HARMONY 4: randomised clinical trial comparing once-weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea

Aims/hypothesis

The aim of this study was to compare the efficacy and safety of once-weekly albiglutide with once-daily insulin glargine (A21Gly,B31Arg,B32Arg human insulin) in patients with type 2 diabetes inadequately controlled on metformin with or without sulfonylurea.

Methods

This was a randomised, open-label, multicentre (n?=?222), parallel-group, non-inferiority out-patient clinical trial, with 779 patients enrolled in the study. The study was conducted in 222 centres located in four countries. Patients aged ≥18 years with type 2 diabetes treated with metformin (±sulfonylurea) for at least 3 months with a baseline HbA_1c 7.0–10.0% (53.0–85.8 mmol/mol) were randomly assigned (2:1) via a computer-generated randomisation sequence with a voice response system to receive albiglutide (30 mg once a week, n?=?504) or insulin glargine (10 U once a day, n?=?241) added to current therapy. Participants and investigators were not masked to treatment assignment. Doses of each medication were adjusted on the basis of the glycaemic response. The primary endpoint was change from baseline in HbA_1c at week 52.

Results

In the albiglutide group, HbA_1c declined from 8.28?±?0.90% (67.0?±?9.8 mmol/mol) (mean?±?SD) at baseline to 7.62?±?1.12% (59.8?±?12.2 mmol/mol) at week 52. A similar reduction occurred in the insulin glargine group (8.36?±?0.95% to 7.55?±?1.04% [67.9?±?10.4 to 59.0?±?11.4 mmol/mol]). The model-adjusted treatment difference of 0.11% (95% CI ?0.04%, 0.27%) (1.2 mmol/mol [95% CI ?0.4, 3.0 mmol/mol]) indicated non-inferiority of albiglutide to insulin glargine based on the pre-specified non-inferiority margin of 0.3% (3.3 mmol/mol, p?=?0.0086). Body weight increased in the insulin glargine group and decreased in the albiglutide group, with a mean treatment difference of ?2.61 kg (95% CI ?3.20, ?2.02; p?p?=?0.0377).

Conclusions/interpretation

Albiglutide was non-inferior to insulin glargine at reducing HbA_1c at week 52, with modest weight loss and less hypoglycaemia. Both drugs were well tolerated. Albiglutide may be considered an alternative to insulin glargine in this patient population. Trial registration: ClinicalTrials.gov NCT00838916 (completed) Funding: This study was planned and conducted by GlaxoSmithKline.     

Preoperative adipocytokines as a predictor of surgical infection after colorectal surgery: a prospective survey

Background

Infections are the leading cause of morbidity and mortality after colorectal surgery. Obesity is a well-known risk factor for wound infection, but it does not seem to increase the risk of other infectious complications. The aim of this study was to look for a relationship between the fatty tissue metabolism measured by adipocytokine levels and the risk of postoperative infection.

Patients and methods

Preoperative plasma levels of eight adipocytokines, cholesterol, triglycerides, insulin and C-reactive protein (CRP) were measured in consecutive patients undergoing elective colorectal surgery between June 2008 and June 2011. Information about epidemiological and clinical characteristics was obtained for each patient. All infections in the 30 days following surgery were recorded.

Results

Among the 174 patients included, 49 (28 %) presented with a postoperative infection: 41 surgical site infections and 8 other infections. Preoperative leptin, insulin and CRP were significantly higher in patients with postoperative infection (p?=?0.025, p?=?0.020 and p?=?0.044, respectively), but only leptin was predictive of infection in multivariate analysis (odds ratio (OR)?=?1.89, 95 % confidence interval (CI) 1.18–3.03, p?=?0.008). The predictive value of leptin was slightly lower for surgical site infection (OR?=?1.65, 95 % CI 1.06–2.55, p?=?0.025). Leptin levels were independent of the other adipocytokine levels but not of the body mass index.

Conclusion

Although markers of inflammation and insulin resistance are also related to the onset of surgical infection, leptin correlates more closely with the risk of infection than does any other factor. However, its effect could be partially mediated by the body mass index.     

