A urinary peptide biomarker set predicts worsening of albuminuria in type 2 diabetes mellitus

Aims/hypothesis

Microalbuminuria is considered the first clinical sign of kidney dysfunction and is associated with a poor renal and cardiovascular prognosis in type 2 diabetes. Detection of patients who are prone to develop micro- or macroalbuminuria may represent an effective strategy to start or optimise therapeutic intervention. Here we assessed the value of a urinary proteomic-based risk score (classifier) in predicting the development and progression of microalbuminuria.

Methods

We conducted a prospective case–control study. Cases (n?=?44) and controls (n?=?44) were selected from the PREVEND (Prevention of Renal and Vascular End-stage Disease) study and from the Steno Diabetes Center (Gentofte, Denmark). Cases were defined by transition from normo- to microalbuminuria or from micro- to macroalbuminuria over a follow-up of 3 years. Controls with no transitions in albuminuria were pair-matched for age, sex and albuminuria status. A model for the progression of albuminuria was built using a proteomic classifier based on 273 urinary peptides.

Results

The proteomic classifier was independently associated with transition to micro- or macroalbuminuria (OR 1.35 [95% CI 1.02, 1.79], p?=?0.035). The classifier predicted the development and progression of albuminuria on top of albuminuria and estimated GFR (eGFR, area under the receiver operating characteristic [ROC] curve increase of 0.03, p?=?0.002; integrated discrimination index [IDI]: 0.105, p?=?0.002). Fragments of collagen and α-2-HS-glycoprotein showed significantly different expression between cases and controls.

Conclusions/interpretation

Although limited by the relatively small sample size, these results suggest that analysis of a urinary biomarker set enables early renal risk assessment in patients with diabetes. Further work is required to confirm the role of urinary proteomics in the prevention of renal failure in diabetes.     

The association between estimated glomerular filtration rate,albuminuria, and risk of cardiovascular hospitalizations and all-cause mortality among patients with type 2 diabetes

Aims

We evaluated the simultaneous effects of all clinically recognized categories of albuminuria and estimated glomerular filtration rate (eGFR) on cardiovascular disease (CVD) and mortality

Estimated glomerular filtration rate and albuminuria are independent predictors of cardiovascular events and death in type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

Aims/hypothesis

We investigated effects of renal function and albuminuria on cardiovascular outcomes in 9,795 low-risk patients with diabetes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.

Methods

Baseline and year 2 renal status were examined in relation to clinical and biochemical characteristics. Outcomes included total cardiovascular disease (CVD), cardiac and non-cardiac death over 5?years.

Results

Lower estimated GFR (eGFR) vs eGFR ??90?ml?min^?1 1.73?m^?2 was a risk factor for total CVD events: (HR [95% CI] 1.14 [1.01?C1.29] for eGFR 60?C89?ml?min^?1 1.73?m^?2; 1.59 [1.28?C1.98] for eGFR 30?C59?ml?min^?1 1.73?m^?2; p?<?0.001; adjusted for other characteristics). Albuminuria increased CVD risk, with microalbuminuria and macroalbuminuria increasing total CVD (HR 1.25 [1.01?C1.54] and 1.19 [0.76?C1.85], respectively; p?=?0.001 for trend) when eGFR ??90?ml?min^?1 1.73?m^?2. CVD risk was further modified by renal status changes over the first 2?years. In multivariable analysis, 77% of the effect of eGFR and 81% of the effect of albumin:creatinine ratio were accounted for by other variables, principally low HDL-cholesterol and elevated blood pressure.

Conclusions/interpretation

Reduced eGFR and albuminuria are independent risk factors for cardiovascular events and mortality rates in a low-risk population of mainly European ancestry. While their independent contributions to CVD risk appear small when other risk factors are considered, they remain excellent surrogate markers in clinical practice because they capture risk related to a number of other characteristics. Therefore, both should be considered when assessing prognosis and treatment strategies in patients with diabetes, and both should be included in risk models.     

Impact of diabetes on overall and cancer-specific mortality in colorectal cancer patients

Purpose

Diabetes is associated with increased risk of developing colorectal cancer (CRC), but its effect on overall and cancer-specific mortality in CRC patients has been little investigated. The aim of this study was to assess the influence of diabetes on overall and cancer-specific mortality in Italian CRC patients.

