Orosomucoid in urine is a powerful predictor of cardiovascular mortality in normoalbuminuric patients with type 2 diabetes at five years of follow-up

Aims/hypothesis To study whether urinary orosomucoid excretion rate (UOER) predicts mortality in normoalbuminuric patients with diabetes at 5 years of follow-up, and to investigate the relationship between orosomucoid in serum and urine.Methods A cohort of 578 patients with diabetes (430 type 2, 148 type 1) was followed prospectively for an average of 5 years. UOER was measured in timed overnight urine samples.Results Eighty-two patients with type 2 diabetes and 17 patients with type 1 diabetes died. Among patients with type 2 diabetes, 251 (58%) had normoalbuminuria; increased UOER independently predicted cardiovascular mortality (OR 4.94, 95% CI 1.60–15.22; p<0.006) in those with normoalbuminuria and in the entire cohort of patients with type 2 diabetes (odds ratio 3.63, 95% CI 1.50–8.81; p<0.005). Patients with increased UOER had a higher all-cause mortality than those with normal UOER (log-rank test, p<0.001 for type 2 patients; p<0.04 for type 1 patients). In patients with type 1 diabetes, there were five cardiovascular deaths and no significant predictive value of UOER. Patients with increased UOER had a subclinical increase in serum orosomucoid.Conclusion/interpretation Increased UOER was an independent, powerful predictor of cardiovascular mortality in normoalbuminuric patients with type 2 diabetes and in the entire cohort of patients with type 2 diabetes. There were indications of UOER as being a valuable marker in type 1 diabetes that showed differences in survival between patients with normal versus increased UOER. Serum orosomucoid was associated with UOER; UOER may be a marker of low-grade inflammation in patients with diabetes.     

Retinopathy as an independent predictor of all-cause mortality in individuals with type 2 diabetes

AimsTo assess whether the presence and grade of diabetic retinopathy (DR) predict all-cause mortality, independent of risk factors for cardiovascular disease (CVD) and other complications, including diabetes-related kidney disease (DKD) and CVD, in individuals with type 2 diabetes mellitus.MethodsProspective cohort study that enroled 15,773 patients in 19 Italian centers in 2006–2008. DR ascertained by fundoscopy, DKD by albuminuria and estimated glomerular filtration rate, and prior CVD by hospital discharge records. All-cause mortality retrieved for 15,656 patients on 31 October 2015.ResultsThe adjusted risk of death was increased in patients with any DR (hazard ratio, 1.136 [95% confidence interval, 1.054;1.224] P < 0.0001), advanced DR, including severe non-proliferative and proliferative DR and diabetic macula edema (1.213 [1.097;1.340] P < 0.0001), and especially proliferative DR alone (1.381 [1.207;1.580] P < 0.0001), compared with those without DR. The impact of DR was more evident in patients without than in those with DKD or CVD. Mortality risk was increased in participants with DR alone, though much less than in those with DKD or CVD alone and particularly in those with both DR and DKD or CVD. DR grade was related to mortality in individuals without DKD or CVD, whereas it conferred no additional risk to those with albuminuric or nonalbuminuric DKD or established CVD.ConclusionsIn patients with type 2 diabetes mellitus, the excess mortality risk conferred by DR is relatively small and higher in those without DKD and CVD, suggesting that it may be mediated by the concurrent presence of these complications, even at a subclinical level.     

Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients

Although various studies reported that pulse pressure, an indirect index of arterial stiffening, was an independent risk factor for mortality, a direct relationship between arterial stiffness and all-cause and cardiovascular mortality remained to be established in patients with essential hypertension. A cohort of 1980 essential hypertensive patients who attended the outpatient hypertension clinic of Broussais Hospital between 1980 and 1996 and who had a measurement of arterial stiffness was studied. At entry, aortic stiffness was assessed from the measurement of carotid-femoral pulse-wave velocity (PWV). A logistic regression model was used to estimate the relative risk of all-cause and cardiovascular deaths. Selection of classic risk factors for adjustment of PWV was based on their influence on mortality in this cohort in univariate analysis. Mean age at entry was 50+/-13 years (mean+/-SD). During an average follow-up of 112+/-53 months, 107 fatal events occurred. Among them, 46 were of cardiovascular origin. PWV was significantly associated with all-cause and cardiovascular mortality in a univariate model of logistic regression analysis (odds ratio for 5 m/s PWV was 2.14 [95% confidence interval, 1.71 to 2.67, P<0.0001] and 2.35 [95% confidence interval, 1.76 to 3.14, P<0.0001], respectively). In multivariate models of logistic regression analysis, PWV was significantly associated with all-cause and cardiovascular mortality, independent of previous cardiovascular diseases, age, and diabetes. By contrast, pulse pressure was not significantly and independently associated to mortality. This study provides the first direct evidence that aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in patients with essential hypertension.     

