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OBJECTIVE: Intensive glycemic control reduced coronary artery disease (CAD) events among the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study participants with the haptoglobin (Hp)2-2 phenotype but not in participants without the Hp2-2 phenotype. It is unknown whether and how these results translate across different demographic/clinical characteristics and treatment strategies. RESEARCH DESIGN AND METHODS: Haptoglobin phenotype was measured in available samples from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) biomarker case-cohort study. Weighted multivariable-adjusted Cox regression models were used to evaluate the association between intensive glycemic control (HbA1c target of ≤6.5%) versus standard therapy (based on local guidelines) and major CAD events among participants with (n = 1,327) and without (n = 2,077) the Hp2-2 phenotype separately and within prespecified stratifications by sex, race, previous cardiovascular disease (CVD), diabetes duration, and HDL-cholesterol. RESULTS: While the hazard ratios (HRs) were in the hypothesized differing directions, compared with standard therapy, intensive glycemic control was not significantly associated with risk of CAD events among participants without (1.04, 95% CI 0.82–1.32) or with (0.84, 0.63–1.14, P interaction = 0.27) the Hp2-2 phenotype overall. Intensive therapy was associated with lower CAD risk among participants with the Hp2-2 phenotype who had no previous CVD (0.47, 0.29–0.76, P interaction = 0.01). CONCLUSIONS: Our findings suggest that intensive glycemic control contributes to the prevention of major CAD events among ADVANCE participants with the Hp2-2 phenotype and no previous CVD and are in alignment with our hypothesis that intensive glycemic control may be beneficial in a subset of people with the Hp2-2 phenotype. [ABSTRACT FROM AUTHOR]

The effectiveness of lifestyle interventions in reducing caloric intake and increasing physical activity for preventing Type 2 Diabetes (T2D) has been previously demonstrated. The use of modern technologies can potentially further improve the success of these interventions, promote metabolic health, and prevent T2D at scale. To test this concept, we built a remote program that uses continuous glucose monitoring (CGM) and wearables to make lifestyle recommendations that improve health. We enrolled 2,217 participants with varying degrees of glucose levels (normal range, and prediabetes and T2D ranges), using continuous glucose monitoring (CGM) over 28 days to capture glucose patterns. Participants logged food intake, physical activity, and body weight via a smartphone app that integrated wearables data and provided daily insights, including overlaying glucose patterns with activity and food intake, macronutrient breakdown, glycemic index (GI), glycemic load (GL), and activity measures. The app furthermore provided personalized recommendations based on users' preferences, goals, and observed glycemic patterns. Users could interact with the app for an additional 2 months without CGM. Here we report significant improvements in hyperglycemia, glucose variability, and hypoglycemia, particularly in those who were not diabetic at baseline. Body weight decreased in all groups, especially those who were overweight or obese. Healthy eating habits improved significantly, with reduced daily caloric intake and carbohydrate-to-calorie ratio and increased intake of protein, fiber, and healthy fats relative to calories. These findings suggest that lifestyle recommendations, in addition to behavior logging and CGM data integration within a mobile app, can enhance the metabolic health of both nondiabetic and T2D individuals, leading to healthier lifestyle choices. This technology can be a valuable tool for T2D prevention and treatment. [ABSTRACT FROM AUTHOR]

Aim: To investigate the association between lactation and maternal risk of type 2 diabetes, including a potential graded association according to lactation duration. Methods: A systematic review and meta‐analysis of observational studies that investigated the reported association between lactation (irrespective of duration, intensity or mode) and maternal risk of type 2 diabetes was conducted. Results: A total of 22 studies (17 cohort studies and five cross‐sectional studies) were included in this systematic review, and 16 contributed to the meta‐analysis. Studies that investigated the association of lactation with risk of type 2 diabetes in the first months after birth in women with gestational diabetes reported conflicting results. Studies with a longer follow‐up showed a graded protective association for lactation and the risk of type 2 diabetes, with a potentially larger risk reduction in women with gestational diabetes than in those without gestational diabetes. Overall, ever versus never lactation was associated with a 27% lower risk of type 2 diabetes (RR 0.73, 95% CI [0.65, 0.83]). Each additional month of lactation was associated with a 1% lower risk of type 2 diabetes (RR 0.99, 95% CI [0.98, 0.99]). However, the overall quality of the studies was modest. Conclusions: Lactation is associated with a significantly reduced risk of maternal type 2 diabetes over the life course, particularly in women with gestational diabetes. The protective effect seems to increase with longer duration of lactation. Further research is warranted to understand whether this association is modified by exposure to other risk factors. [ABSTRACT FROM AUTHOR]

Aim: To estimate the associations between risk factors and cognitive decline (CD)/dementia, and the sex differences in these risk factors in individuals with type 2 diabetes, while accounting for the competing risk of death. Materials and Methods: The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial of 11,140 individuals with type 2 diabetes was used to estimate the odds of CD/dementia using multinomial logistic regression. Results: During a median 5‐year follow‐up, 1827 participants (43.2% women) had CD/dementia (1718 with CD only; 21 with dementia only; 88 with CD and dementia), and 929 (31.0% women) died without CD/dementia. Women had lower odds of CD/dementia than men (odds ratio [OR] [95% confidence interval], 0.88 [0.77, 1.00]); older age, higher total cholesterol, HbA1c, waist circumference, waist‐to‐height ratio, moderately increased albumin‐creatinine ratio, stroke/transient ischaemic attack and retinal disease were each associated with greater odds of CD/dementia; higher years at education completion, baseline cognitive function, taller stature and current alcohol use were inversely associated. Higher waist circumference (women‐to‐men ratio of ORs [ROR], 1.05 [1.00, 1.10] per 5 cm) and presence of anxiety/depression (ROR, 1.28 [1.01, 1.63]) were associated with greater ORs for CD/dementia in women than men. Conclusions: Several risk factors were associated with CD/dementia. Higher waist circumference and mental health symptoms were more strongly associated with CD/dementia in women than men. Further studies should examine the mechanisms that underlie these sex differences. [ABSTRACT FROM AUTHOR]

Objective: To develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), among participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.Research Design and Methods: Cox proportional hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI >0.21) status. The primary outcomes were macro- and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycemia, and discontinuation of BP treatment due to hypotension/dizziness.Results: There were 11,140 participants (mean age, 65.8 years; 42.5% women, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: hazard ratios for combined major macro- and microvascular events 1.03 (95% CI 0.90-1.19) in the frail versus 0.84 (95% CI 0.74-0.94) in the nonfrail (P = 0.02). A similar trend was observed with BP intervention. Severe hypoglycemia rates (per 1,000 person-years) were higher in the frail: 8.39 (6.15-10.63) vs. 4.80 (3.84-5.76) in nonfrail (P < 0.001). There was no significant difference in discontinuation of BP treatment between frailty groups.Conclusions: It was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose-lowering and BP-lowering treatments. [ABSTRACT FROM AUTHOR]

There are limited data on whether estimated glomerular filtration rate (eGFR) variability modifies the risk of future clinical outcomes in type 2 diabetes (T2D). We assessed the association between 20‐month eGFR variability and the risk of major clinical outcomes in T2D among 8241 participants in the ADVANCE trial. Variability in eGFR (coefficient of variation [CVeGFR]) was calculated from three serum creatinine measurements over 20 months. Participants were classified into three groups by thirds of CVeGFR: low (≤6.4; reference), moderate (>6.4 to ≤12.1) and high (>12.1). The primary outcome was the composite of major macrovascular events, new or worsening nephropathy and all‐cause mortality. Cox regression models were used to estimate hazard ratios (HRs). Over a median follow‐up of 2.9 years following the 20‐month period, 932 (11.3%) primary outcomes were recorded. Compared with low variability, greater 20‐month eGFR variability was independently associated with higher risk of the primary outcome (HR for moderate and high variability: 1.07, 95% CI: 0.91–1.27 and 1.22, 95% CI: 1.03–1.45, respectively) with evidence of a positive linear trend (p =.015). These data indicate that eGFR variability predict changes in the risk of major clinical outcomes in T2D. [ABSTRACT FROM AUTHOR]