Methods

Cases of adult (≥15 years) CRC, diagnosed in 2003–2005, most followed-up to the end of 2008, were randomly selected from the Italian Cancer Registries database. Diabetic status, sex, age, tumor stage, subsite, treatment, morphology, and grade were obtained by consultation of patient clinical records. Poisson multivariable regression models, adjusted for potential confounding variables, were used to estimate hazard ratios (HRs) for all-cause and CRC-specific mortality, according to diabetic status.

Results

A total of 1,039 CRC cases with known fasting glucose or diabetic status, archived in 7 cancer registries, was analyzed. Compared to non-diabetics, diabetics (specific diagnosis or glucose ≥126 mg/dl) were older and less likely to receive adjuvant therapy. Diabetics were at higher risk of all-cause death [HR 1.41; 95 % confidence interval (CI) 1.18–1.70] and CRC death (HR 1.36; 95 % CI 1.11–1.67), with no differences by sex or subsite.

Conclusions

Diabetes was significantly associated with increased overall and CRC-specific mortality. Our findings indicate that diabetes is a negative prognostic factor for CRC and suggest that in patients with CRC, diabetes prevention and treatments that stabilize the condition and control its complications might reduce mortality. Further studies are required to ascertain the mechanisms linking diabetes to greater mortality in CRC patients.     

Elevated ALT and GGT predict all-cause mortality and hepatocellular carcinoma in Taiwanese male: a case-cohort study

Purpose

Evidence indicates a positive association between liver enzymes and the risk of death in Western countries; however, the evidence in Asian populations is scarce. We investigated the association between liver enzymes and total, cardiovascular (CVD), cancer and hepatocellular carcinoma (HCC) mortality in a cohort of Taiwanese male free of cancer at baseline.

Methods

From 1996 to 2003, 54,751 Taiwanese male aged 40–80 years without cancer completed a health screening and were followed through 2005 (5.8 ± 2.5 years of follow-up). A random cohort of 3,961 male was selected to compare to 1,864 male who died. We used Cox proportional hazards regression models to assess the risk of all-cause, cardiovascular and cancer mortality associated with alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transferase (GGT).

Results

In this population, higher levels of ALT, AST and GGT were significantly associated with all-cause mortality [hazard ratio (HR) 1.2, 1.8 and 1.6 for ALT, AST and GGT, respectively; all p < 0.05], cancer mortality (HR 1.8–2.8) and HCC mortality (HR 5.5–36.1). GGT was significantly associated with CVD mortality (HR 1.2).

Conclusions

In Taiwanese male free of cancer at baseline, elevations of ALT, AST and GGT were associated with future risk of all-cause death, all cancer and HCC mortality, independent of conventional risk factors, and could be used to identify male who would benefit from HCC screening.     

Prognostic impact of the ankle–brachial index on the development of micro- and macrovascular complications in individuals with type 2 diabetes: the Rio de Janeiro Type 2 Diabetes Cohort Study

Aims/hypothesis

The prognostic importance of the ankle–brachial index (ABI) in individuals with diabetes is controversial. We aimed to evaluate the relationship between the ABI and the occurrence of micro- and macrovascular complications in individuals with type 2 diabetes.

Methods

The ABI was measured at baseline in 668 individuals with type 2 diabetes, and the individuals were followed-up for a median of 10 years. Multivariate Cox analysis was used to examine associations between the ABI and the occurrence of microvascular (retinopathy, microalbuminuria, renal function deterioration and peripheral neuropathy) and macrovascular (total cardiovascular events, major adverse cardiovascular events [MACE] and cardiovascular mortality) complications, and all-cause mortality. The improvement in risk stratification was assessed using the C statistic and the integrated discrimination improvement (IDI) index.

Results

During follow-up, 168 individuals had a cardiovascular event (140 MACE) and 191 individuals died (92 cardiovascular deaths); 156 individuals newly developed or experienced worsening diabetic retinopathy, 194 achieved the renal composite outcome (122 with newly developed microalbuminuria and 93 with deteriorating renal function) and 95 newly developed or experienced worsening peripheral neuropathy. The ABI, either analysed as a continuous or as a categorical variable, was significantly associated with all macrovascular and mortality outcomes, except for non-cardiovascular mortality. Individuals with a baseline ABI of ≤0.90 had a 2.1-fold increased risk of all-cause mortality (95% CI 1.3, 3.5; p?=?0.004), a 2.7-fold excess risk of cardiovascular mortality (95% CI 1.4, 5.4; p?=?0.004) and a 2.5-fold increased risk of MACE (95% CI 1.5, 4.4; p?=?0.001). The ABI improved risk discrimination over classical risk factors, with relative IDIs ranging from 6.3% (for all-cause mortality) to 31% (for cardiovascular mortality). In addition, an ABI of ≤0.90 was associated with the development or worsening of peripheral neuropathy (2.1-fold increased risk [95% CI 1.1, 4.3]; p?=?0.033), but not with retinopathy or renal outcomes.

