Plasma N-terminal pro-brain natriuretic peptide as an independent predictor of mortality in diabetic nephropathy

Aims/hypothesis Raised N-terminal pro-brain natriuretic peptide (NT-proBNP) is independently associated with an increased risk of death in chronic heart failure and acute coronary syndromes in nondiabetic populations. Diabetic nephropathy is characterised by an increased risk of cardiovascular morbidity and mortality. This study investigated the prognostic value of NT-proBNP in a large cohort of type 1 diabetic patients with and without diabetic nephropathy.Methods In a prospective observational follow-up study, 198 type 1 diabetic patients with overt diabetic nephropathy (122 men, age [mean±SD] 41±10 years, duration of diabetes 28±8 years, GFR 74±33 ml min^–1) and a matched control group of 188 patients with longstanding type 1 diabetes and persistent normoalbuminuria (114 men, age 43±10 years, duration of diabetes 27±9 years) were followed for 9.3 (0.0–9.5) years. Plasma NT-proBNP concentration was determined by immunoassay at baseline.Results In patients with diabetic nephropathy, plasma NT-proBNP concentration was elevated to (median [range]) 110 (5–79640) ng l^–1 vs. 27 (5–455) ng l^–1 in normoalbuminuric patients (p<0.0001). Among patients with nephropathy, 39 (39%) patients with plasma NT-proBNP concentrations above the median and 12 (12%) with values below the median died from any cause (unadjusted hazard ratio 3.86 [95% CI 2.02–7.37], p<0.0001; covariate-adjusted hazard ratio 2.28 [1.04–4.99], p=0.04). This lower mortality rate was attributable to fewer cardiovascular deaths: 31 (31%) and 7 (7%) above and below the median NT-proBNP level respectively (unadjusted hazard ratio 5.25 [2.31–11.92], p<0.0001; covariate-adjusted hazard ratio 3.81 [1.46–9.94], p=0.006).Conclusions/interpretation Elevated circulating NT-proBNP is a new independent predictor of the excess overall and cardiovascular mortality in diabetic nephropathy patients without symptoms of heart failure.Per Hildebrandt has received an honorarium and served as consultant in a scientific advisory board for Roche.     

Plasma N-terminal pro-B-type natriuretic peptide and mortality in type 2 diabetes

Aims/hypothesis Raised N-terminal pro-B-type natriuretic peptide (NT-proBNP) is associated with a poor cardiac outcome in non-diabetic populations. Elevated NT-proBNP predicts excess morbidity and mortality in diabetic patients with an elevated urinary albumin excretion rate. This study investigated the prognostic value of NT-proBNP in a cohort of type 2 diabetic patients. Subjects, materials and methods In a prospective observational follow-up study, 315 type 2 diabetic patients with normoalbuminuria (n=188), microalbuminuria (n=80) and macroalbuminuria (n=47) at baseline were followed for a median (range) of 15.5 (0.2–17.0) years. Plasma NT-proBNP concentrations were determined by immunoassay at baseline. Endpoints were overall and cardiovascular mortality. Results Of the patients, 162 died (51%), 119 of them (74%) due to cardiovascular causes. All-cause mortality was increased in patients with NT-proBNP in the second and third tertiles (hazard ratios [95% CI] compared with the first tertile, 1.70 [1.08–2.67] and 5.19 [3.43–7.88], p<0.001). These associations persisted after adjustment for urinary albumin excretion rate, glomerular filtration rate and conventional cardiovascular risk factors (covariate adjusted hazard ratios 1.46 [0.91–2.33] and 2.54 [1.56–4.14], p<0.001). This increased mortality was attributable to more cardiovascular deaths in the second and third NT-proBNP tertile (unadjusted hazard ratios 1.63 [0.96–2.77] and 4.88 [3.01–7.91], p<0.001; covariate adjusted 1.37 [0.79–2.37] and 2.26 [1.27–4.02], p=0.01). When patients with normo-, micro- and macroalbuminuria were analysed separately, NT-proBNP levels above the median (62 ng/l) were consistently associated with increased overall and cardiovascular mortality in all three groups (p<0.001). Conclusions/interpretation In patients with type 2 diabetes, elevated circulating NT-proBNP is a strong predictor of the excess overall and cardiovascular mortality, this predictor status being independent of urinary albumin excretion rate and conventional cardiovascular risk factors.     