Aims: For relatively old patients with diabetes, current guidelines recommend adjustment of glycaemic goals based on patients' cognitive function, or coexisting chronic illnesses. However, the evidence which supports the efficacy and safety of intensive glucose lowering in older patients with diabetes is scarce. The objective of the present study was to compare the efficacy and safety of intensive glucose lowering in patients with type 2 diabetes stratified by age (<65 and ≥ 65 years), and examine whether the effects differ according to patients' characteristics in the older patient group. Materials and Methods: The effects of intensive glucose lowering (to a target glycated haemoglobin [HbA1c] concentration of ≤48 mmol/mol [6.5%]) on major clinical outcomes were evaluated by Cox regression models according to subgroups defined by baseline age of <65 or ≥ 65 years in the ADVANCE trial (n = 11 140). Results: Over a median follow‐up of 5 years, intensive glucose lowering significantly decreased the risk of the composite of major macrovascular and microvascular events (hazard ratio 0.90, 95% confidence interval 0.82‐0.98), with no heterogeneity in the effects across age subgroups (p for heterogeneity = 0.44). Relative effects on all‐cause death, cardiovascular death, and components of major vascular events were also similar (P for heterogeneity ≥0.06), except for severe hypoglycaemia, which was of greater risk for patients aged <65 years. Absolute benefits and harms were broadly consistent across subgroups. Among patients aged ≥65 years, randomized treatment effects did not differ significantly across different levels of cognitive function or coexisting chronic illnesses. Conclusions: Our results suggest that an intensive glycaemic control strategy to reduce HbA1c to 48 mmol/mol (6.5%) provided broadly similar benefits and harms and may be recommended for older, as well as younger, patients. [ABSTRACT FROM AUTHOR]

Objective: Observational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding.Research Design and Methods: Using 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (251,420 women and 212,049 men). Weighted median, MR-Egger, MR-pleiotropy residual sum and outlier, and radial MR from summary-level analyses were used for pleiotropy assessment.Results: MR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio 1.13 [95% CI 1.08-1.18] per 1-log unit increase in odds of type 2 diabetes) and men (1.21 [1.17-1.26] per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy; however, results were similar after correction for outlier SNPs.Conclusions: This MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes. [ABSTRACT FROM AUTHOR]

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Aim: To examine possible sex differences in the excess risk of myocardial infarction (MI) consequent to a range of conventional risk factors in a large‐scale international cohort of patients with diabetes, and to quantify these potential differences both on the relative and absolute scales. Materials and methods: Eleven thousand and sixty‐five participants (42% women) with type 2 diabetes in the ADVANCE trial and its post‐trial follow‐up study, ADVANCE‐ON, were included. Cox regression models were used to estimate hazard ratios (HRs) for associations between risk factors and MI (fatal and non‐fatal) by sex, and the women‐to‐men ratio of HRs (RHR). Results: Over a median of 9.6 years of follow‐up, 719 patients experienced MI. Smoking status, smoking intensity, higher systolic blood pressure (SBP), HbA1c, total and LDL cholesterol, duration of diabetes, triglycerides, body mass index (BMI) and lower HDL cholesterol were associated with an increased risk of MI in both sexes. Furthermore, some variables were associated with a greater relative risk of MI in women than men: RHRs were 1.75 (95% CI: 1.05‐2.91) for current smoking, 1.53 (1.00‐2.32) for former smoking, 1.18 (1.02‐1.37) for SBP, and 1.13 (95% CI, 1.003‐1.26) for duration of diabetes. Although incidence rates of MI were higher in men (9.3 per 1000 person‐years) compared with women (5.8 per 1000 person‐years), rate differences associated with risk factors were greater in women than men, except for HDL cholesterol and BMI. Conclusions: In patients with type 2 diabetes, smoking, higher SBP and longer duration of diabetes had a greater relative and absolute effect in women than men, highlighting the importance of routine sex‐specific approaches and early interventions in women with diabetes. [ABSTRACT FROM AUTHOR]

Objective: To study whether the effects of intensive glycemic control on major vascular outcomes (a composite of major macrovascular and major microvascular events), all-cause mortality, and severe hypoglycemia events differ among participants with different levels of 10-year risk of atherosclerotic cardiovascular disease (ASCVD) and hemoglobin A1c (HbA1c) at baseline.Research Design and Methods: We studied the effects of more intensive glycemic control in 11,071 patients with type 2 diabetes (T2D), without missing values, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, using Cox models.Results: During 5 years' follow-up, intensive glycemic control reduced major vascular events (hazard ratio [HR] 0.90 [95% CI 0.83-0.98]), with the major driver being a reduction in the development of macroalbuminuria. There was no evidence of differences in the effect, regardless of baseline ASCVD risk or HbA1c level (P for interaction = 0.29 and 0.94, respectively). Similarly, the beneficial effects of intensive glycemic control on all-cause mortality were not significantly different across baseline ASCVD risk (P = 0.15) or HbA1c levels (P = 0.87). The risks of severe hypoglycemic events were higher in the intensive glycemic control group compared with the standard glycemic control group (HR 1.85 [1.41-2.42]), with no significant heterogeneity across subgroups defined by ASCVD risk or HbA1c at baseline (P = 0.09 and 0.18, respectively).Conclusions: The major benefits for patients with T2D in ADVANCE did not substantially differ across levels of baseline ASCVD risk and HbA1c. [ABSTRACT FROM AUTHOR]

To assess the effects of intensive glucose control on the risk of major clinical outcomes according to estimated glomerular filtration rate (eGFR) levels in people with type 2 diabetes. Of 11 140 ADVANCE trial participants, 11 096 with baseline eGFR measurements were included, and classified into three eGFR groups: ≥90 mL/min/1.73 m2; 60 to 89 mL/min/1.73 m2; and < 60 mL/min/1.73 m2. Relative risk reduction of randomized intensive glucose control with regard to the composite outcome of major macro‐ and microvascular events, all‐cause death and cardiovascular death did not significantly vary by eGFR level (P for heterogeneity ≥0.49). The risk of severe hypoglycaemia increased with intensive glucose control; however, this risk did not vary across eGFR groups (P for heterogeneity = 0.83). The risk–benefit profile of intensive glucose control in patients with type 2 diabetes and impaired kidney function appears similar to that observed in those with preserved kidney function. [ABSTRACT FROM AUTHOR]

Sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors prevent cardiovascular complications in type 2 diabetes. We aimed to study whether they have similar effects in women and men by summarizing the effects of SGLT2 inhibitors compared to placebo on vascular and safety outcomes stratified by sex. We included patients with type 2 diabetes enrolled in the EMPA‐REG OUTCOME, CANVAS Program, DECLARE TIMI‐58 and CREDENCE trials. There were no differences in the risk ratios between men and women, SGLT2 versus control (placebo), for vascular efficacy outcomes or death (all P for interaction ≥.12), with clear protection shown against major adverse cardiovascular events, heart failure, vascular death and total mortality. SGLT2 inhibitor treatment was also associated with similar relative risks in women and men for the safety outcomes of amputation, fracture, genital infection and urinary tract infection (all P for interaction ≥.17). SGLT2 inhibition provided similar protection against vascular risks and death, and similar risks of serious adverse events, for women and men. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Some studies have reported that annual change in eGFR (eGFR slope) is associated with the future risk of end-stage kidney disease, cardiovascular disease and death in general or chronic kidney disease cohorts. However, the benefits of using eGFR slopes for prediction of major clinical outcomes in diabetes are unclear. Methods: We used data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial and the ADVANCE Post-Trial Observational Study (ADVANCE-ON). After excluding the first 4 months during which an acute fall in eGFR was induced by the initiation of an ACE inhibitor and diuretic combination agent, eGFR slopes were estimated by linear mixed models, using three measurements of eGFR at 4, 12 and 24 months after randomisation over 20 months, and categorised according to quartiles. Cox regression models were used to evaluate adjusted HRs for the study's primary outcome, a composite of major renal events, major macrovascular events and all-cause mortality during the subsequent follow-up from 24 months after randomisation. Results: A total of 8,879 participants (80%) were included in this cohort. The mean age was 65.6 years (SD 6.3), the mean eGFR was 75 ml min−1 (1.73 m)−2 (SD 17) and the median urinary albumin/creatinine ratio was 14 μg/mg (interquartile range 7–38). The mean eGFR slope was −0.63 ml min−1 (1.73 m)−2 year−1 (SD 1.75). Over a median follow-up of 7.6 years following the 20-month eGFR slope ascertainment period, 2,221 participants (25%) met the primary outcome. An annual substantial decrease in eGFR (lowest 25%, <−1.63 ml min−1 [1.73 m]−2 year−1) was significantly associated with the subsequent risk of the primary outcome (HR 1.30 [95% CI 1.17, 1.43]) compared with a stable change in eGFR (middle 50%, −1.63 to 0.33). An annual substantial increase in eGFR (highest 25%, >0.33) had no significant association with the risk of the primary outcome (HR 0.96 [95% CI 0.86, 1.07]). Conclusions/interpretation: Our study supports the utility of eGFR slope in type 2 diabetes as a surrogate endpoint for renal outcomes, as well as a prognostic factor for identifying individuals at high risk of cardiovascular disease and all-cause mortality. Trial registry number: ClinicalTrials.gov registration no. NCT00145925 and no. NCT00949286 [ABSTRACT FROM AUTHOR]

Aims: To evaluate 1,5‐anhydroglucitol (1,5‐AG) according to clinical outcomes and assess the effects of glucose‐ and blood pressure‐lowering interventions on change in 1,5‐AG levels in people with type 2 diabetes. Methods: We measured 1,5‐AG in 6826 stored samples at baseline and in a random subsample of 684 participants at the 1‐year follow‐up visit in the ADVANCE trial. We examined baseline 1,5‐AG [< 39.7, 39.7‐66.2, ≥ 66.2 μmol/L (<6, 6‐10, ≥10 μg/mL)] and microvascular and macrovascular events and mortality using Cox regression models during 5 years of follow‐up. Using an intention‐to‐treat approach, we examined 1‐year change in 1,5‐AG (mean and percent) in response to the glucose‐ and blood pressure‐lowering interventions in the subsample. Results: Low 1,5‐AG level [<39.7 μmol/L vs ≥ 66.2 μmol/L (<6 μg/mL vs ≥10 μg/mL)] was associated with microvascular events (hazard ratio 1.28, 95% confidence interval 1.03‐1.60) after adjustment for risk factors and baseline glycated haemoglobin (HbA1c); however, the associations for macrovascular events and mortality were not independent of HbA1c. The glucose‐lowering intervention was associated with a significant 1‐year increase in 1,5‐AG (vs standard control) of 6.69 μmol/L (SE 2.52) [1.01 μg/mL (SE 0.38)], corresponding to an 8.26% (SE 0.10%) increase from baseline. We also observed an increase in 1,5‐AG of similar magnitude in response to the blood pressure intervention independent of the glucose‐lowering effect. Conclusions: Our results suggest that 1,5‐AG is a marker of risk in adults with type 2 diabetes, but only for microvascular events independently of HbA1c. We found that 1,5‐AG was improved (increased) in response to an intensive glucose‐lowering intervention, although the independent effect of the blood pressure‐lowering intervention on 1,5‐AG suggests potential non‐glycaemic influences. [ABSTRACT FROM AUTHOR]

Aims: Patients with type 2 diabetes have a high risk of cardiovascular disease (CVD). Central obesity has been particularly associated with this risk relationship. We aimed to evaluate waist to height ratio (WHtR) as a predictor of risk in such patients. Methods: WHtR was evaluated as a predictor of the risk of CVD and mortality amongst 11 125 participants with type 2 diabetes in the ADVANCE and ADVANCE‐ON studies, and was compared with body mass index (BMI), waist circumference and waist hip ratio (WHR). Primary outcome was a composite of death from CVD, non‐fatal myocardial infarction or non‐fatal stroke. Secondary outcomes were myocardial infarction, stroke, cardiovascular death and death from any cause. Cox models were used, with bootstrapping to compare associations between anthropometric measures for the primary outcome. Results: Median follow‐up time was 9.0 years. There was a positive association between WHtR and adverse outcomes. The hazard ratio (HR) (confidence interval), per SD higher WHtR, was 1.16 (1.11‐1.22) for the primary endpoint, with no heterogeneity by sex or region, but a stronger effect in individuals aged 66 years or older. The other 3 anthropometric measurements showed similar associations, although there was evidence that WHtR marginally outperformed BMI and WHR. Based on commonly used BMI cut‐points, the equivalent WHtR cut‐points were estimated to be 0.55 and 0.6, with no evidence of a difference across subgroups. Conclusions: In patients with diabetes, WHtR is a useful indicator of future adverse risk, with similar effects in different population subgroups. [ABSTRACT FROM AUTHOR]

Objective: To assess the association between 2-year changes in urine albumin-to-creatinine ratio (UACR) and the risk of clinical outcomes in type 2 diabetes.Research Design and Methods: We analyzed data from 8,766 participants in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Post-Trial Observational Study (ADVANCE-ON). Change in UACR was calculated from UACR measurements 2 years apart, classified into three groups: decrease in UACR of ≥30%, minor change, and increase in UACR of ≥30%. By analyzing changes from baseline UACR groups, categorized into thirds, we repeated these analyses accounting for regression to the mean (RtM). The primary outcome was the composite of major macrovascular events, renal events, and all-cause mortality; secondary outcomes were these components. Cox regression models were used to estimate hazard ratios (HRs).Results: Over a median follow-up of 7.7 years, 2,191 primary outcomes were observed. Increases in UACR over 2 years independently predicted a greater risk of the primary outcome (HR for ≥30% UACR increase vs. minor change: 1.26; 95% CI 1.13-1.41), whereas a decrease in UACR was not significantly associated with lower risk (HR 0.93; 95% CI 0.83-1.04). However, after allowing for RtM, the effect of "real" decrease in UACR on the primary outcome was found to be significant (HR 0.84; 95% CI 0.75-0.94), whereas the estimated effect on an increase was unchanged.Conclusions: Changes in UACR predicted changes in the risk of major clinical outcomes and mortality in type 2 diabetes, supporting the prognostic utility of monitoring albuminuria change over time. [ABSTRACT FROM AUTHOR]

Aims: First, to conduct a detailed exploration of the prospective relations between four commonly used anthropometric measures with incident diabetes and to examine their consistency across different population subgroups. Second, to compare the ability of each of the measures to predict five-year risk of diabetes.Methods: We conducted a meta-analysis of individual participant data on body mass index (BMI), waist circumference (WC), waist-hip and waist-height ratio (WHtR) from the Obesity, Diabetes and Cardiovascular Disease Collaboration. Cox proportional hazard models were used to estimate the association between a one standard deviation increment in each anthropometric measure and incident diabetes. Harrell's concordance statistic was used to test the predictive accuracy of each measure for diabetes risk at five years.Results: Twenty-one studies with 154,998 participants and 9342 cases of incident diabetes were available. Each of the measures had a positive association with incident diabetes. A one standard deviation increment in each of the measures was associated with 64-80% higher diabetes risk. WC and WHtR more strongly associated with risk than BMI (ratio of hazard ratios: 0.95 [0.92,0.99] - 0.97 [0.95,0.98]) but there was no appreciable difference between the four measures in the predictive accuracy for diabetes at five years.Conclusions: Despite suggestions that abdominal measures of obesity have stronger associations with incident diabetes and better predictive accuracy than BMI, we found no overall advantage in any one measure at discriminating the risk of developing diabetes. Any of these measures would suffice to assist in primary diabetes prevention efforts. [ABSTRACT FROM AUTHOR]