Cognitive function and risks of cardiovascular disease and hypoglycaemia in patients with type 2 diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial

Aims/hypothesis

The relationship between cognitive function, cardiovascular disease and premature death is not well established in patients with type 2 diabetes. We assessed the effects of cognitive function in 11,140 patients with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Furthermore, we tested whether level of cognitive function altered the beneficial effects of the BP-lowering and glycaemic-control regimens in the trial.

Methods

Cognitive function was assessed using the Mini Mental State Examination at baseline, and defined by scores 28-30 (‘normal’, n?=?8,689), 24-27 (‘mild dysfunction’, n?=?2,231) and <24 (‘severe dysfunction’, n?=?212). Risks of major cardiovascular events, death and hypoglycaemia and interactions with treatment were assessed using Cox proportional hazards analysis.

Results

Relative to normal function, both mild and severe cognitive dysfunction significantly increased the multiple-adjusted risks of major cardiovascular events (HR 1.27, 95% CI 1.11–1.46 and 1.42, 95% CI 1.01–1.99; both p?<?0.05), cardiovascular death (1.41, 95% CI 1.16–1.71 and 1.56, 95% CI 0.99–2.46; both p?≤?0.05) and all-cause death (1.33, 95% CI 1.16–1.54 and 1.50, 95% CI 1.06–2.12; both p?<?0.03). Severe, but not mild, cognitive dysfunction increased the risk of severe hypoglycaemia (HR 2.10, 95% CI 1.14–3.87; p?=?0.018). There was no evidence of heterogeneity of treatment effects on cardiovascular outcomes in subgroups defined by cognitive function at baseline.

Conclusions/interpretation

Cognitive dysfunction is an independent predictor of clinical outcomes in patients with type 2 diabetes, but does not modify the effects of BP lowering or glucose control on the risks of major cardiovascular events.

Trial registration:

ClinicalTrials.gov NCT00145925

Funding:

Supported by grants from Servier and from the National Health and Medical Research Council of Australia.     

A variant in the G6PC2/ABCB11 locus is associated with increased fasting plasma glucose, increased basal hepatic glucose production and increased insulin release after oral and intravenous glucose loads

Aims/hypothesis

An association between elevated fasting plasma glucose and the common rs560887 G allele in the G6PC2/ABCB11 locus has been reported. In Danes we aimed to examine rs560887 in relation to plasma glucose and serum insulin responses following oral and i.v. glucose loads and in relation to hepatic glucose production during a hyperinsulinaemic–euglycaemic clamp. Furthermore, we examined rs560887 for association with impaired fasting glycaemia (IFG), impaired glucose tolerance (IGT), type 2 diabetes and components of the metabolic syndrome.

Methods

rs560887 was genotyped in the Inter99 cohort (n?=?5,899), in 366 young, healthy Danes, in non-diabetic relatives of type 2 diabetic patients (n?=?196), and in young and elderly twins (n?=?159). Participants underwent an OGTT, an IVGTT or a 2 h hyperinsulinaemic–euglycaemic clamp.

Results

The rs560887 G allele associated with elevated fasting plasma glucose (p?=?2?×?10^?14) but not with plasma glucose levels at 30 min (p?=?0.9) or 120 min (p?=?0.9) during an OGTT. G allele carriers had elevated levels of serum insulin at 30 min during an OGTT (p?=?1?×?10^?4) and relatives of type 2 diabetes patients carrying the G allele had an increased acute insulin response (p?=?4?×?10^?4) during an IVGTT. Among elderly twins, G allele carriers had higher basal hepatic glucose production (p?=?0.04). Finally, the G allele associated with the risk of having IFG (OR 1.26, 95% CI 1.08–1.47, p?=?0.002), but not with IGT (OR 0.94, 95% CI 0.82–1.08, p?=?0.4) or type 2 diabetes (OR 0.93, 95% CI 0.84–1.04, p?=?0.2).

Conclusions/interpretation

The common rs560887 G allele in the G6PC2/ABCB11 locus is associated with increased fasting glycaemia and increased risk of IFG, associations that may be partly related to an increased basal hepatic glucose production rate.     