Changes in the prognostic values of modern cardiovascular biomarkers in relation to duration of diabetes mellitus

BackgroundBased on the complex pathophysiology of type 2 diabetes and atherosclerosis we hypothesized a dynamic change in prognostic value of cardiovascular biomarkers over time.MethodsIn this prospective study 746 patients with type 2 diabetes mellitus, being followed up for 60 months were analysed. The primary endpoint was defined as unplanned hospitalization for cardiovascular disease or death. Beside others, especially the prognostic performance of the biomarkers of interest (GDF-15, NT-proBNP, hs-TnT) was evaluated in relation to quartiles of diabetes duration.ResultsIn patients having a diabetes duration below 7 years lnGDF-15 (HR 2.84; p < 0.01) and lnhs-TnT (HR 2.96; p < 0.01) were significant predictors of the primary endpoint. LnAge (HR 40.01; p < 0.01) and lnNT-proBNP (HR 1.56; p = 0.03) were significant predictors in patients with a diabetes duration between 7 and 12 years. In the third quartile (diabetes duration 12–22 years) lnurinary albumin to creatinine ratio (HR 1.25; p = 0.005) and lnNT-proBNP (HR 2.13, p < 0.001) predicted the endpoint. In patients with a diabetes duration above 22 years, lnAge (HR 75.35; p = 0.001) and lnNT-proBNP (HR 2.0; p < 0.01) were the only significant predictors of the endpoint.ConclusionPrognostic power of cardiovascular biomarkers changes dynamically in relation to duration of type 2 diabetes mellitus. In patients with shorter duration of the disease markers of subclinical cardiovascular dysfunction and inflammation perform better than markers of systemic advanced organ dysfunction and cardiovascular disease.     

QT<Subscript>c</Subscript> interval and resting heart rate as long-term predictors of mortality in type 1 and type 2 diabetes mellitus: a 23-year follow-up

Aims/hypothesis We evaluated the association of QT interval corrected for heart rate (QT_c) and resting heart rate (rHR) with mortality (all-causes, cardiovascular, cardiac, and ischaemic heart disease) in subjects with type 1 and type 2 diabetes. Methods We followed 523 diabetic patients (221 with type 1 diabetes, 302 with type 2 diabetes) who were recruited between 1974 and 1977 in Switzerland for the WHO Multinational Study of Vascular Disease in Diabetes. Duration of follow-up was 22.6 ± 0.6 years. Causes of death were obtained from death certificates, hospital records, post-mortem reports, and additional information given by treating physicians. Results In subjects with type 1 diabetes QT_c, but not rHR, was associated with an increased risk of: (1) all-cause mortality (hazard ratio [HR] 1.10 per 10 ms increase in QT_c, 95% CI 1.02–1.20, p = 0.011); (2) mortality due to cardiovascular (HR 1.15, 1.02–1.31, p = 0.024); and (3) mortality due to cardiac disease (HR 1.19, 1.03–1.36, p = 0.016). Findings for subjects with type 2 diabetes were different: rHR, but not QT_c was associated with mortality due to: (1) all causes (HR 1.31 per 10 beats per min, 95% CI 1.15–1.50, p < 0.001); (2) cardiovascular disease (HR 1.43, 1.18–1.73, p < 0.001); (3) cardiac disease (HR 1.45, 1.19–1.76, p < 0.001); and (4) ischaemic heart disease (HR 1.52, 1.21–1.90, p < 0.001). Effect modification of QT_c by type 1 and rHR by type 2 diabetes was statistically significant (p < 0.05 for all terms of interaction). Conclusions/interpretation QT_c is associated with long-term mortality in subjects with type 1 diabetes, whereas rHR is related to increased mortality risk in subjects with type 2 diabetes.     

