Rijk O. B. Gans

Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population

Background—For the general population, the clinical relevance of an increased urinary albumin excretion rate is still debated. Therefore, we examined the relationship between urinary albumin excretion and all-cause mortality and mortality caused by cardiovascular (CV) disease and non-CV disease in the general population. Methods and Results—In the period 1997 to 1998, all inhabitants of the city of Groningen, the Netherlands, aged between 28 and 75 years (n=85 421) were sent a postal questionnaire collecting information about risk factors for CV disease and CV morbidity and a vial to collect an early morning urine sample for measurement of urinary albumin concentration (UAC). The vital status of the cohort was subsequently obtained from the municipal register, and the cause of death was obtained from the Central Bureau of Statistics. Of these 85 421 subjects, 40 856 (47.8%) responded, and 40 548 could be included in the analysis. During a median follow-up period of 961 days (maximum 1139 days), 516 deaths with known cause were recorded. We found a positive dose-response relationship between increasing UAC and mortality. A higher UAC increased the risk of both CV and non-CV death after adjustment for other well-recognized CV risk factors, with the increase being significantly higher for CV mortality than for non-CV mortality (P =0.014). A 2-fold increase in UAC was associated with a relative risk of 1.29 for CV mortality (95% CI 1.18 to 1.40) and 1.12 (95% CI 1.04 to 1.21) for non-CV mortality. Conclusions—Urinary albumin excretion is a predictor of all-cause mortality in the general population. The excess risk was more attributable to death from CV causes, independent of the effects of other CV risk factors, and the relationship was already apparent at levels of albuminuria currently considered to be normal.

Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16.

OBJECTIVE Several studies have suggested an association between specific diabetes treatment and cancer mortality. We studied the association between metformin use and cancer mortality in a prospectively followed cohort. RESEARCH DESIGN AND METHODS In 1998 and 1999, 1,353 patients with type 2 diabetes were enrolled in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study in the Netherlands. Vital status was assessed in January 2009. Cancer mortality rate was evaluated using standardized mortality ratios (SMRs), and the association between metformin use and cancer mortality was evaluated with a Cox proportional hazards model, taking possible confounders into account. RESULTS Median follow-up time was 9.6 years, average age at baseline was 68 years, and average A1C was 7.5%. Of the patients, 570 died, of which 122 died of malignancies. The SMR for cancer mortality was 1.47 (95% CI 1.22–1.76). In patients taking metformin compared with patients not taking metformin at baseline, the adjusted hazard ratio (HR) for cancer mortality was 0.43 (95% CI 0.23–0.80), and the HR with every increase of 1 g of metformin was 0.58 (95% CI 0.36–0.93). CONCLUSIONS In general, patients with type 2 diabetes are at increased risk for cancer mortality. In our group, metformin use was associated with lower cancer mortality compared with nonuse of metformin. Although the design cannot provide a conclusion about causality, our results suggest a protective effect of metformin on cancer mortality.

Skin Autofluorescence, a Measure of Cumulative Metabolic Stress and Advanced Glycation End Products, Predicts Mortality in Hemodialysis Patients

Tissue advanced glycation end products (AGE) are a measure of cumulative metabolic stress and trigger cytokines driven inflammatory reactions. AGE are thought to contribute to the chronic complications of diabetes and ESRD. Tissue autofluorescence is related to the accumulation of AGE. Therefore, skin autofluorescence (AF) may provide prognostic information on mortality in hemodialysis (HD) patients. Skin AF was measured noninvasively with an AF reader at baseline in 109 HD patients. Overall and cardiovascular mortality was monitored prospectively during a period of 3 yr. The AF reader was validated against AGE contents in skin biopsies from 29 dialysis patients. Forty-two of the 109 (38.5%) HD patients died. Cox regression analysis showed that AF was an independent predictor of overall and cardiovascular mortality (for overall mortality odds ratio [OR] 3.9), as were pre-existing cardiovascular disease (CVD; OR 3.1), C-reactive protein (OR 1.1), and serum albumin (OR 0.3). Multivariate analysis revealed that 65% of the variance in AF could be attributed to the independent effects of age, dialysis and renal failure duration, presence of diabetes, triglycerides levels, and C-reactive protein. AF was also independently linked to the presence of CVD at baseline (OR 8.8; P < 0.001). AF correlated with collagen-linked fluorescence (r = 0.71, P < 0.001), pentosidine (r = 0.75, P < 0.001), and carboxy(m)ethyllysine (both r = 0.45, P < 0.01). Skin AF is a strong and independent predictor of mortality in ESRD. This supports a role for AGE as a contributor to mortality and CVD and warrants interventions specifically aimed at AGE accumulation.