Risk Association Between the NF-κB1 -94ins/delATTG Promoter Polymorphism and Inflammatory Bowel Diseases: A Meta-Analysis

Background

Extensive investigation of the NF-κB1 -94ins/delATTG promoter polymorphism for risk association with ulcerative colitis (UC) and Crohn’s disease (CD) risk has yielded conflicting results.

Aims

The objective of this meta-analysis was to evaluate the risk association between the NF-κB1 -94ins/delATTG promoter polymorphism and UC and CD.

Methods

All eligible case–control studies of the association of NF-κB1 -94ins/delATTG promoter polymorphism with UC and CD were identified in the Pubmed and Embase databases. From these data, odds ratios (OR) with 95?% confidence intervals (CI) were calculated. Meta-analysis was performed for alleles (D vs. W) and genotypes (DD?+?WD vs. WW, DD vs. WW?+?WD, DD vs. WW, WD vs. WW) in a fixed/random effects model.

Results

Nine case–control studies that included 4,447 cases (2,631 UC and 1,816 CD) and 2,195 controls were identified. Results indicated increased risk association of D allele carriers with UC (D vs. W: OR?=?1.08, 95?% CI?=?1.01–1.17, P?=?0.03; DD vs. WW?+?WD: OR?=?1.16, 95?% CI?=?1.01–1.32, P?=?0.04 and DD vs. WW: OR?=?1.20, 95?% CI?=?1.03–1.39, P?=?0.02). No risk association was identified with CD.

Conclusion

This meta-analysis indicated that the NF-κB1 -94ins/delATTG promoter polymorphism is a risk factor for UC but not CD.     

Angiotensin-converting enzyme gene polymorphism in north Indian population with obstructive sleep apnea

Background

A deletion of 287-bp Alu repeat of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene is associated with hypertension.

Purpose

The aim of this study is to determine the frequency of ACE (I/D) polymorphism in patients with obstructive sleep apnea (OSA).

Methods

Genotyping of ACE (I/D) gene polymorphism and estimation of serum angiotensin-converting enzyme (SACE) activity were done in 813 subjects who underwent polysomnography. Of these, 395 were apneics and 418 were non-apneics.

Results

The frequencies of II genotype (OR = 1.8, 95 % CI 1.26–2.60, p?=?0.001) and I allele (OR = 1.4, 95 % CI 1.13–1.69, p?=?0.001) of ACE gene were found to be significantly increased in patients with OSA as compared to patients without OSA. Frequency of II genotype was significantly decreased (OR = 0.46, 95 % CI 0.28–0.77, p?=?0.003) in OSA patients with hypertension. In contrast, the frequencies of ID (OR?=?1.80, 95 % CI 1.08–2.99, p?=?0.024) and DD genotypes (OR?=?2.15, 95 % CI 1.30–3.57, p?=?0.003) were significantly increased in this group. The activity of SACE was significantly decreased in the apneic group as compared to the non-apneic group (OR?=?0.99, 95 % CI 0.98–1.00, p?=?0.04).

Conclusions

The findings suggest that II genotype confers susceptibility towards development of OSA whereas DD genotype confers susceptibility towards hypertension irrespective of OSA.     

Mortality among veterans with type 2 diabetes initiating metformin, sulfonylurea or rosiglitazone monotherapy

Aims/hypotheses

Despite oral hypoglycaemic medications being the most commonly used pharmacological treatments for type 2 diabetes, research is limited on their comparative safety, particularly their effects on overall mortality. We compared mortality risk with monotherapy initiation of four oral hypoglycaemic medications in a nationwide cohort of US veterans with type 2 diabetes.

Methods

We identified new users of oral hypoglycaemic medication monotherapy between 2004 and 2009 who received care for at least 1 year from the Veterans Health Administration. Patients were followed until initial monotherapy discontinuation, addition of another diabetes pharmacotherapy, death or end of follow-up. Mortality HRs were estimated using Cox regression adjusted for potential confounding factors.