Chronic hepatitis B viral infection independently predicts renal outcome in type 2 diabetic patients

Aims/hypothesis We examined the association between chronic hepatitis B virus (HBV) infection and clinical outcomes in a consecutive cohort of Chinese patients with type 2 diabetes.Subjects, materials and methods Between 1995 and 1999, 2,838 type 2 diabetes patients underwent comprehensive assessments and blood screening for hepatitis B surface antigen (HBsAg). The risk of occurrence of cardiovascular events and end-stage renal disease (defined as need for dialysis, doubling of serum creatinine or serum creatinine ≥500 μmol/l) was compared between HBsAg-positive and HBsAg-negative groups.Results At baseline, HBV-infected patients (n=286, 10.1%) were younger (51.0±11.5 vs 53.7±12.7 years, p=0.004), had earlier onset of diabetes (51.0±11.5 vs 53.7±12.7 years, p=0.001) and a higher frequency of retinopathy (28 vs 22%, p=0.03) than non-HBV-infected patients. After a median follow-up of 3.5 years (interquartile range: 1.7–5.9 years) and adjustment of age, glycaemic control and other potential confounding factors, HBV-infected patients were more likely to develop end-stage renal disease than non-HBV infected patients (8.7 vs 6.4%) with a hazard ratio of 4.5 (95% CI 1.1–18.6). The difference in the frequency of cardiovascular endpoints was not statistically significant.Conclusions In Chinese type 2 diabetes patients, chronic HBV infection was associated with increased risk of end-stage renal disease, and this was independent of other potential confounding factors. Early identification of HBV status and close surveillance of renal function are important in patients with type 2 diabetes who are living in areas where HBV is endemic or who are at risk of chronic HBV infection.     

Risk factors for mortality in Type II (non-insulin-dependent) diabetes: evidence of a role for neuropathy and a protective effect of HLA-DR4

Summary To test the hypothesis that interaction between genetic, immunological, clinical and metabolic risk factors influences the outcome of Type II (non-insulin-dependent) diabetes mellitus, we examined which of the above factors present at baseline were associated with mortality in 134 Type II diabetic patients followed for 9 years. Thirty-eight patients (29 %) died during the follow-up period; the majority of whom (68 %) died from cardiovascular disease. At baseline, the deceased patients had higher HbA_{1 c} values (p = 0.002), higher LDL-triglycerides (p = 0.007), lower HDL-cholesterol (p = 0.007), higher non-esterified fatty acid (NEFA) concentrations (p = 0.014), and higher albumin excretion rate (p < 0.0001) than the patients who survived. In addition, the frequency of HLA-DR4 (21 vs 39 %, p = 0.048) and of parietal cell antibodies (5 vs 14 %, p = 0.016) were decreased in the deceased as compared to the living patients. Patients who died during follow-up also had more retinopathy (42 vs 16 %, p = 0.002), neuropathy (57 vs 23 %, p < 0.001), microalbuminuria (45 vs 6 %, p < 0.0001), coronary heart disease (50 vs 13 %, p < 0.0001), and peripheral vascular disease (27 vs 9 %, p = 0.005) at baseline than patients who survived. In a multiple logistic regression analysis macroangiopathy (p = 0.004), neuropathy (p = 0.007), HbA_{1 c} (p = 0.018) and albumin excretion rate (p = 0.016) were independent risk factors for death. In patients free of cardiovascular disease at baseline, conventional risk factors such as LDL-cholesterol (p = 0.005) and age (p = 0.003) were associated with subsequent development of cardiovascular disease. In conclusion, in addition to coexisting macroangiopathy, increased albumin excretion rate, poor glycaemic control and neuropathy are risk factors for cardiovascular mortality in patients with Type II diabetes. The presence of HLA-DR4 and signs of autoimmunity may be associated with decreased risk of cardiovascular disease. [Diabetologia (1998) 41: 1253–1262] Received: 29 December 1997 and in revised form: 27 April 1998     

Cardiovascular Risk Factors in Type I (Insulin-dependent) Diabetic Patients with and without Proteinuria

ABSTRACT. In diabetes mellitus cardiovascular mortality among patients with increased urinary albumin excretion seems to be higher than in patients with normal urinary albumin excretion. Therefore we investigated blood pressure, total cholesterol, fibrinogen and in vivo platelet adhesion in 61 patients with type I (insulin-dependent) diabetes, 39 without complications, such as retinopathy or proteinuria and 22 with proteinuria and slightly elevated serum creatinine. The two groups had similar age, sex, diabetes duration and glucose control. Blood pressure, total cholesterol, fibrinogen and in vivo platelet adhesion were all significantly elevated in patients with proteinuria (p<0.01), whereas these parameters were normal in the uncomplicated diabetic patients, independent of diabetes duration. The mortality of cardiovascular disease during 20 years' follow-up was significantly higher among patients with proteinuria compared with patients without proteinuria (p<0.001), indicating that these risk factors contribute to the increased cardiovascular mortality in patients with clinical nephropathy.     