Background: Microvascular disease is associated with a high risk of macrovascular events in patients with type 2 diabetes, but the impact of macrovascular disease on the risk of microvascular events remains unknown. We sought to evaluate the respective effects of prior microvascular and macrovascular disease on the risk of major outcomes, including microvascular events, in these patients. Methods: Participants in the Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation (ADVANCE) trial (n = 11,140) and the ADVANCE-ON post-trial study (n = 8494) were categorized into 4 groups at baseline: dual absence of microvascular or macrovascular disease (n = 6789), presence of microvascular disease alone (n = 761), macrovascular disease alone (n = 3196), and both (n = 394). Outcomes were all-cause mortality, major macrovascular events (MACE), and major clinical microvascular events. Results: All-cause mortality, MACE, and major clinical microvascular events occurred in 2265 (20%), 2166 (19%), and 807 (7%) participants respectively, during a median follow-up of 9.9 (inter-quartile interval 5.6-10.9) years. The adjusted hazard ratios [95% CI] of death, MACE, and major clinical microvascular events were each greater in patients with baseline microvascular disease (1.43 [1.20-1.71], 1.64 [1.37-1.97], and 4.74 [3.86-5.82], respectively), macrovascular disease (1.43 [1.30-1.57], 2.04 [1.86-2.25], and 1.26 [1.06-1.51]) or both (2.01 [1.65-2.45], 2.92 [2.40-3.55], and 6.30 [4.93-8.06]) compared with those without these conditions. No interaction was observed between baseline microvascular and macrovascular disease for these events. The addition of microvascular disease (change in c-statistic [95% CI] 0.005 [0.002-0.008], p = 0.02) or macrovascular disease (0.005 [0.002-0.007], p < 0.0001) considered separately or together (0.011 [0.007-0.014], p < 0.0001) improved the discrimination and the classification (integrated discrimination improvement (IDI): 0.013 [0.010-0.016], p < 0.001; net reclassification improvement (NRI): 0.021 [0.011-0.032], p < 0.001) of the risk of all-cause mortality. Microvascular disease improved discrimination (0.009 [0.003-0.014]) and classification (IDI: 0.008 [0.006-0.010]; NRI: 0.011 [0.001-0.020]) of MACE. Baseline macrovascular disease modestly enhanced IDI (0.002 [0.001-0.002]) and NRI (0.041 [0.002-0.087]), but not discrimination, of major clinical microvascular events. Conclusions: Microvascular and macrovascular disease are independently associated with the 10-year risk of death, MACE, and major clinical microvascular events in patients with type 2 diabetes. The coexistence of these conditions was associated with the highest risks. [ABSTRACT FROM AUTHOR]

Objective: The burden of vascular diseases remains substantial in patients with type 2 diabetes, requiring identification of further risk markers. We tested the absence of dorsalis pedis and posterior tibial pulses as predictors of major macrovascular and microvascular events, death, and cognitive decline in this population.Research Design and Methods: Data were derived from 11,120 patients with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) study. Absent peripheral pulses at baseline were defined as absence of at least one dorsalis pedis or posterior tibial pulse.Results: Absent compared with present peripheral pulses (n = 2,218) were associated with increased 5-year risks for major macrovascular events (hazard ratio 1.47 [95% CI 1.28-1.69], P < 0.0001), myocardial infarction (1.45 [1.13-1.87], P = 0.003), stroke (1.57 [1.23-2.00], P = 0.0003), cardiovascular death (1.61 [1.33-1.95], P < 0.0001), heart failure (1.49 [1.21-1.84], P = 0.0002), all-cause mortality (1.48 [1.29-1.71], P < 0.0001), major microvascular events (1.17 [1.00-1.36], P = 0.04), nephropathy (1.24 [1.00-1.54], P = 0.04), end-stage renal disease or renal death (2.04 [1.12-3.70], P = 0.02), and peripheral neuropathy (1.13 [1.05-1.21], P = 0.0008) after multiple adjustment. Participants with absent dorsalis pedis or posterior tibial pulses had comparable hazard ratios. Risks increased proportionally with the number of absent peripheral pulses, with the highest risks observed in patients with three or four absent pulses. Every additional absent pulse increases the risk of all outcomes.Conclusions: Absent dorsalis pedis and/or posterior tibial pulses are independent predictors of major vascular outcomes in patients with type 2 diabetes. These simple clinical indicators should be used to improve risk stratification and treatment of these patients. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Intensive glucose control reduces the risk of vascular complications while increasing the risk of severe hypoglycaemia at a group level. We sought to estimate individual beneficial and adverse effects of intensive glucose control in patients with type 2 diabetes. Methods: We performed a post hoc analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial, a randomised controlled trial evaluating standard vs intensive glucose control (HbA target ≤6.5% [48 mmol/mol]). In 11,140 participants, we estimated the individual 5 year absolute risk reduction (ARR) for the composite outcome of major micro- and macrovascular events and absolute risk increase (ARI) for severe hypoglycaemia for intensive vs standard glucose control. Predictions were based on competing risks models including clinical characteristics and randomised treatment. Results: Based on these models, 76% of patients had a substantial estimated 5 year ARR for major vascular events (>1%, 5 year number-needed-to-benefit [NNTB] <100) and 1% had a small ARR (<0.5%, NNTB >200). Similarly, 36% of patients had a substantial estimated ARI for severe hypoglycaemia (5 year number-needed-to-harm [NNTH] <100) and 29% had a small ARI (NNTH >200). When assigning similar or half the weight to severe hypoglycaemia compared with a major vascular event, net benefit was positive in 85% or 99% of patients, respectively. Limiting intensive treatment to the 85% patient subgroup had no significant effect on the overall incidence of major vascular events and severe hypoglycaemia compared with treating all patients. Conclusions/interpretation: Taking account of the effects of intensive glucose control on major micro- and macrovascular events and severe hypoglycaemia for individual patients, the estimated net benefit was positive in the majority of the participants in the ADVANCE trial. The estimated individual effects can inform treatment decisions once individual weights assigned to positive and adverse effects have been specified. Trial registration:: ClinicalTrials.gov NCT00145925 [ABSTRACT FROM AUTHOR]

Objective: Experimental evidence has shown potential cardioprotective actions of phosphodiesterase type-5 inhibitors (PDE5is). We investigated whether PDE5i use in patients with type 2 diabetes, with high-attendant cardiovascular risk, was associated with altered mortality in a retrospective cohort study.Research Design and Methods: Between January 2007 and May 2015, 5956 men aged 40-89 years diagnosed with type 2 diabetes before 2007 were identified from anonymised electronic health records of 42 general practices in Cheshire, UK, and were followed for 7.5 years. HRs from multivariable survival (accelerated failure time, Weibull) models were used to describe the association between on-demand PDE5i use and all-cause mortality.DC1SM110.1136/heartjnl-2015-309223.supp1Supplementary appendix RESULTS: Compared with non-users, men who are prescribed PDE5is (n=1359) experienced lower percentage of deaths during follow-up (19.1% vs 23.8%) and lower risk of all-cause mortality (unadjusted HR=0.69 (95% CI: 0.64 to 0.79); p<0.001)). The reduction in risk of mortality (HR=0.54 (0.36 to 0.80); p=0.002) remained after adjusting for age, estimated glomerular filtration rate, smoking status, prior cerebrovascular accident (CVA) hypertension, prior myocardial infarction (MI), systolic blood pressure, use of statin, metformin, aspirin and β-blocker medication. PDE5i users had lower rates of incident MI (incidence rate ratio (0.62 (0.49 to 0.80), p<0.0001) with lower mortality (25.7% vs 40.1% deaths; age-adjusted HR=0.60 (0.54 to 0.69); p=0.001) compared with non-users within this subgroup.Conclusion: In a population of men with type 2 diabetes, use of PDE5is was associated with lower risk of overall mortality and mortality in those with a history of acute MI. [ABSTRACT FROM AUTHOR]

