Vladimír Soška

Effect of valsartan on the incidence of diabetes and cardiovascular events

BACKGROUND It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance. METHODS In this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization. RESULTS The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P=0.85). CONCLUSIONS Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)

Effect of nateglinide on the incidence of diabetes and cardiovascular events

BACKGROUND The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown. METHODS In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization. RESULTS After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16). Nateglinide did, however, increase the risk of hypoglycemia. CONCLUSIONS Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)

Role of diuretics, β blockers, and statins in increasing the risk of diabetes in patients with impaired glucose tolerance: reanalysis of data from the NAVIGATOR study.

Objective To examine the degree to which use of β blockers, statins, and diuretics in patients with impaired glucose tolerance and other cardiovascular risk factors is associated with new onset diabetes. Design Reanalysis of data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. Setting NAVIGATOR trial. Participants Patients who at baseline (enrolment) were treatment naïve to β blockers (n=5640), diuretics (n=6346), statins (n=6146), and calcium channel blockers (n=6294). Use of calcium channel blocker was used as a metabolically neutral control. Main outcome measures Development of new onset diabetes diagnosed by standard plasma glucose level in all participants and confirmed with glucose tolerance testing within 12 weeks after the increased glucose value was recorded. The relation between each treatment and new onset diabetes was evaluated using marginal structural models for causal inference, to account for time dependent confounding in treatment assignment. Results During the median five years of follow-up, β blockers were started in 915 (16.2%) patients, diuretics in 1316 (20.7%), statins in 1353 (22.0%), and calcium channel blockers in 1171 (18.6%). After adjusting for baseline characteristics and time varying confounders, diuretics and statins were both associated with an increased risk of new onset diabetes (hazard ratio 1.23, 95% confidence interval 1.06 to 1.44, and 1.32, 1.14 to 1.48, respectively), whereas β blockers and calcium channel blockers were not associated with new onset diabetes (1.10, 0.92 to 1.31, and 0.95, 0.79 to 1.13, respectively). Conclusions Among people with impaired glucose tolerance and other cardiovascular risk factors and with serial glucose measurements, diuretics and statins were associated with an increased risk of new onset diabetes, whereas the effect of β blockers was non-significant. Trial registration ClinicalTrials.gov NCT00097786.

The role of exercise echocardiography in the diagnostics of heart failure with normal left ventricular ejection fraction

AIMS Few data are available on the exercise-induced abnormalities of myocardial function in patients with exertional dyspnoea and normal left ventricular ejection fraction (LV EF). The main aims of this study were to determine the prevalence of isolated exercise-induced heart failure with normal ejection fraction (HFNEF) and to assess whether disturbances in LV or right ventricular longitudinal systolic function are associated with the diagnosis of HFNEF. METHODS AND RESULTS Eighty-four patients with exertional dyspnoea and normal LV EF and 14 healthy controls underwent spirometry, NT-proBNP plasma analysis, and exercise echocardiography. Doppler LV inflow and tissue mitral and tricuspid annular velocities were analysed at rest and immediately after the termination of exercise. Of the 30 patients with the evidence of HFNEF, 6 (20%) patients had only isolated exercise-induced HFNEF. When compared with the remaining patients, those with HFNEF had a significantly lower resting and exercise peak mitral annular systolic velocity (Sa) and the mitral annular velocity during atrial contraction, lower exercise peak mitral annular velocity at early diastole, and lower exercise peak systolic velocity of tricuspid annular motion. The multivariate logistic regression analysis including both parameters standardly defining HFNEF and the new Doppler variables potentially associated with the diagnosis of HFNEF revealed that NT-proBNP, LV mass index, left atrial volume index, and Sa significantly and independently predict the diagnosis of HFNEF. CONCLUSION A significant proportion of patients require exercise to diagnose HFNEF. Sa appears to be a significant independent predictor of HFNEF, which may increase the diagnostic value of models utilizing the variables recommended by the European Society of Cardiology guidelines.

Threshold for diagnosing hypertension by automated office blood pressure using random sample population data.