Results

Among new users of metformin, sulfonylureas and rosiglitazone (185,360 men, 7,812 women), 4,256 (2.2%) died during follow-up. Average duration of medication use ranged from 1.4 to 1.7 years. Significantly higher mortality risk was seen for glibenclamide (known as glyburide in the USA and Canada) (HR 1.38, 95% CI 1.27, 1.50) or glipizide (HR 1.55, 95% CI 1.43, 1.67) compared with metformin monotherapy, and for glipizide compared with rosiglitazone (HR 1.27, 95% CI 1.01, 1.59) or glibenclamide monotherapy (HR 1.12, 95% CI 1.02, 1.23). A significant sex–rosiglitazone interaction was seen (p?=?0.034) compared with metformin monotherapy, with women having a higher HR (HR 4.36, 95% CI 1.34, 14.20) than men (HR 1.19, 95% CI 0.95, 1.49).

Conclusions/interpretations

Significantly higher mortality was associated with glibenclamide, glipizide and rosiglitazone use compared with metformin, and with glipizide use compared with rosiglitazone or glibenclamide. The potential for residual confounding by indication should be considered in interpreting these results.     

Contrast-induced acute kidney injury and adverse clinical outcomes risk in acute coronary syndrome patients undergoing percutaneous coronary intervention: a meta-analysis

Background

Recent studies have shown associations between contrast-induced acute kidney injury (CI-AKI) and increased risk of adverse clinical outcomes in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI); however, the estimates are inconsistent and vary widely. Therefore, this meta-analysis aimed to evaluate the precise associations between CI-AKI and adverse clinical consequences in patients undergoing PCI for ACS.

Methods

EMBASE, PubMed, Web of Science? and Cochrane Library databases were systematically searched from inception to December 16, 2016 for cohort studies assessing the association between CI-AKI and any adverse clinical outcomes in ACS patients treated with PCI. The results were demonstrated as pooled risk ratios (RRs) with 95% confidence intervals (CI). Heterogeneity was explored by subgroup analyses.

Results

We identified 1857 articles in electronic search, of which 22 (n?=?32,781) were included. Our meta-analysis revealed that in ACS patients undergoing PCI, CI-AKI significantly increased the risk of adverse clinical outcomes including all-cause mortality (18 studies; n?=?28,367; RR?=?3.16, 95% CI 2.52–3.97; I²?=?56.9%), short-term all-cause mortality (9 studies; n?=?13,895; RR?=?5.55, 95% CI 3.53–8.73; I²?=?60.1%), major adverse cardiac events (7 studies; n?=?19,841; RR?=?1.49, 95% CI: 1.34–1.65; I² =?0), major adverse cardiovascular and cerebrovascular events (3 studies; n?=?2768; RR?=?1.86, 95% CI: 1.42–2.43; I² =?0) and stent restenosis (3 studies; n?=?130,678; RR?=?1.50, 95% CI: 1.24–1.81; I² =?0), respectively. Subgroup analyses revealed that the studies with prospective cohort design, larger sample size and lower prevalence of CI-AKI might have higher short-term all-cause mortality risk.

Conclusions

CI-AKI may be a prognostic marker of adverse outcomes in ACS patients undergoing PCI. More attention should be paid to the diagnosis and management of CI-AKI.

     

Sleep-disordered breathing and daytime napping are associated with maternal hyperglycemia

Objectives

Sleep disturbances in pregnancy may impair glucose mechanism. This study aimed to examine associations of sleep-disordered breathing, sleep, and nap duration with 1-h glucose challenge test (GCT) levels in pregnant women after controlling for known risk factors for gestational diabetes.

Methods

This is a case–control study of 104 pregnant women. All women underwent full polysomnography and a GCT and completed the multivariable apnea prediction and Pittsburgh Sleep Quality indexes. The primary outcome was maternal hyperglycemia measured by GCT. Bivariate and multivariable logistic regression analyses were performed.