Objective: Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis in type 2 diabetes, but the relationship between other vascular diseases and PAD has been poorly investigated. We examined the impact of previous microvascular and macrovascular disease on the risk of major PAD in patients with type 2 diabetes.Research Design and Methods: We analyzed 10,624 patients with type 2 diabetes free from baseline major PAD in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) clinical trial. The primary composite outcome was major PAD defined as PAD-induced death, peripheral revascularization, lower-limb amputation, or chronic ulceration. The secondary end points were the PAD components considered separately.Results: Major PAD occurred in 620 (5.8%) participants during 5 years of follow-up. Baseline microvascular and macrovascular disease were both associated with subsequent risk of major PAD after adjustment for age, sex, region of origin, and randomized treatments. However, only microvascular disease remained significantly associated with PAD after further adjustment for established risk factors. The highest risk was observed in participants with a history of macroalbuminuria (hazard ratio 1.91 [95% CI 1.38-2.64], P < 0.0001) and retinal photocoagulation therapy (1.60 [1.11-2.32], P = 0.01). Baseline microvascular disease was also associated with a higher risk of chronic lower-limb ulceration (2.07 [1.56-2.75], P < 0.0001) and amputation (1.59 [1.15-2.22], P = 0.006), whereas baseline macrovascular disease was associated with a higher rate of angioplasty procedures (1.75 [1.13-2.73], P = 0.01).Conclusions: Microvascular disease, particularly macroalbuminuria and retinal photocoagulation therapy, strongly predicts major PAD in patients with type 2 diabetes, but macrovascular disease does not. [ABSTRACT FROM AUTHOR]

Background: Peripheral arterial disease (PAD) is known to be associated with high cardiovascular risk, but the individual impact of PAD presentations on risk of macrovascular and microvascular events has not been reliably compared in patients with type 2 diabetes. We aimed to evaluate the impact of major PAD, and its different presentations, on the 10-year risk of death, major macrovascular events, and major clinical microvascular events in these patients. Methods: Participants in the action in diabetes and vascular disease: PreterAx and DiamicroN modified-release controlled evaluation (ADVANCE) trial and the ADVANCE-ON post-trial study were followed for a median of 5.0 (in-trial), 5.4 (post-trial), and 9.9 (overall) years. Major PAD at baseline was subdivided into lower-extremity chronic ulceration or amputation secondary to vascular disease and history of peripheral revascularization by angioplasty or surgery. Results: Among 11,140 participants, 516 (4.6 %) had major PAD at baseline: 300 (2.7 %) had lower-extremity ulceration or amputation alone, 190 (1.7 %) had peripheral revascularization alone, and 26 (0.2 %) had both presentations. All-cause mortality, major macrovascular events, and major clinical microvascular events occurred in 2265 (20.3 %), 2166 (19.4 %), and 807 (7.2 %) participants, respectively. Compared to those without PAD, patients with major PAD had increased rates of all-cause mortality (HR 1.35, 95 % CI 1.15–1.60, p = 0.0004), and major macrovascular events (1.47 [1.23–1.75], p < 0.0001), after multiple adjustments for region of origin, cardiovascular risk factors and treatments, peripheral neuropathy markers, and randomized treatments. We have also observed a trend toward an association of baseline PAD with risk of major clinical microvascular events [1.31 (0.96–1.78), p = 0.09]. These associations were comparable for patients with a lower-extremity ulceration or amputation and for those with a history of peripheral revascularization. Furthermore, the risk of retinal photocoagulation or blindness, but not renal events, increased in patients with lower-extremity ulceration or amputation [1.53 (1.01–2.30), p = 0.04]. Conclusions: Lower-extremity ulceration or amputation, and peripheral revascularization both increased the risks of death and cardiovascular events, but only lower-extremity ulceration or amputation increased the risk of severe retinopathy in patients with type 2 diabetes. Screening for major PAD and its management remain crucial for cardiovascular prevention in patients with type 2 diabetes (ClinicalTrials.gov number, NCT00949286). [ABSTRACT FROM AUTHOR]

Aim: To estimate and compare the results from all randomised trials of triple combinations of anti-diabetes therapies that reported the reduction of glycated haemoglobin (HbA1c) and associated effects on body weight and hypoglycaemia.Methods: PubMed and the Cochrane Library were searched for trials with at least one study arm on triple therapy and which reported the differences in mean change in HbA1c between two study arms. These were included in a network meta-analysis.Results: Altogether, 15,182 participants from 40 trials with treatment duration of 6-12months were included. Compared with none/placebo added to dual therapy, the addition of a drug therapy from six of eight drug classes to existing dual therapy resulted in significant additional mean reductions in HbA1c from -0.56% (-6.2mmol/mol; dipeptidyl peptidase 4 inhibitors) to -0.94% (-10.3mmol/mol; thiazolidinediones). Of the six drug classes, three were associated with less favourable weight change and two were associated with more favourable weight change when compared with none/placebo added to dual therapy. Furthermore, five drug classes were associated with greater odds of hypoglycaemia. Similar results were observed in analyses of studies with a 6month treatment duration and after excluding study arms that contained insulin.Conclusions: Overall triple therapy combinations were similar in improving diabetes control although there were some differences in adverse effects. By balancing the risks and benefits of each therapy, the estimates of pairwise comparisons of triple therapies for HbA1c, body weight and hypoglycaemia provided in this study may further inform evidence based practice. [ABSTRACT FROM AUTHOR]

Objective: The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial reported that intensive glucose control prevents end-stage kidney disease (ESKD) in patients with type 2 diabetes, but uncertainty about the balance between risks and benefits exists. Here, we examine the long-term effects of intensive glucose control on risk of ESKD and other outcomes.Research Design and Methods: Survivors, previously randomized to intensive or standard glucose control, were invited to participate in post-trial follow-up. ESKD, defined as the need for dialysis or kidney transplantation, or death due to kidney disease, was documented overall and by baseline CKD stage, along with hypoglycemic episodes, major cardiovascular events, and death from other causes.Results: A total of 8,494 ADVANCE participants were followed for a median of 5.4 additional years. In-trial HbA1c differences disappeared by the first post-trial visit. The in-trial reductions in the risk of ESKD (7 vs. 20 events, hazard ratio [HR] 0.35, P = 0.02) persisted after 9.9 years of overall follow-up (29 vs. 53 events, HR 0.54, P < 0.01). These effects were greater in earlier-stage CKD (P = 0.04) and at lower baseline systolic blood pressure levels (P = 0.01). The effects of glucose lowering on the risks of death, cardiovascular death, or major cardiovascular events did not differ by levels of kidney function (P > 0.26).Conclusions: Intensive glucose control was associated with a long-term reduction in ESKD, without evidence of any increased risk of cardiovascular events or death. These benefits were greater with preserved kidney function and with well-controlled blood pressure. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes confers a greater excess risk of cardiovascular disease in women than in men. Diabetes is also a risk factor for dementia, but whether the association is similar in women and men remains unknown. We performed a meta-analysis of unpublished data to estimate the sex-specific relationship between women and men with diabetes with incident dementia.Research Design and Methods: A systematic search identified studies published prior to November 2014 that had reported on the prospective association between diabetes and dementia. Study authors contributed unpublished sex-specific relative risks (RRs) and 95% CIs on the association between diabetes and all dementia and its subtypes. Sex-specific RRs and the women-to-men ratio of RRs (RRRs) were pooled using random-effects meta-analyses.Results: Study-level data from 14 studies, 2,310,330 individuals, and 102,174 dementia case patients were included. In multiple-adjusted analyses, diabetes was associated with a 60% increased risk of any dementia in both sexes (women: pooled RR 1.62 [95% CI 1.45-1.80]; men: pooled RR 1.58 [95% CI 1.38-1.81]). The diabetes-associated RRs for vascular dementia were 2.34 (95% CI 1.86-2.94) in women and 1.73 (95% CI 1.61-1.85) in men, and for nonvascular dementia, the RRs were 1.53 (95% CI 1.35-1.73) in women and 1.49 (95% CI 1.31-1.69) in men. Overall, women with diabetes had a 19% greater risk for the development of vascular dementia than men (multiple-adjusted RRR 1.19 [95% CI 1.08-1.30]; P < 0.001).Conclusions: Individuals with type 2 diabetes are at ∼60% greater risk for the development of dementia compared with those without diabetes. For vascular dementia, but not for nonvascular dementia, the additional risk is greater in women. [ABSTRACT FROM AUTHOR]

