Diabetes associated residual atherosclerotic cardiovascular risk in statin-treated patients with prior atherosclerotic cardiovascular disease.

AIM: In statin-treated persons with atherosclerotic cardiovascular disease (ASCVD) the further ASCVD risk that diabetes mellitus (DM) adds is not well-quantified. We examined this residual risk for initial and total recurrent ASCVD events. METHODS: We studied 3271 patients with ASCVD on statin therapy in the AIM-HIGH clinical trial cohort. Cox regression and the Prentice, Williams, and Peterson model examined the excess risk of initial and total recurrent ASCVD events associated with DM over a 3- year mean follow-up. Predictors of first and total ASCVD events in those with and without DM were also examined. RESULTS: Of our cohort with ASCVD on statin therapy 40% also had DM. Those with vs. without DM were older, were less likely to be male or white. They had higher systolic blood pressure, lower HDL-C, LDL-C, lipoprotein (a), but higher triglycerides and BMI (all p < 0.01). Adjusted HRs were 1.21 (95% CI; 1.01-1.46, p = 0.038) and 1.23 (95% CI: 1.05-1.44, p = 0.012) for first and total recurrent ASCVD events, respectively. Homocysteine and lipoprotein(a) most strongly predicted events in those with and without DM, respectively. CONCLUSION: In statin-treated patients with ASCVD, DM was associated with significantly greater residual risk over ASCVD alone for both first and total recurrent ASCVD events.

Five-Year Residual Atherosclerotic Cardiovascular Disease Risk Prediction Model for Statin Treated Patients With Known Cardiovascular Disease.

Despite statin therapy, many patients with atherosclerotic cardiovascular disease (ASCVD) still suffer from ASCVD events. Predictors of residual ASCVD risk are not well-delineated. We aimed to develop an ASCVD risk prediction model for patients with previous ASCVD on statin use. We utilized statin-treated patients with ASCVD from the AIM-HIGH trial cohort. A 5-year risk score for subsequent ASCVD events with known ASCVD was developed using Cox regression, including potential risk factors with age, sex, and race forced in the model. Internal discrimination and calibration were evaluated. We included 3,271 patients with ASCVD (85.4% male, mean age 63.6 years, 65% on moderate- and 24% on high-intensity statin) with complete risk factor data and mean follow-up of 4.18 years. Overall, the estimated 5-year ASCVD risk was 21.1%: 10.2% of patients had a 5-year risk of >30%, and 38.8% had risk of between 20% and 30%. In the model, male sex, hemoglobin A1c, alcohol use (inversely), family history of cardiovascular disease, homocysteine, history of carotid artery disease, and lipoprotein(a) best predicted residual ASCVD risk. Niacin treatment status did not enter the model. A C-statistic of 0.59 was obtained, with the Greenwood-Nam-D'Agostino test showing excellent calibration. We developed a risk prediction risk model for predicting 5-year residual ASCVD risk in statin-treated patients with known ASCVD that may help in identifying such persons at the highest risk of recurrent events. Validation in larger samples with patients on high-intensity statin is needed.

Lipoprotein(a) Particle Production as a Determinant of Plasma Lipoprotein(a) Concentration Across Varying Apolipoprotein(a) Isoform Sizes and Background Cholesterol-Lowering Therapy.

Background Elevated lipoprotein(a) (Lp(a)), a low-density lipoprotein-like particle bound to the polymorphic apolipoprotein(a) (apo(a)), may be causal for cardiovascular disease. However, the metabolism of Lp(a) in humans is poorly understood. Methods and Results We investigated the kinetics of Lp(a)-apo(a) and low-density lipoprotein-apoB-100 in 63 normolipidemic men. The fractional catabolic rate ( FCR ) and production rate PR ) were studied. Plasma apo(a) concentration was significantly and inversely associated with apo(a) isoform size ( r=-0.536, P<0.001) and apo(a) FCR ( r=-0.363, P<0.01), and positively with apo(a) PR ( r=0.877, P<0.001). There were no significant associations between the FCR s of apo(a) and low-density lipoprotein-apoB-100. Subjects with smaller apo(a) isoform sizes (≤22 kringle IV repeats) had significantly higher apo(a) PR ( P<0.05) and lower apo(a) FCR ( P<0.01) than those with larger sizes. Plasma apo(a) concentration was significantly associated with apo(a) PR ( r=0.930, P<0.001), but not with FCR ( r=-0.012, P>0.05) in subjects with smaller apo(a) isoform size. In contrast, both apo(a) PR and FCR were significantly associated with plasma apo(a) concentrations ( r=0.744 and -0.389, respectively, P<0.05) in subjects with larger isoforms. In multiple regression analysis, apo(a) PR and apo(a) isoform size were significant predictors of plasma apo(a) concentration independent of low-density lipoprotein-apoB-100 FCR and background therapy with atorvastatin and evolocumab. Conclusions In normolipidemic men, the plasma Lp(a) concentration is predominantly determined by the rate of production of Lp(a) particles, irrespective of apo(a) isoform size and background therapy with a statin and a proprotein convertase subtilisin-kexin type 9 inhibitor. Our findings underscore the importance of therapeutic targeting of the hepatic synthesis and secretion of Lp(a) particles. Lp(a) particle catabolism may only play a modest role in determining Lp(a) concentration in subjects with larger apo(a) isoform size. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 02189837.

