Glucose and lipopolysaccharide differentially regulate fibroblast growth factor 21 in healthy male human volunteers - A prospective cross-over trial.

Fibroblast growth factor 21 (FGF21) affects the regulation of metabolism. Additionally, anti-inflammatory properties are attributed to FGF21, and studies in animals and humans show conflicting results. This study aimed to investigate how FGF21 is affected by glucose and lipopolysaccharide (LPS) in humans. Therefore, FGF21 was measured eight times at different time points within 48 h in this prospective cross-over trial after glucose and LPS on two different study days. The study included ten healthy, non-smoking male subjects aged 18-40. Repeated measures analysis of variance and paired t-test as post hoc analysis were applied. The administration of glucose and LPS resulted in a significant difference in regulating FGF21 (p < 0.001). After glucose administration, FGF21 declined sharply at 360 min, with a subsequent steep increase that exceeded baseline levels. LPS induced a drop in FGF21 after 180 min, while the baseline concentrations were not reached. After 180 min and 24 h, a statistically significant difference was demonstrated after adjusting the Bonferroni-Holm method. So, our results support the hypothesis that glucose and LPS differentially affect the human expression of FGF21 over 48 h.

Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial.

BACKGROUND: Administration of lipopolysaccharide (LPS) from Gram-negative bacteria, also known as the human endotoxemia model, is a standardized and safe model of human inflammation. Experimental studies have revealed that peripheral administration of LPS leads to induction of the kynurenine pathway followed by depressive-like behavior and cognitive dysfunction in animals. The aim of the present study is to investigate how acute intravenous LPS administration affects the kynurenine pathway in healthy male human subjects. METHODS: The present study is a prospective, single-blinded, randomized, placebo-controlled cross-over study to investigate the effects of intravenously administered LPS (Escherichia coli O113, 2 ng/kg) on tryptophan and kynurenine metabolites over 48 h and their association with interleukin-6 (IL-6) and C-reactive protein (CRP). The study included 10 healthy, non-smoking men (18-40 years) free from medication. Statistical differences in tryptophan and kynurenine metabolites as well as associations with IL-6 and CRP in LPS and placebo treated subjects were assessed with linear mixed-effects models. RESULTS: Systemic injection of LPS was associated with significantly lower concentrations of plasma tryptophan and kynurenine after 4 h, as well as higher concentrations of quinolinic acid (QUIN) after 48 h compared to the placebo injection. No differences were found in kynurenic acid (KYNA) or picolinic acid plasma concentrations between LPS or placebo treatment. The KYNA/kynurenine ratio peaked at 6 h post LPS injection while QUIN/kynurenine maintained significantly higher from 3 h post LPS injection until 24 h. The kynurenine/tryptophan ratio was higher at 24 h and 48 h post LPS treatment. Finally, we report an association between the kynurenine/tryptophan ratio and CRP. CONCLUSIONS: Our findings strongly support the concept that an inflammatory challenge with LPS induces the kynurenine pathway in humans, activating both the neurotoxic (QUIN) and neuroprotective (KYNA) branch of the kynurenine pathway. TRIAL REGISTRATION: This study is based on a study registered at ClinicalTrials.gov, NCT03392701 . Registered 21 December 2017.

Performance of the recommended ESC/EASD cardiovascular risk stratification model in comparison to SCORE and NT-proBNP as a single biomarker for risk prediction in type 2 diabetes mellitus.