Aims: Diabetes has been associated with a greater excess risk of cardiovascular disease (CVD) in women than men. We investigated whether there are also sex differences in the association of diabetes duration and the risk of CVD.Methods: Data were used from 18,961 (40% women) individuals with type 2 diabetes, without a history of CVD, in the UK Biobank. Sex-specific incidence rates were calculated by diabetes duration. Cox proportional hazards analyses estimated multiple-adjusted sex-specific hazard ratios (HR) and women-to-men ratio of HRs (RHR).Results: Over a median follow-up of 11 years, 1,506 (29% women) CVD events were documented. Compared with men, women had lower multiple-adjusted incidence rates of CVD per 10,000 person-years for all categories of diabetes duration. Duration of diabetes was associated with an increased risk of CVD in both sexes. A 5-year increase in diabetes duration was associated with an approximately similar excess risk of about 20% for each of the three endpoints, in both sexes.Conclusions/interpretation: The increased risk of CVD associated with longer duration of diabetes is similar in women and men, and thus cannot explain the higher excess risk from diabetes in women in this study population. [ABSTRACT FROM AUTHOR]

OBJECTIVE There is no consensus on the importance of visit-to-visit glycemic variability in diabetes. Therefore, we assessed the effects of visit-to-visit variability (VVV) in HbA1c and fasting glucose on major outcomes in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) trial. RESEARCH DESIGN AND METHODS ADVANCE was a factorial randomized controlled trial of intensive glucose control and blood pressure lowering in patients with type 2 diabetes. VVV in the intensive glucose treatment group was defined using the SD of five measurements of HbA1c and glucose taken 3-24 months after randomization. Outcomes were combined macro- and microvascular events and all-cause mortality occurring post 24 months. Sensitivity analyses were performed using other indices of variability and in the standard glucose treatment group. RESULTS Among 4,399 patients in the intensive group, an increase in VVV of HbA1c was associated with an increased risk of vascular events (P = 0.01) and with mortality (P< 0.001): highest versus lowest tenth hazard ratio (95% CI) 1.64 (1.05-2.55) and 3.31 (1.57-6.98), respectively, after multivariable adjustment. A clear association was also observed between VVV of fasting glucose and increased risk of vascular events (P < 0.001; 2.70 [1.65-4.42]). HbA1c variability was positively associated with the risk of macrovascular events (P = 0.02 for trend), whereas glucose variability was associated with both macro- and microvascular events (P = 0.005 and P < 0.001 for trend, respectively). Sensitivity analyses using other indices, and patients in the standard glucose treatment group, were broadly consistent with these results. CONCLUSIONS Consistency of glycemic control is important to reduce the risks of vascular events and death in type 2 diabetes. [ABSTRACT FROM AUTHOR]

C-reactive protein (CRP), fibrinogen, and interleukin-6 (IL-6) are associated with cardiovascular disease (CVD) and death in general populations. However, studies of these factors in type 2 diabetes are limited. We studied their associations with the risk of major macrovascular events, microvascular complications, and mortality in patients with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) Study. Plasma CRP, fibrinogen, and IL-6 levels were determined in a case-cohort study (n = 3,865) nested within the 11,140 men and women with type 2 diabetes and baseline CVD or risk factors in the ADVANCE Study. All three biomarkers of inflammation were associated with an increased risk of macrovascular events and death in analyses adjusted for age, sex, and treatment groups. After further adjustment, only IL-6 was an independent predictor of macrovascular events (hazard ratio per SD increase 1.37 [95% CI 1.24-1.51]) and death (1.35 [1.23-1.49]). IL-6 significantly improved the prediction of macrovascular events and death. After adjustment, none of the markers predicted microvascular complications. We conclude that IL-6 levels, but not CRP or fibrinogen levels, add significantly to the prediction of macrovascular events and mortality in individuals with type 2 diabetes who have baseline CVD or risk factors. [ABSTRACT FROM AUTHOR]

OBJECTIVE Current methods of risk stratification in patients with type 2 diabetes are sub-optimal. The current study assesses the ability of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) to improve the prediction of cardiovascular events and death in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A nested case-cohort study was performed in 3,862 patients who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. RESULTS Seven hundred nine (18%) patients experienced a major cardiovascular event (composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and 706 (18%) died during a median of 5 years of follow-up. In Cox regression models, adjusting for all established risk predictors, the hazard ratio for cardiovascular events for NT-proBNP was 1.95 per 1SD increase (95% CI 1.72,2.20) and the hazard ratio for hs-cTnT was 1.50 per 1 SD increase (95% CI 1.36,1.65). The hazard ratios for death were 1.97 (95% CI 1.73, 2.24) and 1.52 (95% CI 1.37,1.67), respectively. The addition of either marker improved 5-year risk classification for cardiovascular events (net reclassification index in continuous model, 39% for NT-proBNP and 46% for hs-cTnT). Likewise, both markers greatly improved the accuracy with which the 5-year risk of death was predicted. The combination of both markers provided optimal risk discrimination. CONCLUSIONS NT-proBNP and hs-cTnT appear to greatly improve the accuracy with which the risk of cardiovascular events or death can be estimated in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Endpoint adjudication committees (EPAC) are widely used in clinical trials. The aim of the present analysis is to assess the effects of the endpoint adjudication process on the main findings of the ADVANCE trial (Trial registration: ClinicalTrials.gov NCT00145925). Methods and Findings: The ADVANCE trial was a multicentre, 2×2 factorial randomised controlled trial of blood pressure lowering and intensive blood glucose control in 11140 patients with type 2 diabetes. Primary outcomes were major macrovascular (nonfatal myocardial infarction, nonfatal stroke and cardiovascular death) and microvascular (new or worsening nephropathy and retinopathy) events. Suspected primary outcomes were initially reported by the investigators at the 215 sites with subsequent adjudication by the EPAC. The EPAC also adjudicated upon potential events identified directly by ongoing screening of all reported events. Over a median follow-up of 5 years, the site investigators reported one or more primary outcomes among 2443 participants. After adjudication these events were confirmed for 2077 (85%) with 48 further events added through the EPAC-led database screening process. The estimated relative risk reductions (95% confidence intervals) in the primary outcome for the blood pressure lowering comparison were 8% (−1 to 15%) based on the investigator-reported events and 9% (0 to 17%) based on the EPAC-based events (P for homogeneity = 0.70). The corresponding findings for the glucose comparison were 8% (1 to 15%) and 10% (2% to 18%) (P for homogeneity = 0.60). The effect estimates were also highly comparable when studied separately for macrovascular events and microvascular events for both comparisons (all P for homogeneity>0.6). Conclusions: The endpoint adjudication process had no discernible impact on the main findings in ADVANCE. These data highlight the need for careful consideration of the likely impact of an EPAC on the findings and conclusions of clinical trials prior to their establishment. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Although low HDL cholesterol (HDL-C) is an established risk factor for atherosclerosis, data on HDL-C and the risk of microvascular disease are limited. We tested the association between HDL-C and microvascular disease in a cohort of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS--A total of 11,140 patients with type 2 diabetes and at least one additional vascular risk factor were followed a median of 5 years. Cox proportional hazards models were used to assess the association between baseline HDL-C and the development of new or worsening microvascular disease, defined prospectively as a composite of renal and retinal events. RESULTS--The mean baseline HDL-C level was 1.3 mmol/L (SD 0.45mmol/L [range 0.1-4.0]). During follow-up, 32% of patients developed new or worsening microvascular disease, with 28% experiencing a renal event and 6%a retinal event. Compared with patients in the highest third, those in the lowest third had a 17% higher risk of microvascular disease (adjusted hazard ratio 1.17 [95% CI 1.06-1.28], P = 0.001) after adjustment for potential confounders and regression dilution. This was driven by a 19% higher risk of renal events (1.19 [1.08-1.32], P = 0.0005). There was no association between thirds of HDL-C and retinal events (1.01 [0.82-1.25], P = 0.9). CONCLUSIONS--In patients with type 2 diabetes, HDL-C level is an independent risk factor for the development of microvascular disease affecting the kidney but not the retina. [ABSTRACT FROM AUTHOR]