Uric acid is not an independent predictor of cardiovascular mortality in type 2 diabetes: a population-based study

ObjectiveAlthough some studies have suggested that uric acid is a risk factor for mortality, this relationship is still uncertain in people with type 2 diabetes.MethodsThe study base was the population-based cohort of 1540 diabetic subjects (median age 68.9 years) of the Casale Monferrato Study. The role of serum uric acid on 15-years all-cause, cardiovascular and non-cardiovascular mortality was assessed by multivariate Cox proportional hazards modeling.ResultsBaseline levels of serum uric acid were negatively correlated with HbA1c, were higher in men and in the elderly and were independently associated with components of the metabolic syndrome. Out of 14,179 person-years, 1000 deaths (514 due to cardiovascular diseases) were observed. Compared to the lower quartile of uric acid, HRs (95% CI) in the upper quartile were 1.47 (1.22–1.76) for all-cause mortality; 1.40 (1.09–1.80) for cardiovascular mortality and 1.50 (1.15–1.96) for non-cardiovascular mortality. In multiple adjusted models, however, HRs were 1.30 (1.06–1.60) for all-cause mortality, 1.13 (0.85–1.50) for cardiovascular mortality and 1.50 (1.11–2.02) for non-cardiovascular mortality (men 1.87, 1.19–2.95; women 1.20, 0.80–1.80); the latter appeared to be due to neoplastic diseases (HR in all combined quartiles vs. lower quartile: both sexes 1.59, 1.05–2.40; men 1.54, 0.83–2.84, women 1.68, 0.95–2.92).ConclusionsIn diabetic people, uric acid is associated with components of the metabolic syndrome but it may not be accounted as an independent risk factor for cardiovascular mortality. The increased all-cause mortality risk with higher levels of uric acid might be due to increased neoplastic mortality and deserves future studies.     

Serum adiponectin concentration is a positive predictor of all-cause and cardiovascular mortality in type 1 diabetes

Abstract. Forsblom C, Thomas MC, Moran J, Saraheimo M, Thorn L, Wadén J, Gordin D, Frystyk J, Flyvbjerg A, Groop P‐H, on behalf of the FinnDiane Study Group (Folkhälsan Institute of Genetics, Helsinki; Department of Medicine Helsinki University Central Hospital, Helsinki, Finland; The Baker IDI Heart and Diabetes Institute, Melbourne, Vic.; The Queen Elizabeth Hospital, Woodville, SA, Australia; and Aarhus University Hospital, Aarhus C., Denmark). Serum adiponectin concentration is a positive predictor of all‐cause and cardiovascular mortality in type 1 diabetes. J Intern Med 2011; 270 : 346–355. Background. Adiponectin is widely regarded as an anti‐atherogenic, antioxidant and anti‐inflammatory molecule. However, adiponectin concentration is paradoxically increased in individuals with type 1 diabetes, in whom it is positively associated with adverse clinical outcomes. Objective. To explore the association between serum adiponectin concentration and mortality outcomes in adults with type 1 diabetes. Design. Multicentre prospective cohort study. Setting. Primary and tertiary care. Subjects. Finnish adults with type 1 diabetes (n = 2034). Main outcome measures. All‐cause and cardiovascular mortality. Independent predictors of mortality were determined using the Cox and the Fine and Gray competing risks proportional hazards models. Results. During a median of 11 years of follow‐up, there were 173 deaths (8.5%, 1.0 per hundred person‐years). Adiponectin was linearly associated with all‐cause mortality [Cox model: hazard ratio (HR) 1.02, 95% confidence interval (CI) 1.01–1.03, P < 0.001] and cardiovascular mortality (Fine and Gray model: HR 1.02, 95% CI 1.00–1.04, P = 0.035); patients with the highest adiponectin concentrations had the shortest survival. The mortality risk associated with adiponectin was independent of glycaemic and lipid control, pre‐existing cardiovascular disease, markers of inflammation and the presence and severity of kidney disease. Conclusions. Although adiponectin is generally considered to be a protective molecule, increased concentrations of adiponectin in type 1 diabetes are independently associated with all‐cause and cardiovascular mortality. Moreover, the fact that this association was observed for the first time in patients with normal urinary albumin levels, who have few comorbidities, suggests that adiponectin is specifically linked with vascular damage in type 1 diabetes.     