Conclusions/interpretation

A low ABI is associated with excess risk of adverse cardiovascular outcomes, mortality and peripheral neuropathy development or worsening, and improves cardiovascular risk stratification. The ABI should therefore be routinely evaluated in individuals with type 2 diabetes.

     

DEVOTE 3: temporal relationships between severe hypoglycaemia,cardiovascular outcomes and mortality

Aims/hypothesis

The double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality.

Methods

In DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population.

Results

There was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA_1c, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group.

Conclusions/interpretation

The results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect.

Trial registration

ClinicalTrials.gov NCT01959529

     

A polymorphism in the gene encoding carnosinase (CNDP1) as a predictor of mortality and progression from nephropathy to end-stage renal disease in type 1 diabetes mellitus

Aims/hypothesis

Homozygosity for a five leucine repeat (5L–5L) in the carnosinase gene (CNDP1) has been found to be cross-sectionally associated with a low frequency of diabetic nephropathy (DN), mainly in type 2 diabetes. We prospectively investigated in patients with type 1 diabetes whether: (1) 5L–5L is associated with mortality; (2) there is an interaction of 5L–5L with DN or sex for prediction of mortality; and (3) 5L–5L is associated with progression to end-stage renal disease (ESRD).

Methods

In this prospective study in white European patients with type 1 diabetes, individuals with DN were defined by persistent albuminuria ≥300 mg/24 h. Controls without nephropathy were defined by persistent (>15 years) normoalbuminuria <30 mg/24 h. Leucine repeats were assessed with a fluorescent DNA analysis system. Onset of ESRD was defined by need to start chronic dialysis or kidney transplantation.

Results

The study involved 916 patients with DN and 1,170 controls. During follow-up for 8.8 years, 107 patients (14%) with 5L–5L died compared with 182 patients (13.8%) with other genotypes (p?=?0.99). There was no significant interaction of 5L–5L with DN for prediction of mortality (p?=?0.57), but a trend towards interaction with sex (p?=?0.08). In patients with DN, HR for ESRD in 5L–5L vs other genotypes was not constant over time, with increased risk for 5L–5L beyond 8 years of follow-up (p?=?0.03).

Conclusions/interpretation

CNDP1 polymorphism was not associated with mortality, and nor was there an interaction of this polymorphism with DN for prediction of mortality in patients with type 1 diabetes. CNDP1 polymorphism predicts progression to ESRD in patients with DN, but only late after baseline measurements.     

Impact of Long-Acting Bronchodilators and Exposure to Inhaled Corticosteroids on Mortality in COPD: A Real-Life Retrospective Cohort Study

Introduction

We performed a real-life retrospective analysis to assess the impact of long-acting bronchodilator therapy and associated exposure to inhaled corticosteroids (ICS) on all-cause and cardiovascular mortality in patients with chronic obstructive pulmonary disease (COPD).

Methods

We used record linkage data from patients with a diagnosis of COPD in Tayside, Scotland, between 2001 and 2010. All-cause and cardiovascular mortality were assessed using Cox proportional hazard regression.

Results

A total of 4,133 patients were included, mean FEV₁ of 59.5 %, mean age of 68.9 years and mean follow-up of 4.6 years. There were 623 who were exposed to long-acting bronchodilators only and 3,510 to long-acting bronchodilators plus ICS. 1,372 patients (33 %) died during the study period. Compared with controls taking only long-acting bronchodilators either alone or in combination, all-cause mortality was reduced in patients taking long-acting muscarinic antagonist (LAMA) + ICS as dual therapy: adjusted hazard ratio 0.62 (95 % CI 0.45–0.85), but not by long-acting beta-agonist (LABA) + ICS: adjusted hazard ratio 1.02 (95 % CI 0.80–1.31). Cardiovascular mortality was not reduced by dual therapy with either LABA or LAMA and concomitant ICS exposure. All-cause and cardiovascular mortality were both reduced in patients taking triple therapy with LABA + LAMA + ICS: adjusted hazard ratio 0.51 (95 % CI 0.41–0.64) and 0.56 (95 % CI 0.35–0.90), respectively.

