Biomarker-based prediction of fatal and non-fatal cardiovascular outcomes in individuals with diabetes mellitus.

AIMS: The role of biomarkers in predicting cardiovascular outcomes in high-risk individuals is not well established. We aimed to investigate benefits of adding biomarkers to cardiovascular risk assessment in individuals with and without diabetes. METHODS AND RESULTS: We used individual-level data of 95 292 individuals of the European population harmonized in the Biomarker for Cardiovascular Risk Assessment across Europe consortium and investigated the prognostic ability of high-sensitivity cardiac troponin I (hs-cTnI), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hs-CRP). Cox-regression models were used to determine adjusted hazard ratios of diabetes and log-transformed biomarkers for fatal and non-fatal cardiovascular events. Models were compared using the likelihood ratio test. Stratification by specific biomarker cut-offs was performed for crude time-to-event analysis using Kaplan-Meier plots. Overall, 6090 (6.4%) individuals had diabetes at baseline, median follow-up was 9.9 years. Adjusting for classical risk factors and biomarkers, diabetes [HR 2.11 (95% CI 1.92, 2.32)], and all biomarkers (HR per interquartile range hs-cTnI 1.08 [95% CI 1.04, 1.12]; NT-proBNP 1.44 [95% CI 1.37, 1.53]; hs-CRP 1.27 [95% CI 1.21, 1.33]) were independently associated with cardiovascular events. Specific cut-offs for each biomarker identified a high-risk group of individuals with diabetes losing a median of 15.5 years of life compared to diabetics without elevated biomarkers. Addition of biomarkers to the Cox-model significantly improved the prediction of outcomes (likelihood ratio test for nested models P < 0.001), accompanied by an increase in the c-index (increase to 0.81). CONCLUSION: Biomarkers improve cardiovascular risk prediction in individuals with and without diabetes and facilitate the identification of individuals with diabetes at highest risk for cardiovascular events.

In this work, the role of cardiac biomarkers measured from blood to predict cardiovascular events and death is tested in individuals of the general population and particularly in those with known diabetes. The work is based on a cooperation of different population studies across Europe and includes more than 90 000 individuals, with more than 6000 having diabetes. We could demonstrate that the determination of three cardiac biomarkers helps to identify individuals at highest risk for cardiovascular events (e.g. myocardial infarction or stroke) and death, despite accounting for known cardiovascular risk factors in these individuals. Therefore, these biomarkers should be considered for routine risk assessment for cardiovascular diseases and could improve the early identification of high-risk individuals, consequently leading to an earlier initiation of preventive therapies.

Association of Aldosterone with Mortality in the General Population.

INTRODUCTION: Aldosterone excess is linked to cardiovascular events and mortality as well as to low-grade inflammation in the context of metabolic diseases. Whether mildly elevated aldosterone levels in the general population promote cardiovascular risk is still under debate. We analyzed the association of plasma aldosterone concentrations with incident cardiovascular events, cardiovascular and all-cause mortality as well as with biomarkers of subclinical inflammation in the population-based KORA F4 study. METHODS: Plasma aldosterone concentrations were measured with an in-house immunoflurometric assay. The analyses included 2935 participants (n=1076 for selected biomarkers of subclinical inflammation) with a median follow-up of 8.7 (8.2; 9.1) years. The associations were estimated using Cox proportional hazard and linear regression models adjusted for renin, sex, age, body mass index, arterial hypertension, diabetes, estimated glomerular filtration rate, low- and high-density lipoprotein cholesterol, physical activity, smoking, use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, diuretics and calcium channel blockers. RESULTS: Aldosterone was significantly associated with all-cause mortality (hazard ratio per standard deviation increase: 1.20; 95% confidence interval 1.04-1.37), but not with cardiovascular mortality, incident cardiovascular events, or with biomarkers of subclinical inflammation. CONCLUSIONS: Aldosterone was associated with all-cause mortality in the population-based KORA F4 study, but the previously described associations of excess aldosterone with cardiovascular complications and biomarkers of subclinical inflammation could not be shown.

