). Design and Participants A randomized, parallel 3-group study was performed in 72 men with mild hypercholesterolemia and without apparent cardiovascular disease. Each group of 24 subjects received a 14-day treatment with either simvastatin 40 mg, ezetimibe 10 mg, or their combination. Results: Baseline irisin concentrations were not significantly correlated with age, BMI, estimated GFR, thyroid parameters, glucose, insulin, lipoproteins, non-cholesterol sterols, adipokines, inflammation markers and various molecular markers of cholesterol metabolism. Circulating irisin increased significantly in simvastatin-treated but not in ezetimibe-treated subjects. The changes were independent of changes in LDL-cholesterol and were not correlated with changes in creatine kinase levels. In HSKMCs, simvastatin significantly increased irisin secretion as well as mRNA expression of its parent peptide hormone FNDC5. Simvastatin significantly induced cellular reactive oxygen species levels along with expression of pro- and anti-oxidative genes such as Nox2, and MnSOD and catalase, respectively. Markers of cellular stress such as atrogin-1 mRNA and Bax protein expression were also induced by simvastatin. Decreased cell viability and increased irisin secretion by simvastatin was reversed by antioxidant mito-TEMPO, implying in part that irisin is secreted as a result of increased mitochondrial oxidative stress and subsequent myocyte damage. Conclusions: Simvastatin increases irisin concentrations in vivo and in vitro. It remains to be determined whether this increase is a result of muscle damage or a protective mechanism against simvastatin-induced cellular stress. Trial Registration ClinicalTrials.gov NCT00317993 NCT00317993

A randomized controlled trial on the efficacy of carbohydrate-reduced or fat-reduced diets in patients attending a telemedically guided weight loss program

<p>Abstract</p> <p>Background</p> <p>We investigated whether macronutrient composition of energy-restricted diets influences the efficacy of a telemedically guided weight loss program.</p> <p>Methods</p> <p>Two hundred overweight subjects were randomly assigned to a conventional low-fat diet and a low-carbohydrate diet group (target carbohydrate content: >55% energy and <40% energy, respectively). Both groups attended a weekly nutrition education program and dietary counselling by telephone, and had to transfer actual body weight data to our clinic weekly with added Bluetooth^®technology by mobile phone. Various fatness and fat distribution parameters, energy and macronutrient intake, and various biochemical risk markers were measured at baseline and after 6, and 12 months.</p> <p>Results</p> <p>In both groups, energy intake decreased by 400 kcal/d compared to baseline values within the first 6 months and slightly increased again within the second 6 months. Macronutrient composition differed significantly between the groups from the beginning to month 12. At study termination, weight loss was 5.8 kg (SD: 6.1 kg) in the low-carbohydrate group and 4.3 kg (SD: 5.1 kg) in the low-fat group (p = 0.065). In the low-carbohydrate group, triglyceride and HDL-cholesterol levels were lower at month 6 and waist circumference and systolic blood pressure were lower at month 12 compared with the low-fat group (P = 0.005–0.037). Other risk markers improved to a similar extent in both groups.</p> <p>Conclusion</p> <p>Despite favourable effects of both diets on weight loss, the carbohydrate-reduced diet was more beneficial with respect to cardiovascular risk factors compared to the fat-reduced diet. Nevertheless, compliance with a weight loss program appears to be even a more important factor for success in prevention and treatment of obesity than the composition of the diet.</p> <p>Trial registration</p> <p>Clinicaltrials.gov as NCT00868387</p

Association between the Interleukin-6 Promoter Polymorphism −174G/C and Serum Lipoprotein(a) Concentrations in Humans