BACKGROUND: Recently, the European Society of Cardiology (ESC) and European Association for the Society of Diabetes (EASD) introduced a new cardiovascular disease (CVD) risk stratification model to aid further treatment decisions in individuals with diabetes. Our study aimed to investigate the prognostic performance of the ESC/EASD risk model in comparison to the Systematic COronary Risk Evaluation (SCORE) risk model and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in an unselected cohort of type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: A total of 1690 T2DM patients with a 10-year follow up for fatal CVD and all-cause death and a 5-year follow up for CVD and all-cause hospitalizations were analyzed. According to ESC/EASD risk criteria 25 (1.5%) patients were classified as moderate, 252 (14.9%) high, 1125 (66.6%) very high risk and 288 (17.0%) were not classifiable. Both NT-proBNP and SCORE risk model were associated with 10-year CVD and all-cause death and 5-year CVD and all-cause hospitalizations while the ESC/EASD model was only associated with 10-year all-cause death and 5-year all-cause hospitalizations. NT-proBNP and SCORE showed significantly higher C-indices than the ESC/EASD risk model for CVD death [0.80 vs. 0.53, p < 0.001; 0.64 vs. 0.53, p = 0.001] and all-cause death [0.73, 0.66 vs. 0.52, p < 0.001 for both]. The performance of SCORE improved in a subgroup without CVD aged 40-64 years compared to the unselected cohort, while NT-proBNP performance was robust across all groups. CONCLUSION: The new introduced ESC/EASD risk stratification model performed limited compared to SCORE and single NT-proBNP assessment for predicting 10-year CVD and all-cause fatal events in individuals with T2DM.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Is Not Induced in Artificial Human Inflammation and Is Not Correlated with Inflammatory Response.

Lipoproteins, as well as proprotein convertase subtilisin/kexin type 9 (PCSK9), have been shown to play a key role in the innate immune response. However, knowledge about the role and kinetics of PCSK9 in human inflammation is currently insufficient. This study aimed to investigate the interaction between inflammation and lipid metabolism, including the possible role of PCSK9. A single-blinded, placebo-controlled cross-over study using the human endotoxin model was performed. Ten healthy men received lipopolysaccharide (LPS) or placebo on two different study days after overnight fasting. Lipoproteins as well as PCSK9 were measured repetitively over 48 h. PCSK9 plasma concentrations were not induced by LPS infusion, and no correlation between PCSK9 plasma concentrations and the degree of inflammation could be identified. The observed low-density lipoprotein (LDL) response to inflammation was more complex than anticipated, especially in the very early phase after the inflammatory stimulus. Baseline concentrations of LDL, as well as high-density lipoprotein (HDL), correlated negatively with inflammatory response. Our data suggest that the lipoprotein response to inflammation is independent of PCSK9. The proposed elevations of PCSK9 and suspected correlations between PCSK9 levels and inflammatory response are not supported by our data. (This study has been registered at ClinicalTrials.gov under registration no. NCT03392701.).

GDF-15 Is Associated with Cancer Incidence in Patients with Type 2 Diabetes.

BACKGROUND: Diabetes has been linked epidemiologically to increased cancer incidence and mortality. Growth differentiation factor 15 (GDF-15) is increased in patients with diabetes and has recently been linked to the occurrence of cancer. We investigated whether circulating GDF-15 concentrations can predict the incidence of malignant diseases in a diabetic patient cohort already facing increased risk for cancer. METHODS: We prospectively enrolled a total of 919 patients with type 2 diabetes and no history of malignant disease, who were clinically followed up for 60 months. GDF-15, N-terminal pro-B-type natriuretic peptide and troponin T were measured at baseline; an additional 4 cardiovascular biomarkers were determined for a subpopulation (n = 259). Study end point was defined as the first diagnosis of any type of cancer during the follow-up period. RESULTS: During a median follow-up of 60 months, 66 patients (7.2%) were diagnosed with cancer. Baseline circulating GDF-15 concentrations were higher in patients that developed cancer over the follow-up period when compared to cancer-free patients. Increased GDF-15 concentrations were significantly associated with cancer incidence [crude hazard ratio (HR) per 1-IQR (interquartile range) increase 2.13, 95% CI 1.53-2.97, P < 0.001]. This effect persisted after multivariate adjustment with an adjusted HR of 1.86 (95% CI 1.22-2.84; P = 0.004). Among the 4 additionally tested cardiovascular markers in the subpopulation, only troponin T and C-terminal proendothelin-1 showed a significant association with future cancer incidence with unadjusted HRs of 1.71 (95% CI 1.28-2.28, P < 0.001) and 1.68 (95% CI 1.02-2.76, P = 0.042), respectively. CONCLUSIONS: Increased circulating concentrations of GDF-15 are associated with increased cancer incidence in patients with type 2 diabetes.

[Position paper: Open-source technology in the treatment of people living with diabetes mellitus-an Austrian perspective : Technology Committee of the Austrian Diabetes Association]. / Positionspapier: Open-source-Technologie in der Behandlung von Menschen mit Diabetes mellitus ­ eine österreichische Perspektive : Technologieausschuss der Österreichischen Diabetes Gesellschaft.

