Correction to: Intravenous Ferric Carboxymaltose in Patients with Type 2 Diabetes Mellitus and Iron Deficiency: CLEVER Trial Study Design and Protocol.

In the original publication, the text in Table 2 stated 'Hypersensitivity to the active substance, to Ferinject, or to any of its excipients'.

Intravenous Ferric Carboxymaltose in Patients with Type 2 Diabetes Mellitus and Iron Deficiency: CLEVER Trial Study Design and Protocol.

INTRODUCTION: HbA1c is the gold standard for glycemic control in pre-diabetes and diabetes. However, its validity has been questioned, especially in the presence of imbalanced iron homeostasis. The CLEVER trial aims to evaluate the relationship between iron deficiency and HbA1c (a biomarker for the diagnosis and therapeutic monitoring of type 2 diabetes) in a randomized, placebo-controlled, multicenter clinical trial. METHODS: The CLEVER (intravenous ferric CarboxymaLtosE for improVement of mEtabolic parameters in type 2 diabetes patients with iRon deficiency) trial is a randomized, single-blind, proof-of-concept study with two treatment arms. 140 men and women diagnosed with type 2 diabetes and iron deficiency will receive either placebo or ferric carboxymaltose (500 or 1000 mg) as intravenous infusions. The primary outcome measure is the change in HbA1c level between baseline and after 12 weeks of treatment. Secondary endpoints include change of iron status and metabolic markers as well as treatment safety and tolerability. Furthermore, the potential clinical improvement in quality of life and the reliability of HbA1c measurement in patients with type 2 diabetes and iron deficiency will be investigated. RESULTS: Both excessive iron and iron deficiency are associated with metabolic disorders; excessive iron is a risk factor for the development of diabetes, whereas iron deficiency is associated with obesity and insulin resistance. It has been suggested that iron increases insulin secretion in pancreatic beta-cells. CLEVER is the first study to investigate the hypothesis that intravenous substitution with ferric carboxymaltose reduces HbA1c levels in patients with type 2 diabetes and iron deficiency, thereby improving metabolic status and quality of life. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT01513369). FUNDING: GWT-TUD GmbH acts as sponsor of the clinical trial. Financial support is provided by Vifor Pharma.

Intra-individual variability and circadian rhythm of vascular endothelial growth factors in subjects with normal glucose tolerance and type 2 diabetes.

Increased levels of systemic vascular endothelial growth factors (VEGFs) in patients with diabetes are associated with increased risk of microvessel disease. On the other hand, low VEGF levels after intravitreal antibody application may be associated with acute cardiovascular complications and treatment failure. Individual levels of systemic VEGF vary in a wide range depending on analytical methods and quality of diabetes control. So far only limited information exists on intraindividual fluctuations over longer periods and circadian rhythms. We analysed the intraindividual variance of VEGF-A, VEGF-C and placental growth factor (PLGF) in CTAD (citrate-theophylline-adenine-dipyridamol) plasma as well as VEGF-A in serum over a period of 6 months in patients with stable controlled type 2 diabetes (10 M, 10 F) and age and sex matched subjects with normal glucose tolerance (NGT). Furthermore, circadian levels of VEGFs were controlled hourly from 7:30 a.m. to 7:30 p.m. under standardized metabolic ward conditions. In addition, the relationship to metabolic, hormonal and inflammatory biomarkers was analyzed. VEGF-A, VEGF-C and PLGF remained stable in plasma and VEGF-A in serum over 6 months in both groups. No circadian change was observed in VEGF-A serum and plasma concentrations. A minor decrease of VEGF-C plasma levels was evident after 5 p.m. in both groups and a significant peak of PLGF concentrations occurred after lunch, which was more pronounced in T2DM. In multivariate analysis, only serum VEGF-A correlated to diabetes duration, whereas VEGF-C only correlated to HbA1c and fasting blood glucose. We did not observe significant intraindividual variances for VEGF-A in serum and VEGF-A, VEGF-C and PLGF in CTAD plasma over a period of 6 months. Taken together, a single morning measurement of systemic VEGF levels after 7:30 am appears to be a reliable parameter for the individual risk associated with abnormal VEGF concentrations in blood. TRIAL REGISTRATION: NCT02325271.

Differences in Glycemic Variability Between Normoglycemic and Prediabetic Subjects.