Plasma sex steroid hormones and risk of developing type 2 diabetes in women: a prospective study

Aims/hypothesis Prospective data directly investigating the role of endogenous sex hormones in diabetes risk have been scant, particularly in women. We aimed to examine comprehensively plasma sex hormones in connection with risk of developing type 2 diabetes in postmenopausal women. Methods We conducted a prospective, nested case–control study of plasma oestradiol, testosterone and dehydroepiandrosterone sulfate and risk of type 2 diabetes in a cohort of women health professionals with a mean age of 60.3 and 12.2 years since menopause. Among women not using hormone therapy and free of baseline cardiovascular disease, cancer and diabetes, 359 incident cases of type 2 diabetes were matched with 359 controls during an average follow-up of 10 years. Results Oestradiol and testosterone were each strongly and positively associated with risk of type 2 diabetes. After adjustment for BMI, family history, lifestyle and reproductive variables, the multivariable relative risks (95% CI) comparing the highest vs lowest quintile were 12.6 (2.83–56.3) for total oestradiol (p = 0.002 for trend), 13.1 (4.18–40.8) for free oestradiol (p < 0.001 for trend), 4.15 (1.21–14.2) for total testosterone (p = 0.019 for trend) and 14.8 (4.44–49.2) for free testosterone (p < 0.001 for trend). These associations remained robust after adjusting and accounting for other metabolic syndrome components and baseline HbA_1c levels. Conclusions/interpretation In postmenopausal women, higher plasma levels of oestradiol and testosterone were strongly and prospectively related to increased risk of developing type 2 diabetes. These prospective data indicate that endogenous levels of sex hormones may play important roles in the pathogenesis of type 2 diabetes. ClinicalTrials.gov ID no.: NCT00000479.     

NT-proBNP levels may be influenced by inflammation in active ankylosing spondylitis receiving TNF blockers: a pilot study

N-terminal pro-brain natriuretic peptide (NT-proBNP) is a strong marker of cardiovascular disease with recent evidence that inflammation may also influence its levels; discrimination of this confounding variable is of particular interest in rheumatic diseases. Therefore, we evaluated NT-proBNP in ankylosing spondylitis (AS) patients pre- and post-TNF blocker to determine the possible association between NT-proBNP levels and inflammatory parameters. Forty-five consecutive AS patients without previous/current cardiovascular disease or systolic myocardial dysfunction, who were eligible to anti-TNF therapy, were prospectively enrolled. All patients received TNF blockers and they were evaluated for circulating NT-proBNP levels, clinical and laboratory parameters of disease activity, traditional cardiovascular risk factors, and conventional and tissue Doppler imaging echocardiography at baseline (BL) and 6 months after (6M) treatment. At BL, all patients had active AS, NT-proBNP levels had a median of 36 (20–72)?pg/mL and 11 % were high in spite of no systolic alteration. Multiple linear regression analysis revealed that this peptide, at BL, was independently correlated with erythrocyte sedimentation rate (ESR) (p?<?0.001), age (p?=?0.01), and pulse pressure (p?=?0.01). After 6M, all disease parameters improved and NT-proBNP levels were significantly reduced [24 (16–47)?pg/mL, p?=?0.037] compared to BL. Changes in NT-proBNP were positively correlated with ESR changes (r?=?0.41, p?=?0.006). Cardiovascular risk factors remained stable during follow-up. In conclusion, our data suggest that elevations of NT-proBNP should be interpreted with caution in active AS patients with no other evidence of cardiovascular disease. The short-term reduction of NT-proBNP levels in these patients receiving anti-TNF therapy appears to reflect an improvement in inflammatory status.     

