Impact of diabetes duration and cardiovascular risk factors on mortality in type 2 diabetes: the Hoorn Study

BACKGROUND: Several studies have reported differences in the mortality risk between diabetic subjects detected by screening and known diabetic patients. We studied mortality in relation to diabetes duration, and the contribution of other cardiovascular risk factors to the elevated risk. MATERIALS AND METHODS: Participants were type 2 diabetic subjects (n = 174) of a population-based cohort study. Of these, 95 were diagnosed by screening. Known diabetic subjects were grouped into two categories of diabetes duration, with a median duration of 2.4 and 11.2 years, respectively. We assessed the contribution of classical cardiovascular risk factors (dyslipidaemia, hypertension, and prior myocardial infarction), and of new cardiovascular risk factors (microalbuminuria, von Willebrand factor, sVCAM-1 and C-reactive protein) to the mortality risk during nearly 10 years of follow up. Cox's proportional hazards model was used to study the association of diabetes duration and mortality. RESULTS: The age- and sex-adjusted relative risks of mortality were 2.06 (95% C.I. 1.04-4.10) and 3.19 (1.64-6.20) for the patients with short- and long-term diabetes compared with the screening-detected diabetic subjects, respectively. Adjustment for cardiovascular risk factors resulted in a reduction of mortality risk in both groups: 1.13 (0.51-2.50) and 2.39 (1.18-4.83), respectively. Mortality risk significantly increased with increasing diabetes duration, even after multiple adjustment (P-value for trend ranged from < 0.001-0.018). CONCLUSIONS: Mortality risk increased with increasing diabetes duration. In subjects with short diabetes duration the mortality risk could largely be attributed to other risk factors. In subjects with a longer diabetes duration, however, the elevated mortality risk was independent of these cardiovascular risk factors.     

A prospective cohort study of predictive value of homocysteine in patients with type 2 diabetes and coronary artery disease

BACKGROUND: Little evidence exists on the role of homocysteine as a predictor of mortality in patients with type 2 diabetes. The aim of this study was to investigate whether elevated plasma homocysteine levels are independently associated with all-cause or cardiovascular mortality in patients with type 2 diabetes and coronary artery disease. METHODS: This is a prospective cohort study that included 507 patients with type 2 diabetes and angiographically proven coronary artery disease. Patients were divided into 2 groups according to homocysteine level above or below median value (12.4 micromol/L): the high homocysteine group (255 patients) and the low homocysteine group (252 patients). The primary end-point of the study was all-cause mortality. RESULTS: There were 103 deaths during a 4-year follow-up: 62 deaths in the high homocysteine group and 41 deaths in the low homocysteine group (Kaplan-Meier estimates of mortality 25.6% and 17.4%, respectively (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.03-2.27, P=0.031). Sixty-two of 103 deaths (60.2%) were of cardiovascular origin: 37 deaths (14.5%) occurred in the high homocysteine group and 25 deaths (9.9%) occurred in the low homocysteine group (P=0.115). Cox proportional hazards model showed that plasma homocysteine was not an independent correlate of all-cause (adjusted hazard ratio [HR] 1.10, 95% CI 0.89-1.33; P=0.397 for 5 micromol/L increase in concentration) or cardiovascular (adjusted HR 1.04, 95% CI 0.80-1.36, P=0.753, for 5 micromol/L increase in concentration) mortality. CONCLUSION: In patients with type 2 diabetes and coronary artery disease, elevated level of homocysteine is an associate of increased cardiovascular risk but not an independent predictor of cardiovascular mortality.     

Cardiac autonomic neuropathy predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy

OBJECTIVE: Cardiac autonomic neuropathy (CAN) has been associated with a poor prognosis in patients with diabetes. Because CAN is common in patients with diabetic nephropathy, we evaluated the predictive value of CAN in type 1 diabetic patients with and without diabetic nephropathy. RESEARCH DESIGN AND METHODS: In a prospective observational follow-up study, 197 type 1 diabetic patients with diabetic nephropathy and a matched group of 191 patients with long-standing type 1 diabetes and normoalbuminuria were followed for 10.1 years (range 0.0-10.3 years). At baseline, CAN was assessed by heart rate variation (HRV) during deep breathing. HRV was evaluated as a predictor of the primary end point: cardiovascular morbidity and mortality. As secondary end points, all-cause mortality and the influence of HRV on progression of diabetic nephropathy (decline in glomerular filtration rate [GFR]) was evaluated. RESULTS: During the follow-up, 79 patients (40%) with nephropathy reached the combined primary end point vs. 19 patients (10%) with normoalbuminuria (log-rank test, P < 0.0001). The unadjusted hazard ratio (HR) for reaching the primary end point when having an abnormal HRV (< or =10 bpm) measured at baseline compared with a normal HRV was 7.7 (range 1.9-31.5; P = 0.004) in patients with nephropathy. Similarly in the normoalbuminuric patients, the unadjusted HR was 4.4 (1.4-13.6; P = 0.009). In patients with nephropathy, abnormal HRV was significantly associated with fatal and nonfatal cardiovascular disease after adjustment for cardiovascular risk factors. The adjusted HR for reaching the primary end point in a patient with nephropathy and an abnormal HRV was 6.4 (1.5-26.3, P = 0.010), as compared with a normal HRV. The unadjusted HR for dying when having an abnormal HRV compared with a normal HRV was 3.3 (95% CI 1.0-10.7; P = 0.043) in patients with diabetic nephropathy. After adjustment for confounding factors, the impact of HRV on all-cause mortality in patients with nephropathy was no longer significant (P = 0.293). There was no relationship between abnormal HRV and rate of decline in GFR. CONCLUSIONS: HRV is an independent risk factor for cardiovascular morbidity and mortality in type 1 diabetic patients with nephropathy.     

Relation of lower-extremity amputation to all-cause and cardiovascular disease mortality in American Indians: the Strong Heart Study

OBJECTIVE: To compare risk of all-cause and cardiovascular disease (CVD) mortality in people with a lower-extremity amputation (LEA) attributable to diabetes and people without an LEA. RESEARCH DESIGN AND METHODS: The Strong Heart Study is a study of CVD and its risk factors in 13 American-Indian communities. LEA was ascertained at baseline by direct examination of the legs and feet. Mortality surveillance is complete through 2000. RESULTS: Of 2,108 participants with diabetes at baseline, 134 participants (6.4%) had an LEA. Abnormal ankle-brachial index (53%), albuminuria (87%), and long diabetes duration (mean 19.8 years) were common among diabetic subjects with LEA. Mean diabetes duration among diabetic participants without LEA and in those with toe and below-the-knee amputations was 11.9, 18.6, and 21.1 years, respectively. During 8.7 (+/-2.9) years of follow-up, 102 of the participants with LEA (76%) died from all causes and 35 (26%) died from CVD. Of the 1,974 diabetic participants without LEA at baseline, 604 (31%) died from all causes and 206 (10%) died from CVD. The unadjusted hazard ratios (HRs) for all-cause and CVD mortality in diabetic participants with LEA compared with those without were 4.0 and 4.1, respectively. Adjusting for known and suspected confounders, LEA persisted as a predictor of all-cause (HR 2.2, 95% CI 1.7-2.9) and CVD mortality (HR 1.9, 95% CI 1.3-2.9). We observed a significant interaction between baseline LEA and sex on CVD mortality, with female sex conferring added risk of CVD mortality. CONCLUSIONS: LEA is a potent predictor of all-cause and CVD mortality in diabetic American Indians. The combination of female sex and LEA is associated with greater risk of CVD mortality than either factor alone.     

Retinopathy predicts cardiovascular mortality in type 2 diabetic men and women

OBJECTIVE: To investigate the association of retinopathy with the risk of all-cause, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality in type 2 diabetic subjects in a population-based 18-year follow-up study with particular emphasis on sex differences. RESEARCH DESIGN AND METHODS: Our study cohort comprised 425 Finnish type 2 diabetic men and 399 type 2 diabetic women who were free of CVD at baseline. The findings were classified based on standardized clinical ophthalmoscopy to categories of no retinopathy, background retinopathy, and proliferative retinopathy. The study end points were all-cause, CVD, and CHD mortality. RESULTS: Adjusted Cox model hazard ratios (95% CIs) of all-cause, CVD, and CHD mortality in men were 1.34 (0.98-1.83), 1.30 (0.86-1.96), and 1.18 (0.74-1.89), respectively, for background retinopathy and 3.05 (1.70-5.45), 3.32 (1.61-6.78), and 2.54 (1.07-6.04), respectively, for proliferative retinopathy and in women 1.61 (1.17-2.22), 1.71 (1.17-2.51), and 1.79 (1.13-2.85), respectively, for background retinopathy and 2.92 (1.41-6.06), 3.17 (1.38-7.30), and 4.98 (2.06-12.06), respectively, for proliferative retinopathy. CONCLUSIONS: Proliferative retinopathy in both sexes and background retinopathy in women predicted all-cause, CVD, and CHD death. These associations were independent of current smoking, hypertension, total cholesterol, HDL cholesterol, glycemic control of diabetes, duration of diabetes, and proteinuria. This suggests the presence of common background pathways for diabetic microvascular and macrovascular disease other than those included in the conventional risk assessment of CVD. The sex difference observed in the association of background retinopathy with macrovascular disease warrants closer examination.     