Objective: Manual office blood pressure (BP) is still recommended for diagnosing hypertension. However, its predictive value is decreased by errors in measurement technique and the white-coat effect. The errors can be eliminated by automated office BP (AOBP) measurement taking multiple readings with the participant resting quietly alone. Therefore, use of AOBP in clinical practice requires a threshold value for hypertension diagnosis. The aim of the present study was to determine an AOBP threshold corresponding to the 140/90 mmHg manual office BP using data from a large random population sample. Methods: In 2145 participants (mean age 47.3 ± 11.3 years) randomly selected from a Brno population aged 25–64 years, BP was measured using manual mercury and automated office sphygmomanometers. Results: Manual SBP (mean difference 6.39 ± 9.76 mmHg) and DBP (mean difference 2.50 ± 6.54 mmHg) were higher than the automated BP. According to polynomial regression, automated systole of 131.06 (95% confidence interval 130.43–131.70) and diastole of 85.43 (95% confidence interval 85.03–85.82) corresponded to the manual BP of 140/90 mmHg. Using this cut-off, the white-coat hypertension was present in 24% of participants with elevated manual BP, whereas 10% had masked hypertension and 11% masked uncontrolled hypertension. In individuals with masked uncontrolled hypertension, only AOBP was associated with the urinary albumin–creatinine ratio, whereas there was no association with manual BP. Conclusion: AOBP of 131/85 mmHg corresponds to the manual BP of 140/90 mmHg. This value may be used as a threshold for diagnosing hypertension using AOBP. However, outcome-driven studies are required to confirm this threshold.

Genomic characterization of large rearrangements of the LDLR gene in Czech patients with familial hypercholesterolemia

BackgroundMutations in the LDLR gene are the most frequent cause of Familial hypercholesterolemia, an autosomal dominant disease characterised by elevated concentrations of LDL in blood plasma. In many populations, large genomic rearrangements account for approximately 10% of mutations in the LDLR gene.MethodsDNA diagnostics of large genomic rearrangements was based on Multiple Ligation dependent Probe Amplification (MLPA). Subsequent analyses of deletion and duplication breakpoints were performed using long-range PCR, PCR, and DNA sequencing.ResultsIn set of 1441 unrelated FH patients, large genomic rearrangements were found in 37 probands. Eight different types of rearrangements were detected, from them 6 types were novel, not described so far. In all rearrangements, we characterized their exact extent and breakpoint sequences.ConclusionsSequence analysis of deletion and duplication breakpoints indicates that intrachromatid non-allelic homologous recombination (NAHR) between Alu elements is involved in 6 events, while a non-homologous end joining (NHEJ) is implicated in 2 rearrangements. Our study thus describes for the first time NHEJ as a mechanism involved in genomic rearrangements in the LDLR gene.

Comparison of the Efficacy and Tolerability of fluvastatin extended-release and immediate-release formulations in the treatment of primary hypercholesterolemia: a randomized trial

BACKGROUND A new extended-release (ER) formulation of fluvastatin 80 mg has been developed for once-daily treatment of primary hypercholesterolemia. OBJECTIVE The purpose of this study was to compare the lipid-lowering efficacy and tolerability of fluvastatin ER (80 mg once daily) versus fluvastatin immediate-release (IR) (40 mg once or twice daily). METHODS Following a 4-week placebo/dietary run-in period, patients with primary hypercholesterolemia type IIa or IIb (low-density lipoprotein cholesterol ILDL-C] > or = 160 mg/dL and triglycerides [TG] < or = 400 mg/dL) were randomized (2:1:1) to receive fluvastatin ER 80 mg once daily at bedtime (QPM), fluvastatin IR 40 mg QPM, or fluvastatin IR 40 mg BID for 24 weeks. Patients who had homozygous familial hypercholesterolemia; type I, III, IV, V, or secondary hyperlipoproteinemia; diabetes; or evidence of liver or renal impairment were excluded. At weeks 0, 2, 4, 8, 12, 16, 20, and 24 of the active-treatment period, levels of LDL-C, high-density lipoprotein cholesterol (HDL-C), TG, and total cholesterol (TC) were measured. RESULTS Of the 1183 patients enrolled, 695 were randomly assigned to treatment--346 to fluvastatin ER 80 mg QPM, 174 to fluvastatin IR 40 mg QPM, and 175 to fluvastatin IR 40 mg BID. Patients were well matched between groups, with a mean age of approximately 56 years and body mass index of 27 kg/m2; 56.0% of patients (389/695) were female and 97.7% (679/695) were white. Fluvastatin ER 80 mg QPM lowered LDL-C levels significantly more than did fluvastatin IR 40 mg QPM (33.7% vs 24.4%; P < 0.001) and as effectively as fluvastatin IR 40 mg BID (33.9%). More than half of the patients administered fluvastatin ER 80 mg QPM and IR 40 mg BID achieved reductions in LDL-C levels of > or = 35%; more than half of those administered fluvastatin IR 40 mg QPM experienced reductions in LDL-C levels of > or = 25%. The mean reductions in LDL:HDL ratio, TC, and apolipoprotein B levels in the fluvastatin ER 80 mg QPM group were significantly greater than the reductions in the IR 40 mg QPM group (P < 0.001). In patients with mixed dyslipidemia, fluvastatin ER 80 mg reduced triglycerides by 21.8% (median 28%) and increased HDL-C by 14.5%. Fluvastatin ER 80 mg QPM was well tolerated, with incidences of clinically notable elevations in alanine aminotransferase, aspartate aminotransferase, and creatine kinase levels and musculoskeletal adverse events comparable to those in the IR 40 mg QPM group. CONCLUSION The ER 80-mg formulation of fluvastatin is effective and well tolerated as a once-daily starting and maintenance treatment for primary hypercholesterolemia.