Aims Individuals with diabetes and chronic kidney disease (CKD) are at high risk for cardiovascular disease. In these analyses of the ADVANCE trial, we assessed the effects of a fixed combination of perindopril–indapamide on renal and cardiovascular outcomes in patients with type 2 diabetes according to baseline CKD stage. Methods and results Patients with type 2 diabetes were randomized to perindopril–indapamide (4 mg/1.25 mg) or placebo. Treatment effects on cardiovascular (cardiovascular death, myocardial infarction, or stroke) and renal outcomes were compared in subgroups defined by baseline Kidney Disease Outcome Quality Initiative CKD stage. Homogeneity in treatment effect was tested by adding interaction terms to the relevant Cox models. The study included 10 640 participants with known CKD status, of whom 6125 did not have CKD, 2482 were classified as CKD stage 1 or 2, and 2033 as CKD stage ≥3. The relative treatment effects on major cardiovascular events were similar across all stages of CKD, with no heterogeneity in the magnitude of the effects for any outcome. In contrast, the absolute treatment effects approximately doubled in those with CKD stage ≥3 when compared to those with no CKD. For every 1000 patients with CKD stage ≥3 treated for 5 years, active treatment prevented 12 cardiovascular events when compared with six events per 1000 patients with no CKD. Conclusion The treatment benefits of a routine administration of a fixed combination of perindopril–indapamide to patients with type 2 diabetes on cardiovascular and renal outcomes, and death, are consistent across all stages of CKD at baseline. Absolute risk reductions are larger in patients with CKD highlighting the importance of blood pressure-lowering in this population. [ABSTRACT FROM PUBLISHER]

The article discusses a study to determine the cost-effectiveness of lowering blood pressure with a fixed-dose combination of perindopril and indapamide in patients with type 2 diabetes mellitus. Results of the study showed that the combination of perindopril and indapamide in patients with type 2 diabetes appears to be cost-effective. Meanwhile, no difference in quality of life between groups was observed, but applying the average quality-of-life score results in a cost per quality-adjusted life year (QALY) of around 10,600 Australian dollars.

OBJECTIVE -- The objective of this study was to develop and evaluate a risk score to predict people at high risk of diabetes in Thailand. RESEARCH DESIGN AND METHODS -- A Thai cohort of 2,677 individuals, aged 35-55 years, without diabetes at baseline, was resurveyed after 12 years. Logistic regression models were used to identify baseline risk factors that predicted the incidence of diabetes; a simple model that included only those risk factors as significant (P < 0.05) when adjusted for each other was developed. The coefficients from this model were transformed into components of a diabetes score. This score was tested in a Thai validation cohort of a different 2,420 individuals. RESULTS -- A total of 361 individuals developed type 2 diabetes in the exploratory cohort during the follow-up period. The significant predictive variables in the simple model were age, BMI, waist circumference, hypertension, and history of diabetes in parents or siblings A cutoff score of 6 of 17 produced the optimal sum of sensitivity (77%) and specificity (60%). The area under the receiver-operating characteristic curve (AUC) was 0.74. Adding impaired fasting glucose or impaired glucose tolerance status to the model slightly increased the AUC to 0.78; adding low HDL cholesterol and/or high triglycerides barely improved the model. The validation cohort demonstrated similar results. CONCLUSIONS -- A simple diabetes risk score, based on a set of variables not requiring laboratory tests, can be used for early intervention to delay or prevent the disease in Thailand. Adding impaired fasting glucose or impaired glucose tolerance or triglyceride and HDL cholesterol status to this model only modestly improves the predictive ability. [ABSTRACT FROM AUTHOR]

Philip Clarke and colleagues examined patient-level data for over 11,000 participants with type 2 diabetes from 20 countries and find that major complications of diabetes significantly increased hospital use and costs across settings. Background: Diabetes imposes a substantial burden globally in terms of premature mortality, morbidity, and health care costs. Estimates of economic outcomes associated with diabetes are essential inputs to policy analyses aimed at prevention and treatment of diabetes. Our objective was to estimate and compare event rates, hospital utilization, and costs associated with major diabetes-related complications in high-, middle-, and low-income countries. Methods and Findings: Incidence and history of diabetes-related complications, hospital admissions, and length of stay were recorded in 11,140 patients with type 2 diabetes participating in the Action in Diabetes and Vascular Disease (ADVANCE) study (mean age at entry 66 y). The probability of hospital utilization and number of days in hospital for major events associated with coronary disease, cerebrovascular disease, congestive heart failure, peripheral vascular disease, and nephropathy were estimated for three regions (Asia, Eastern Europe, and Established Market Economies) using multiple regression analysis. The resulting estimates of days spent in hospital were multiplied by regional estimates of the costs per hospital bed-day from the World Health Organization to compute annual acute and long-term costs associated with the different types of complications. To assist, comparability, costs are reported in international dollars (Int$), which represent a hypothetical currency that allows for the same quantities of goods or services to be purchased regardless of country, standardized on purchasing power in the United States. A cost calculator accompanying this paper enables the estimation of costs for individual countries and translation of these costs into local currency units. The probability of attending a hospital following an event was highest for heart failure (93%–96% across regions) and lowest for nephropathy (15%–26%). The average numbers of days in hospital given at least one admission were greatest for stroke (17–32 d across region) and heart failure (16–31 d) and lowest for nephropathy (12–23 d). Considering regional differences, probabilities of hospitalization were lowest in Asia and highest in Established Market Economies; on the other hand, lengths of stay were highest in Asia and lowest in Established Market Economies. Overall estimated annual hospital costs for patients with none of the specified events or event histories ranged from Int$76 in Asia to Int$296 in Established Market Economies. All complications included in this analysis led to significant increases in hospital costs; coronary events, cerebrovascular events, and heart failure were the most costly, at more than Int$1,800, Int$3,000, and Int$4,000 in Asia, Eastern Europe, and Established Market Economies, respectively. Conclusions: Major complications of diabetes significantly increase hospital use and costs across various settings and are likely to impose a high economic burden on health care systems.