Conclusion

In patients exposed to ICS, concomitant use of LAMA alone as dual therapy or in combination with LABA as triple therapy were associated with reductions in all-cause mortality, while concomitant use of LABA without LAMA conferred no reduction. Moreover, only triple therapy was found to confer benefits on cardiovascular mortality.     

Glucose patterns during an oral glucose tolerance test and associations with future diabetes,cardiovascular disease and all-cause mortality rate

Aims/hypothesis

In addition to blood glucose concentrations measured in the fasting state and 2 h after an OGTT, intermediate measures during an OGTT may provide additional information regarding a person’s risk of future diabetes and cardiovascular disease (CVD). First, we aimed to characterise heterogeneity of glycaemic patterns based on three time points during an OGTT. Second, we compared the incidences of diabetes and CVD and all-cause mortality rates among those with different patterns.

Methods

Our cohort study included 5861 participants without diabetes at baseline from the Danish Inter99 study. At baseline, all participants underwent an OGTT with measurements of plasma glucose levels at 0, 30 and 120 min. Latent class mixed-effects models were fitted to identify distinct patterns of glycaemic response during the OGTT. Information regarding incident diabetes, CVD and all-cause mortality rates during a median follow-up time of 11, 12 and 13 years, respectively, was extracted from national registers. Cox proportional hazard models with adjustment for several cardiometabolic risk factors were used to compare the risk of diabetes, CVD and all-cause mortality among individuals in the different latent classes.

Results

Four distinct glucose patterns during the OGTT were identified. One pattern was characterised by high 30 min but low 2 h glucose values. Participants with this pattern had an increased risk of developing diabetes compared with participants with lower 30 min and 2 h glucose levels (HR 4.1 [95% CI 2.2, 7.6]) and participants with higher 2 h but lower 30 min glucose levels (HR 1.5 [95% CI 1.0, 2.2]). Furthermore, the all-cause mortality rate differed between the groups with significantly higher rates in the two groups with elevated 30 min glucose. Only small non-significant differences in risk of future CVD were observed across latent classes after confounder adjustment.

Conclusions/interpretation

Elevated 30 min glucose is associated with increased risk of diabetes and all-cause mortality rate independent of fasting and 2 h glucose levels. Therefore, subgroups at high risk may not be revealed when considering only fasting and 2 h glucose levels during an OGTT.

     

Prevalence of systolic and diastolic dysfunction in patients with type 1 diabetes without known heart disease: the Thousand & 1 Study

Aims/hypothesis

Heart failure is one of the leading causes of mortality in type 1 diabetes. Early identification is vitally important. We sought to determine the prevalence and clinical characteristics associated with subclinical impaired systolic and diastolic function in type 1 diabetes patients without known heart disease.

Methods

In this cross-sectional examination of 1,093 type 1 diabetes patients without known heart disease, randomly selected from the Steno Diabetes Center, complete clinical and echocardiographic examinations were performed and analysed in uni- and multivariable regression models.

Results

The mean (SD) age was 49.6 (15)?years, 53% of participants were men, and the mean duration of diabetes was 25.5 (15)?years. Overall, 15.5% (n?=?169) of participants had grossly abnormal systolic or diastolic function, including 1.7% with left ventricular ejection fraction (LVEF)?<?45% and 14.4% with evidence of long-standing diastolic dysfunction. In univariable models, clinical characteristics associated with abnormal myocardial function were: age (per 10 years), OR (95% CI) 2.1 (1.8, 2.4); diabetes duration (per 10 years), 1.7 (1.4, 1.9); systolic BP?≥?140 mmHg, 2.7 (1.9, 3.8); diastolic BP?≥?90 mmHg, 1.8 (1.0, 3.1); estimated (e)GFR?<?60 ml min^?1 1.73 m^?2, 3.8 (2.5, 5.9); microalbuminuria, 2.0 (1.3, 3.0); macroalbuminuria, 5.9 (3.8, 9.3); proliferative retinopathy, 3.6 (2.3, 5.8); blindness, 10.1 (3.2, 31.6); and peripheral neuropathy, 3.8 (2.7, 5.3). In multivariable models only age (2.1 [1.7, 2.5]), female sex, (1.9 [1.2, 2.8]) and macroalbuminuria (5.2 [2.9, 10.3]) remained significantly associated with subclinical grossly abnormal myocardial function.