Background: Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease. The interleukin-6 (IL-6) receptor antagonist tocilizumab has been shown to lower serum Lp(a) concentrations. We investigated whether the IL-6 single nucleotide polymorphism 2174G/C is associated with baseline serum Lp(a) concentrations. Methodology/Principal Findings: We divided 2321 subjects from the Lipid Analytic Cologne (LIANCO) cohort into 2 groups, the ones with substantially elevated Lp(a), defined as concentrations $60 mg/dl (n = 510), and the ones with Lp(a),60 mg/ dl (n = 1811). The association with the genotypes GG (33.7%), GC (50.75%) and CC (15.55%) was investigated. The GC and the CC genotype were associated with a significantly increased odds ratio of having substantially elevated Lp(a) concentrations (OR = 1.3, 95 % CI 1.04 to 1.63, P = 0.02 and OR = 1.44, 95 % CI 1.06 to 1.93, P = 0.018). These associations remained significant after adjusting for age, sex, smoking behavior, body mass index, serum lipoproteins, hypertension and diabetes. Of these covariates, only LDL cholesterol was significantly and independently associated with elevated Lp(a) concentrations. Conclusions/Significance: The IL-6 single nucleotide polymorphism 2174G/C is associated with increased odds of having elevated Lp(a). Whether this association plays a role in the Lp(a)-lowering effects of IL-6 receptor antagonists remains to b

Evaluation of Bioelectrical Impedance Analysis for Identifying Overweight Individuals at Increased Cardiometabolic Risk:A Cross-Sectional Study

OBJECTIVE: To investigate whether bioelectrical impedance analysis could be used to identify overweight individuals at increased cardiometabolic risk, defined as the presence of metabolic syndrome and/or diabetes.DESIGN AND METHODS: Cross-sectional study of a Scottish population including 1210 women and 788 men. The diagnostic performance of thresholds of percentage body fat measured by bioelectrical impedance analysis to identify people at increased cardiometabolic risk was assessed using receiver-operating characteristic curves. Odds ratios for increased cardiometabolic risk in body mass index categories associated with values above compared to below sex-specific percentage body fat thresholds with optimal diagnostic performance were calculated using multivariable logistic regression analyses. The validity of bioelectrical impedance analysis to measure percentage body fat in this population was tested by examining agreement between bioelectrical impedance analysis and dual-energy X-ray absorptiometry in a subgroup of individuals.RESULTS: Participants were aged 16-91 years and the optimal bioelectrical impedance analysis cut-points for percentage body fat for identifying people at increased cardiometabolic risk were 25.9% for men and 37.1% for women. Stratifying by these percentage body fat cut-points, the prevalence of increased cardiometabolic risk was 48% and 38% above the threshold and 24% and 19% below these thresholds for men and women, respectively. By comparison, stratifying by percentage body fat category had little impact on identifying increased cardiometabolic risk in normal weight and obese individuals. Fully adjusted odds ratios of being at increased cardiometabolic risk among overweight people with percentage body fat ?25.9/37.1% compared with percentage body fat &lt;25.9/37.1% as a reference were 1.93 (95% confidence interval: 1.20-3.10) for men and 1.79 (1.10-2.92) for women.CONCLUSION: Percentage body fat measured using bioelectrical impedance analysis above a sex-specific threshold could be used in overweight people to identify individuals at increased cardiometabolic risk, who could benefit from risk factor management

Estimation of CT-derived abdominal visceral and subcutaneous adipose tissue depots from anthropometry in Europeans, South Asians and African Caribbeans

Background South Asians and African Caribbeans experience more cardiometabolic disease than Europeans. Risk factors include visceral (VAT) and subcutaneous abdominal (SAT) adipose tissue, which vary with ethnicity and are difficult to quantify using anthropometry. Objective We developed and cross-validated ethnicity and gender-specific equations using anthropometrics to predict VAT and SAT. Design 669 Europeans, 514 South Asians and 227 African Caribbeans (70±7 years) underwent anthropometric measurement and abdominal CT scanning. South Asian and African Caribbean participants were first-generation migrants living in London. Prediction equations were derived for CT-measured VAT and SAT using stepwise regression, then cross-validated by comparing actual and predicted means. Results South Asians had more and African Caribbeans less VAT than Europeans. For basic VAT prediction equations (age and waist circumference), model fit was better in men (R2 range 0.59-0.71) than women (range 0.35-0.59). Expanded equations (+ weight, height, hip and thigh circumference) improved fit for South Asian and African Caribbean women (R2 0.35 to 0.55, and 0.43 to 0.56 respectively). For basic SAT equations, R2 was 0.69-0.77, and for expanded equations it was 0.72-0.86. Cross-validation showed differences between actual and estimated VAT of <7%, and SAT of <8% in all groups, apart from VAT in South Asian women which disagreed by 16%. Conclusion We provide ethnicity- and gender-specific VAT and SAT prediction equations, derived from a large tri-ethnic sample. Model fit was reasonable for SAT and VAT in men, while basic VAT models should be used cautiously in South Asian and African Caribbean women. These equations will aid studies of mechanisms of cardiometabolic disease in later life, where imaging data are not available