Low ankle-brachial pressure index predicts increased risk of cardiovascular disease independent of the metabolic syndrome and conventional cardiovascular risk factors in the Edinburgh Artery Study

OBJECTIVE: To investigate whether a low ankle-brachial pressure index (ABI) predicts increased risk of cardiovascular disease (CVD) independent of the metabolic syndrome and conventional cardiovascular risk factors. RESEARCH DESIGN AND METHODS: The Edinburgh Artery Study is a population-based cohort study in which subjects were followed up until their death or for approximately 15 years. Low ABI at baseline was defined as <0.9; subjects with ABI >1.4 (n = 13) were excluded from the analyses. We used a modified version of the definition of the metabolic syndrome published in the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, replacing waist circumference criteria with BMI criteria. Data on relevant parameters were available for 1,467 men and women ages 55-74 years at baseline. Cox proportional hazards models were used to study cardiovascular morbidity and mortality before and after adjusting for potential confounding factors. RESULTS: We determined that 25% of the study population had the metabolic syndrome and that a low ABI was more prevalent among people with than without the metabolic syndrome (24 vs. 15%; P < 0.001). During the follow-up period, there were 226 deaths from CVD and 462 nonfatal cardiovascular events. The hazard ratio (95% CI) for low ABI after adjusting for age, sex, baseline CVD, diabetes, smoking status, LDL cholesterol, and metabolic syndrome was 1.5 (1.1-2.1) for CVD mortality and 1.5 (1.2-1.8) for all CVD outcomes. CONCLUSIONS: Low ABI is associated with increased risk of CVD independent of the metabolic syndrome and other major CVD risk factors.     

Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence

OBJECTIVE: In recent years, several major organizations have endorsed the concept of the metabolic syndrome and developed working definitions for it. How well these definitions predict the risk for adverse events in people with the metabolic syndrome is only now being learned. The purpose of this study was to summarize the estimates of relative risk for all-cause mortality, cardiovascular disease, and diabetes reported from prospective studies in samples from the general population using definitions of the metabolic syndrome developed by the National Cholesterol Education Program (NCEP) and World Health Organization (WHO). RESEARCH DESIGN AND METHODS: The author reviewed prospective studies from July 1998 through August 2004. RESULTS: For studies that used the exact NCEP definition of the metabolic syndrome, random-effects estimates of combined relative risk were 1.27 (95% CI 0.90-1.78) for all-cause mortality, 1.65 (1.38-1.99) for cardiovascular disease, and 2.99 (1.96-4.57) for diabetes. For studies that used the most exact WHO definition of the metabolic syndrome, the fixed-effects estimates of relative risk were 1.37 (1.09-1.74) for all-cause mortality and 1.93 (1.39-2.67) for cardiovascular disease; the fixed-effects estimate was 2.60 (1.55-4.38) for coronary heart disease. CONCLUSIONS: These estimates suggest that the population-attributable fraction for the metabolic syndrome, as it is currently conceived, is approximately 6-7% for all-cause mortality, 12-17% for cardiovascular disease, and 30-52% for diabetes. Further research is needed to establish the use of the metabolic syndrome in predicting risk for death, cardiovascular disease, and diabetes in various population subgroups.     

Mini-Mental State Examination score and B-type natriuretic peptide as predictors of cardiovascular and total mortality in an elderly general population

