TY - JOUR A1 - Schneider, Andreas A1 - Schneider, Markus P. A1 - Scharnagl, Hubert A1 - Jardine, Alan G. A1 - Wanner, Christoph A1 - Drechsler, Christiane T1 - Predicting erythropoietin resistance in hemodialysis patients with type 2 diabetes JF - BMC Nephrology N2 - Background: Resistance to ESAs (erythropoietin stimulating agents) is highly prevalent in hemodialysis patients with diabetes and associated with an increased mortality. The aim of this study was to identify predictors for ESA resistance and to develop a prediction model for the risk stratification in these patients. Methods: A post-hoc analysis was conducted of the 4D study, including 1015 patients with type 2 diabetes undergoing hemodialysis. Determinants of ESA resistance were identified by univariate logistic regression analyses. Subsequently, multivariate models were performed with stepwise inclusion of significant predictors from clinical parameters, routine laboratory and specific biomarkers. Results: In the model restricted to clinical parameters, male sex, shorter dialysis vintage, lower BMI, history of CHF, use of ACE-inhibitors and a higher heart rate were identified as independent predictors of ESA resistance. In regard to routine laboratory markers, lower albumin, lower iron saturation, higher creatinine and higher potassium levels were independently associated with ESA resistance. With respect to specific biomarkers, higher ADMA and CRP levels as well as lower Osteocalcin levels were predictors of ESA resistance. Conclusions: Easily obtainable clinical parameters and routine laboratory parameters can predict ESA resistance in diabetic hemodialysis patients with good discrimination. Specific biomarkers did not meaningfully further improve the risk prediction of ESA resistance. Routinely assessed data can be used in clinical practice to stratify patients according to the risk of ESA resistance, which may help to assign appropriate treatment strategies. KW - type 2 diabetes KW - heodialysis patients Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128695 VL - 14 IS - 67 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 - 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 - Wagner, Martin A1 - Ashby, Damien R. A1 - Kurtz, Caroline A1 - Alam, Ahsan A1 - Busbridge, Mark A1 - Raff, Ulrike A1 - Zimmermann, Josef A1 - Heuschmann, Peter U. A1 - Wanner, Christoph A1 - Schramm, Lothar T1 - Hepcidin-25 in diabetic chronic kidney disease is predictive for mortality and progression to end stage renal disease JF - PLoS One N2 - Background Anemia is common and is associated with impaired clinical outcomes in diabetic chronic kidney disease (CKD). It may be explained by reduced erythropoietin (EPO) synthesis, but recent data suggest that EPO-resistance and diminished iron availability due to inflammation contribute significantly. In this cohort study, we evaluated the impact of hepcidin-25—the key hormone of iron-metabolism—on clinical outcomes in diabetic patients with CKD along with endogenous EPO levels. Methods 249 diabetic patients with CKD of any stage, excluding end-stage renal disease (ESRD), were enrolled (2003–2005), if they were not on EPO-stimulating agent and iron therapy. Hepcidin-25 levels were measured by radioimmunoassay. The association of hepcidin-25 at baseline with clinical variables was investigated using linear regression models. All-cause mortality and a composite endpoint of CKD progression (ESRD or doubling of serum creatinine) were analyzed by Cox proportional hazards models. Results Patients (age 67 yrs, 53% male, GFR 51 ml/min, hemoglobin 131 g/L, EPO 13.5 U/L, hepcidin-25 62.0 ng/ml) were followed for a median time of 4.2 yrs. Forty-nine patients died (19.7%) and forty (16.1%) patients reached the composite endpoint. Elevated hepcidin levels were independently associated with higher ferritin-levels, lower EPO-levels and impaired kidney function (all p<0.05). Hepcidin was related to mortality, along with its interaction with EPO, older age, greater proteinuria and elevated CRP (all p<0.05). Hepcidin was also predictive for progression of CKD, aside from baseline GFR, proteinuria, low albumin- and hemoglobin-levels and a history of CVD (all p<0.05). Conclusions We found hepcidin-25 to be associated with EPO and impaired kidney function in diabetic CKD. Elevated hepcidin-25 and EPO-levels were independent predictors of mortality, while hepcidin-25 was also predictive for progression of CKD. Both hepcidin-25 and EPO may represent important prognostic factors of clinical outcome and have the potential to further define “high risk” populations in CKD. KW - diabetes mellitus KW - inflammation KW - type 2 diabetes KW - hemoglobin KW - chronic kidney disease KW - anemia KW - ferritin KW - proteinuria Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125514 VL - 10 IS - 4 ER -