Effects of Evolocumab on the ApoA1 Remnant Ratio: A Pooled Analysis of Phase 3 Studies.

INTRODUCTION: The apolipoprotein A1 (apoA1) remnant ratio has been identified as an independent cardiovascular (CV) risk factor. Higher apoA1 remnant ratios may predict lower CV risk in some patients. This analysis aimed to evaluate the effects of evolocumab on the change from baseline in the apoA1 remnant ratio compared with placebo. METHODS: This pooled post hoc analysis included 2464 patients with mixed dyslipidemia treated with evolocumab 140 mg every 2 weeks (Q2W) or 420 mg once monthly (QM) in three phase 3 evolocumab trials. The apoA1 remnant ratio was calculated by dividing apoA1 by the difference between non-high-density lipoprotein cholesterol (non-HDL-C) and low-density lipoprotein cholesterol (LDL-C). ApoA1 remnant ratio strata were generated using previously published tertile (< 4.7, 4.7-6.8, and > 6.8) and partitioning categories (< 3.6, 3.6-6.0, and > 6.0). RESULTS: The baseline apoA1 remnant ratio in evolocumab and placebo treatment arms was 7.1 and 7.3, respectively. At week 12, evolocumab 140 mg Q2W and 420 mg QM increased the apoA1 remnant ratio by 25.0% and 33.6%, respectively, versus placebo (p < 0.0001 for both groups). When patients were categorized by week 12 apoA1 remnant ratio thresholds (< 3.6 vs. > 3.6, and < 4.7 vs. > 4.7), those with higher week 12 apoA1 remnant ratios were significantly more likely to have also achieved a target non-HDL-C level of < 100 mg/dl. In the subset of women > 50 years of age, the proportion of patients at apoA1 remnant ratio thresholds < 3.6, 3.6-6.0, and > 6.0 at baseline shifted toward or remained at higher thresholds at week 12. CONCLUSIONS: This post hoc analysis suggests that evolocumab increases the apoA1 remnant ratio. FUNDING: Amgen Inc. Plain language summary available for this article.

Trends in Statin Use Among US Adults With Chronic Kidney Disease, 1999-2014.

Background The 2013 American College of Cardiology/American Heart Association cholesterol guidelines recognize cardiovascular disease and diabetes mellitus but not chronic kidney disease ( CKD ) as high-risk conditions warranting statin therapy. Statin use may be lower for adults with CKD compared with adults with conditions that have guideline indications for statin use. Methods and Results We analyzed data from the National Health and Nutrition Examination Surveys from 1999-2002 through 2011-2014 to determine trends in the percentage of US adults ≥20 years of age with and without CKD taking statins. CKD was defined by an estimated glomerular filtration rate <60 mL/min per 1.73m2 or albumin-to-creatinine ratio ≥30 mg/g. Statin use was identified through a medication inventory. Between 1999-2002 and 2011-2014, the percentage of adults taking statins increased from 17.6% to 35.7% among those with CKD and from 6.8% to 14.7% among those without CKD . After multivariable adjustment, adults with CKD were not more likely to be taking statins compared with those without CKD (prevalence ratio, 1.01; 95% CI] 0.96-1.08). Among adults without a history of cardiovascular disease, those with CKD but not diabetes mellitus were less likely to be taking statins compared with those with diabetes mellitus but not CKD (prevalence ratio, 0.54; 95% CI , 0.44-0.66). Among adults with a history of cardiovascular disease, there was no difference in statin use between those with CKD but not diabetes mellitus versus those with diabetes mellitus but not CKD (prevalence ratio, 0.95; 95% CI , 0.79-1.15). Conclusions CKD does not appear to be a major stimulus for statin use among US adults.

Long-term safety, tolerability, and efficacy of evolocumab in patients with heterozygous familial hypercholesterolemia.