Soluble receptor for AGE (RAGE) is a novel independent predictor of all-cause and cardiovascular mortality in type 1 diabetes

Aims/hypothesis  

Activation of the receptor for AGE (RAGE) is implicated in the development and progression of vascular complications of diabetes. In this study, we explore factors and mortality outcomes associated with soluble RAGE (sRAGE) in a multicentre nationwide cohort of Finnish adults with type 1 diabetes.     

Microalbuminuria in Type 2 diabetes: an independent predictor of cardiovascular mortality

Background: Microalbuminuria has been shown to be associated with cardiovascular mortality in type 2 diabetic subjects. It is unclear to what extent this is due to the increased prevalence of other cardiac risk factors. Aims: To examine the relationship of urine albumin excretion to cardiovascular mortality and to determine its status as an independent risk factor. Methods: In a prospective longitudinal study from 1986–1999 we followed 666 type 2 diabetic subjects from a diabetes outpatient service. Cardiovascular risk factors including urine albumin concentration were measured at study entry. Cox proportional hazards regression was used to determine risk factors for mortality. The hazard ratios of microalbuminuria and macroalbuminuria for all cause, cardiovascular and coronary heart disease mortality were determined after accounting for other cardiac risk factors including blood pressure, glycated haemoglobin, total cholesterol, HDL cholesterol, triglycerides, urea, smoking, body mass index, patient age and disease duration. Results: The prevalence of urine albumin of 30–300 mg/L at study entry was 31.7%. A total of 167 deaths occurred (80 from cardiovascular disease). Mortality hazard ratios in subjects with urine albumin of 30–300 mg/L as compared to <30 mg/L, adjusted for age, sex and other cardiovascular risk factors were 1.77 (95% CI 1.22–2.57, p=0.002) for all causes, 2.34 (95% CI 1.38–3.99, p=0.002) for cardiovascular and 1.78 (95% CI 0.97–3.26, p=0.061) for coronary heart disease (CHD) mortality. Other factors significantly associated with cardiovascular mortality included diastolic blood pressure, HDL cholesterol and glycated haemoglobin. Total cholesterol and log triglyceride were significantly associated with CHD mortality. Disease duration, age at diagnosis, smoking and body mass index were not related to cardiovascular or CHD mortality. Conclusions: We confirm microalbuminuria as an independent predictor of mortality in type 2 diabetes despite its association with a number of conventional cardiovascular risk factors.     

Adiponectin is an independent predictor of all-cause mortality, cardiac mortality, and myocardial infarction in patients presenting with chest pain.

AIMS: To determine the prognostic value of baseline plasma adiponectin levels in patients with known or suspected coronary artery disease referred for coronary angiography. METHODS AND RESULTS: Adiponectin was measured in 325 male patients with stable angina, troponin-negative unstable angina, and non-ST-segment elevation myocardial infarction (MI) undergoing coronary angiography at a Veterans Administration Medical Center. The patients were then followed prospectively for the occurrence of all-cause mortality, cardiac mortality, and MI. Follow-up data at 24 months were available for 97% of the patients. Adiponectin was the only biomarker to independently predict the individual endpoints of all-cause mortality, cardiac mortality, and MI. The 24-month survival rates for patients in the lower (< or =4.431 mg/L), middle (>4.431 and < or =8.008 mg/L), and upper (>8.008 mg/L) tertiles of plasma adiponectin values were 95.0, 90.4, and 83.5%, respectively (P = 0.0232 by log-rank test). Furthermore, when patients with chest pain were risk-stratified into those with and without a non-ST-segment elevation acute coronary syndrome (NSTEACS), adiponectin remained an independent predictor of both all-cause mortality and cardiac mortality in the NSTEACS subgroup. CONCLUSION: In a cohort of male patients undergoing coronary angiography, a single baseline determination of plasma adiponectin is independently predictive of the subsequent risk of death and MI.     