Glucose-insulin-potassium infusion inpatients treated with primary angioplasty for acute myocardial infarction ☆: The glucose-insulin-potassium study: a randomized trial

OBJECTIVES In this study we considered the question of whether adjunction of glucose-insulin-potassium (GIK) infusion to primary coronary transluminal angioplasty (PTCA) is effective in patients with an acute myocardial infarction (MI). BACKGROUND A combined treatment of early and sustained reperfusion of the infarct-related coronary artery and the metabolic modulation with GIK infusion has been proposed to protect the ischemic myocardium. METHODS From April 1998 to September 2001, 940 patients with an acute MI and eligible for PTCA were randomly assigned, by open-label, to either a continuous GIK infusion for 8 to 12 h or no infusion. RESULTS The 30-day mortality was 23 of 476 patients (4.8%) receiving GIK compared with 27 of 464 patients (5.8%) in the control group (relative risk [RR] 0.82, 95% confidence interval [CI] 0.46 to 1.46). In 856 patients (91.1%) without signs of heart failure (HF) (Killip class 1), 30-day mortality was 5 of 426 patients (1.2%) in the GIK group versus 18 of 430 patients (4.2%) in the control group (RR 0.28, 95% CI 0.1 to 0.75). In 84 patients (8.9%) with signs of HF (Killip class > or =2), 30-day mortality was 18 of 50 patients (36%) in the GIK group versus 9 of 34 patients (26.5%) in the control group (RR 1.44, 95% CI 0.65 to 3.22). CONCLUSIONS Glucose-insulin-potassium infusion as adjunctive therapy to PTCA in acute MI did not result in a significant mortality reduction in all patients. In the subgroup of 856 patients without signs of HF, a significant reduction was seen. The effect of GIK infusion in patients with signs of HF (Killip class > or =2) at admission is uncertain.

Skin Autofluorescence: A Tool to Identify Type 2 Diabetic Patients at Risk for Developing Microvascular Complications

OBJECTIVE—Skin autofluorescence is a noninvasive measure of the level of tissue accumulation of advanced glycation end products, representing cumulative glycemic and oxidative stress. Recent studies have already shown a relationship between skin autofluorescence and diabetes complications, as well as the predictive value of skin autofluorescence for total and cardiovascular mortality in type 2 diabetes. Our aim was to investigate the predictive value of skin autofluorescence for the development of microvascular complications in type 2 diabetes. RESEARCH DESIGN AND METHODS—At baseline, skin autofluorescence of 973 type 2 diabetic patients with well-controlled diabetes was noninvasively measured with an autofluorescence reader. The aggregate clinical outcome was defined as the development of any diabetes-associated microvascular complication of 881 surviving patients, which was assessed at baseline and at the end of follow-up. Single end points were the development of diabetes-associated retinopathy, neuropathy, and (micro)albuminuria. RESULTS—After a mean follow-up period of 3.1 years, baseline skin autofluorescence was significantly higher in patients who developed any microvascular complication, neuropathy, or (micro)albuminuria but not in those who developed retinopathy. Multivariate analyses showed skin autofluorescence as a predictor for development of any microvascular complication along with A1C, for development of neuropathy along with smoking, and for development of (micro)albuminuria together with sex, A1C, and diabetes duration. Skin autofluorescence did not have predictive value for the development of retinopathy, albeit diabetes duration did. CONCLUSIONS—Our study is the first observation of skin autofluorescence measurement as an independent predictor of development of microvascular complications in type 2 diabetes.

N-terminal pro-B-type natriuretic peptide is an independent predictor of cardiovascular morbidity and mortality in the general population

AIMS Natriuretic peptides including N-terminal pro-B-type natriuretic peptide (NT-proBNP) are established biomarkers in heart failure. However, their prognostic value in the general population is less well established. The purpose of our study was to investigate the prognostic properties of NT-proBNP for death and cardiovascular (CV) events in the general population. METHODS AND RESULTS In the population-based Prevention of Renal and Vascular End-stage Disease (PREVEND) study, 8383 subjects were prospectively followed for a median period of 7.5 years. There were 4181 (49.9%) males and 4202 (50.1%) females, mean age was 49.3 +/- 12.7 years (range 28-75). Median NT-proBNP at baseline was 37.7 pg/mL (IQR 16.8-73.8). All-cause death occurred in 437 (5.2%) subjects and there were 557 (6.6%) CV events. Higher levels of plasma NT-proBNP were related to higher event rates. When adjusted for age, gender, and other relevant covariates, each doubling of NT-proBNP remained significantly associated with a 22% increased risk for all-cause mortality (P < 0.001) and a 16% increased risk of CV events (P < 0.001). CONCLUSION In this large community-based cohort, plasma NT-proBNP was a strong predictor of death and a wide range of CV events.

Lipid-soluble components in cigarette smoke induce mitochondrial production of reactive oxygen species in lung epithelial cells

Reactive oxygen species (ROS) present in cigarette smoke (CS) are thought to contribute to the development of COPD. Although CS-ROS can hardly enter airway epithelial cells, and certainly not the circulation, systemic levels of ROS have been found to be elevated in COPD patients. We hypothesize that lipophilic components present in CS can enter airway epithelial cells and increase intracellular ROS production by disturbing mitochondrial function. Different airway epithelial cells were exposed to CS extract (CSE), hexane-treated CSE (CSE without lipophilic components), gaseous-phase CS, and water-filtered CS (gaseous-phase CS without ROS). Mitochondrial membrane potential (Deltapsi(m)) and ATP levels were assessed using the bronchial epithelial cell line Beas-2b. ROS generation measured directly by DCF fluorescence and indirectly by measuring free thiol groups (-SH) upon exposure to CS was assessed using lung alveolar epithelial cells devoid of functional mitochondria (A549-rho0), with normal A549 cells serving as controls. In Beas-2b cells, CSE (4 h) caused a dose-dependent decrease in Deltapsi(m) and ATP levels, whereas hexane-treated CSE did not. DCF fluorescence in A549 cells increased in response to CSE, whereas this was not the case in A549-rho0 cells. Exposure of A549 cells to CS resulted in a rapid decrease in free -SH, whereas exposure to ROS-depleted CS only resulted in a delayed decrease. This delayed decrease was less pronounced in A549-rho0 cells. Lipophilic components in CS disturb mitochondrial function, which contributes to increased intracellular generation of ROS. Our results are of importance in understanding the systemic effects of smoking observed in patients with COPD.