Results

Over 13 % subjects reported habitual snoring in the first trimester. Only 9.3 % women with normoglycemia (GCT?<?135) were habitual snorers, whereas 45.5 % women with hyperglycemia (GCT?≥?135) had habitual snoring (p?<?0.001). Sleep-disordered breathing symptoms (loud snoring, snorting/gasping, and apneas) (odds ratio (OR) 2.85; 95 % confidence interval (CI) 1.50–5.41; p?=?0.001) and total nap duration (OR 1.48; 95 % CI 0.96–2.28; p?=?0.08) were associated with hyperglycemia. After adjusting for confounders, sleep-disordered breathing symptoms (OR 3.37; 95 % CI 1.44–8.32; p?=?0.005) and nap duration (OR 1.64; 95 % CI 1.00–2.681.02; p?=?0.05) continued to be associated with hyperglycemia. However, the primary exposure measure, the apnea/hypopnea index in the first trimester was not significantly associated with hyperglycemia (OR 1.03; 95 % CI 0.83–1.28; p?=?0.77).

Conclusions

Sleep-disordered breathing symptoms and nap duration are associated with hyperglycemia. Sleep duration was not associated with hyperglycemia. Research is needed concerning whether women with sleep-disordered breathing and/or daytime napping are at risk for gestational diabetes.     

The Association Between Receipt of Guideline-Concordant Long-Term Opioid Therapy and All-Cause Mortality

Purpose

For patients receiving long-term opioid therapy (LtOT), the impact of guideline-concordant care on important clinical outcomes—notably mortality—is largely unknown, even among patients with a high comorbidity and mortality burden (e.g., HIV-infected patients). Our objective was to determine the association between receipt of guideline-concordant LtOT and 1-year all-cause mortality.

Methods

Among HIV-infected and uninfected patients initiating LtOT between 2000 and 2010 through the Department of Veterans Affairs, we used Cox regression with time-updated covariates and propensity-score matched analyses to examine the association between receipt of guideline-concordant care and 1-year all-cause mortality.

Results

Of 17,044 patients initiating LtOT between 2000 and 2010, 1048 patients (6%) died during 1 year of follow-up. Patients receiving psychotherapeutic co-interventions (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.51–0.75; P?<?0.001) or physical rehabilitative therapies (HR 0.81; 95% CI 0.67–0.98; P?=?0.03) had a decreased risk of all-cause mortality compared to patients not receiving these services, whereas patients prescribed benzodiazepines concurrent with opioids had a higher risk of mortality (HR 1.39; 95% CI 1.12–1.66; P?<?0.001). Among patients with a current substance use disorder (SUD), those receiving SUD treatment had a lower risk of mortality than untreated patients (HR 0.47; 95% CI 0.32–0.68; P?=?< 0.001). No association was found between all-cause mortality and primary care visits (HR 1.12; 95% CI 0.90–1.26; P?=?0.32) or urine drug testing (HR 0.96; 95% CI 0.78–1.17; P?=?0.67).

Conclusions

Providers should use caution in initiating LtOT in conjunction with benzodiazepines and untreated SUDs. Patients receiving LtOT may benefit from multi-modal treatment that addresses chronic pain and its associated comorbidities across multiple disciplines.

     

Major adverse cardiovascular events in non-valvular atrial fibrillation with chronic obstructive pulmonary disease: the ARAPACIS study

Chronic obstructive pulmonary disease (COPD) increases the risk of mortality in non-valvular atrial fibrillation (NVAF) patients. Data on the relationship of COPD to major cardiovascular events (MACE) in AF have not been defined. The aim of the study is to assess the predictive value of COPD on incident MACE in NVAF patients over a 3-year follow-up. In the Atrial Fibrillation Registry for Ankle-Brachial Index Prevalence Assessment-Collaborative Italian Study (ARAPACIS) cohort, we evaluate the impact of COPD on the following clinical endpoints: MACE (including vascular death, fatal/non-fatal MI and stroke/TIA), cardiovascular (CV) death and all-cause mortality. Among 2027 NVAF patients, patients with COPD (9%) are more commonly male, elderly and at higher thromboembolic risk. During a median 36.0 months follow-up, 186 patients experienced MACE: vascular death (n?=?72), MI (n?=?57), stroke/TIA (n?=?57). All major outcomes (including stroke/TIA, MI, vascular death, and all-cause death) are centrally adjudicated. Kaplan–Meier curves show that NVAF patients with COPD are at higher risk for MACE (p?<?0.001), CV death (p?<?0.001) and all-cause death (p?<?0.001). On Cox proportional hazard analysis, COPD is an independent predictor of MACE (Hazard ratio [HR] 1.77, 95% Confidence Intervals [CI] 1.20–2.61; p?=?0.004), CV death (HR 2.73, 95% CI 1.76–4.23; p?<?0.0001) and all-cause death (HR 2.16, 95% CI 1.48–3.16; p?<?0.0001). COPD is an independent predictor of MACE, CV death and all-cause death during a long-term follow-up of NVAF patients.     