Elevated plasma phospholipid transfer protein activity is a determinant of carotid intima-media thickness in type 2 diabetes mellitus

Aim/hypothesis The plasma activity of phospholipid transfer protein (PLTP), which has putative pro- and anti-atherogenic roles in lipoprotein metabolism, is increased in type 2 diabetes mellitus. We analysed the relationship between carotid artery intima–media thickness (IMT), an established marker of atherosclerosis, and PLTP activity in diabetic patients and control subjects. Methods The IMT (mean of three segments in both carotid arteries by ultrasonography), clinical variables, plasma PLTP activity (phospholipid vesicle–HDL system), lipoproteins, C-reactive protein and insulin were measured in 87 non-smoking men and women, who had type 2 diabetes mellitus, no cardiovascular disease, and were not on insulin or lipid-lowering medication, and in 83 age-matched control subjects. Results In diabetic patients, carotid IMT (p=0.02), pulse pressure (p=0.003), plasma PLTP activity (p<0.001), triglycerides (p=0.01), C-reactive protein (p<0.01) and insulin (p<0.001) were higher, whereas HDL cholesterol was lower (p<0.001) than in control subjects. Multiple stepwise linear regression analysis demonstrated that in type 2 diabetic patients IMT was independently associated with age (p<0.001), sex (p=0.001), pulse pressure (p=0.003), plasma PLTP activity (p=0.03) and HDL cholesterol (p=0.03), but not with very low density lipoprotein+LDL cholesterol, triglycerides, C-reactive protein and insulin (all p>0.20). The relationship between plasma PLTP activity and IMT was not significant in control subjects. Conclusions/interpretation Plasma PLTP activity is a positive determinant of IMT in type 2 diabetes mellitus, suggesting that high PLTP activity is involved in accelerated atherosclerosis in this disease.     

Sympathetic nerve hyperactivity in non-diabetic offspring of patients with type 2 diabetes mellitus

Aims/hypothesis Type 2 diabetes mellitus with hyperinsulinaemia is a state of sympathetic nerve hyperactivity, which can develop subsequently in non-diabetic first-degree offspring of patients with type 2 diabetes. Although both type 2 diabetes and sympathetic activation are major cardiovascular risk factors, the level of sympathetic nerve activity is as yet unknown in offspring of type 2 diabetic patients who are ostensibly normal. We therefore sought to quantify sympathetic nerve activity and its relationship to plasma insulin levels in ostensibly normal offspring of patients with type 2 diabetes, relative to a matched normal control group with no family history of type 2 diabetes.Subjects and methods In two closely matched groups comprising 23 non-diabetic offspring of type 2 diabetic patients and 23 normal control individuals we measured resting muscle sympathetic nerve activity (MSNA) as the mean frequency of multi-unit bursts of MSNA and single units of MSNA (s-MSNA) with defined vasoconstrictor properties.Results In offspring of type 2 diabetic patients, the fasting plasma levels of insulin (7.4±0.80 μU/ml) and s-MSNA (45±3.2 impulses/100 beats) were greater (p<0.009 and p<0.003) than those in control persons (4.6±0.76 μU/ml and 32±3.1 impulses/100 beats, respectively). MSNA bursts and derived insulin resistance followed similar trends. Sympathetic nerve activity was significantly correlated to insulin levels (p<0.0002) and resistance (p<0.0001) in offspring of type 2 diabetic patients, but not in control subjects.Conclusions/interpretation Sympathetic activation occurred in normal non-diabetic offspring of patients with type 2 diabetes in proportion to their plasma insulin levels. Our data indicate the presence of a mechanistic link between hyperinsulinaemia and sympathetic activation, both of which could play a role in the subsequent development of cardiovascular risk factors.     