Associations of the vasoactive peptides CT-proET-1 and MR-proADM with incident type 2 diabetes: results from the BiomarCaRE Consortium.

BACKGROUND: Endothelin-1 (ET-1) and adrenomedullin (ADM) are commonly known as vasoactive peptides that regulate vascular homeostasis. Less recognised is the fact that both peptides could affect glucose metabolism. Here, we investigated whether ET-1 and ADM, measured as C-terminal-proET-1 (CT-proET-1) and mid-regional-proADM (MR-proADM), respectively, were associated with incident type 2 diabetes. METHODS: Based on the population-based Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium data, we performed a prospective cohort study to examine associations of CT-proET-1 and MR-proADM with incident type 2 diabetes in 12,006 participants. During a median follow-up time of 13.8 years, 862 participants developed type 2 diabetes. The associations were examined in Cox proportional hazard models. Additionally, we performed two-sample Mendelian randomisation analyses using published data. RESULTS: CT-proET-1 and MR-proADM were positively associated with incident type 2 diabetes. The multivariable hazard ratios (HRs) [95% confidence intervals (CI)] were 1.10 [1.03; 1.18], P = 0.008 per 1-SD increase of CT-proET-1 and 1.11 [1.02; 1.21], P = 0.016 per 1-SD increase of log MR-proADM, respectively. We observed a stronger association of MR-proADM with incident type 2 diabetes in obese than in non-obese individuals (P-interaction with BMI < 0.001). The HRs [95%CIs] were 1.19 [1.05; 1.34], P = 0.005 and 1.02 [0.90; 1.15], P = 0.741 in obese and non-obese individuals, respectively. Our Mendelian randomisation analyses yielded a significant association of CT-proET-1, but not of MR-proADM with type 2 diabetes risk. CONCLUSIONS: Higher concentrations of CT-proET-1 and MR-proADM are associated with incident type 2 diabetes, but our Mendelian randomisation analysis suggests a probable causal link for CT-proET-1 only. The association of MR-proADM seems to be modified by body composition.

Association of C-Terminal Pro-Endothelin-1 with Mortality in the Population-Based KORA F4 Study.

Introduction: Endothelin-1 and its prohormone C-terminal pro-endothelin-1 (CT-proET-1) have been linked to metabolic alterations, inflammatory responses and cardiovascular events in selected study populations. We analyzed the association of CT-proET-1 with cardiovascular events and mortality, carotid intima-media-thickness as surrogate for early atherosclerotic lesions, biomarkers of subclinical inflammation and adipokines in a population-based study. Methods: The cross-sectional and prospective analyses used data from the KORA F4 study with a median follow-up time of 9.1 (8.8-9.4) years. Data on CT-proET-1 and mortality were available for 1554 participants, data on the other outcomes in subgroups (n = 596-1554). The associations were estimated using multivariable linear regression and Cox proportional hazard models adjusted for sex, age, body mass index, estimated glomerular filtration rate, arterial hypertension, diabetes, low-density and high-density lipoprotein cholesterol, current and former smoking and physical activity. The Bonferroni method was used to correct for multiple testing. Results: In the fully adjusted model, CT-proET-1 was associated with cardiovascular (hazard ratio (HR) per standard deviation increase: 1.66; 95% confidence interval (CI): 1.10-2.51; p = 0.017) and all-cause mortality (HR: 2.03; 95% CI 1.55-2.67; p < 0.001), but not with cardiovascular events, and was inversely associated with the intima-media thickness (ß: -0.09 ± 0.03; p = 0.001). CT-proET-1 was positively associated with five out of ten biomarkers of subclinical inflammation and with two out of five adipokines after correction for multiple testing. After inclusion of biomarkers of subclinical inflammation in the Cox proportional hazard model, the association of CT-proET-1 with all-cause mortality persisted (p < 0.001). Conclusion: These results emphasize the complexity of endothelin-1 actions and/or indicator functions of CT-proET-1. CT-proET-1 is a risk marker for all-cause mortality, which is likely independent of vascular endothelin-1 actions, cardiovascular disease and inflammation.