Association of peripheral arterial disease with all-cause and cardiovascular mortality in hemodialysis patients: a meta-analysis

Background

Recent studies have shown an association between peripheral arterial disease (PAD) and increased risk of mortality in hemodialysis (HD) patients; however, the estimates vary widely and are inconsistent. It is necessary to elucidate the degree of mortality risk for PAD patients in HD population.

Methods

PubMed, EMBASE, Web of Science and Cochrane Library (from inception to September 4th, 2016) were systematically searched for cohort studies assessing the association between PAD and mortality in HD patients. We calculated the pooled risk ratios (RRs) with 95% confidence intervals (CI) of all-cause and cardiovascular (CV) mortality using random effects models. Subgroup analyses were conducted to explore the source of heterogeneity.

Results

The search identified 2,973 potentially eligible records and 10 studies (n?=?32,864) were included. Our meta-analysis revealed that PAD significantly increased the risk of all-cause mortality (RR 2.15, 95 % CI 1.67–2.77, n?=?32,864) and CV mortality (RR 2.99, 95 % CI 1.66-5.38, n?=?31,794) in HD patients after multivariate adjustment. Subgroup analyses showed the study design and follow-up time might be two sources of heterogeneity.

Conclusion

PAD may be a prognostic marker of all-cause and CV mortality in HD patients. More attention should be paid to diagnosis and management of PAD in HD patients.

     

Association of NQO1 rs1800566 polymorphism and the risk of colorectal cancer: a meta-analysis

Introduction

NAD(P)H:quinone oxidoreductase 1 (NQO1) rs1800566 polymorphism is found to have a lower enzymatic activity, which may result in increased incidence of several kinds of carcinomas including colorectal cancer. Results from published studies on the association of NQO1 rs1800566 genetic polymorphism with the risk of colorectal cancer are inconsistent. We performed a meta-analysis to summarize the possible association.

Materials and methods

All eligible published studies were searched from PubMed and Elsevier ScienceDirect. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were analyzed for additive, dominant, and recessive models to assess the association using fixed- or random-effect model.

Results

We identified 12 case-control studies that include 5,525 cases and 6,272 controls for the present meta-analysis. Significant associations between NQO1 rs1800566 genetic polymorphism and risk of colorectal cancer were observed in additive (OR?=?1.09, 95% CI?=?1.02–1.16, p?=?0.009) and dominant models (OR?=?1.12, 95% CI?=?1.04–1.21, p?=?0.004 for TT?+?CT vs. CC). Moreover, in the subgroup analysis based on ethnicity, significant associations were observed in Caucasians but not in Asians.

Conclusions

This meta-analysis provided evidence that NQO1 rs1800566 genetic polymorphism was associated with increased risk of colorectal cancer and that the T allele probably acts as an important risk factor.     

Walking Cadence and Mortality Among Community-Dwelling Older Adults

BACKGROUND

Older adults are encouraged to walk ≥100 steps?minute^?1 for moderate-intensity physical activity (i.e., brisk walking). It is unknown if the ability to walk ≥100 steps?minute^?1 predicts mortality.

OBJECTIVE

To determine if the ability to walk ≥100 steps?minute^?1 predicts mortality among older adults.

DESIGN, SETTING, AND PATIENTS

A population-based cohort study among 5,000 older adults from the Third National Health and Nutrition Survey (NHANES III; 1988–1994). Vital status and cause of death were collected through December 31, 2006. Median follow-up was 13.4 years. Average participant age was 70.6 years.

MEASUREMENTS

Walking cadence (steps?minute^?1) was calculated using a timed 2.4-m walk. Walking cadence was dichotomized at 100 steps?minute^?1 (≥100 steps?minute^?1 versus <100 steps?minute^?1) to demarcate the lower threshold of absolutely defined moderate-intensity physical activity. Walking cadence was also analyzed as a continuous variable. Predicted survival was compared between walking cadence and gait speed. The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular-specific and cancer-specific mortality and mortality from other causes.