Conclusions/interpretation

Subclinical myocardial dysfunction is a common finding in type 1 diabetes patients without known heart disease. Type 1 diabetes patients with albuminuria are at greatly increased risk of having subclinical abnormal myocardial function compared with patients without albuminuria. Echocardiography may be particularly warranted in patients with albuminuria.     

Toe–brachial index as a predictor of cardiovascular disease and all-cause mortality in people with type 2 diabetes and microalbuminuria

Aims/hypothesis

The study aimed to evaluate toe–brachial index (TBI) and ankle–brachial index (ABI) as determinants of incident cardiovascular disease (CVD) and all-cause mortality in people with type 2 diabetes and microalbuminuria.

Methods

This was a prospective study including 200 participants. Unadjusted and adjusted (traditional risk factors and additional inclusion of N-terminal pro-brain natriuretic peptide [NT-proBNP] and coronary artery calcification) Cox regression models were performed. C statistics and relative integrated discrimination improvement (rIDI) evaluated risk prediction improvement.

Results

Median follow-up was 6.1 years; 40 CVD events and 26 deaths were recorded. Lower TBI was associated with increased risk of CVD (HR per 1 SD decrease: 1.55 [95% CI 1.38, 1.68]) and all-cause mortality (1.41 [1.22, 1.60]) unadjusted and after adjustment for traditional risk factors (CVD 1.50 [1.27, 1.65] and all-cause mortality 1.37 [1.01, 1.60]). Lower ABI was a determinant of CVD (1.49 [1.32, 1.61]) and all-cause mortality (1.37 [1.09, 1.57]) unadjusted and after adjustment for traditional risk factors (CVD 1.44 [1.23, 1.59] and all-cause mortality 1.39 [1.07, 1.60]). After additional adjustment for NT-proBNP and coronary artery calcification, lower TBI remained a determinant of CVD (p = 0.023). When TBI was added to traditional risk factors, the AUC increased significantly for CVD, by 0.063 (95% CI 0.012, 0.115) from 0.743 (p = 0.016), but not for all-cause mortality; adding ABI did not improve the AUC significantly. The rIDI for TBI was 46.7% (p < 0.001) for CVD and 46.0% (p = 0.002) for all-cause mortality; for ABI, the rIDI was 51.8% (p = 0.004) for CVD and 53.6% (p = 0.031) for all-cause mortality.

Conclusions/interpretation

Reduced TBI and ABI were associated with increased risk of CVD and all-cause mortality, independent of traditional risk factors in type 2 diabetes, and improved prognostic accuracy.

     

Intensive glucose control and macrovascular outcomes in type 2 diabetes

Aims/hypothesis

Improved glucose control in type 2 diabetes is known to reduce the risk of microvascular events. There is, however, continuing uncertainty about its impact on macrovascular disease. The aim of these analyses was to generate more precise estimates of the effects of more-intensive, compared with less-intensive, glucose control on the risk of major cardiovascular events amongst patients with type 2 diabetes.

Methods

A prospectively planned group-level meta-analysis in which characteristics of trials to be included, outcomes of interest, analyses and subgroup definitions were all pre-specified.

Results

A total of 27,049 participants and 2,370 major vascular events contributed to the meta-analyses. Allocation to more-intensive, compared with less-intensive, glucose control reduced the risk of major cardiovascular events by 9% (HR 0.91, 95% CI 0.84–0.99), primarily because of a 15% reduced risk of myocardial infarction (HR 0.85, 95% CI 0.76–0.94). Mortality was not decreased, with non-significant HRs of 1.04 for all-cause mortality (95% CI 0.90–1.20) and 1.10 for cardiovascular death (95% CI 0.84–1.42). Intensively treated participants had significantly more major hypoglycaemic events (HR 2.48, 95% CI 1.91–3.21). Exploratory subgroup analyses suggested the possibility of a differential effect for major cardiovascular events in participants with and without macrovascular disease (HR 1.00, 95% CI 0.89–1.13, vs HR 0.84, 95% CI 0.74–0.94, respectively; interaction p?=?0.04).