People living with diabetes mellitus can be supported in the daily management by diabetes technology with automated insulin delivery (AID) systems to reduce the risk of hypoglycemia and improve glycemic control as well as the quality of life. Due to barriers in the availability of AID-systems, the use and development of open-source AID-systems have internationally increased. This technology provides a necessary alternative to commercially available products, especially when approved systems are inaccessible or insufficiently adapted to the specific needs of the users. Open-source technology is characterized by worldwide free availability of codes on the internet, is not officially approved and therefore the use is on the individual's own responsibility. In the clinical practice a lack of expertise with open-source AID technology and concerns about legal consequences, lead to conflict situations for health-care professionals (HCP), sometimes resulting in the refusal of care of people living with diabetes mellitus. This position paper provides an overview of the available evidence and practical guidance for HCP to minimize uncertainties and barriers. People living with diabetes mellitus must continue to be supported in education and diabetes management, independent of the chosen diabetes technology including open-source technology. Check-ups of the metabolic control, acute and chronic complications and screening for diabetes-related diseases are necessary and should be regularly carried out, regardless of the chosen AID-system and by a multidisciplinary team with appropriate expertise.

[Postoperative management]. / Postoperatives Management.

Bariatric surgery results in significant weight loss, reduction or even remission of obesity-associated comorbidities, reduced mortality, and improved quality of life in many patients; however, obesity is a chronic disease, thus follow-up care is required after bariatric surgery. Furthermore, specific issues, such as micronutrient deficiencies and subsequent complications, can arise both in the short-term and the long-term. Abdominal pain after bariatric surgery must always be regarded as a serious symptom. A further focus should be on the diagnosis and treatment of dumping syndrome. Patients with type 2 diabetes should be regularly screened for recurrent hyperglycemia as well as specific sequelae, even though blood glucose levels may be substantially improved or normalized. In addition to centers with multidisciplinary teams, primary care and, in particular, general practitioners will play an increasingly more important role in the follow-up care after bariatric surgery.

[Obesity and type 2 diabetes (Update 2023)]. / Adipositas und Typ-2-Diabetes (Update 2023).

The body mass index (BMI) is a very crude measure of body fatness in individuals. Even normal weight persons can have too much body fat in cases of a lack of muscle mass (sarcopenia), which is why additional measurements of waist circumference and body fatness, e.g. bioimpedance analysis (BIA), are recommended. Lifestyle management including nutrition modification and increase in physical activity are important measures for the prevention and treatment of diabetes. Regarding the treatment of type 2 diabetes, body weight is increasingly used as a secondary target parameter. The choice of anti-diabetic treatment and additional concomitant therapies is increasingly influenced by body weight. The importance of modern GLP­1 agonists and dual GLP­1 GIP agonists increases since these drugs target obesity and type 2 diabetes. Bariatric surgery is at present indicated with a BMI > 35 kg/m2 with concomitant risk factors, such as diabetes and can lead at least to partial diabetes remission but has to be incorporated into an appropriate lifelong care concept.

[Diabetes mellitus, coronary artery disease and heart disease (Update 2023)]. / Diabetes mellitus, koronare Herzkrankheit und Herzinsuffizienz (Update 2023).

Diabetes mellitus, cardiovascular disease and heart failure are interacting dynamically. Patients being diagnosed with cardiovascular disease should be screened for diabetes mellitus. Enhanced cardiovascular risk stratification based on biomarkers, symptoms and classical risk factors should be performed in patients with preexisting diabetes mellitus. In patients with previously diagnosed arterosclerotic cardiovascular disease an agent proven to reduce major adverse cardiovascular events or cardiovascular mortality is recommended.

[Hospital diabetes management (Update 2023)]. / Diabetesmanagement im Krankenhaus (Update 2023).

This position statement presents the recommendations of the Austrian Diabetes Association for diabetes management of adult patients during inpatient stay. It is based on the current evidence with respect to blood glucose targets, insulin therapy and treatment with oral/injectable antidiabetic drugs during inpatient hospitalization. Additionally, special circumstances such as intravenous insulin therapy, concomitant therapy with glucocorticoids and use of diabetes technology during hospitalization are discussed.