Chromium Treatment Has No Effect in Patients With Type 2 Diabetes in a Western Population A randomized, double-blind, placebo-controlled trial

OBJECTIVE—Chromium treatment has been reported to improve glycemic control in patients with type 2 diabetes. However, concern exists about the possible toxic effects of chromium picolinate. The aim of this study was to determine the effect of chromium treatment in the form of chromium yeast on glycemic control in a Western population of patients with type 2 diabetes who were being treated with oral hypoglycemic agents. RESEARCH DESIGN AND METHODS—In this 6-month, double-blind study, patients with moderate glycemic control, being treated with oral hypoglycemic agents, were randomly assigned to receive either a placebo or treatment with 400 μg of chromium daily in the form of chromium yeast. The primary efficacy parameter was a change in A1C. Secondary end points were changes in lipid profile, BMI, blood pressure, body fat, and insulin resistance. RESULTS—No differences were found for the change in A1C between the intervention and placebo groups, nor were any differences found between the groups for the secondary end points. CONCLUSIONS—There is no evidence that chromium in the form of chromium yeast is effective in improving glycemic control in Western patients with type 2 diabetes who are taking oral hypoglycemic agents.

Low Physical Activity and Risk of Cardiovascular and All-Cause Mortality in Renal Transplant Recipients

BACKGROUND AND OBJECTIVES Low physical activity (PA) is a risk factor for mortality in the general population. This is largely unexplored in renal transplant recipients (RTRs). We studied whether PA is associated with cardiovascular and all-cause mortality in a prospective cohort of RTR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Between 2001 and 2003, 540 RTRs were studied (age, 51 ± 12 years; 54% male). PA was assessed using validated questionnaires (Tecumseh Occupational Activity Questionnaire and the Minnesota Leisure Time Physical Activity Questionnaire). Cardiovascular and all-cause mortality were recorded until August 2007. RESULTS Independent of age, PA was inversely associated with metabolic syndrome, history of cardiovascular disease, fasting insulin, and triglyceride concentration, and positively associated with kidney function and 24-hour urinary creatinine excretion (i.e., muscle mass). During follow-up for 5.3 years (range, 4.7 to 5.7 years), 81 RTRs died, with 37 cardiovascular deaths. Cardiovascular mortality was 11.7, 7.2, and 1.7%, respectively, according to gender-stratified tertiles of PA (P=0.001). All-cause mortality was 24.4, 15.0, and 5.6% according to these tertiles (P<0.001). In Cox regression analyses, adjustment for potential confounders including history of cardiovascular disease, muscle mass, and traditional risk factors for cardiovascular disease did not materially change these associations. CONCLUSIONS Low PA is strongly associated with increased risk for cardiovascular and all-cause mortality in RTRs. Intervention studies are necessary to investigate whether PA improves long-term survival after renal transplantation.

Health-Related Quality of Life and Mortality in a General and Elderly Population of Patients With Type 2 Diabetes (ZODIAC-18)

OBJECTIVE Diabetes negatively impacts the health-related quality of life (HRQOL) of patients with type 2 diabetes. An earlier analysis showed HRQOL to be associated with mortality, which suggests that measuring HRQOL could have clinical implications. We studied the association between HRQOL and total and cardiovascular mortality in patients with type 2 diabetes during long-term follow-up and specifically focused on old age and sex differences. RESEARCH DESIGN AND METHODS HRQOL was measured in a prospectively followed cohort of 1,353 patients with type 2 diabetes using the RAND-36. Cox proportional hazard models were used to measure the independent effect of baseline HRQOL on mortality. RESULTS During a mean follow-up of 9.6 years, 570 (42%) patients died, 280 of whom died of cardiovascular disease (49%). The Physical Component Score (PCS) and the Mental Component Score (MCS) were inversely associated with total mortality, with hazard ratios of 0.988 (95% CI 0.983–0.993) and 0.990 (95% CI 0.985–0.995), respectively. A 10-point-higher score on the PCS and MCS decreased the risk for total mortality by 11 and 10%, respectively. An inverse relationship with mortality was also seen for men, women, and for patients aged >75 years. Mental health was significantly related to mortality in men but not in women. CONCLUSIONS Lower physical and mental HRQOL was associated with a higher total mortality and cardiovascular mortality in patients with type 2 diabetes; this is also the case when studying men and women and the elderly separately. The dimension mental health, related to depression and anxiety, was only associated with mortality in men, not in women.