Increased plasma levels of N-terminal brain natriuretic peptide (NT-proBNP) in type 2 diabetic patients with vascular complications

AIMS: The plasma levels of either brain natriuretic peptide (BNP) or the N-terminal fragment of the prohormone (NT-proBNP) have recently gained extreme importance as markers of myocardial dysfunction. Patients with type 2 diabetes are at high risk of developing cardiovascular complications. This study was aimed to assess whether plasma NT-proBNP levels are at similar levels in type 2 diabetics with or without overt cardiovascular diseases. METHODS: We assayed plasma NT-proBNP in 54 type 2 diabetics, 27 of whom had no overt macro- and/or microvascular complications, while the remaining ones had either or both. The same assay was carried out in 38 healthy control subjects age and sex matched as a group with the diabetics. RESULTS: Plasma NT-proBNP was higher in diabetics (median 121 pg/ml, interquartile range 50-240 pg/ml, ) than in those without complications (37 pg/ml, 21-54 pg/ml, P<0.01). Compared with the controls (55 pg/ml, 40-79 pg/ml), only diabetics with vascular complications had significantly increased plasma NT-proBNP levels (P<0.001). In the diabetics, coronary heart disease and nephropathy (defined according to urinary excretion of albumin) were each independently associated with elevated values of plasma NT-proBNP. CONCLUSIONS: In type 2 diabetes mellitus, patients with macro- and/or micro-vascular complications exhibit an elevation of plasma NT-proBNP levels compared to corresponding patients with no evidence of vascular disease. The excessive secretion of this peptide is independently associated with coronary artery disease and overt nephropathy. The measurement of circulating NT-proBNP concentration may therefore be useful to screen for the presence of macro- and/or microvascular disease.     

Risk prediction in acute coronary syndrome from serial in-hospital measurements of N-terminal pro-B-type natriuretic peptide

There is limited information about the in-hospital plasma profile of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with non-ST-elevation acute coronary syndrome (NSTACS) and furthermore, the prognostic influence of the timing of NT-proBNP measurements in NSTACS is unsettled. These subject matters are elucidated in this study composed of 455 patients with NSTACS (symptoms <24 h). NT-proBNP was measured at 0, 6, 12, 24, 36, 48, 72 and 96 h following admission. Any death was registered at follow-up (median: 2.3 years). The study demonstrated a monophasic profile of the plasma NT-proBNP values, reaching a maximum at 6 hours, and it showed an independent prognostic significance of NT-proBNP irrespective of the sampling time. Risk prediction by NT-proBNP was improved by combining the baseline measurement and one value taken between 24 and 96 h (at 48 h, P<0.001). No additional prognostic information was provided by including more than one late in-hospital NT-proBNP value. Conclusions: The in-hospital NT-proBNP measurements exhibit a monophasic profile in patients with NSTACS and these values provide independent prognostic information as regards mortality irrespective of the sampling time. Moreover, risk prediction of NT-proBNP is strengthened by combining the admission measurement with an additional value during the hospitalization.     

A Four-year Follow-up Study on the Incidence of Diabetic Retinopathy in Older Onset Diabetes Mellitus

Out of 369 diabetic patients with an age at onset of diabetes ≧ 30 years previously studied, 325 (88%) were included in an ophthalmological follow-up examination 4 years later. In patients treated with oral drugs at baseline, the incidence of any type of retinopathy was 30.8% and of severe retinopathy 5.7%. All patients who developed severe retinopathy received insulin during the follow-up period. At baseline, duration of diabetes, diastolic blood pressure, and signs of nephropathy (p < 0.05 in all cases) as well as degree of metabolic control (p < 0.01) differed between patients who developed retinopathy and those who did not. At follow-up, there were no longer any differences regarding degree of metabolic control and diastolic blood pressure. In patients treated with insulin at baseline, the incidence of any type of retinopathy was 41.0% and of severe retinopathy 16.1%. At baseline, duration of diabetes (p < 0.01), degree of metabolic control, and insulin dosage (p < 0.05 in both cases) differed between patients who developed retinopathy and those who did not. At follow-up, there was no longer any difference in insulin dosage.     