Increased urinary orosomucoid excretion is not related to impaired renal function in patients with type 2 diabetes

ObjectivesIncreased urinary orosomucoid excretion rate (UOER) independently predicted cardiovascular mortality in patients with type 2 diabetes at 5-years of follow-up. To further explore UOER in relation to local renal physiological phenomena, we studied renal glomerular and tubular functions in patients with type 2 diabetes and normal or increased UOER.MethodsWe performed a cross-sectional study of 40 patients with type 2 diabetes (normal UOER, n=16; increased UOER, n=24) who displayed no signs of cardiovascular disease and 21 healthy control persons. The renal clearance values of [⁵¹Cr]ethylenediaminetetraacetic acid ([⁵¹Cr]EDTA), lithium, orosomucoid, albumin, and sodium were measured.ResultsPatients with type 2 diabetes had normal glomerular filtration rate (GFR) measured by [⁵¹Cr]EDTA clearance. The clearance value of orosomucoid was highly increased in patients with increased UOER. The clearance values of albumin were similar in patients with increased UOER and in healthy controls. Investigations of renal tubular function revealed normal and similar levels of lithium clearance and proximal and distal reabsorption of sodium and water. Serum values of orosomucoid were higher in patients with increased UOER than in healthy controls (P<.001), but were still within reference limits, suggesting chronic low-grade inflammation. UOER was associated with increasing values of orosomucoid clearance (P<.0001) independently of serum orosomucoid.ConclusionsPatients with type 2 diabetes and increased UOER had normal GFR and showed no signs of renal glomerular or tubular dysfunction. We therefore hypothesize that increased levels of UOER may be caused by local renal production of orosomucoid due to chronic low-grade inflammation.     

Anaemia, independent of chronic kidney disease, predicts all-cause and cardiovascular mortality in type 2 diabetic patients

Objective

There is limited and controversial information on whether anaemia is a risk factor for cardiovascular mortality in type 2 diabetes, and whether this risk is modified by the presence of chronic kidney disease (CKD). We assessed the predictive role of lower hemoglobin concentrations on all-cause and cardiovascular mortality in a cohort of type 2 diabetic individuals.

Methods

The cohort included 1153 type 2 diabetic outpatients, who were followed for a mean period of 4.9 years. The independent association of anaemia (i.e., hemoglobin <120 g/l in women and <130 g/l in men) with all-cause and cardiovascular mortality was evaluated by Cox proportional hazards regression models and adjusted for several potential confounders, including kidney function measures.

Results

During follow-up, 166 (14.4%) patients died, 42.2% (n = 70) of them from cardiovascular causes. In univariate analysis, anaemia was associated with increased risk of all-cause (hazard ratio HR 2.62, 95% confidence intervals 1.90–3.60, p < 0.001) and cardiovascular mortality (HR 2.70, 1.67–4.37, p < 0.001). After adjustment for age, sex, body mass index, smoking, hypertension, dyslipidemia, diabetes duration, hemoglobin A1c, medication use (hypoglycemic, anti-hypertensive, lipid-lowering and anti-platelet drugs) and kidney function measures, the association of anaemia with all-cause (adjusted HR 2.11, 1.32–3.35, p = 0.002) and cardiovascular mortality (adjusted HR 2.23, 1.12–4.39, p = 0.020) remained statistically significant.

Conclusions

Anaemia is associated with increased risk of all-cause and cardiovascular mortality in type 2 diabetic individuals, independently of the presence of CKD and other potential confounders. The advantage to treat anaemia in type 2 diabetes for reducing the risk of adverse cardiovascular outcomes remains to be demonstrated.     

Serum sclerostin is an independent predictor of mortality in hemodialysis patients

Background

Sclerostin (Scl) has recently emerged as a novel marker of bone remodeling and vascular calcification. However, whether high circulating Scl is also a risk factor for death is not well established. The purpose of this study was to test whether serum Scl would be associated with mortality.

Methods

we measured serum Scl in a hemodialysis patients’ cohort, which was followed during a ten-year period. Competing risk regression models were applied, as during the follow-up, patients were exposed to both events kidney transplant and death.

Results

Ninety-one patients aged 42.3?±?18.8 years (55% of male gender, 15% of diabetes) were included. During the follow-up, 32 patients underwent kidney transplant and 26 patients died. Non-survivals presented higher FGF23, higher Scl and lower creatinine. There was an association between all-cause mortality and higher Scl (HR =?2.2), higher age (HR =?1.04) and presence of diabetes (HR =?2.27), by competing risk analyses. Even including potential markers of mortality, as creatinine, FGF 23, and gender, Scl, age and diabetes remained significantly related to higher mortality.