Transapical electrosurgical laceration and stabilization of mitral clips followed by transcatheter mitral valve replacement-A one-stop shop.

Objective: Electrosurgical laceration and stabilization of mitral clips (ELASTA-CLIP) is a bail-out technique to recreate a single-orifice mitral valve after transcatheter edge-to-edge repair (TEER) with subsequent transcatheter mitral valve replacement (TMVR). This technique is a novel option for patients with significant residual mitral regurgitation after TEER with high risk for conventional surgery. The original ELASTA CLIP procedure features a transseptal approach, whereas the TMVR with the Tendyne bioprosthesis has a transapical access. Hereby we tested the hypothesis that a modified transapical ELASTA CLIP technique can be safely applied transapically allowing a straightforward one-stop shop access strategy. Methods: We developed the procedural steps in a porcine passive-beating heart model and applied the modified technique with subsequent TMVR in 2 consecutive patients with severe mitral regurgitation after previous TEER. Patients were followed up to 30 days. Results: The modified transapical ELASTA CLIP procedure was successful in both patients. The mean total procedure time was 118 minutes, and the mean fluoroscopy duration 22 minutes. At 30 days' follow-up, both patients were alive without bleeding complications, reintervention, or prosthetic valve dysfunction. Conclusions: The modified transapical ELASTA CLIP procedure is technically feasible and safe at 30 days. Procedure times are lower compared with previous reports of the original transseptal approach.

[Other specific types of diabetes and exocrine pancreatic insufficiency (update 2023)]. / Andere spezifische Diabetesformen und exokrine Pankreasinsuffizienz (Update 2023).

The heterogenous category "specific types of diabetes due to other causes" encompasses disturbances in glucose metabolism due to other endocrine disorders such as acromegaly or hypercortisolism, drug-induced diabetes (e.g. antipsychotic medications, glucocorticoids, immunosuppressive agents, highly active antiretroviral therapy (HAART), checkpoint inhibitors), genetic forms of diabetes (e.g. Maturity Onset Diabetes of the Young (MODY), neonatal diabetes, Down­, Klinefelter- and Turner Syndrome), pancreatogenic diabetes (e.g. postoperatively, pancreatitis, pancreatic cancer, haemochromatosis, cystic fibrosis), and some rare autoimmune or infectious forms of diabetes. Diagnosis of specific diabetes types might influence therapeutic considerations. Exocrine pancreatic insufficiency is not only found in patients with pancreatogenic diabetes but is also frequently seen in type 1 and long-standing type 2 diabetes.

[Insulin pump therapy and continuous glucose monitoring]. / Diabetestechnologie (Update 2023).

This Guideline represents the recommendations of the Austrian Diabetes Association (ÖDG) on the use of diabetes technology (insulin pump therapy; continuous glucose monitoring, CGM; hybrid closed-loop systems, HCL; diabetes apps) and access to these technological innovations for people with diabetes mellitus based on current scientific evidence.

[Overweight and obesity in adults: general principles of treatment and conservative management]. / Übergewicht und Adipositas bei Erwachsenen: allgemeine Behandlungsgrundsätze und konservatives Management.

The prevalence of overweight and obesity is steadily increasing in Austria as well as internationally. Obesity in particular is associated with multiple health risks, comorbidities, functional disability, and social stigma. Obesity is an independent, complex, chronic disease and should be treated as such by a multidisciplinary team of appropriately qualified personnel. In addition to recent international guidelines, this consensus paper outlines the overall principles of the management of overweight and obesity and provides guidance for the diagnosis and conservative treatment, focusing on lifestyle modifications and pharmacotherapy. Using the "5A" framework of behavioral health intervention, guidelines for a structured, pragmatic, and patient-centered medical care of adults with overweight or obesity are presented.

[Antihyperglycemic treatment guidelines for diabetes mellitus type 2 (Update 2023)]. / Antihyperglykämische Therapie bei Diabetes mellitus Typ 2 (Update 2023).

Hyperglycemia significantly contributes to complications in patients with diabetes mellitus. While lifestyle interventions remain cornerstones of disease prevention and treatment, most patients with type 2 diabetes will eventually require pharmacotherapy for glycemic control. The definition of individual targets regarding optimal therapeutic efficacy and safety as well as cardiovascular effects is of great importance. In this guideline we present the most current evidence-based best clinical practice data for healthcare professionals.