Conclusions/interpretation

Targeting more-intensive glucose lowering modestly reduced major macrovascular events and increased major hypoglycaemia over 4.4 years in persons with type 2 diabetes. The analyses suggest that glucose-lowering regimens should be tailored to the individual.     

Progression to microalbuminuria in type 1 diabetes: development and validation of a prediction rule

Aims/hypothesis

Microalbuminuria is common in type 1 diabetes and is associated with an increased risk of renal and cardiovascular disease. We aimed to develop and validate a clinical prediction rule that estimates the absolute risk of microalbuminuria.

Methods

Data from the European Diabetes Prospective Complications Study (n?=?1115) were used to develop the prediction rule (development set). Multivariable logistic regression analysis was used to assess the association between potential predictors and progression to microalbuminuria within 7 years. The performance of the prediction rule was assessed with calibration and discrimination (concordance statistic [c-statistic]) measures. The rule was validated in three other diabetes studies (Pittsburgh Epidemiology of Diabetes Complications [EDC] study, Finnish Diabetic Nephropathy [FinnDiane] study and Coronary Artery Calcification in Type 1 Diabetes [CACTI] study).

Results

Of patients in the development set, 13% were microalbuminuric after 7 years. Glycosylated haemoglobin, AER, WHR, BMI and ever smoking were found to be the most important predictors. A high-risk group (n?=?87 [8%]) was identified with a risk of progression to microalbuminuria of 32%. Predictions showed reasonable discriminative ability, with c-statistic of 0.71. The rule showed good calibration and discrimination in EDC, FinnDiane and CACTI (c-statistic 0.71, 0.79 and 0.79, respectively).

Conclusions/interpretation

We developed and validated a clinical prediction rule that uses relatively easily obtainable patient characteristics to predict microalbuminuria in patients with type 1 diabetes. This rule can help clinicians to decide on more frequent check-ups for patients at high risk of microalbuminuria in order to prevent long-term chronic complications.     

High BNP level as risk factor for acute kidney injury and predictor of all-cause mortality in STEMI patients

Objectives

The aim of this study was to evaluate the predictive value of brain natriuretic peptide (BNP) in the development of acute kidney injury (AKI) and 6-month all-cause mortality after primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) in a modest-risk population.

Background

The prognostic value of BNP has been well documented in patients with acute coronary syndrome. However, its value in development of AKI and 6-month all-cause mortality in patients with STEMI undergoing primary PCI remains unclear.

Methods

We prospectively enrolled 424 consecutive STEMI patients (mean age 53.6?±?12.1 years) undergoing primary PCI. The population was divided into two groups: a high (n?=?110) and a low (n?=?314) admission BNP group according to the cut-off value (>?88.7 pg/ml) determined by ROC analysis to have the best predictive accuracy for 6-month all-cause mortality. The clinical characteristics as well as the in-hospital and 6-month outcomes of patients undergoing primary PCI were analyzed.

Results

Cox multivariate analysis showed that a high-admission BNP value (>?88.7 pg/ml) was an independent predictor of AKI development (odds ratio, 1.002; 95?% confidence interval, 1.000–1.003; p?=?0.02) and 6-month all-cause mortality (odds ratio, 1.003; 95?% confidence interval; 1.001–1.004; p?=?0.004).

Conclusion

These results suggest that a high-admission BNP level is associated with an increased risk of AKI development and 6-month all-cause mortality in patients with STEMI undergoing primary PCI.     

Efficacy of Angiotensin-Converting Enzyme Inhibitors and Angiotensin-Receptor Blockers in Coronary Artery Disease without Heart Failure in the Modern Statin Era: a Meta-Analysis of Randomized-Controlled Trials

Purpose

Current practice guidelines support the use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARBs) in patients with coronary artery disease (CAD) without heart failure (HF). However, a number of cited trials were performed prior to the era of prevalent statin use. Our objective was to evaluate the effectiveness of ACEi and ARBs in reducing cardiovascular events as well as the impact of statin therapy.

Methods

We searched the MEDLINE and EMBASE databases for randomized-controlled trials (1/1/1980 – 8/31/2015) with ACEi or ARBs as the single intervention for patients with CAD without HF. We assessed the outcomes of non-fatal myocardial infarction (MI), stroke, cardiovascular mortality and all-cause mortality. The relationship between these outcomes and the percentages of patients on statin therapy was evaluated using meta-regression analysis.