INTRODUCTION. The aim of the present study was to examine the power of B-type natriuretic peptide (BNP) and mild cognitive impairment as independent predictors of total and cardiovascular mortality in combination with established cardiovascular risk markers in an elderly general population without severe cognitive impairment. METHODS. A total of 499 individuals, aged more than 75 years, were examined and followed up for a median of 7.9 years in a prospective population-based stratified cohort study carried out in eastern Finland. The Cox proportional hazards regression model was used to determine the impact of multiple factors on total and cardiovascular mortality. RESULTS. In a multivariable model including established cardiovascular risk factors and conditions, both continuous BNP (adjusted hazard ratio (HR) 1.44 for a 1-SD change; 95% confidence interval (CI) 1.22-1.77; P < 0.001) and continuous MMSE score (HR 0.81 for a 1-SD change; 95% CI 0.70-0.94; P = 0.007) were independently associated with all-cause mortality. In a multivariable model, BNP remained a significant predictor of cardiovascular mortality, while MMSE score lost its significance. CONCLUSIONS. BNP, a measure of cardiovascular burden, and MMSE score 18-23, an indicator of mild cognitive impairment, are both independent predictors of total mortality. BNP and MMSE score may potentially be useful in screening elderly patients for elevated risk of mortality.     

Cardiovascular morbidity and mortality associated with the metabolic syndrome

OBJECTIVE: To estimate the prevalence of and the cardiovascular risk associated with the metabolic syndrome using the new definition proposed by the World Health Organization RESEARCH DESIGN AND METHODS: A total of 4,483 subjects aged 35-70 years participating in a large family study of type 2 diabetes in Finland and Sweden (the Botnia study) were included in the analysis of cardiovascular risk associated with the metabolic syndrome. In subjects who had type 2 diabetes (n = 1,697), impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) (n = 798) or insulin-resistance with normal glucose tolerance (NGT) (n = 1,988), the metabolic syndrome was defined as presence of at least two of the following risk factors: obesity, hypertension, dyslipidemia, or microalbuminuria. Cardiovascular mortality was assessed in 3,606 subjects with a median follow-up of 6.9 years. RESULTS: In women and men, respectively, the metabolic syndrome was seen in 10 and 15% of subjects with NGT, 42 and 64% of those with IFG/IGT, and 78 and 84% of those with type 2 diabetes. The risk for coronary heart disease and stroke was increased threefold in subjects with the syndrome (P < 0.001). Cardiovascular mortality was markedly increased in subjects with the metabolic syndrome (12.0 vs. 2.2%, P < 0.001). Of the individual components of the metabolic syndrome, microalbuminuria conferred the strongest risk of cardiovascular death (RR 2.80; P = 0.002). CONCLUSIONS: The WHO definition of the metabolic syndrome identifies subjects with increased cardiovascular morbidity and mortality and offers a tool for comparison of results from diferent studies.     

Associations of mortality and diabetes complications in patients with type 1 and type 2 diabetes: early treatment diabetic retinopathy study report no. 27

OBJECTIVE: Diabetes is a leading cause of morbidity and mortality. The purpose of this study is to assess the associations between diabetes complications and mortality in the Early Treatment Diabetic Retinopathy Study (ETDRS). RESEARCH DESIGN AND METHODS: We examined demographic, clinical, and laboratory characteristics of the 3,711 subjects enrolled in the ETDRS, a randomized controlled clinical trial designed to evaluate the role of laser photocoagulation and aspirin therapy for diabetic retinopathy. The outcome assessed was all-cause mortality. Multivariable Cox proportional hazards regression was used to assess associations between diabetes complications and mortality for type 1 and type 2 diabetes separately. RESULTS: The 5-year estimates of all-cause mortality were 5.5 and 18.9% for patients with type 1 and type 2 diabetes, respectively. In patients with type 1 diabetes, amputation (hazard ratio [HR] 5.08 [95% CI 2.06-12.54]) and poor visual acuity (1.74 [1.10-2.75]) remained significantly associated with mortality, after adjusting for other diabetes complications and baseline characteristics. In patients with type 2 diabetes, macrovascular disease and worsening levels of nephropathy, neuropathy, retinopathy, and visual acuity are associated with progressively increasing risks of mortality, after controlling for other baseline risk factors. CONCLUSIONS: Amputation is the strongest predictor for mortality in patients with type 1 diabetes. All complications independently predict mortality in patients with type 2 diabetes. There is an increased risk for mortality as the degree of each complication worsens. Additional studies are needed to investigate the effectiveness of tertiary prevention to decrease mortality in these patients.     

Osteoprotegerin and mortality in type 2 diabetic patients

OBJECTIVE

Plasma osteoprotegerin (OPG) is an emerging strong and independent predictor of cardiovascular disease (CVD) in high-risk populations. OPG is a bone-related glycopeptide produced by vascular smooth muscle cells, and increased plasma OPG levels may reflect arterial vascular damage. We aimed to investigate the prognostic value of OPG in relation to all-cause and cardiovascular mortality in a cohort of type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

In a prospective observational follow-up study, 283 type 2 diabetic patients (172 men; aged 53.9 ± 8.8 years) were followed for a median of 16.8 years (range 0.2–23.0). Baseline plasma OPG concentrations were determined by immunoassay.