Type 1 diabetes risk assessment: improvement by follow-up measurements in young islet autoantibody-positive relatives

Aims/hypothesis Combinations of autoantibody characteristics, including antibody number, titre, subclass and epitope have been shown to stratify type 1 diabetes risk in islet autoantibody-positive relatives. The aim of this study was to determine whether autoantibody characteristics change over time, the nature of such changes, and their implications for the development of diabetes.Methods Five-hundred and thirteen follow-up samples from 141 islet autoantibody-positive first-degree relatives were tested for islet autoantibody titre, IgG subclass, and GAD and IA-2 antibody epitope. All samples were categorised according to four risk stratification models. Relatives had a median follow-up of 6.8 years and 48 developed diabetes during follow-up. Survival analysis was used to determine the probability of change in risk category and of progression to diabetes.Results For each stratification model, the majority of relatives (71–81%) remained in the same risk category throughout follow-up. In the remainder, changes occurred both from lower to higher and from higher to lower risk categories. For all four models, relatives aged < 15 years were more likely to change risk category than those aged >15 years (0.001 < p < 0.03). Relatives whose autoantibody status changed from low- to high-risk categories had a higher risk of diabetes than relatives who remained in low-risk categories, and inclusion of autoantibody status during follow-up improved diabetes risk stratification in Cox proportional hazards models (p < 0.001).Conclusions/interpretation Changes in islet autoantibodies are relevant to pathogenesis, and are likely to signal alterations in the disease process. Detection of changes through follow-up measurement will improve diabetes risk stratification, particularly in young individuals.     

Lower levels of plasma 25-hydroxyvitamin D among young adults at diagnosis of autoimmune type 1 diabetes compared with control subjects: results from the nationwide Diabetes Incidence Study in Sweden (DISS)

Aims/hypothesis Low plasma vitamin D concentrations may promote the development of type 1 diabetes. To test this hypothesis, we measured plasma 25-hydroxyvitamin D (25OHD) in young adults with type 1 diabetes.Methods The nationwide Diabetes Incidence Study in Sweden (DISS) covers 15- to 34-year-old people with newly diagnosed diabetes. Blood samples at diagnosis were collected during the 2-year period 1987/1988. Patients with islet antibodies (islet cell antibodies, GAD antibodies or tyrosine phosphatase-like protein antibodies) were defined as having autoimmune type 1 diabetes. Plasma 25OHD was measured in samples taken from 459 patients at the time of diagnosis, and in 138 of these subjects 8 years later. The results were compared with age- and sex-matched control subjects (n=208).Results At diagnosis, plasma 25OHD levels were significantly lower in patients with type 1 diabetes than in control subjects (82.5±1.3 vs 96.7±2.0 nmol/l; p<0.0001). Eight years later, plasma 25OHD had decreased in patients (81.5±2.6 nmol/l; p=0.04). Plasma 25OHD levels were significantly lower in diabetic men than in diabetic women at diagnosis (77.9±1.4 vs 90.1±2.4 nmol/l; p<0.0001) and at follow-up (77.1±2.8 nmol/l vs 87.2±4.5 nmol/l; p=0.048).Conclusions/interpretation The plasma 25OHD level was lower at diagnosis of autoimmune type 1 diabetes than in control subjects, and may have a role in the development of type 1 diabetes. Plasma 25OHD levels were lower in men than in women with type 1 diabetes. This difference may be relevant to the high incidence of type 1 diabetes among young adult men.     

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.     

Effect of age on the association of non-high-density-lipoprotein cholesterol and apolipoprotein B with cardiovascular mortality in a Mediterranean population with type 2 diabetes: the Casale Monferrato study

Aims/hypothesis Measurement of plasma apolipoprotein (Apo) B may improve prediction of cardiovascular risk, as it provides a measure of the total number of atherogenic particles. The aim of this population-based study was to compare the association of non-HDL-cholesterol, ApoB and the ApoB:ApoA-I ratio with cardiovascular mortality in people with type 2 diabetes.Subjects and methods We assessed the association of lipids, lipoprotein lipids and apolipoproteins with 11-year mortality from cardiovascular disease in the population-based cohort of the Casale Monferrato Study (1,565 people with diabetes; median age 68.9 years), and determined the effect of age (≤70 and >70 years) on these relationships.Results On the basis of 341 deaths from cardiovascular disease in 10,809 person-years of observation, there was a decreasing trend in risk adjusted for multiple factors across quartiles of total cholesterol, and LDL- and non-HDL-cholesterol in people aged >70 years, but no trend in those aged ≤70 years. Age did not affect the protective effect of HDL-cholesterol. ApoB and ApoB:ApoA-I were associated with outcome in people in both age groups independently of non-HDL-cholesterol. After adjustment for multiple factors, including non-HDL-cholesterol, the hazard ratios for ApoB:ApoA-I in the upper vs lower quartile were 2.98 (95% CI 1.15–7.75; p for trend=0.009) for people aged ≤70 years and 1.94 (95% CI 1.20–3.13; p for trend=0.003) for those aged >70 years.Conclusions/interpretation In this cohort of Mediterranean subjects with diabetes, ApoB and the ApoB:ApoA-I ratio were associated with cardiovascular disease mortality independently of non-HDL-cholesterol. Our findings support the recommendation that ApoB and ApoA-I should be measured routinely in all people with diabetes, particularly in the elderly.     