SUBCLINICAL KIDNEY INJURY IS CAUSED BY A MODERATE SINGLE INFLAMMATORY EVENT.

ABSTRACT: Background: Current means of diagnosis of acute kidney injury (AKI) based on serum creatinine have poor sensitivity and may miss possible therapeutic windows in subclinical kidney injury, especially in septic AKI. Kidney injury molecule-1 (KIM-1) may be a valuable biomarker to improve diagnostic algorithms for AKI. The understanding of septic AKI is still insufficient, and knowledge about KIM-1 kinetics in inflammation is scarce. The aim of this study was to investigate the possible effect of lipopolysaccharide (LPS) on KIM-1 as a marker of structural kidney injury in healthy volunteers. Methods: A single-blinded, placebo-controlled cross-over study using the human endotoxin model (LPS administration) was performed in 10 healthy men. Kidney injury molecule-1 and serum creatinine were measured repetitively for 48 hours. Results: We observed a significant elevation of serum KIM-1 levels after the administration of LPS ( P < 0.001). Furthermore, LPS caused a significant elevation of serum creatinine at an early time point ( P = 0.013) as compared with placebo. Conclusion: Even a relatively small inflammatory stimulus is sufficient to cause subclinical structural kidney injury with elevated KIM-1 and serum creatinine in healthy volunteers. This outlines the insufficiency of the current diagnostic approach regarding AKI and the urgency to develop novel diagnostic algorithms including markers of kidney injury. Clinical Trial Registration:www.clinicaltrials.gov . Unique identifier: NCT03392701 (August 1, 2018).

Effect of repeated bolus and continuous glucose infusion on a panel of circulating biomarkers in healthy volunteers.

HYPOTHESIS: Glycaemic variability (GV) refers to fluctuations in the blood glucose level and may contribute to complications in patients suffering from Diabetes. Several studies show negative effects of GV on the cardiovascular system, however there is still a lack of conclusive evidence. Using an explorative cardiovascular panel, it is possible to simultaneously measure the effects on proteins relevant for cardiovascular processes. The aim of this study was to investigate the effects of rapid glucose excursions on cardiovascular and metabolic parameters in healthy individuals. METHODS: An explorative single-blinded cross-over study was performed in ten healthy men. Subjects received 3 times 20 grams of glucose i.v. over 5 minutes or 60 grams of glucose continuously over 3 hours. Blood was taken for repeated measurements of the cardiovascular panel over the following 6 hours and again after 24 and 48 hours. RESULTS: We observed a significant elevation of 7 cardiovascular biomarkers (BMP6, SLAMF7, LOX-1, ADAMTS13, IL-1RA, IL-4RA, PTX3) at t = 360min after rapid glucose infusion compared to a continuous glucose infusion. CONCLUSIONS: Intraday GV seems to have acute effects on cardiovascular proteins in healthy test persons. Rapid glucose administration compared to continuous administration showed significant changes in BMP6, SLAMF7, ADAMTS13, IL1RA, PTX3, IL-4RA and LOX-1. CLINICAL TRIAL REGISTRATION: NCT04488848.

High Anti-CoV2S Antibody Levels at Hospitalization Are Associated with Improved Survival in Patients with COVID-19 Vaccine Breakthrough Infection.

BACKGROUND: Although vaccination against COVID-19 is highly effective, breakthrough infections occur, often leading to severe courses and death. The extent of protection provided by individual antibody levels in breakthrough infections is still unknown and cut-off levels have yet to be determined. METHODS: In 80 consecutive fully vaccinated patients hospitalized between August and December 2021 with COVID-19 breakthrough infection (Delta variant), anti-CoV2S antibody levels were analyzed for the endpoint of death. RESULTS: Ten out of the 12 patients who died (83.3%) had antibody levels < 600 U/mL; 5 (41.7%) of these had antibody levels < 200 U/mL. Only 2 patients with a level of >600 U/mL died from vaccine breakthrough infection. Correction for the number of comorbidities and age revealed that anti-CoV2S antibody levels at the time of hospitalization were a significant predictor for reduced risk of death (OR = 0.402 for every 1000 U/mL, p = 0.018). CONCLUSIONS: In this retrospective data analysis, we show that almost all patients who died from COVID-19 vaccine breakthrough infection had antibody levels < 600 U/mL, most of them below 200 U/mL. In logistic regression corrected for the number of comorbidities and age, anti-CoV2S antibody levels at the time of hospitalization proved to be a significantly protective predictor against death.