Results

A total of ten ACEi trials and five ARB trials were included for analysis, with 78,761 patients followed for a mean of 36 months. Treatment with ACEi was associated with decreased non-fatal MI (RR 0.83; 95 % CI 0.75–0.91), stroke (RR 0.76; 95 % CI 0.68–0.86), cardiovascular mortality (RR 0.83; 95 % CI 0.72–0.95), and all-cause mortality (RR 0.86; 95 % CI 0.80–0.93). Treatment with ARBs was associated only with a decreased incidence of stroke (RR 0.92; 95 % CI 0.87–0.98). When adjusted for statin use, there was a trend towards an attenuated effect of ACEi in reducing cardiovascular mortality with increased use of statins (p-value?=?0.063).

Conclusion

In CAD patients without HF, ACEi, but not ARBs decreases the risk of non-fatal MI, cardiovascular mortality and all-cause mortality, while both ACEi and ARBs decrease the risk of stroke.

     

Structured personal care of type 2 diabetes: a 19 year follow-up of the study Diabetes Care in General Practice (DCGP)

Aims/hypothesis

This study is a 19 year observational follow-up of a pragmatic open multicentre cluster-randomised controlled trial of 6 years of structured personal diabetes care starting from diagnosis.

Methods

A total of 1,381 patients aged ≥40 years and newly diagnosed with type 2 diabetes were followed up in national registries for 19 years. Clinical follow-up was at 6 and 14 years after diabetes diagnosis. The original 6 year intervention included regular follow-up and individualised goal setting, supported by prompting of doctors, clinical guidelines, feedback and continuing medical education (ClinicalTrials.gov NCT01074762). The registry-based endpoints were: incidence of any diabetes-related endpoint; diabetes-related death; all-cause mortality; myocardial infarction (MI); stroke; peripheral vascular disease; and microvascular disease.

Results

At 14 year clinical follow-up, group differences in risk factors from the 6 year follow-up had levelled out, although the prevalence of (micro)albuminuria and level of triacylglycerols were lower in the intervention group. During 19 years of registry-based monitoring, all-cause mortality was not different between the intervention and comparison groups (58.9 vs 62.3 events per 1,000 patient-years, respectively; for structured personal care, HR 0.94, 95% CI 0.83, 1.08, p?=?0.40), but a lower risk emerged for fatal and non-fatal MI (27.3 vs 33.5, HR 0.81, 95% CI 0.68, 0.98, p?=?0.030) and any diabetes-related endpoint (69.5 vs 82.1, HR 0.83, 95% CI 0.72, 0.97, p?=?0.016). These differences persisted after extensive multivariable adjustment.

Conclusions/interpretation

In concert with features such as prompting, feedback, clinical guidelines and continuing medical education, individualisation of goal setting and drug treatment may safely be applied to treat patients newly diagnosed with type 2 diabetes to lower the risk of diabetes complications.     

Nonlinear association of BMI with all-cause and cardiovascular mortality in type 2 diabetes mellitus: a systematic review and meta-analysis of 414,587 participants in prospective studies

Aims/hypothesis

The relationship between BMI and mortality has been extensively investigated in the general population; however, it is less clear in people with type 2 diabetes. We aimed to assess the association of BMI with all-cause and cardiovascular mortality in individuals with type 2 diabetes mellitus.

Methods

We searched electronic databases up to 1 March 2016 for prospective studies reporting associations for three or more BMI groups with all-cause and cardiovascular mortality in individuals with type 2 diabetes mellitus. Study-specific associations between BMI and the most-adjusted RR were estimated using restricted cubic splines and a generalised least squares method before pooling study estimates with a multivariate random-effects meta-analysis.

Results

We included 21 studies including 24 cohorts, 414,587 participants, 61,889 all-cause and 4470 cardiovascular incident deaths; follow-up ranged from 2.7 to 15.9 years. There was a strong nonlinear relationship between BMI and all-cause mortality in both men and women, with the lowest estimated risk from 31–35 kg/m² and 28–31 kg/m² (p value for nonlinearity <0.001) respectively. The risk of mortality at higher BMI values increased significantly only in women, whilst lower values were associated with higher mortality in both sexes. Limited data for cardiovascular mortality were available, with a possible inverse linear association with BMI (higher risk for BMI <27 kg/m²).