Association of renin and aldosterone with glucose metabolism in a Western European population: the KORA F4/FF4 study.

INTRODUCTION: Primary aldosteronism is associated with impaired glucose tolerance. Whether plasma aldosterone and/or renin concentrations are associated with type 2 diabetes and continuous measures of glucose metabolism in the general population is still under debate. RESEARCH DESIGN AND METHODS: The analyses included 2931 participants of the KORA F4 study at baseline and 2010 participants of the KORA FF4 study after a median follow-up of 6.5 years. The associations of active plasma renin and aldosterone concentrations with type 2 diabetes and continuous measures of glucose metabolism were assessed using logistic and linear regression models. Results were adjusted for sex, age, body mass index (BMI), estimated glomerular filtration rate, potassium, use of ACE inhibitors, angiotensin receptor blockers, beta blockers, diuretics and calcium channel blockers. RESULTS: Cross-sectionally, renin was associated with type 2 diabetes (OR per SD: 1.25, 95% CI 1.10 to 1.43, p<0.001), fasting glucose, 2-hour glucose, insulin, proinsulin, HOMA-B (homeostasis model assessment of beta cell function) and HOMA-IR (homeostasis model assessment of insulin resistance) (all p values <0.001). Aldosterone was not associated with type 2 diabetes (OR: 1.04, 95% CI 0.91 to 1.19; p=0.547) but with insulin, proinsulin and HOMA-IR (all p values <0.001). The aldosterone-renin ratio was inversely associated with type 2 diabetes and several measures of glucose metabolism. Longitudinally, neither renin (OR: 1.12, 95% CI 0.92 to 1.36) nor aldosterone (OR: 0.91, 95% CI 0.74 to 1.11) were associated with incident type 2 diabetes. Renin was inversely associated with changes of insulin concentrations. CONCLUSIONS: In the KORA F4/FF4 study, renin and aldosterone were not associated with incident type 2 diabetes and largely unrelated to changes of measures of glucose metabolism. Cross-sectionally, aldosterone was associated with surrogate parameters of insulin resistance. However, these associations were not independent of renin.

Association of circulating MR-proADM with all-cause and cardiovascular mortality in the general population: Results from the KORA F4 cohort study.

BACKGROUND AND AIM: Despite its vasodilatory effect, adrenomedullin and its surrogate mid-regional pro-adrenomedullin (MR-proADM) have been found to be positively associated with all-cause and cardiovascular mortality. However, the underlying mechanisms thereof remain unclear and the associations were mostly shown in geriatric cohorts or in patients with chronic diseases. Therefore, we aimed to investigate the possible involvement of abdominal obesity, selected adipokines, and biomarkers of subclinical inflammation in the association of MR-proADM with mortality in a population based study cohort. METHODS: Prospective analysis of the KORA F4 study; median follow-up 9.1 (8.8-9.4) years. Complete data on MR-proADM and mortality was available for 1551 participants, aged 56.9±12.9 years (mean±SD). Correlation and regression analyses of MR-proADM with overall (BMI) and abdominal obesity (waist circumference), selected adipokines and biomarkers of subclinical inflammation. Cox proportional hazard models on the association of MR-proADM with all-cause and cardiovascular mortality with adjustment for cardiovascular risk factors and selected biomarkers in study subgroups (n = 603-1551). RESULTS: MR-proADM associated with all-cause (HR (95%CI): 2.37 (1.72-3.26) and 2.31 (1.67-3.20)) and cardiovascular mortality (4.28 (2.19-8.39) and 4.44 (2.25-8.76)) after adjustment for traditional cardiovascular risk factors including BMI or waist circumference, respectively. MR-proADM was further associated with four out of seven examined adipokines (leptin, retinol-binding protein-4, chemerin, and adiponectin) and with five out of eleven examined biomarkers of subclinical inflammation (high-sensitivity C-reactive protein, interleukin-6, myeloperoxidase, interleukin-22, and interleukin-1 receptor antagonist) after multivariable adjustment and correction for multiple testing. However, only IL-6 substantially attenuated the association of MR-proADM with all-cause mortality. CONCLUSIONS: We found an association of MR-proADM with (abdominal) obesity, selected adipokines, and biomarkers of subclinical inflammation. However, the association of MR-proADM with mortality was independent of these parameters. Future studies should investigate the role of IL-6 and further characteristics of subclinical inflammation in the association between MR-proADM and all-cause mortality.