RESULTS

Among 5,000 participants, 3,039 (61 %) walked ≥100 steps?minute^?1. During follow-up, 3,171 subjects died. In multivariable-adjusted analysis, ability to walk ≥100 steps?minute^?1 predicted a 21 % reduction in all-cause mortality (hazard ratio [HR], 0.79; 95 % confidence interval [95 % CI], 0.71–0.89, p?p??1 predicted reductions in cardiovascular-specific mortality (HR, 0.79 [0.67–0.92], p?=?0.002), cancer-specific mortality (HR, 0.76 [0.58–0.99], p?=?0.050), and mortality from other causes (HR, 0.82 [0.68–0.97], p?=?0.025). Predicted survival, adjusted for age and sex, was not different using walking cadence versus gait speed.

LIMITATIONS

Walking cadence was a cross-sectional measurement.

CONCLUSIONS

The ability to walk ≥100 steps?minute^?1 predicts a reduction in mortality among a sample of community-dwelling older adults.     

Pre-transplant Left Ventricular Diastolic Dysfunction Is Associated with Post Transplant Acute Graft Rejection and Graft Failure

Introduction

Acute cellular rejection (ACR) is a significant cause of morbidity and graft failure in liver transplant recipients (LTR). Diastolic dysfunction (DD) is frequently present in patients with cirrhosis undergoing liver transplantation. However, it is unclear if DD leads to ACR.

Methods

Data was collected retrospectively for consecutive LTR between January 2000 and December 2010. Demographic data and mortality related data was obtained from social security index. Primary outcome was biopsy proven ACR. Graft failure and all-cause mortality were also evaluated. DD was evaluated as a predictor of these outcomes. Other echocardiographic indices were also assessed as predictors of ACR by using Cox proportional hazard modeling adjusted for covariates.

Results

A total of 970 LTR (mean age 53.2 ± 10 years, women 34.6 % and white 64.5 %) were followed for 5.3 ± 3.4 years. Patients with DD (n = 145, 14.9 %) were significantly more likely to develop ACRs (HR 10.56; 95 % CI 6.78–16.45, p value = 0.0001) as well as graft failure (HR 2.09; 95 % CI 1.22–3.59, p value = 0.007) and all-cause mortality (HR 1.52; 95 % CI 1.08–2.13, p = 0.01). There was an increase in the risk of these outcomes with worsening of DD, when adjusted for various risk factors such as donor and recipient age, gender, race, Framingham risk score, pre-transplant MELD, transplant etiology and cold ischemia time.

Conclusion

Pre-transplant DD is significantly associated with increased risk of allograft rejection, graft failure and mortality. This signifies the importance of cardiac evaluation during the pre-transplant period.     

Electrocardiographic left ventricular hypertrophy predicts arrhythmia and mortality in patients with ischemic cardiomyopathy

Purpose

The relatively low incidence of device-treated ventricular arrhythmias in patients with ischemic cardiomyopathy (ICM) who receive implantable cardioverter defibrillators (ICDs) for primary prevention makes improved risk stratification of ICM patients a priority. Although Cornell product (CP) ECG left ventricular hypertrophy (LVH) has been associated with increased mortality in hypertensive patients and population-based studies, whether CP LVH can improve risk stratification of high-risk ICM patients is unclear. The aim of this study is to examine if electrocardiographic LVH predicts mortality and incident ventricular arrhythmia in patients with ICM.

Methods

All-cause mortality was examined in 317 patients with ICM and a history of non-sustained ventricular tachycardia (VT) who underwent electrophysiology testing. Incident VT and ventricular fibrillation (VF) were assessed in ICD recipients (n?=?186). ECG LVH was defined by CP criteria: [(R _aVL?+?S _V3)?+?6?mm in women]?×?QRS duration >2,440?mm?ms.