RESULTS

During follow-up, 193 (68%) patients died. High versus low levels of OPG predicted all-cause mortality (covariate-adjusted for urinary albumin excretion rate [UAER], estimated glomerular filtration rate, and conventional risk factors); hazard ratio (HR) 1.81 [95% CI 1.21–2.69]. The all-cause predictive effect of OPG was independent of NH₂-terminal pro-brain natriuretic peptide (NT-proBNP) and was also useful within groups divided according to level of UAER. In total, 103 (73%) patients died because of CVD. High and medium versus low levels of OPG predicted cardiovascular mortality (unadjusted HR 1.86 [95% CI 1.07–3.23] and 3.51 [2.10–5.85], respectively). However, after adjustment for the covariates, HRs were no longer significant.

CONCLUSIONS

Elevated plasma OPG is a strong predictor of all-cause mortality in type 2 diabetic patients. The effect of OPG on all-cause mortality was independent of conventional cardiovascular risk factors, UAER, and NT-proBNP levels.Plasma osteoprotegerin (OPG) is a promising strong and independent predictor of cardiovascular disease (CVD) in high-risk individuals, such as type 1 diabetic patients with nephropathy and nondiabetic patients after kidney transplantation or myocardial infarction (1–4). OPG is a member of the tumor necrosis factor receptor superfamily acting as a soluble decoy receptor for the receptor activator of nuclear factor-κβ ligand (RANKL) to prevent osteoclast activation and bone resorption (5). OPG mRNA has been detected in a variety of human tissues, including the lung, heart, and kidney (5). This bone-related glycoprotein is present in the arterial wall, and plasma OPG has been suggested to reflect the increased OPG content in arterial tissue observed in diabetic patients (6). OPG is upregulated in calcified coronary plaques (7) and associated with angiographic disease severity and cardiovascular events independent of conventional risk factors (8,9). Therefore, increased plasma OPG levels are suggested to be a marker of arterial vascular damage.CVD is the major determinant of morbidity and mortality in patients with type 2 diabetes and, in particular, patients with an elevated urinary albumin excretion rate (UAER) (10). Increased OPG levels are associated with diabetes (11). Recently, an elevated plasma OPG level was shown to predict increased mortality in patients with type 1 diabetes and diabetic nephropathy (4) and also to predict increased incidence of cardiovascular events among patients with uncomplicated type 2 diabetes who were followed for 18 months (12). However, the prognostic importance of OPG in type 2 diabetic patients with long follow-up and elevated UAER is unknown. Therefore, this study examines the predictive value of plasma OPG in relation to all-cause and cardiovascular mortality in a large cohort of type 2 diabetic patients followed prospectively for 17 years.     

Similar 9-year mortality risks and reproducibility for the World Health Organization and American Diabetes Association glucose tolerance categories: the Hoorn Study

OBJECTIVE: To compare the risks of all-cause and cardiovascular disease (CVD) mortality in the American Diabetes Association (ADA) and World Health Organization (WHO) glucose tolerance categories after 9 years of follow-up in the Hoorn Study and to study the test-retest reproducibility of those categories. RESEARCH DESIGN AND METHODS: In this population-based cohort study of 2,468 elderly men and women, subjects were classified according to both the WHO and the ADA criteria. Causes of death were extracted from the medical records. Age- and sex-adjusted relative risks were estimated by Cox's proportional hazards model. Reproducibility of the diagnostic criteria was assessed in a sample of 1,109 subjects with duplicate oral glucose tolerance tests. RESULTS: Subjects with known diabetes had a four to five times higher risk of all-cause and CVD mortality compared with normal subjects (P<0.05). The relative risks of all-cause mortality were 1.67 (95% CI 1.09-2.57) and 1.56 (1.00-2.43) for newly diagnosed diabetic subjects according to the WHO and ADA criteria, respectively. The WHO and ADA criteria had similar levels of reproducibility The overall K was 0.59 (0.54-0.64) for WHO criteria and 0.61 (0.56-0.66) for ADA criteria. For the category of newly diagnosed diabetes according to WHO or ADA, the percentages of agreement for the second test compared with the first test were 77% (85/110) and 74% (74/100), respectively. CONCLUSIONS: Both sets of diagnostic criteria identify criteria-specific diabetic subjects with an increased mortality risk compared with normal subjects, and the reproducibility of both criteria is similar.     