BACKGROUND: Evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9, is safe and effective when dosed biweekly (Q2W) or monthly (QM) in patients with heterozygous familial hypercholesterolemia (HeFH) as demonstrated in two 12-week trials: Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD; phase 2) and RUTHERFORD-2 (phase 3). OBJECTIVE: The objective of the study was to evaluate long-term efficacy, safety, and tolerability of evolocumab during open-label extension trials. METHODS: Patients completing parent trials were re-randomized 2:1 to evolocumab plus standard of care (SOC) or SOC alone for 52 weeks (Open-Label Study of Long-term Evaluation Against LDL-C [OSLER-1]) or 48 weeks (OSLER-2). Evolocumab dosing was 420 mg QM (OSLER-1) and 140 mg Q2W or 420 mg QM (OSLER-2). A pooled analysis of OSLER data was performed from this subset of HeFH patients. RESULTS: Four hundred forty HeFH patients from RUTHERFORD (n = 147) and RUTHERFORD-2 (n = 293) (mean [standard deviation] age 51 [12] years, 58% male, 90% White) were randomized to evolocumab plus SOC (n = 289) or SOC (n = 151). The 48-week period was completed by 425 patients (96.6%). Eight patients discontinued evolocumab plus SOC (2.8%) and 7 discontinued SOC (4.6%). Compared to parent study baseline, patients receiving evolocumab plus SOC experienced a mean 53.6% reduction in low-density lipoprotein cholesterol after 48 weeks. No patient experienced an adverse event leading to permanent evolocumab discontinuation during the 1-year SOC-controlled period. Serious adverse event rates were similar between groups (evolocumab plus SOC, 7.3%; SOC, 8.6%). CONCLUSION: Continued use of evolocumab added to SOC in patients with HeFH yields persistent and marked low-density lipoprotein cholesterol reductions during 48 weeks of follow-up. Long-term dosing of evolocumab with SOC was safe and well tolerated.

Longitudinal Assessment of the Effect of Atrasentan on Thoracic Bioimpedance in Diabetic Nephropathy: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Fluid retention is a common adverse event in patients who receive endothelin (ET) receptor antagonist therapy, including the highly selective ETA receptor antagonist, atrasentan. OBJECTIVE: We performed longitudinal assessments of thoracic bioimpedance in patients with type 2 diabetes mellitus and nephropathy to determine whether a decrease in bioimpedance accurately reflected fluid retention during treatment with atrasentan. STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled study in 48 patients with type 2 diabetes mellitus and nephropathy who were receiving stable doses of renin angiotensin system inhibitors and diuretics. METHODS: Patients were randomized 1:1:1 to placebo, atrasentan 0.5 mg, or atrasentan 1.25 mg once daily for 8 weeks. Thoracic bioimpedance, vital signs, clinical exams, and serologies were taken at weeks 1, 2, 4, 6, and 8, with the exception of serum hemoglobin, which was not taken at week 1, and serum brain natriuretic peptide, which was only taken at baseline, week 4, and week 8. RESULTS: Alterations in bioimpedance were more often present in those who received atrasentan than in those who received placebo, though overall differences were not statistically significant. Transient declines in thoracic bioimpedance during the first 2 weeks of atrasentan exposure occurred before or during peak increases in body weight and hemodilution (decreased serum hemoglobin). CONCLUSIONS: We conclude that thoracic bioimpedance did not reflect changes in weight gain or edema with atrasentan treatment in this study. However, the sample size was small, and it may be of interest to explore the use of thoracic bioimpedance in a larger population to understand its potential clinical use in monitoring fluid retention in patients with chronic kidney disease who receive ET receptor antagonists.

Comparison of exposure response relationship of atrasentan between North American and Asian populations.

AIMS: The selective endothelin (ET) A receptor antagonist atrasentan has been shown to lower albuminuria in North American and Asian patients with type 2 diabetes and nephropathy. As drug responses to many drugs may differ between North American and Asian populations, we assessed the influence of geographical region on the albuminuria and fluid retention response to atrasentan. MATERIALS AND METHODS: Two 12-week double-blind randomised controlled trials were performed with atrasentan 0.75 or 1.25 mg/d vs placebo in patients with type 2 diabetes and nephropathy. The efficacy endpoint was the percentage change in albuminuria. Bodyweight change, a proxy of fluid retention, was used as a safety endpoint. Pharmacodynamics were determined in Asians (N = 77) and North Americans (N = 134). Atrasentan plasma concentration was measured in 161 atrasentan-treated patients. RESULTS: Mean albuminuria reduction in Asian, compared to North American, patients was, respectively, -34.4% vs -26.3% for 0.75 mg/d ( P = .44) and -48.0% vs -28.9% for 1.25 mg/d ( P = .035). Bodyweight gain did not differ between North American and Asian populations. Atrasentan plasma concentrations were higher in Asians compared to North Americans and correlated with albuminuria response (7.2% albuminuria reduction per doubling atrasentan concentration; P = .024). Body surface area (ß = -1.09 per m2 ; P < .001) and bilirubin, as a marker of hepatic organic anion transporter activity, (ß = 0.69 per mg/dL increment; P = .010) were independent determinants of atrasentan plasma concentration; correction by body surface area and bilirubin left no significant difference in plasma concentration between Asian and North American populations. CONCLUSION: The higher exposure and albuminuria reduction of atrasentan in Asian patients is not associated with more fluid retention, suggesting that Asian patients are less sensitive to atrasentan-induced sodium retention.

The effects of atrasentan on urinary metabolites in patients with type 2 diabetes and nephropathy.