Conclusion

Serum Scl is an independent predictor of mortality in dialysis patients. However, whether clinical interventions to modulate Scl would be able to improve these patients survival needs to be determined.

     

Coffee consumption and risk of cardiovascular events and all-cause mortality among women with type 2 diabetes

Aims/hypothesis  Coffee has been linked to both beneficial and harmful health effects, but data on its relationship with cardiovascular disease and mortality in patients with type 2 diabetes are sparse. Methods  This was a prospective cohort study including 7,170 women with diagnosed type 2 diabetes but free of cardiovascular disease or cancer at baseline. Coffee consumption was assessed in 1980 and then every 2–4 years using validated questionnaires. A total of 658 incident cardiovascular events (434 coronary heart disease and 224 stroke) and 734 deaths from all causes were documented between 1980 and 2004. Results  After adjustment for age, smoking and other cardiovascular risk factors, the relative risks were 0.76 (95% CI 0.50–1.14) for cardiovascular diseases (p trend = 0.09) and 0.80 (95% CI 0.55–1.14) for all-cause mortality (p trend = 0.05) for the consumption of ≥4 cups/day of caffeinated coffee compared with non-drinkers. Similarly, multivariable RRs were 0.96 (95% CI 0.66–1.38) for cardiovascular diseases (p trend = 0.84) and 0.76 (95% CI 0.54–1.07) for all-cause mortality (p trend = 0.08) for the consumption of ≥2 cups/day of decaffeinated coffee compared with non-drinkers. Higher decaffeinated coffee consumption was associated with lower concentrations of HbA_1c (6.2% for ≥2 cups/day versus 6.7% for <1 cup/month; p trend = 0.02). Conclusions  These data provide evidence that habitual coffee consumption is not associated with increased risk of cardiovascular diseases or premature mortality among diabetic women. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

男性糖尿病患者踝臂指数与全因和心血管病死亡率关系的前瞻性研究

目的研究男性糖尿病患者外周动脉疾病（PDA）的危险因素及踝臂指数（ABI）与全因和心血管病（CVD）死亡率的关系。方法研究对象来自2004年7月至2005年1月北京及上海地区8所医院的有完整ABI基线资料的男性糖尿病患者815例，于2005年11月至2006年1月对其进行随访调查。结果815例男性糖尿病患者中，ABI降低的PAD组250例（30．67％），ABI正常的非PAD组565例（69．33％），年龄和吸烟史是PAD的独立危险因素，在13．6个月的随访中，有70例死亡，其中27例为CVD死亡。经Cox回归分析，PAD患者发生全因及CVD死亡的相对危险度分别为1．744（1．056—2．877）和3．677（1．588～8．509）。PAD组的生存率显著低于非PAD组。随ABI水平的降低，发生死亡及CVD死亡的危险增加。结论低ABI是男性糖尿病患者死亡和CVD死亡的独立危险因素，在男性糖尿病人群中运用无创性ABI测定对全因死亡及CVD。死亡具有预测价值。     

Wide pulse pressure is an independent predictor of cardiovascular mortality in Puerto Rican men

BACKGROUND AND AIM: Emerging evidence suggests that pulse pressure is an independent predictor of risk for cardiovascular mortality. New studies in diverse populations are needed to further establish the applicability of this finding. Thus, the purpose of this study is to examine the relationship between pulse pressure and cardiovascular mortality in a cohort of Puerto Rican men after 12 years of follow-up. METHODS AND RESULTS: The Puerto Rico Heart Health Program is a study of coronary disease risk factors in men aged 35-79 years at baseline who had an initial examination during the years 1962-1965. It was attended by 9824 subjects representing 80% of the total age-specific male residents in 4 rural and 3 urban areas of Puerto Rico. Cardiovascular risk factors including systolic and diastolic blood pressures were monitored prospectively. This study includes 9106 men free of overt CHD at baseline who were stratified by quartiles of pulse pressure in mmHg: quartile 1, or=57. The odds ratio of cardiovascular mortality was calculated using logistic regression analysis. After adjusting for age, education, smoking status, hypercholesterolemic status, physical activity, diabetic status and mean arterial pressure, we found that those in the highest quartile of pulse pressure (pulse pressure>=57) had significantly higher cardiovascular mortality than those in the lowest quartile (reference group) (OR=1.38 95% CI=1.01-1.88). CONCLUSION: Our findings showed that a wide pulse pressure is independently associated with cardiovascular mortality in this group of Puerto Rican men.