N-terminal pro-brain natriuretic peptide and risk of cardiovascular events in older patients with type 2 diabetes: the Edinburgh Type 2 Diabetes Study

Aims/hypothesis

The aim of this study was to investigate the association of N-terminal pro-brain natriuretic peptide (NT-proBNP) with traditional cardiovascular risk factors and incident cardiovascular events in older people with type 2 diabetes.

Methods

In the prospective phase of the Edinburgh Type 2 Diabetes Study, 1066 men and women aged 60 to 75 years with type 2 diabetes mellitus were followed for 4 years; 112 participants had an incident cardiovascular event. At baseline, cardiovascular risk factors, pre-existing cardiovascular disease and levels of NT-proBNP were evaluated.

Results

Raised plasma NT-proBNP levels were associated with these classical cardiovascular risk factors: increased duration of diabetes, use of insulin, raised BMI, reduced HDL-cholesterol, reduced renal function and use of lipid-lowering and anti-hypertensive medication (all p?Conclusions/interpretation In older people with type 2 diabetes, NT-proBNP is associated with the development of coronary and cerebrovascular events, independent of a wide range of other vascular and metabolic risk factors, and may prove a useful addition to current vascular risk scores in diabetes populations.     

High normal 2-hour plasma glucose is associated with insulin sensitivity and secretion that may predispose to type 2 diabetes

Aims/hypothesis The aim of this study was to evaluate differences in insulin sensitivity, insulin secretion and risk factors for cardiovascular disease between subjects with a 2-h plasma glucose (2hPG) level within the normal range (NPG) and subjects with IGT, following a 75-g OGTT. We also aimed to determine the respective contributions made by 2hPG and fasting plasma glucose to the metabolic risk profile.Methods We compared cardiovascular risk factors and insulin sensitivity and insulin secretion by using several indices calculated using measurements obtained during an OGTT. Subjects (n=643, age 18–71 years) were participants in the Québec Family Study and were categorised according to 2hPG as having low NPG (2hPG <5.6 mmol/l, the group median for normal values), high NPG (2hPG 5.6–7.7 mmol/l) or IGT (2hPG 7.8–11.0 mmol/l). Subjects with type 2 diabetes were excluded from all analyses.Results Beta cell function and insulin sensitivity progressively decreased with increasing 2hPG. Compared with subjects with low NPG, subjects with high NPG were more insulin-resistant (p<0.05) and had reduced insulin secretion (adjusted for insulin resistance) (p<0.001). They also had higher plasma triglyceride concentrations (p<0.01) and cholesterol:HDL cholesterol ratios (p<0.05). These differences remained even after adjustment for age, sex, BMI and waist circumference. Multivariate analyses showed that 2hPG was closely associated with risk factors for diabetes and with cardiovascular variables, including triglycerides (p<0.0001) and apolipoprotein B (p<0.01).Conclusions/interpretation These results show that deteriorations in glucose–insulin metabolism, which may predispose individuals to type 2 diabetes and cardiovascular disease, are already present in subjects with 2hPG concentrations within the high normal range. Independently of obesity, 2hPG was found to explain, in part, the variance observed in cardiovascular and diabetes risk factors. In addition, elevated 2hPG was associated with metabolic alterations that appear to be the most detrimental to metabolic health. Thus, 2hPG values within the high normal range may be an important marker for the identification of people at risk of complications related to type 2 diabetes.