We assessed the effect of atrasentan therapy on a pre-specified panel of 13 urinary metabolites known to reflect mitochondrial function in patients with diabetic kidney disease. This post-hoc analysis was performed using urine samples collected during the RADAR study which was a randomized, double-blind, placebo-controlled trial that tested the effects of atrasentan on albuminuria reduction in patients with type 2 diabetes and nephropathy. At baseline, 4 of the 13 metabolites, quantified by gas-chromatography mass spectrometry, were below detectable levels, and 6 were reduced in patients with eGFR < 60 mL/min/1.73 m2 . After 12 weeks of atrasentan treatment in patients with eGFR < 60 mL/min/1.73 m2 , a single-value index of the metabolites changed by -0.31 (95%CI -0.60 to -0.02; P = .035), -0.08 (-12 to 0.29; P = .43) and 0.01 (-0.21 to 0.19; P = .913) in placebo, atrasentan 0.75 and 1.25 mg/d, respectively. The metabolite index difference compared to placebo was 0.13 (-0.17 to 0.43; P = .40) and 0.35 (0.05-0.65; P = .02) for atrasentan 0.75 and 1.25 mg/d, respectively. These data corroborate previous findings of mitochondrial dysfunction in patients with type 2 diabetes, nephropathy and eGFR < 60 mL/min/1.73 m2 , suggesting that atrasentan may prevent the progression of mitochondrial dysfunction common to this specific patient population. Future studies of longer treatment duration with atrasentan are indicated.

Doubling of serum creatinine and the risk of cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes mellitus: a cohort study.

BACKGROUND: Doubling of serum creatinine is often used as a marker for worsening kidney function in nephrology trials. Most people with chronic kidney disease die of other causes before reaching end-stage renal disease. We were interested in the association between doubling of serum creatinine and the risk of a first-time diagnosis of angina pectoris, congestive heart failure (CHF), myocardial infarction (MI), stroke, or transient ischemic attack in patients with chronic kidney disease and with diagnosed type 2 diabetes mellitus. METHODS: We identified all adult patients registered in the "Clinical Practice Research Datalink" between 2002 and 2011 with incident chronic kidney disease and type 2 diabetes mellitus and did a cohort study with a Cox proportional hazard analysis. RESULTS: We identified in total 27,811 patients, 693 developed angina pectoris, 1,069 CHF, 508 MI, 970 stroke, and 578 transient ischemic attacks. Patients whose serum creatinine doubled during follow-up had increased risks of CHF (hazard ratio [HR] 2.98, 95% confidence interval [CI] 2.27-3.89), MI (HR 2.53, 95% CI 1.62-3.96), and stroke (HR 1.93, 95% CI 1.38-2.69), as compared with patients whose serum creatinine did not double. The relative risks of angina pectoris (HR 1.18, 95% CI 0.66-2.10) or a transient ischemic attack (HR 1.32, 95% CI 0.78-2.22) were similar in both groups. CONCLUSION: Diabetic patients with a doubling of serum creatinine were at an increased risk of CHF, MI, or stroke, compared with diabetic patients whose serum creatinine did not double during follow-up.

Prediction of the effect of atrasentan on renal and heart failure outcomes based on short-term changes in multiple risk markers.

BACKGROUND: A recent phase II clinical trial (Reducing Residual Albuminuria in Subjects with Diabetes and Nephropathy with AtRasentan trial and an identical trial in Japan (RADAR/JAPAN)) showed that the endothelin A receptor antagonist atrasentan lowers albuminuria, blood pressure, cholesterol, hemoglobin, and increases body weight in patients with type 2 diabetes and nephropathy. We previously developed an algorithm, the Parameter Response Efficacy (PRE) score, which translates short-term drug effects into predictions of long-term effects on clinical outcomes. DESIGN: We used the PRE score on data from the RADAR/JAPAN study to predict the effect of atrasentan on renal and heart failure outcomes. METHODS: We performed a post-hoc analysis of the RADAR/JAPAN randomized clinical trials in which 211 patients with type-2 diabetes and nephropathy were randomly assigned to atrasentan 0.75 mg/day, 1.25 mg/day, or placebo. A PRE score was developed in a background set of completed clinical trials using multivariate Cox models. The score was applied to baseline and week-12 risk marker levels of RADAR/JAPAN participants, to predict atrasentan effects on clinical outcomes. Outcomes were defined as doubling serum creatinine or end-stage renal disease and hospitalization for heart failure. RESULTS: The PRE score predicted renal risk changes of -23% and -30% for atrasentan 0.75 and 1.25 mg/day, respectively. PRE scores also predicted a small non-significant increase in heart failure risk for atrasentan 0.75 and 1.25 mg/day (+2% vs. +7%). Selecting patients with >30% albuminuria reduction from baseline (responders) improved renal outcome to almost 50% risk reduction, whereas non-responders showed no renal benefit. CONCLUSIONS: Based on the RADAR/JAPAN study, with short-term changes in risk markers, atrasentan is expected to decrease renal risk without increased risk of heart failure. Within this population albuminuria responders appear to contribute to the predicted improvements, whereas non-responders showed no benefit. The ongoing hard outcome trial (SONAR) in type 2 diabetic patients with >30% albuminuria reduction to atrasentan will allow us to assess the validity of these predictions.