So far the criteria for NGT and abnormal glucose tolerance (AGT) are based on HbA1c and 75 g oGTT. We present data on GV and diurnal profiles in stratified cohorts with AGT versus controls. 28 NGT, 42 AGT (15 IGT, 11 IFG, 16 CGI) matched for age and BMI classified by 75 g oGTT underwent a CGM with test meal (TM). Diurnal profiles, glucose excursion after TM, and GV (SD, MAGE) were calculated for day 2 and 3. HbA1c, with its values of 5.5 ± 0.37% versus 5.65 ± 0.36%, was within normal range. Average interstitial glucose (AiG) was 5.84 ± 0.52 mmol/l) in NGT and 6.35 ± 0.65 mmol/l in AGT (P = .002). The 2 h incremental area under curve (iAUC) from TM until 2 h after TM was 1.94 ± 1.31 mmol/l*h versus 2.89 ( ± 1.75) mmol/l*h (P = .012), AiG 2 hours after TM was 5.99 ± 1.14 mmol/l*d versus 6.64 ± 1.30 mmol/l (P = .035). Peaks of AiG after TM were 7.69 ± 1.48 mmol/l*d versus 9.18 ± 1.67 mmol/l*d (P = .001). SD was significantly higher for AGT (1.12 ± 0.37 vs. 0.85 ± 0.32 mmol/l, P = .01) and MAGE 2.26 ± 0.84 vs. 1.60 ± 0.69 mmol/l, P = .005). In this comparative analysis NGT and AGT well matched for age, BMI, and comorbidities, CGM revealed significant differences in daytime AiG, pp glucose excursion and postprandial peaks. SD and MAGE was significantly higher for subjects with AGT. I Impaired glucose homeostasis a better characterizes degree of AGTe than HbA1c and 75 g OGTT.

[Metabolic syndrome: "common soil" for diabetes and atherosclerosis. Novel approaches to an integrated therapy]. / Das metabolische Syndrom: "common soil" für Diabetes und Atherosklerose: Neue Möglichkeiten für eine integrierte Therapie.

Type 2 diabetes and atherosclerotic vascular disease develop in parallel. Prospective epidemiologic studies have shown a striking communality of major risk factors for both diseases. This raises the question of a "common soil". The traits of the metabolic syndrome including dyslipidemia, visceral obesity and hypertension are predictors of type 2 diabetes as well as coronary heart disease. The same applies to the environmental factors: overnutrition, physical inertia and smoking. Visceral obesity, insulin resistance and low-grade inflammation are known as major components of the common soil for metabolic syndrome and coronary heart disease. Depending on the quality of metabolic control diabetes will accelerate the progression of atherosclerosis via unstable plaque formation. The "common soil" concept provides a paradigm for an integrated therapeutic approach. This applies to a lifestyle intervention as well as a rational use of drugs in diseases of the metabolic syndrome. The medication should consider coexisting disorders of the metabolic syndrome to use pleiotropic effects. On the other hand, side effect such as the worsening of blood glucose levels caused by beta-blockers and diuretics should be avoided. The following medication should be preferred in context of the metabolic syndrome: oral antidiabetics such as acarbose, metformin and thiazolidinediones, antihypertensives such as ACE inhibitors and ARBs (angiotensin receptor blockers) and lipid-lowering drugs such as atorvastatin, rosuvastatin, and the modern nicotinic acid derivative Niaspan, respectively. The strategy using synergies in drug treatment can reduce polypharmacy and costs and improve the patients' compliance.

Coagulation factor V G allele and HR2 haplotype: factor V activity, activated protein C resistance and risk of venous thrombosis.

Factor V Leiden is a well-known risk factor for venous thrombosis. The dual role of factor V as a coagulatory and anticoagulatory cofactor permits the assumption that further mutations in the factor V gene are of importance in the study of the risk of thrombosis. Relevant studies to date have given rise to a controversy over this risk for the HR2 haplotype. For the G allele, defined in our work group as a G at the nucleotide positions 2391, 2663, 2684 and 2863, there have been to date no other investigations of thrombotic risk. In a case-control study on 347 patients with deep venous thrombosis (DVT) and 282 controls, we investigated the association of the HR2 haplotype and the G allele with DVT. We found no association between HR2 haplotype and DVT [odds ratio (OR) 0.87; 95% confidence interval (CI) 0.58-1.30; P = 0.537]. The frequency of the G allele was, on the contrary, higher in the control group than among the patients (OR 0.68, 95% CI: 0.53 to 0.89; P = 0.005). The factor V activity of the HR2 carriers was lower than that of the wild type and G allele carriers. The HR2 haplotype exhibited a moderate influence on activated protein C response. This study presented no evidence of thrombotic risk for the HR2 haplotype alone. The results here permit the assumption of a protective effect of the G allele. The source of a possible protective influence of the G allele on thrombotic risk is at present unclear.

[The metabolic syndrome and its epidemiologic dimensions in historical perspective]. / Das Metabolische Syndrom im Wandel: Historische Perspektive und epidemiologische Dimension.

During the last five decades the metabolic syndrome has turned into an epidemic in countries with overnutrition and low levels of physical activity. About 15% of the population aged 40-75 in these countries exhibit exhibit the 'metabolic syndrome' cluster diseases. We define the metabolic syndrome as a cluster of diseases with at least three of the following components diagnosed in any one subject: ITG/type 2 diabetes, android obesity, dyslipidemia, hypertension, hyperuricemia, albuminuria and atherosclerosis. Insulin resistance was found in more than 80% of both the clinical type 2 diabetics and the subjects with IGT in the RIAD study. Intra-abdominal obesity and lipotoxicity are other important causes. Today the metabolic syndrome is--and for the near future will continue to be--the most important source of new diabetics, as well as a major cause of coronary heart disease.