The relationship between insulin resistance and the cardiovascular biomarker growth differentiation factor-15 in obese patients.

BACKGROUND: Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine linked to obesity comorbidities such as cardiovascular disease, inflammation, and cancer. GDF-15 also has adipokine properties and recently emerged as a prognostic biomarker for cardiovascular events. METHODS: We evaluated the relationship of plasma GDF-15 concentrations with parameters of obesity, inflammation, and glucose and lipid metabolism in a cohort of 118 morbidly obese patients [mean (SD) age 37.2 (12) years, 89 females, 29 males] and 30 age- and sex-matched healthy lean individuals. All study participants underwent a 75-g oral glucose tolerance test; 28 patients were studied before and 1 year after Roux-en-Y gastric bypass surgery. RESULTS: Obese individuals displayed increased plasma GDF-15 concentrations (P < 0.001), with highest concentrations observed in patients with type 2 diabetes. GDF-15 was positively correlated with age, waist-to-height ratio, mean arterial blood pressure, triglycerides, creatinine, glucose, insulin, C-peptide, hemoglobin A(1c), and homeostatic model assessment insulin resistance index and negatively correlated with oral glucose insulin sensitivity. Age, homeostatic model assessment index, oral glucose insulin sensitivity, and creatinine were independent predictors of GDF-15 concentrations. Roux-en-Y gastric bypass led to a significant reduction in weight, leptin, insulin, and insulin resistance, but further increased GDF-15 concentrations (P < 0.001). CONCLUSIONS: The associations between circulating GDF-15 concentrations and age, insulin resistance, and creatinine might account for the additional cardiovascular predictive information of GDF-15 compared to traditional risk factors. Nevertheless, GDF-15 changes following bariatric surgery suggest an indirect relationship between GDF-15 and insulin resistance. The clinical utility of GDF-15 as a biomarker might be limited until the pathways directly controlling GDF-15 concentrations are better understood.

Repeat measurements of glycated haemoglobin A(1c) and N-terminal pro-B-type natriuretic peptide: divergent behaviour in diabetes mellitus.

BACKGROUND: Patients with diabetes mellitus have a substantially increased risk of developing cardiovascular disease. However, the absolute risk greatly varies not only among patients, but the risk profile for an individual patient may also change over time. We investigated the prognostic role of repetitive measurements of Glycated haemoglobin A(1c) (HbA(1c) ) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with longstanding diabetes. MATERIALS AND METHODS: For this prospective, observational study data from 544 consecutive patients were collected between 2005 and 2008. HbA(1c) and NT-proBNP were measured at baseline and after 1 year. The median observation period was 40 months. Endpoints were all-cause mortality, cardiac, cardiovascular and all-cause hospitalizations. RESULTS: N-terminal pro-B-type natriuretic peptide concentrations significantly increased from 230 ± 385 to 280 ± 449 pg mL(-1) (P < 0·001); during the same time, HbA(1c) significantly decreased from 7·6 ± 1·5 to 7·3 ± 1·2 (P < 0·001). NT-proBNP was the best baseline predictor in a Cox regression model consisting of NT-proBNP, HbA(1c) , age, gender and duration of diabetes for all endpoints (P < 0·001). NT-proBNP at follow-up was the best predictor for the remaining period (P < 0·001, all endpoints). HbA(1c) at baseline and follow-up was predictive for all-cause hospitalizations (P = 0·005 both). In a third model that investigated the plasticity of both markers, changes in HbA(1c) concentration had no predictive value, but a change of NT-proBNP concentration was highly predictive (P = 0·025 all-cause mortality, P < 0·001 all other endpoints). CONCLUSIONS: N-terminal pro-B-type natriuretic peptide and HbA(1c) concentrations significantly diverged over a 1-year period. NT-proBNP was the most potent predictor of outcome at baseline and follow-up, and changes in NT-proBNP concentrations were linked to an altered risk profile, unlike changes in HbA(1c) levels.