Results

During 3?years of follow-up, mortality was 20% (64 of 317) and death or incident VT or VF occurred in 35% of ICD recipients. CP LVH was associated with significantly greater 3-year mortality (28% vs 15%, p?=?0.015) and 3-year mortality or incident VT/VF in ICD patients (48% vs 35%, p?=?0.011). In Cox multivariate models, CP LVH was an independent predictor of mortality in all patients (hazard ratio (HR) 1.81, 95% confidence interval (CI) 1.11?C2.97, p?=?0.020) and of the composite endpoint of mortality or incident ventricular arrhythmia in ICD patients (HR 1.82, 95% CI 1.12?C3.00, p?=?0.016).

Conclusions

ECG LVH using CP criteria may enhance risk stratification in high-risk patients with ICM.     

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.

     

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.     

Type 2 diabetes risk alleles near ADCY5, CDKAL1 and HHEX-IDE are associated with reduced birthweight

Aims/hypothesis

The fetal insulin hypothesis suggests that variation in the fetal genotype influencing insulin secretion or action may predispose to low birthweight and type 2 diabetes. We examined associations between 25 confirmed type 2 diabetes risk variants and birthweight in individuals from the Danish Inter99 population and in meta-analyses including Inter99 data and reported studies.

Methods

Midwife records from the Danish State Archives provided information on mother’s age and parity, as well as birthweight, length at birth and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. We genotyped 25 risk alleles showing genome-wide associations with type 2 diabetes.

Results

Birthweight was inversely associated with the type 2 diabetes risk alleles of ADCY5 rs11708067 (β?=??33 g [95% CI ?55, ?10], p?=?0.004) and CDKAL1 rs7756992 (β?=??22 g [95% CI ?43, ?1], p?=?0.04). The association for the latter locus was confirmed in a meta-analysis (n?=?24,885) (β?=??20 g [95% CI ?29, ?11], p?=?5?×?10^?6). The HHEX-IDE rs1111875 variant showed no significant association among Danes (p?=?0.09); however, in a meta-analysis (n?=?25,164) this type 2 diabetes risk allele was associated with lower birthweight (β?=??16 g [95% CI ?24, ?8], p?=?8?×?10^?5). On average, individuals with high genetic risk (≥25 type 2 diabetes risk alleles) weighed marginally less at birth than those with low genetic risk (<25 type 2 diabetes risk alleles) (β?=??35 g [95% CI ?69, ?2], p?=?0.037).

Conclusions/interpretation

We report a novel association between the fetal ADCY5 type 2 diabetes risk allele and decreased birthweight, and confirm in meta-analyses associations between decreased birthweight and the type 2 diabetes risk alleles of HHEX-IDE and CDKAL1. No strong general effect on birthweight can be ascribed to the 25 common type 2 diabetes risk alleles.     

Prognostic value of treatment-related factors in metastatic colorectal cancer using a stop-and-go strategy

Purpose

The purpose of this study is to identify treatment-related factors prognostic of survival in a cohort of patients with metastatic colorectal cancer (mCRC) receiving a palliative, stop-and-go chemotherapy regimen.

Methods

Consecutive patients receiving first-line treatment with biweekly FLIRI plus bevacizumab were included. The outcome was overall survival. Cox regression analysis was used to identify predictors of outcome. We analysed reduction in chemotherapy dosage (no vs. ≤25 or >25 % reduction), bevacizumab administrated to <50, or ≥50 % to chemotherapy treatments, best response during the first 24 weeks of treatment, and local treatment of metastases.

Results

We included 257 patients. Median survival was 23.6 months. Chemotherapy reduction did not influence outcome. Bevacizumab administrations (≥50 %) were associated with improved outcome: hazard ratios (HR) 0.56 (95 % confidence interval (CI) 0.34–0.90, p?=?0.018). Partial response (PR) vs. no change (NC) was borderline significant: HR 0.66 (95 % CI 0.43–0.99, p?=?0.048), whereas progressive disease (PD) vs. NC increased mortality HR 2.48 (95 % CI 1.19–5.19, p?=?0.016). Local treatment of metastases improved outcome: HR 0.30 (95 % CI 0.15–0.61, p?=?0.001).

Conclusions

In a cohort of mCRC patients, receiving a palliative, stop-and-go regimen, administration of bevacizumab to ