TY - JOUR A1 - Schneider, Andreas A1 - Gutjahr-Lengsfeld, Lena A1 - Ritz, Eberhard A1 - Scharnagl, Hubert A1 - Gelbrich, Götz A1 - Pilz, Stefan A1 - Macdougall, Iain C. A1 - Wanner, Christoph A1 - Drechsler, Christiane T1 - Longitudinal Assessments of Erythropoietin-Stimulating Agent Responsiveness and the Association with Specific Clinical Outcomes in Dialysis Patients JF - Nephron Clinical Practice N2 - Background: Dose requirements of erythropoietin-stimulating agents (ESAs) can vary considerably over time and may be associated with cardiovascular outcomes. We aimed to longitudinally assess ESA responsiveness over time and to investigate its association with specific clinical end points in a time-dependent approach. Methods: The German Diabetes and Dialysis study (4D study) included 1,255 diabetic dialysis patients, of whom 1,161 were receiving ESA treatment. In those patients, the erythropoietin resistance index (ERI) was assessed every 6 months during a median follow-up of 4 years. The association between the ERI and cardiovascular end points was analyzed by time-dependent Cox regression analyses with repeated ERI measures. Results: Patients had a mean age of 66 ± 8.2 years; 53% were male. During follow-up, a total of 495 patients died, of whom 136 died of sudden death and 102 of infectious death. The adjusted and time-dependent risk for sudden death was increased by 19% per 5-unit increase in the ERI (hazard ratio, HR = 1.19, 95% confidence interval, CI = 1.07-1.33). Similarly, mortality increased by 25% (HR = 1.25, 95% CI = 1.18-1.32) and infectious death increased by 27% (HR = 1.27, 95% CI = 1.13-1.42). Further analysis revealed that lower 25-hydroxyvitamin D levels were associated with lower ESA responsiveness (p = 0.046). Conclusions: In diabetic dialysis patients, we observed that time-varying erythropoietin resistance is associated with sudden death, infectious complications and all-cause mortality. Low 25-hydroxyvitamin D levels may contribute to a lower ESA responsiveness. KW - dialysis KW - erythropoietin KW - diabetes KW - epidemiology Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196511 SN - 1660-2110 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 128 IS - 1-2 ER - TY - JOUR A1 - Locatelli, Francesco A1 - Spasovski, Goce A1 - Dimkovic, Nada A1 - Wanner, Christoph A1 - Dellanna, Frank A1 - Pontoriero, Giuseppe T1 - The effects of colestilan versus placebo and sevelamer in patients with CKD 5D and hyperphosphataemia: a 1-year prospective randomized study JF - Nephrology Dialysis Transplantation N2 - BACKGROUND: This study compared the effects of short-term titrated colestilan (a novel non-absorbable, non-calcium, phosphate binder) with placebo, and evaluated the safety and efficacy of colestilan over 1 year compared with sevelamer, in patients with chronic kidney disease (CKD) 5D. METHODS: This prospective multicentre study comprised a 4-week phosphate binder washout period, a 16-week short-term, flexible-dose, treatment period (including a 4-week placebo-controlled withdrawal period) and a 40-week extension treatment phase. RESULTS: At Week 16 (the end of the 4-week placebo-controlled withdrawal period), serum phosphorus level was 0.43 mmol/L (1.32 mg/dL) lower with colestilan than placebo (P < 0.001; primary end point). Serum LDL-C level was also lower with colestilan than with placebo (P < 0.001). Both colestilan and sevelamer produced significant reductions from baseline in serum phosphorus levels (P < 0.001), maintained for 1 year, and the proportion of patients achieving target levels of ≤1.78 mmol/L (5.5 mg/dL) or ≤1.95 mmol/L (6.0 mg/dL) at study end were similar (65.3 and 73.3%, respectively, for colestilan, and 66.9 and 77.4%, respectively, for sevelamer). Serum calcium level remained stable in the colestilan group but tended to increase slightly in the sevelamer group (end-of-study increase of 0.035 mmol/L over baseline). Both binders produced similar reductions from baseline in LDL-C level (P < 0.001), and responder rates after 1 year, using a target of <1.83 mmol/L (70 mg/dL) or <2.59 mmol/L (100 mg/dL) were similar in both groups (50.7 and 85.3% for colestilan and 54.0 and 80.6% for sevelamer). Colestilan was generally well tolerated. CONCLUSIONS: Colestilan is effective and safe for the treatment of hyperphosphataemia in patients with CKD 5D, and affords similar long-term phosphorus and cholesterol reductions/responder rates to sevelamer. KW - chronic