Association of serum uromodulin with adipokines in dependence of type 2 diabetes.

BACKGROUND: The renal tubular glycoprotein uromodulin is associated with obesity and type 2 diabetes, but the underlying mechanisms are elusive. We investigated the association of serum uromodulin with adipokines and tested the effect modification by diabetes status. METHODS: The associations of serum uromodulin with eight adipokines were assessed in 795-1080 participants of the KORA F4 study aged 62-81 years using linear regression models adjusted for sex, age, BMI, estimated glomerular filtration rate and diabetes. Significant associations were assessed for effect modification by diabetes status. We further tested using logistic regression whether adjustment for the significant adipokines affected the association of uromodulin with type 2 diabetes. RESULTS: Serum uromodulin was inversely associated with chemerin and retinol-binding protein-4 after multivariable adjustment (p < 0.001) and Bonferroni correction for multiple testing. No significant association was observed between uromodulin and the other adipokines (leptin, adiponectin, secreted frizzled-related protein 5, progranulin, omentin-1 and vaspin) after correcting for multiple testing. The association of uromodulin with chemerin and retinol-binding protein-4 was stronger in participants with type 2 diabetes than in participants without diabetes (p for interaction < 0.05). However, inclusion of chemerin and retinol-binding protein-4 in logistic regression models did not attenuate the association of serum uromodulin with diabetes. CONCLUSIONS: Serum uromodulin was inversely associated with the predominantly pro-inflammatory adipokines chemerin and retinol-binding protein-4. The associations were stronger in participants with type 2 diabetes compared to participants without diabetes. However, the association of serum uromodulin with type 2 diabetes was independent of chemerin and retinol-binding protein-4.

Natriuretic Peptides and Risk of Type 2 Diabetes: Results From the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium.

OBJECTIVE: Natriuretic peptide (NP) concentrations are increased in cardiovascular diseases (CVDs) but are associated with a lower diabetes risk. We investigated associations of N-terminal pro-B-type NP (NT-proBNP) and midregional proatrial NP (MR-proANP) with incident type 2 diabetes stratified by the presence of CVD. RESEARCH DESIGN AND METHODS: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium, we included 45,477 participants with NT-proBNP measurements (1,707 developed type 2 diabetes over 6.5 years of median follow-up; among these, 209 had CVD at baseline) and 11,537 participants with MR-proANP measurements (857 developed type 2 diabetes over 13.8 years of median follow-up; among these, 106 had CVD at baseline). The associations were estimated using multivariable Cox regression models. RESULTS: Both NPs were inversely associated with incident type 2 diabetes (hazard ratios [95% CI] per 1-SD increase of log NP: 0.84 [0.79; 0.89] for NT-proBNP and 0.77 [0.71; 0.83] for MR-proANP). The inverse association between NT-proBNP and type 2 diabetes was significant in individuals without CVD but not in individuals with CVD (0.81 [0.76; 0.86] vs. 1.04 [0.90; 1.19]; P multiplicative interaction = 0.001). There was no significant difference in the association of MR-proANP with type 2 diabetes between individuals without and with CVD (0.75 [0.69; 0.82] vs. 0.81 [0.66; 0.99]; P multiplicative interaction = 0.236). CONCLUSIONS: NT-proBNP and MR-proANP are inversely associated with incident type 2 diabetes. However, the inverse association of NT-proBNP seems to be modified by the presence of CVD. Further investigations are warranted to confirm our findings and to investigate the underlying mechanisms.

Associations of cardiac stress biomarkers with incident type 2 diabetes and changes in glucose metabolism: KORA F4/FF4 study.

BACKGROUND: High N-terminal pro-brain-type natriuretic peptide levels have been associated with a lower risk of type 2 diabetes mellitus (T2D). However, less is known about other cardiac stress biomarkers in this context. Here we evaluated the association of mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-arginine vasopressin (copeptin), C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM) with incident T2D and changes in glucose metabolism. METHODS: We performed a prospective cohort study using data from the population-based KORA F4/FF4 study. 1773 participants (52.3% women) with MR-proANP measurements and 960 (52.7% women) with copeptin, CT-proET-1 and MR-proADM measurements were included. We examined associations of circulating plasma levels of MR-proANP, copeptin, CT-proET-1 and MR-proADM with incident T2D, the combined endpoint of incident prediabetes/T2D and with fasting and 2 h-glucose, fasting insulin, HOMA-IR, HOMA-B and HbA1c at follow-up. Logistic and linear regression models adjusted for age, sex, waist circumference, height, hypertension, total/HDL cholesterol ratio, triglycerides, smoking, physical activity and parental history of diabetes were used to compute effect estimates. RESULTS: During a median follow-up time of 6.4 years (25th and 75th percentiles: 6.0 and 6.6, respectively), 119 out of the 1773 participants and 72 out of the 960 participants developed T2D. MR-proANP was inversely associated with incident T2D (odds ratio [95% confidence interval]: 0.75 [0.58; 0.96] per 1-SD increase of log MR-proANP). Copeptin was positively associated with incident prediabetes/T2D (1.29 [1.02; 1.63] per 1-SD increase of log copeptin). Elevated levels of CT-proET-1 were associated with increased HOMA-B at follow-up, while elevated MR-proADM levels were associated with increased fasting insulin, HOMA-IR and HOMA-B at follow-up. These associations were independent of previously described diabetes risk factors. CONCLUSIONS: High plasma concentrations of MR-proANP contributed to a lower risk of incident T2D, whereas high plasma concentrations of copeptin were associated with an increased risk of incident prediabetes/T2D. Furthermore, high plasma concentrations of CT-proET-1 and MR-proADM were associated with increased insulin resistance. Our study provides evidence that biomarkers implicated in cardiac stress are associated with incident T2D and changes in glucose metabolism.

Association of fetuin-A with incident type 2 diabetes: results from the MONICA/KORA Augsburg study and a systematic meta-analysis.

OBJECTIVE: We investigated the association of circulating fetuin-A with incident T2D particularly examining potential sex differences. Additionally, we determined whether putative associations were independent of subclinical inflammation, adiponectin and liver fat content. DESIGN: Case-cohort study plus systematic meta-analysis. METHODS: We investigated the association between baseline fetuin-A levels and incident T2D in the MONICA/KORA Augsburg study using Cox proportional hazards analyses. Furthermore, we conducted a systematic review within PubMed and EMBASE and pooled association estimates of eligible studies with the MONICA/KORA Augsburg data using a DerSimonian-Laird random effects model. RESULTS: Within MONICA/KORA Augsburg, 930 participants developed incident T2D (median follow-up: 14 years). We observed a significant association between fetuin-A and T2D risk after multivariable adjustment including C-reactive protein and adiponectin. The strength of the association was similar in males and females (P value for sex interaction >0.55). Seven eligible published studies were identified in addition to the MONICA/KORA Augsburg study for the meta-analysis. The pooled hazard ratio (95% CI) for incident T2D per 1 standard deviation (s.d.) increment of fetuin-A was 1.24 (1.14-1.34) for the multivariable adjusted model. Our sex-stratified meta-analysis yielded relative risk estimates per 1 s.d. of 1.19 (1.04-1.38) in males and 1.29 (1.15-1.46) in females. Further individual adjustment for subclinical inflammation, adiponectin and liver fat content had almost no impact on the strength of the association. CONCLUSIONS: Higher fetuin-A levels are associated with incident T2D in both males and females independently of subclinical inflammation, adiponectin and liver fat content.