The ACCORD study investigators have published the results of an extended follow-up of the trial, focused on patients with type 2 diabetes mellitus who had been initially assigned to different intensities of glucose control. These data add to existing knowledge on the benefits of glycemic control in this patient population. [ABSTRACT FROM AUTHOR]

Background: Standard measures of blood pressure (BP) do not account for both the magnitude and duration of exposure to elevated BP over time.Objectives: The purpose of this study was to assess the association between cumulative systolic blood pressure (SBP) load and risk of cardiovascular events in patients with type 2 diabetes.Methods: A post hoc analysis of patients with type 2 diabetes followed by the ADVANCE-ON (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation - Observational Study). Cumulative SBP load was defined as the area under curve for SBP values ≥130 mm Hg divided by the area under curve for all measured SBP values over a 24-month exposure period. HRs for the association between cumulative SBP load with major cardiovascular events and death were estimated using Cox models.Results: Over a median 7.6 years of follow-up, 1,469 major cardiovascular events, 1,615 deaths, and 660 cardiovascular deaths were observed in 9,338 participants. Each 1-SD increase in cumulative SBP load was associated with a 14% increase in major cardiovascular events (HR: 1.14; 95% CI: 1.09-1.20), 13% increase in all-cause mortality (HR: 1.13; 95% CI: 1.13-1.18), and 21% increase in cardiovascular death (HR: 1.21; 95% CI: 1.13-1.29). For the prediction of cardiovascular events and death, cumulative SBP load outperformed mean SBP, time-below-target SBP, and visit-to-visit SBP variability in terms of Akaike information criterion and net reclassification indexes.Conclusions: Cumulative SBP load may provide better prediction of major cardiovascular events compared with traditional BP measures among patients with type 2 diabetes. These findings reinforce the importance of both the magnitude and duration of exposure to elevated SBP in assessing cardiovascular risk. (Action in Diabetes and Vascular Disease Preterax and Diamicron MR Controlled Evaluation Post Trial Observational Study [ADVANCE-ON]; NCT00949286). [ABSTRACT FROM AUTHOR]

Objective: To measure the impact of complications on summary measures of health-related quality of life among people with type 2 diabetes.Methods: Patients participating in the Action in Diabetes and Vascular Disease:Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial were administered a health-related quality-of-life questionnaire, the three-level EuroQol five-dimensional questionnaire (EQ-5D-3L), on four occasions over a 5-year period. We used two-way fixed-effects longitudinal regression models to investigate the impact of incident diabetes complications (stroke, heart failure, myocardial infarction, ischemic heart disease, renal failure, blindness, and amputation) on EQ-5D-3L utility score (where 1 = perfect health), while controlling for characteristics of individuals that do not vary over time.Results: The effect of having any one of the seven complications was to reduce the EQ-5D-3L utility score by 0.054 (95% confidence interval 0.044-0.064), and this was not significantly affected by baseline age, sex, economic region, or the value set used to derive utilities. The complication with the largest disutility was amputation (0.122), followed by stroke (0.099), blindness (0.083), renal failure (0.049), heart failure (0.045), and myocardial infarction (0.026). Ischemic heart disease did not significantly reduce the utility score. Quality of life also declined with elapsed time-by an average of 0.006 per year, in addition to the effect of complications.Conclusions: Common complications significantly reduce health-related quality of life. Utility scores derived from the EQ-5D-3L provide a potential measure that can be used to summarize patient-reported outcomes and inform health economic models. Prevention of complications is critical to reduce the progressive burden of declining quality of life for people with diabetes. [ABSTRACT FROM AUTHOR]

Observational data suggest a potential for subclinical cardiac damage from intensive blood glucose or blood pressure (BP) control, particularly in adults with very low blood glucose and BP levels. However, this has not been tested in a randomized trial. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Research Controlled Evaluation (ADVANCE) study was a factorial, randomized trial designed to test the effects of intensive blood glucose (hemoglobin A1c ≤6.5% versus usual care) and intensive BP (combination of perindopril-indapamide versus placebo) control on vascular events in adults with diabetes. Using mixed effects tobit models, we determined the effect of the randomized interventions on change in subclinical cardiac injury (high sensitivity cardiac troponin T [hs-cTnT]) and strain (N-terminal b-type pro natriuretic peptide [NT-proBNP]), 1 year after randomization. Among the 682 participants, mean age was 66.1 (SD, 6.5) years; 40% were women. Mean baseline hemoglobin A1c was 7.4% (SD, 1.5) and systolic/diastolic BP was 147 (SD,21)/81 (SD,11) mmHg. After 1 year, intensive versus standard glucose control did not significantly change hs-cTnT (1.5%; 95%CI:-4.9,8.2) or NT-proBNP (−10.3%; 95%CI: −20.2%,0.9%). Intensive versus standard BP control also did not affect hs-cTnT (−2.9%; 95%CI: −8.9,3.6), but did significantly lower NT-proBNP by 21.6% (95%CI:-30.2%,-11.9%). Changes in systolic BP at 1 year (versus baseline) were strongly associated with NT-proBNP (P = 0.004), but not hs-cTnT (P = 0.95). In adults with diabetes, intensive BP control reduced NT-proBNP without increasing hs-cTnT, supporting the benefits and safety of intensive BP control in adults with diabetes. This trial is registered at clinicaltrials.gov , number: NCT00145925. • Intensive glucose control did not lower subclinical cardiac injury or strain. • Intensive blood pressure control lowered subclinical cardiac strain. • Intensive blood pressure control did not increase subclinical cardiac injury. • Intensive BP control is important and safe for adults with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Albuminuria and a reduced glomerular filtration rate are conventional predictors of a future decline in kidney function in patients with type 2 diabetes mellitus. Using a nested case-control study we assessed whether circulating transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-7 (BMP-7) levels more accurately predict renal end points than the conventional markers. Cases were defined as those who developed a renal end point (doubling of serum creatinine to at least 200 μmol/l, the need for renal replacement therapy, or death due to renal disease) during the study. Using propensity scoring, two controls were selected for each of 281 cases. Participants who developed renal end points had significantly higher total TGF-β1, lower BMP-7 levels, and a higher total TGF-β1 to BMP-7 ratio at baseline. A graded increase in risk was found in individuals with lower BMP-7 levels (odds ratio 24.07, for the lowest to the highest tertile), or significantly higher TGF-β1 levels (odds ratio for the highest to the lowest tertile, 8.43). The area under the receiver operating characteristic curve (c-statistic) for the conventional predictors was 0.73. Using BMP-7 and total and active TGF-β1, the c-statistic was 0.94 (significantly higher to conventional predictors). Thus, our results suggest these novel kidney markers are better predictors of renal progression than the conventional predictors in patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background Early detection of changes in cardiac structure and function associated with type 2 diabetes (T2DM) is important. However when multiple abnormalities are present, combining individual measurements can be subjective. This study sought to create a simple echo score that summarises measurements that may detect early and prognostically important changes in cardiac function. Methods Standard echocardiography was performed on 849 people with T2DM (median age 65 years, 40% female, median duration of diabetes 5.5 years). Principal components analysis was performed on measurements of LV mass, LA volume, E:e', and s', to create an objective summary score. The score was included in two Cox proportional hazard models adjusted for CV risk factors: one estimated the development of heart failure (HF) and the second estimated any CV event. Results The first two principal components represented 75% of the variation between the four echo measurements. A continuous score that represents the residual difference between these two components was derived that only requires measurement of medial E:e' and s'. The score was significantly associated with the development of HF within four years (hazard ratio 1.34; 95% CI 1.15, 1.56). Conclusions We have developed a simple, objective score that enhances the use of echocardiography in the detection of sub-clinical cardiac disease in people with T2DM. Initial findings suggest that it may help identify those at increased risk of developing HF within four years. [ABSTRACT FROM AUTHOR]