kidney disease KW - colestilan KW - hyperphosphataemia KW - placebo KW - sevelamer Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121114 VL - 29 IS - 5 ER - TY - JOUR A1 - Fruchart, Jean-Charles A1 - Davignon, Jean A1 - Hermans, Michael P. A1 - Al-Rubeaan, Khalid A1 - Amarenco, Pierre A1 - Assmann, Gerd A1 - Barter, Philip A1 - Betteridge, John A1 - Bruckert, Eric A1 - Cuevas, Ada A1 - Farnier, Michel A1 - Ferrannini, Ele A1 - Fioretto, Paola A1 - Genest, Jacques A1 - Ginsberg, Henry N. A1 - Gotto Jr., Antonio M. A1 - Hu, Dayi A1 - Kadowaki, Takashi A1 - Kodama, Tatsuhiko A1 - Krempf, Michel A1 - Matsuzawa, Yuji A1 - Núñez-Cortés, Jesús Millán A1 - Monfil, Calos Calvo A1 - Ogawa, Hisao A1 - Plutzky, Jorge A1 - Rader, Daniel J. A1 - Sadikot, Shaukat A1 - Santos, Raul D. A1 - Shlyakhto, Evgeny A1 - Sritara, Piyamitr A1 - Sy, Rody A1 - Tall, Alan A1 - Tan, Chee Eng A1 - Tokgözoğlu, Lale A1 - Toth, Peter P. A1 - Valensi, Paul A1 - Wanner, Christoph A1 - Zambon, Albertro A1 - Zhu, Junren A1 - Zimmet, Paul T1 - Residual macrovascular risk in 2013: what have we learned? JF - Cardiovascual Diabetology N2 - Cardiovascular disease poses a major challenge for the 21st century, exacerbated by the pandemics of obesity, metabolic syndrome and type 2 diabetes. While best standards of care, including high-dose statins, can ameliorate the risk of vascular complications, patients remain at high risk of cardiovascular events. The Residual Risk Reduction Initiative (R(3)i) has previously highlighted atherogenic dyslipidaemia, defined as the imbalance between proatherogenic triglyceride-rich apolipoprotein B-containing-lipoproteins and antiatherogenic apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL), as an important modifiable contributor to lipid-related residual cardiovascular risk, especially in insulin-resistant conditions. As part of its mission to improve awareness and clinical management of atherogenic dyslipidaemia, the R(3)i has identified three key priorities for action: i) to improve recognition of atherogenic dyslipidaemia in patients at high cardiometabolic risk with or without diabetes; ii) to improve implementation and adherence to guideline-based therapies; and iii) to improve therapeutic strategies for managing atherogenic dyslipidaemia. The R(3)i believes that monitoring of non-HDL cholesterol provides a simple, practical tool for treatment decisions regarding the management of lipid-related residual cardiovascular risk. Addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe are all options for combination with a statin to further reduce non-HDL cholesterol, although lacking in hard evidence for cardiovascular outcome benefits. Several emerging treatments may offer promise. These include the next generation peroxisome proliferator-activated receptor alpha agonists, cholesteryl ester transfer protein inhibitors and monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9. However, long-term outcomes and safety data are clearly needed. In conclusion, the R(3)i believes that ongoing trials with these novel treatments may help to define the optimal management of atherogenic dyslipidaemia to reduce the clinical and socioeconomic burden of residual cardiovascular risk. KW - phospholipid fatty acids KW - term fenofibrate therapy KW - cardiovascular munster procam KW - residual cardiovascular risk KW - atherogenic dyslipidaemia KW - type 2 diabetes KW - therapeutic options KW - high denisty lipoprotein KW - randomized controlled-trial KW - coronary artery disease KW - type-2 diabetes mellitus KW - triglyceride-rich lipoproteins KW - alpha/delta agonist GFT505 KW - placebo-controlled trial Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117546 SN - 1475-2840 VL - 13 IS - 26 ER - TY - JOUR A1 - Zinman, Bernard A1 - Inzucchi, Silvio E. A1 - Lachin, John M. A1 - Wanner, Christoph A1 - Ferrari, Roberto A1 - Fitchett, David A1 - Bluhmki, Erich A1 - Hantel, Stefan A1 - Kempthorne-Rawson, Joan A1 - Newman, Jennifer A1 - Johansen, Odd Erik A1 - Woerle, Hans-Juergen A1 - Broedl, Uli C. T1 - Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME (TM)) JF - Cardiovascular Diabetology N2 - Background: Evidence concerning the importance of glucose lowering in the prevention of cardiovascular (CV) outcomes remains controversial. Given the multi-faceted pathogenesis of atherosclerosis in diabetes, it is likely that any intervention to mitigate this risk must address CV risk factors beyond glycemia alone. The SGLT-2 inhibitor empagliflozin improves glucose control, body weight and blood pressure when used as monotherapy or add-on to other antihyperglycemic agents in patients with type 2 diabetes. The aim of the ongoing EMPA-REG OUTCOME (TM) trial is to determine the long-term CV safety of empagliflozin, as well as investigating potential benefits on macro-/microvascular outcomes. Methods: Patients who were drug naive (HbA(1c) >= 7.0% and <= 9.0%), or on background glucose-lowering therapy (HbA(1c) >= 7.0% and <= 10.0%), and were at high risk of CV events, were randomized (1:1:1) and treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo (double blind, double dummy) superimposed upon the standard of care. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. CV events will be prospectively adjudicated by an independent Clinical Events Committee. The trial will continue until >= 691 confirmed primary outcome events have occurred, providing a power of 90% to yield an upper limit of the adjusted 95% CI for a hazard ratio of <1.3 with a one-sided a of 0.025, assuming equal risks between placebo and empagliflozin (both doses pooled). Hierarchical testing for superiority will follow for the primary outcome and key secondary outcomes (time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina pectoris) where non-inferiority is achieved. Results: Between Sept 2010 and April 2013, 592 clinical sites randomized and treated 7034 patients (41% from Europe, 20% from North America, and 19% from Asia). At baseline, the mean age was 63 +/- 9 years, BMI 30.6 +/- 5.3 kg/m(2), HbA1c 8.1 +/- 0.8%, and eGFR 74 +/- 21 ml/min/1.73 m(2). The study is expected to report in 2015. Discussion: EMPA REG OUTCOME (TM) will determine the CV safety of empagliflozin in a cohort of patients with type 2 diabetes and high CV risk, with the potential to show cardioprotection. KW - glycemic control KW - blood pressure KW - macrovascular KW - doule blind KW - chronic kidney disease KW - type-1 diabetes mellitus KW - safety KW - metformin KW - add-on KW - albuminuria KW - sulfonylurea KW - efficacy KW - canagliflozin KW - microvascular KW - SGLT2 inhibitor KW - type 2 diabetes KW - body weight KW - empagliflozin Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116036 SN - 1475-2840 VL - 13 IS - 102 ER - TY - JOUR A1 - Wagner, Martin A1 - Krämer, Johannes A1 - Blohm, Elisabeth A1 - Vergho, Dorothee A1 - Weidemann, Frank A1 - Breunig, Frank A1 - Wanner, Christoph T1 - Kidney function as an underestimated factor for reduced health related quality of life in patients with Fabry disease N2 - Background: Impairments of health related quality of life (HRQoL) are frequently observed in Fabry disease (FD) and are known to be related to neuropathic pain and cardiovascular events. This study aimed to explore the role of chronic kidney disease (CKD) in a large cohort of patients with FD. Methods: In 96 patients (53% female; age 40 ± 12 yrs) with genetically proven FD, HRQoL was assessed by the Medical Outcomes Study (SF-36) questionnaire. All patients were naïve to enzyme replacement therapy. Three categories for kidney dysfunction were chosen, eGFR ≥/<60 ml/min/1.73 m2 or need of renal replacement therapy (RRT). Minor (e.g. arrhythmia, angina pectoris, etc.) and major (e.g. myocardial infarction, coronary artery bypass, stroke or implantable cardioverter-defibrillator) vascular events as well as pain and pain therapy were considered in linear regression analyses with the dimensions of HRQoL. Results: Ten patients (10%) had impaired kidney function and a further nine were on RRT (9.4%). Kidney function and pain emerged as the main factors associated with lower scores on the SF 36, in particular on physical components (PCS beta-coefficients for CKD −6.2, for RRT −11.8, for pain −9.1, p < 0.05, respectively), while controlling for gender, vascular event and pain-therapy. Relationships were found for mental aspects of HRQoL. Age and history of vascular events were not related to HRQoL. Conclusion: Cardiovascular events and pain are important factors related to HRQoL, social functioning and depression. Our study highlights impaired chronic kidney disease, in particular after initiation of RRT, as a strong determinant of reduced HRQoL in FD. KW - Quality of life KW - SF-36 KW - Chronic kidney disease KW - Fabry disease Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-111159 UR - http://www.biomedcentral.com/1471-2369/15/188 ER -