Predictors of Atrasentan-Associated Fluid Retention and Change in Albuminuria in Patients with Diabetic Nephropathy.

BACKGROUND AND OBJECTIVES: Endothelin A receptor antagonists (ERAs) decrease residual albuminuria in patients with diabetic kidney disease; however, their clinical utility may be limited by fluid retention. Consequently, the primary objective of this study was to identify predictors for ERA-induced fluid retention among patients with type 2 diabetes and CKD. A secondary objective was to determine if the degree of fluid retention necessarily correlated with the magnitude of albuminuria reduction in those patients receiving ERAs. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A post hoc analysis was conducted of the phase IIb atrasentan trials assessing albuminuria reduction in 211 patients with type 2 diabetes, urine albumin/creatinine ratios of 300-3500 mg/g, and eGFRs of 30-75 ml/min per 1.73 m(2) who were randomly assigned to receive placebo (n=50) or atrasentan 0.75 mg/d (n=78) or 1.25 mg/d (n=83) for 12 weeks. Changes in body weight and hemoglobin (Hb) after 2 weeks of treatment were used as surrogate markers of fluid retention. RESULTS: Baseline predictors of weight gain after 2 weeks of atrasentan treatment were higher atrasentan dose, lower eGFR, higher glycated hemoglobin, higher systolic BP, and lower homeostatic metabolic assessment product. Higher atrasentan dose and lower eGFR also predicted decreases in Hb. There were no changes in B-type natriuretic peptide. There was no correlation between reduction in albuminuria after 2 weeks of atrasentan treatment and changes in body weight or Hb. CONCLUSIONS: In the Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With Atrasentan/JAPAN trials, atrasentan-associated fluid retention was more likely in patients with diabetes and nephropathy who had lower eGFR or received a higher dose of atrasentan. Finding that albuminuria reduction was not associated with changes in body weight and Hb suggests that the albuminuria-reducing efficacy of atrasentan is not impaired by fluid retention.

Carotid adventitial vasa vasorum and intima-media thickness in a primary prevention population.

BACKGROUND: Vasa vasorum (VV) vessels are critical in the genesis of atherosclerosis. Therefore, we assessed measures of carotid VV, intima-media thickness (CIMT), and patient risk factors in a primary prevention population. METHODS: We used multivariable linear models to evaluate the relationship between baseline covariates and a measure of carotid VV (VV ratio) and CIMT among 324 diabetics and 141 nondiabetics. RESULTS: Median CIMT (in mm) and VV ratio among nondiabetics were 0.82 ± 0.22 and 0.80 ± 0.19, respectively, and 1.06 ± 0.19 and 1.21 ± 0.26 among diabetics (P < 0.0001). Diabetes was associated with 36% (95% CI: 24.3-48.0, P < 0.001) higher VV ratio whereas a unit change in BMI was associated with ≈1% (95% CI: 0.5-1.4, P < 0.001) change in VV ratio. A 10-year increase in age was associated with 4% (95% CI: 1-7, P = 0.005) higher CIMT. Each 10 mmHg increase in mean systolic blood pressure was associated with 2% (95% CI: 1-4, P = 0.003) higher CIMT whereas diabetes conferred 31% (95% CI: 19.1-42.1, P < 0.001) higher CIMT. Female sex was associated with a 9% (95% CI: -12.9 to -4.1, P < 0.001) lower CIMT. Low density lipoprotein (LDL) cholesterol, blood pressure, and CIMT were not significantly associated with VV ratio. CONCLUSION: In this cohort of patients with low CIMT, VV ratio, and CIMT were distinctly unrelated, but each independently associated with diabetes. VV ratio and CIMT relationships warrant further investigation in large-scale studies and across a spectrum of atherosclerostic states.

The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy.

Despite optimal treatment, including renin-angiotensin system (RAS) inhibitors, patients with type 2 diabetic nephropathy have high cardiorenal morbidity and mortality related to residual albuminuria. We evaluated whether or not atrasentan, a selective endothelin A receptor antagonist, further reduces albuminuria when administered concomitantly with maximum tolerated labeled doses of RAS inhibitors. We enrolled 211 patients with type 2 diabetes, urine albumin/creatinine ratios of 300-3500 mg/g, and eGFRs of 30-75 ml/min per 1.73 m(2) in two identically designed, parallel, multinational, double-blind studies. Participants were randomized to placebo (n=50) or to 0.75 mg/d (n=78) or 1.25 mg/d (n=83) atrasentan for 12 weeks. Compared with placebo, 0.75 mg and 1.25 mg atrasentan reduced urine albumin/creatinine ratios by an average of 35% and 38% (95% confidence intervals of 24 to 45 and 28 to 47, respectively) and reduced albuminuria≥30% in 51% and 55% of participants, respectively. eGFR and office BP measurements did not change, whereas 24-hour systolic and diastolic BP, LDL cholesterol, and triglyceride levels decreased significantly in both treatment groups. Use of atrasentan was associated with a significant increase in weight and a reduction in hemoglobin, but rates of peripheral edema, heart failure, or other side effects did not differ between groups. However, more patients treated with 1.25 mg/d atrasentan discontinued due to adverse events. After stopping atrasentan for 30 days, measured parameters returned to pretreatment levels. In conclusion, atrasentan reduced albuminuria and improved BP and lipid spectrum with manageable fluid overload-related adverse events in patients with type 2 diabetic nephropathy receiving RAS inhibitors.

Papel de la ecografía carotídea en la reclasificación del riesgo cardiovascular de sujetos de riesgo bajo-intermedio / The role of carotid ultrasound in assessing carotid atherosclerosis in individuals at low-to-intermediate cardiovascular risk

Introducción y objetivos. Detectar la ateromatosis carotídea puede ser útil para mejorar la identificación de individuos susceptibles de padecer eventos cardiovasculares. Por ello, el objetivo de este estudio es cuantificar a los sujetos con riesgo cardiovascular bajo-intermedio según las fórmulas basadas en factores de riesgo tradicionales que presentan ateromatosis carotídea y, por lo tanto, tienen un riesgo alto de eventos cardiovasculares. Métodos. Se trata de un estudio transversal y observacional llevado a cabo por la Fundación Española del Corazón, en un programa de cribado poblacional. De los 3.778 voluntarios, se identificó y estudió a los que presentaban riesgo bajo-intermedio (n = 2.354). Se aplicaron los procedimientos estándar de examen físico y análisis de sangre. Se examinaron mediante ecografía las arterias carótidas común, bulbo e interna de ambos lados, para identificar la presencia de placa y se midió el grosor íntima-media en la carótida común. Se calculó el riesgo cardiovascular según la fórmula SCORE. Se realizó análisis estadístico bivariable y multivariable de los datos obtenidos. Resultados. La media de edad de los participantes era 58,9 ± 15 años y el 43,8% eran varones. El 23,7% presentaba hipertensión y el 20,5%, hipercolesterolemia. La media de riesgo según la fórmula SCORE fue 1,47 ± 1,4. Tanto el grosor íntima-media como la prevalencia de placa carotídea aumentaron progresiva y significativamente (p > 0,005) en paralelo con las décadas de la vida. Las variables significativamente relacionadas con la presencia de placa carotídea fueron edad, sexo masculino y presión arterial sistólica. Hay que destacar que se reclasificó a 592 (25,1%) sujetos a riesgo más elevado debido a la presencia de placa carotídea. Conclusiones. Existe una clara disociación entre la estratificación del riesgo cardiovascular mediante los factores de riesgo tradicionales y la presencia de placa ateromatosa, ya que 1/4 sujetos con riesgo cardiovascular bajo-intermedio presentaba ateromatosis carotídea (AU)

Introduction and objectives. Detection of carotid atherosclerosis might help to better identify individuals susceptible to cardiovascular events. We aimed to quantify the number of participants with carotid atherosclerosis and low-to-intermediate cardiovascular risk according to the traditional risk factor scoring, and therefore with an elevated risk of cardiovascular events. Methods. Cross-sectional, observational study performed during a cardiovascular screening program. From a total of 3778 volunteers, low-to-intermediate cardiovascular risk individuals (N=2354) were identified and studied. Physical examination, blood test, and carotid ultrasound followed standard procedures. Common, bulb, and internal carotid arteries were examined and common carotid intima-media thickness was measured. SCORE risk value was calculated for all participants. Univariate and multivariate statistical analysis was performed. Results. Mean age of participants was 58.9 (15) years, 43.8% were men, 23.7% had hypertension, and 20.5% had hypercholesterolemia. The mean SCORE value was 1.47 (1.4). Both carotid intima-media thickness and the prevalence of carotid plaques increased steadily and significantly (P<.005) as advanced decades of life were analyzed. Variables significantly related with the presence of carotid atherosclerosis were age, male sex, and systolic blood pressure. Interestingly, 592 (25.1%) individuals were reclassified to a higher risk due to the presence of carotid atherosclerosis. Conclusions. There was a clear dissociation between cardiovascular risk scoring and the presence of atherosclerosis, because 1 of 4 study participants at low-to-intermediate cardiovascular risk had carotid atherosclerosis (AU)