Rapid progression of albumin excretion is an independent predictor of cardiovascular mortality in patients with type 2 diabetes and microalbuminuria.

OBJECTIVE: In patients with type 2 diabetes, microalbuminuria is associated with an increase in predominantly cardiovascular mortality. Considerable interindividual variability in the rate of progression of microalbuminuria exists. The prognostic significance of rate of progression of microalbuminuria with regard to cardiovascular and renal clinical end points is, however, unknown. The purpose of this study was to determine the prognostic significance of rate of progression of microalbuminuria for cardiovascular end points and renal function. RESEARCH DESIGN AND METHODS: In a previous prospective cohort study, progression of microalbuminuria (expressed as mean yearly change in albumin-to-creatinine ratio) was assessed in 58 patients with type 2 diabetes. During a median follow-up of 7 years after progression of microalbuminuria was determined, we registered all-cause mortality and coronary heart disease mortality as primary end points and coronary heart disease (fatal or nonfatal), peripheral vascular disease, ischemic stroke, retinopathy, macroalbuminuria, and change in serum creatinine as secondary end points. RESULTS: Seven subjects died during the study; five of these subjects died of coronary heart disease. Cox's regression analysis identified progression of microalbuminuria as a significant predictor of all-cause mortality (hazard ratio 1.46 per point increase in albumin-to-creatinine ratio per year, P < 0.001), coronary heart disease mortality (hazard ratio 2.32, P = 0.006), and macroalbuminuria (hazard ratio 1.79, P < 0.001). Adjustment for multiple cardiovascular risk factors did not affect these results. Identical analyses for baseline level of microalbuminuria instead of progression rate of microalbuminuria did not show significant hazard ratios. In addition, progression of microalbuminuria significantly predicted an increase in serum creatinine (r = 0.29, P = 0.04). CONCLUSIONS: In patients with type 2 diabetes and microalbuminuria, the rate of progression of albumin excretion seems to be a powerful independent predictor of mortality caused mainly by coronary heart disease.     

Proinsulin concentration is an independent predictor of all-cause and cardiovascular mortality: an 11-year follow-up of the Hoorn Study

OBJECTIVE: High proinsulin concentration may be a better predictor for cardiovascular disease (CVD) mortality than insulin concentration. Previous observations may have been confounded by glucose tolerance status or lack of precision because of high intraindividual variability. We investigated the longitudinal relation of means of duplicate measurements of insulin and proinsulin with all-cause and CVD mortality in a population-based cohort taking glucose tolerance status into account. RESEARCH DESIGN AND METHODS: Fasting and post-75-g glucose-load (2-h) glucose, insulin, and proinsulin values were determined in duplicate on separate days in 277 participants with normal glucose metabolism, 208 participants with impaired glucose metabolism, and 119 newly detected patients with type 2 diabetes of the Hoorn Study. Insulin resistance and beta-cell function were estimated by homeostasis model assessment (HOMA-IR and HOMA-B, respectively), and the fasting proinsulin-to-insulin ratio was calculated. Subjects were followed with respect to mortality until January 2003. RESULTS: Fasting proinsulin levels were significantly associated with all-cause and CVD mortality. The hazard ratios (HRs) per increase in interquartile range adjusted for age and sex were 1.21 (95% CI 1.04-1.42) for all-cause mortality and 1.33 (1.06-1.66) for CVD mortality. Adjustment for glucose tolerance status and HOMA-IR did not substantially change the associations. CONCLUSIONS: Fasting proinsulin was associated with all-cause and CVD mortality, independent of glucose tolerance status and insulin resistance and largely independent of other CVD risk factors. Proinsulin might play a role in the relationship between insulin resistance and CVD.     

Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study.