Conclusions/interpretation

In type 2 diabetes, BMI is nonlinearly associated with all-cause mortality with lowest risk in the overweight group in both men and women. Further research is needed to clarify the relationship with cardiovascular mortality and assess causality and sex differences.

     

Non-albuminuric renal impairment is a strong predictor of mortality in individuals with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicentre study

Aims/hypothesis

Non-albuminuric renal impairment has become the prevailing diabetic kidney disease (DKD) phenotype in individuals with type 2 diabetes and an estimated GFR (eGFR) <60 ml min^?1 1.73 m^?2. In the present study, we compared the rate and determinants of all-cause death in individuals with this phenotype with those in individuals with albuminuric phenotypes.

Methods

This observational prospective cohort study enrolled 15,773 individuals with type 2 diabetes in 2006–2008. Based on baseline albuminuria and eGFR, individuals were classified as having: no DKD (Alb^?/eGFR^?), albuminuria alone (Alb⁺/eGFR^?), reduced eGFR alone (Alb^?/eGFR⁺), or both albuminuria and reduced eGFR (Alb⁺/eGFR⁺). Vital status on 31 October 2015 was retrieved for 15,656 individuals (99.26%).

Results

Mortality risk adjusted for confounders was lowest for Alb^?/eGFR^? (reference category) and highest for Alb⁺/eGFR⁺ (HR 2.08 [95% CI 1.88, 2.30]), with similar values for Alb⁺/eGFR^? (1.45 [1.33, 1.58]) and Alb^?/eGFR⁺ (1.58 [1.43, 1.75]). Similar results were obtained when individuals were stratified by sex, age (except in the lowest age category) and prior cardiovascular disease. In normoalbuminuric individuals with eGFR <45 ml min^?1 1.73 m^?2, especially with low albuminuria (10–29 mg/day), risk was higher than in microalbuminuric and similar to macroalbuminuric individuals with preserved eGFR. Using recursive partitioning and amalgamation analysis, prevalent cardiovascular disease and lower HDL-cholesterol were the most relevant correlates of mortality in all phenotypes. Higher albuminuria within the normoalbuminuric range was associated with death in non-albuminuric DKD, whereas the classic ‘microvascular signatures’, such as glycaemic exposure and retinopathy, were correlates of mortality only in individuals with albuminuric phenotypes.

Conclusions/interpretation

Non-albuminuric renal impairment is a strong predictor of mortality, thus supporting a major prognostic impact of renal dysfunction irrespective of albuminuria. Correlates of death partly differ from the albuminuric forms, indicating that non-albuminuric DKD is a distinct phenotype.

Trial registration:

ClinicalTrials.gov NCT00715481

     

Decreasing Trend of Upper Gastrointestinal Bleeding Mortality Risk Over Three Decades

Background

Upper gastrointestinal bleeding (UGIB) causes over $1 billion in medical expenses annually.

Aims

The purpose of this study was to examine changes of UGIB mortality risks and trends over the last three decades.

Methods

We analyzed the National Hospital Discharge Sample from 1979 to 2009. Patients with primary ICD-9 code representing a diagnosis of UGIB were included. The UGIB mortality risks and trends in each decade by anatomical sites, bleeding causes, comorbidities, and other important variables were analyzed.

Results

UGIB mortality risk decreased by 35.4 % from 4.8 % in the first decade to 3.1 % in the third decade (P < 0.001). Age and number of hospitalization days were significant risk factors in all decades. Most significant decreases were observed in patients over 65 years and during the first day of admission. Gastric (P < 0.001) and esophageal (P = 0.018) bleedings showed significant decreasing mortality risk trends. Duodenal bleeding mortality risk was stable in three decades. Mortality risk declined significantly among patients with renal failure (from 50.0 to 4.0 %) and heart failure (from 17.9 to 5.2 %; both P < 0.001) while changes in cases with ischemic heart disease, cancer, and liver failure were less significant.

Conclusion

UGIB morality risks, especially of the first hospital day and geriatric patients, significantly decreased over the last three decades, presumably from recent advances in emergency medical care. Mortality risk of gastric, but not duodenal, bleeding had the most significant reduction. Critical care improvements in patients with various comorbidities may explain significant UGIB mortality risk reductions. This study provides invaluable insight into the causes and trends of UGIB mortality risks for future studies.