Depression as a prominent cause of sexual dysfunction in women with epilepsy

The etiology of sexual dysfunction in patients with epilepsy is perceived as multifactorial, with seizure and medication effects being the most often discussed and analyzed factors. We used common statistical methods to evaluate the impact of type of epilepsy, antiepileptic medication, hormones, seizure control, and symptoms of depression and anxiety on sexual function in a group of 78 women with epilepsy. To assess sexual function, we used the Female Sexual Function Index (FSFI). To assess symptoms of depression and anxiety, we used the Beck Depression and Anxiety Inventories (BDI, BAI). Of all the observed factors, only BDI score was significantly correlated with FSFI score. There was no correlation between FSFI, hormonal levels, seizure frequency, and symptoms of anxiety. No differences were found between patients with focal and those with generalized epilepsies; between seizure-free and non-seizure-free patients; or in relation to the number and type of antiepileptic medications.

Increased Cardio-ankle Vascular Index in Hyperlipidemic Patients without Diabetes or Hypertension

AIM The cardio-ankle vascular index (CAVI) is a sensitive non-invasive marker of arterial stiffness and atherosclerosis. The aim of this work was to compare the CAVI values in patients with dyslipidemia (without diabetes mellitus and hypertension) and healthy controls. METHODS A Total 248 subjects with dyslipidemia (104 men, 144 women), 55.0 (95% CI 30-70) years of age with combined hyperlipidemia or primary hypercholesterolemia and 537 healthy controls (244 men, 293 women) 40.0 (95% CI 26-62) years of age were included in this study. Fasting blood samples were collected to measure the serum total cholesterol, triglyceride, HDL-cholesterol and apolipoprotein A1 and B levels. The LDL cholesterol level was also calculated, and the CAVI was measured using the VaSera(®) 1500 system. RESULTS The CAVI values were significantly higher in the dyslipidemic patients (8.08, 95% CI 6.00-10.05) than in the controls (7.11, 95% CI 5.77-9.05; p < 0.01). In addition, the CAVI values were elevated in both subgroups of patients with hypercholesterolemia (7.95, 95% CI 5.85-6.90; p < 0.01) and combined hyperlipidemia (8.30, 95% CI 6.60-10.15; p < 0.01) in comparison with those observed in the controls. After adopting the propensity score method in order to balance the confounding factors (age, gender, body mass index) and adjust the analysis for diastolic blood pressure, the CAVI values in the dyslipidemic patients remained significantly high (7.78, 95% CI 5.80-9.69) compared to that observed in the controls (7.31, 95% CI 5.44-9.35; p < 0.001). However, the CAVI values did not differ significantly between the controls and both subgroups of dyslipidemic patients(primary hypercholesterolemia, combined hyperlipidemia). CONCLUSIONS The present findings demonstrated that dyslipidemia increases the CAVI values in comparison to that seen in healthy subjects.

The logarithm of the triglyceride/HDL-cholesterol ratio is related to the history of cardiovascular disease in patients with familial hypercholesterolemia.

OBJECTIVES The aim of this study was to determine whether the atherogenic index of plasma (AIP=log[triglycerides/HDL-cholesterol]) differs in heterozygous familial hypercholesterolemia (FH) patients with and without a history of cardiovascular disease (CVD). DESIGN AND METHODS A total of 555 FH patients with known mutations in the LDL receptor or the apolipoprotein B gene, of whom 53 had a history of CVD (CVD+ group), were retrospectively analyzed. RESULTS Compared to patients without CVD (CVD- group), CVD+ patients showed significantly higher fasting LDL-cholesterol, triglycerides and AIP as well as lower HDL-cholesterol. After both adjustment for age and diabetes and using analysis based on age and sex matched groups, only the increase in triglycerides and AIP in the CVD+ vs. the CVD- group remained significant. CONCLUSION The results of the present study indicate that AIP, which reflects the presence of atherogenic small LDL and small HDL particles, may be connected to the risk of CVD in FH patients.