OBJECTIVE: This population-based study, carried out in the framework of the Verona Diabetes Study, investigated mortality from specific causes in known type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A cohort of 7,148 known type 2 diabetic patients (3,366 men and 3,782 women) was identified on 31 December 1986 and followed up for 5 years (1987-1991). Underlying causes of death were obtained from death certificates and were coded according to the International Classification of Diseases, Ninth Revision. Cause-specific death rates of diabetic subjects were compared with those of the inhabitants of Verona. By 31 December 1991, 1,550 diabetic subjects (744 men and 806 women) had died. RESULTS: The standardized mortality ratio (SMR) for all causes of death was 1.42 (95% CI 1.35-1.50). The highest SMRs were for the following specific causes: diabetes (SMR 4.47 [3.91-5.10]), gastrointestinal diseases (1.83 [1.50-2.21])--particularly liver cirrhosis (2.52 [1.96-3.20])--and cardiovascular diseases (1.34 [1.23-1.44]), particularly cerebrovascular (1.48 [1.25-1.73]) and ischemic heart diseases (1.41 [1.24-1.62]). A significantly higher than expected risk of mortality for cardiovascular causes was already present in the first 5 years after diagnosis and decreased with age. Type 2 diabetic patients treated with insulin had a higher risk of dying than those treated orally or by diet. CONCLUSIONS: The highest SMRs in the diabetic cohort were for diabetes and liver cirrhosis. The mortality risk for cardiovascular diseases, although significantly higher than expected, was much lower in Italian type 2 diabetic patients than that reported for American patients. The evidence of an early effect on mortality suggests that prevention, early diagnosis, and treatment should be improved.     

New-onset diabetes and risk of all-cause and cardiovascular mortality: the Cardiovascular Health Study

OBJECTIVE: Cardiovascular risk associated with new-onset diabetes is not well characterized. We hypothesized that risk of all-cause and cardiovascular mortality would be similar among participants with and without new-onset diabetes in the first years of follow-up and rise over time for new-onset diabetes. RESEARCH DESIGN AND METHODS: The Cardiovascular Health Study (CHS) is a longitudinal study of cardiovascular risk factors in adults aged > or =65 years. We used CHS participants to define a cohort (n = 282) with new-onset diabetes during 11 years of follow-up. New-onset diabetes was defined by initiation of antidiabetes medication or by fasting plasma glucose >125 mg/dl among CHS participants without diabetes at study entry. Three CHS participants without diabetes were matched for age, sex, and race to each participant with new-onset diabetes at the time of diabetes identification (n = 837). Survival analysis provided adjusted hazard ratios (HRs) for all-cause and cardiovascular mortality. RESULTS: During a median of 5.9 years of follow-up, there were 352 deaths, of which 41% were cardiovascular. In adjusted analyses, new-onset diabetes was associated with an HR of 1.9 (95% CI 1.4-2.5) for all-cause and 2.2 (1.4-3.4) for cardiovascular mortality compared with no diabetes. Mortality risks were elevated within 2 years of onset, especially cardiovascular risk (4.3 [95% CI 1.7-10.8]), and did not increase over time. CONCLUSIONS: Our findings indicate that there may be a mortality differential soon after diabetes onset in older adults and suggest that long-term macrovascular damage from atherosclerosis may not be primarily responsible for increased risk.     

Predictive properties of impaired glucose tolerance for cardiovascular risk are not explained by the development of overt diabetes during follow-up

OBJECTIVE: To evaluate the relationship of impaired glucose tolerance (IGT) at baseline to coronary heart disease (CHD) incidence, and cardiovascular disease (CVD) and total mortality at follow-up, and to analyze whether the relationship is independent of the subsequent development of diabetes during follow-up. RESEARCH DESIGN AND METHODS: A baseline screening survey for diabetes was performed in 1987 using a 2-h 75-g oral glucose tolerance test. A total of 1234 men and 1386 women aged 45-64 years, who were free of diabetes at baseline, were followed up for 10 years. During the follow-up, 153 subjects had an incident CHD event, 224 died, and 100 deaths were due to cardiovascular causes. Multivariate adjusted (adjusted for age, sex, waist-to-hip ratio, systolic blood pressure, cholesterol, HDL cholesterol, and smoking) hazard ratio (HR) was estimated using Cox regression analysis. RESULTS: In subjects who had IGT at baseline and who did not progress to diabetes during the follow-up, the multivariate adjusted HR (95% CI) was 1.49 (0.95-2.34) for CHD incidence, 2.34 (1.42-3.85) for CVD mortality, and 1.65 (1.13-2.40) for all-cause mortality. CONCLUSIONS: Baseline IGT was an independent risk predictor for cardiovascular morbidity and mortality and for total mortality, which was not confounded by the subsequent development of overt diabetes.     

Mini-Mental State Examination score and B-type natriuretic peptide as predictors of cardiovascular and total mortality in an elderly general population

Abstract

Introduction. The aim of the present study was to examine the power of B-type natriuretic peptide (BNP) and mild cognitive impairment as independent predictors of total and cardiovascular mortality in combination with established cardiovascular risk markers in an elderly general population without severe cognitive impairment.