Lipoprotein(a): Current Perspectives

Recent data from genetic and epidemiological studies strongly support a causal relationship between elevated lipoprotein(a) [Lp(a)] concentrations and the development of atherosclerosis and cardiovascular disease. This relationship is continuous, without an Lp(a) threshold, and it is independent of low density lipoprotein and high density lipoprotein cholesterol (LDL-C and HDL-C, respectively) levels. Although the mechanism(s) through which Lp(a) promotes atherosclerosis are not clearly understood, proposed mechanisms include an increased Lp(a)-associated cholesterol entrapment in the arterial intima, inflammatory cell recruitment, carrying of proinflammatory oxidized phospholipids, impairing fibrinolysis by inhibition of plasminogen activation and enhancing coagulation by inhibition of the tissue factor pathway inhibitor. Phenotypically there are two forms, isolated hyperlipoproteinemia(a) in the presence of normal LDL-C, and combined elevations of Lp(a) and LDL-C. There are no drugs or other therapeutic options available that selectively decrease Lp(a). Those that can lower Lp(a) levels only have a moderate effect and their actions include decreasing LDL-C levels. The strongest effects are seen with niacin at high doses. Nevertheless, there is no convincing evidence that decreasing isolated elevations of Lp(a) offers cardiovascular benefit. This review considers the evidence supporting the association between Lp(a) and atherosclerotic disease, discusses the potential mechanisms involved in the pro-atherosclerotic potential of Lp(a), and evaluates the therapeutic options that decrease elevated Lp(a) levels

Current Options for the Pharmacotherapy of Obesity

650 millions of adults are obese worldwide - in the US alone, forty percent of the adults are obese. Although the obesity pandemic is constantly expanding at very high costs for health care systems, the currently available options of pharmacotherapy for obesity are rather limited. Despite intensive research efforts, the vast majority of the anti-obesity drugs developed up to now have a rather limited efficacy and/or safety profile. In the last filly years, various drugs reached advanced states of clinical development but were either never marketed or were initially approved but withdrawn later due to safety issues. However, the understanding of the pathophysiology of obesity has been steadily improving and new, promising drugs targeting various selective obesity-associated and energy-homeostasis-related pathways are now available. When lifestyle changes alone fail to combat, then additional pharmacotherapy with an acceptable efficacy and safety profile could provide a useful therapeutic option

Vitamin D and Vascular Disease

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Vitamin D deficiency has been identified as a potential risk factor for a number of diseases unrelated to the classical skeletal pathophysiology, such as cancer and CVD, but the effects of vitamin D supplementation are less clear. Purpose of this narrative review is to discuss the evidence suggesting an association between vitamin D status and CVD as well as the results of supplementation studies. Vitamin D deficiency has been associated with CVD risk factors such as hypertension, dyslipidemia and diabetes mellitus as well as with cardiovascular events such as myocardial infarction, stroke and heart failure. While vitamin D deficiency might contribute to the development of CVD through its association with risk factors, direct effects of vitamin D on the cardiovascular system may also be involved. Vitamin D receptors are expressed in a variety of tissues, including cardiomyocytes, vascular smooth muscle cells and endothelial cells. Moreover, vitamin D has been shown to affect inflammation, cell proliferation and differentiation. While observational studies support an association between low plasma vitamin D levels and increased risk of CVD, Mendelian randomization studies do not support a causal association between the two. At present, high quality randomized trials do not find evidence of significant effects on CVD endpoints and do not support supplementation of vitamin D to decrease CVD events