Soluble TWEAK is associated with atherosclerotic burden in patients with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is characterized by a high mortality rate, primarily due to cardiovascular disease. Reduced soluble TNF-like weak inducer of apoptosis (sTWEAK) levels have been related with endothelial function in CKD patients. However, there are no data on the relationship between sTWEAK and its scavenger receptor CD163 and atherosclerotic burden in CKD. METHODS: A cross-sectional, observational study was conducted in 58 patients with CKD stages 1-3, 86 with CKD stages 4-5, 195 on dialysis and 86 healthy controls. The severity of atherosclerosis was estimated with the atherosclerosis score (AS), combining the results of ankle-brachial index and carotid ultrasound. sTWEAK and CD163 plasma concentrations were measured by ELISA. RESULTS: sTWEAK plasma levels were diminished and CD163 concentrations were increased in patients with CKD compared with controls (sTWEAK: median [interquartile range] 308 pg/mL [258-378] vs. 371 pg/mL [319-455]; p<0.001; and CD163: 1,047 ng/mL [740-1,495] vs. 540 ng/mL [319-765]; p<0.001; respectively). A weak but statistically significant association between sTWEAK or CD163 and carotid intima-media thickness (r = -0.109, p = 0.025; r = 0.179, p<0.001; respectively) was observed. Patients with more severe atherosclerosis presented a higher reduction in sTWEAK concentrations (312 pg/mL [302-322] vs. 368 pg/mL [351-385]; p<0.001) and a higher increment in CD163 levels (1,182 ng/mL [1,107-1,258] vs. 826 ng/mL [733-919]; p<0.001). After multivariable analysis, only elevated sTWEAK levels were associated with reduced risk of atherosclerosis (0.34 [0.14-0.86], p = 0.02). CONCLUSIONS: A significant reduction in sTWEAK and increment in CD163 plasma levels were observed in patients with more severe atherosclerosis. Our results indicate that sTWEAK could be a novel biomarker of atherosclerotic burden in CKD patients.

High-dose statin monotherapy versus low-dose statin/ezetimibe combination on fasting and postprandial lipids and endothelial function in obese patients with the metabolic syndrome: The PANACEA study.

BACKGROUND: Low-dose statin therapy in combination with ezetimibe, an inhibitor of intestinal cholesterol absorption, lowers plasma LDL-cholesterol levels to a similar degree as high-dose statin monotherapy. This study assessed whether similar LDL-cholesterol lowering with simvastatin/ezetimibe combination therapy improves fasting and postprandial arterial endothelial function compared to high-dose statin therapy alone. METHODS: Multicenter, double-blind, crossover trial in 100 abdominally obese patients with the metabolic syndrome, randomized to 6 weeks' treatment with simvastatin 80 mg or simvastatin/ezetimibe 10/10 mg. Flow mediated dilatation (FMD) and peripheral arterial tonometry (EndoPAT) as well as plasma lipids were measured in the fasting state and after an oral lipid load at baseline and after both treatments. RESULTS: Fasting LDL-cholesterol levels (3.57 mmol/L at baseline) were reduced to 1.79 mmol/L following treatment with simvastatin 80 mg and 1.81 mmol/L with simvastatin/ezetimibe 10/10 mg, respectively. Plasma lipids were similar at 4 h after an oral lipid load following both treatments for 6 weeks. Fasting endothelial function was also similar with both treatments when assessed by FMD (adjusted mean ± SE: 4.35 ± 0.19 vs. 4.43 ± 0.18; P = 0.777) and EndoPAT (2.12 ± 0.05 vs 2.20 ± 0.05; P = 0.304). After an oral fat load, changes in endothelial function were also comparable for both treatments as assessed by FMD (-0.34 ± 0.21 vs. -0.43 ± 0.20; P = 0.766) and EndoPAT (0.00 ± 0.07 vs. -0.04 ± 0.08; P = 0.712). CONCLUSION: Treatment with simvastatin/ezetimibe 10/10 mg induced no difference in endothelial function in the fasting and postprandial state compared to simvastatin 80 mg while attaining similar LDL-c levels in obese patients with metabolic syndrome.

The role of carotid ultrasound in assessing carotid atherosclerosis in individuals at low-to-intermediate cardiovascular risk.

INTRODUCTION AND OBJECTIVES: Detection of carotid atherosclerosis might help to better identify individuals susceptible to cardiovascular events. We aimed to quantify the number of participants with carotid atherosclerosis and low-to-intermediate cardiovascular risk according to the traditional risk factor scoring, and therefore with an elevated risk of cardiovascular events. METHODS: Cross-sectional, observational study performed during a cardiovascular screening program. From a total of 3778 volunteers, low-to-intermediate cardiovascular risk individuals (N=2354) were identified and studied. Physical examination, blood test, and carotid ultrasound followed standard procedures. Common, bulb, and internal carotid arteries were examined and common carotid intima-media thickness was measured. SCORE risk value was calculated for all participants. Univariate and multivariate statistical analysis was performed. RESULTS: Mean age of participants was 58.9 (15) years, 43.8% were men, 23.7% had hypertension, and 20.5% had hypercholesterolemia. The mean SCORE value was 1.47 (1.4). Both carotid intima-media thickness and the prevalence of carotid plaques increased steadily and significantly (P<.005) as advanced decades of life were analyzed. Variables significantly related with the presence of carotid atherosclerosis were age, male sex, and systolic blood pressure. Interestingly, 592 (25.1%) individuals were reclassified to a higher risk due to the presence of carotid atherosclerosis. CONCLUSIONS: There was a clear dissociation between cardiovascular risk scoring and the presence of atherosclerosis, because 1 of 4 study participants at low-to-intermediate cardiovascular risk had carotid atherosclerosis.

The relationship between walking speed and changes in cardiovascular risk factors during a 12-day walking tour to Santiago de Compostela: a cohort study.

OBJECTIVES: Physical exercise has beneficial effects on cardiovascular risk factors. Knowledge about the effect of exercise intensity, specifically walking speed, on cardiovascular risk factors is limited. We report the relationship between walking speed and changes in cardiovascular risk factors in participants of a 12-day walking tour to Santiago de Compostela. DESIGN: Prospective cohort study. SETTING: Single-centre study with healthy middle-aged volunteers. PARTICIPANTS: Healthy middle-aged men (n=15) and women (n=14). Subjects using lipid-lowering medication were excluded. INTERVENTION: Participants walked 281±10 km of the classical route to Santiago de Compostela in 12 days in 2009. PRIMARY AND SECONDARY OUTCOME MEASURES: Walking speed was recorded and blood pressure, weight, waist circumference, lipids and glucose were measured every other day. Changes in risk factors were compared between gender-pooled groups with faster and slower walking speed. Second, the relationship between walking speed and changes in risk factors was quantified using a linear mixed effects model. RESULTS: In the faster walking speed (4.6±0.2 km/h) group, high-density lipoprotein cholesterol (HDL-c) increased more than in the slower walking speed (4.1±0.2 km/h) group (difference in change between groups: 0.20; 95% CI -0.02 to 0.42 mmol/l), while low-density lipoprotein cholesterol (LDL-c) and total cholesterol decreased more in the slower walking speed group (differences in changes between groups: LDL-c: -0.50; 95% CI -0.88 to -0.12 mmol/l and total cholesterol: -0.75; 95% CI -1.19 to -0.31 mmol/l). A 1 km/h higher walking speed was related to an increase in HDL-c (0.24; 95% CI 0.12 to 0.30 mmol/l), LDL-c (0.18; 95% CI -0.16 to 0.42 mmol/l) and total cholesterol (0.36; 95% CI 0.12 to 0.60 mmol/l), adjusted for age, gender, smoking, body mass index and heart rate, during the whole walking tour. CONCLUSIONS: Walking the same distance faster improves HDL-c more, while LDL-c and total cholesterol decrease more with lower walking speed independent of changes in body weight in healthy middle-aged subjects.

Clinical efficacy of the selective endothelin A receptor antagonist, atrasentan, in patients with diabetes and chronic kidney disease (CKD).

AIMS: Progression of chronic kidney disease (CKD) in patients with diabetes is a growing problem. Diabetes is associated with elevated endothelin-1 (ET-1) and enhanced renal expression of the endothelin A receptor (ETAR). Atrasentan, a highly selective ETAR antagonist, reduces albuminuria in patients with DN. KEY METHODS: This was a randomized, double-blind trial of subjects with type 2 diabetes on renin-angiotensin system (RAS) inhibitors having eGFR >20 ml/min, and urine albumin-to-creatinine ratio (UACR) of 100-3000 mg/g, who were allocated to placebo, 0.25, 0.75 or 1.75 mg atrasentan. KEY FINDINGS: UACR was reduced in the 0.75 mg and 1.75 mg groups (42% and 35% vs placebo, P<0.011) over the 8 week treatment period. Edema was reported in 21 subjects: 62% of edema events emerged during the first 4 weeks. There were no significant changes in serum hsCRP, IL-6, NT-pro-BNP, ET-1, urine TGFb or MCP-1. Urine NGAL was reduced 24% in the 1.75 mg group (P=0.044). Hispanic subjects (58% of total) tended to have greater UACR reductions than non-Hispanics (0.75 mg dose: Hispanic: 41-60%; non-Hispanic: 18-37%; P=0.012 and 0.048 vs placebo, respectively) without different rates of edema. Mean UACR reduction in subjects receiving maximum doses of RAS inhibitors (38%) was 32% and 35% in the 0.75 and 1.75 mg groups, respectively, and similar to overall UACR changes. SIGNIFICANCE: Edema formation was dose-dependent and occurred early. The decrease in urine NGAL warrants further study in renal tubular disease attenuation. UACR responses based on ethnicity need further characterization. Results suggest atrasentan may have additive effects to RAS inhibition in treatment of DN.