Methods. A total of 499 individuals, aged more than 75 years, were examined and followed up for a median of 7.9 years in a prospective population-based stratified cohort study carried out in eastern Finland. The Cox proportional hazards regression model was used to determine the impact of multiple factors on total and cardiovascular mortality.

Results. In a multivariable model including established cardiovascular risk factors and conditions, both continuous BNP (adjusted hazard ratio (HR) 1.44 for a 1-SD change; 95% confidence interval (CI) 1.22–1.77; P < 0.001) and continuous MMSE score (HR 0.81 for a 1-SD change; 95% CI 0.70–0.94; P = 0.007) were independently associated with all-cause mortality. In a multivariable model, BNP remained a significant predictor of cardiovascular mortality, while MMSE score lost its significance.

Conclusions. BNP, a measure of cardiovascular burden, and MMSE score 18–23, an indicator of mild cognitive impairment, are both independent predictors of total mortality. BNP and MMSE score may potentially be useful in screening elderly patients for elevated risk of mortality.     

Diabetic hypertensive patients. Is this a group in need of particular care and attention?

Morbidity and mortality in diabetes are caused mainly by its vascular complications, both in the microcirculation and in the large vessels. Diabetic nephropathy and retinopathy are the clinical hallmarks of microangiopathy, which may lead to end-stage renal failure and blindness. The cardiovascular complications in diabetes consist mainly of an accelerated form of atherosclerosis. Systemic hypertension is an early and frequent phenomenon. Nocturnal hypertension is also more frequent in people with diabetes compared with the nondiabetic population. Capillary hypertension has been demonstrated in type 1 diabetic patients. Poor metabolic control may induce elevation in blood pressure, but data are conflicting. The prevalence of white-coat hypertension in the diabetic population is comparable with that in the nondiabetic population. Prospective observational studies in type 1 and type 2 patients have revealed that abnormally increased urinary albumin excretion and other potentially modifiable risk factors--such as hypertension, smoking, poor metabolic control, and social class--predict increased all-cause mortality and cardiovascular mortality. Arterial hypertension is a risk factor in the initiation and progression of diabetic micro- and macroangiopathy. Diabetes, hypertension, and smoking are the three most important risk factors for fatal and nonfatal stroke. A randomized, double-blind, parallel study has revealed that the 5-year major cardiovascular disease rate was lowered by 34% for antihypertensive treatment compared with placebo. Furthermore, the study found a trend for lower all-cause mortality for low-dose antihypertensive-treated diabetic patients. Effective blood pressure reduction with ACE inhibitors and/or non-ACE inhibitors, frequently in combination with diuretics, reduces albuminuria, delays the progression of nephropathy, postpones end-stage renal failure, and improves survival in diabetic nephropathy.     

Abdominal obesity is essential for the risk of venous thromboembolism in the metabolic syndrome: the Tromsø study

Summary.  Background:  The metabolic syndrome is a cluster of cardiovascular risk factors, including abdominal obesity, hypertension, dyslipidemia and insulin resistance, associated with increased risk of cardiovascular diseases and all cause mortality. Objectives:  The purpose of the study was to assess the impact of the metabolic syndrome, and its individual components, on the risk of venous thromboembolism (VTE) in a prospective population-based study. Methods:  Individual components of the metabolic syndrome were registered in 6170 subjects aged 25–84 years in the Tromsø Study in 1994–1995, and first ever VTE events were registered until 1 September 2007. Results:  The metabolic syndrome was present in 21.9% (1350 subjects) of the population. There were 194 validated first VTE events (2.92 per 1000 person-years) during a mean of 10.8 years of follow-up. Presence of metabolic syndrome was associated with increased risk of VTE (HR, 1.65; 95% CI, 1.22–2.23) in age- and gender-adjusted analysis. The risk of VTE increased with the number of components in the metabolic syndrome ( P  < 0.001). Abdominal obesity was the only component significantly associated with VTE in multivariable analysis including age, gender, and the individual components of the syndrome (HR, 2.03; 95% CI, 1.49–2.75). When abdominal obesity was omitted as a diagnostic criterion, none of the other components, alone or in cluster, was associated with increased risk of VTE. Conclusions:  Our study provides evidence for the metabolic syndrome as a risk factor for TE. Abdominal obesity appeared to be the pivotal risk factor among the individual components of the syndrome.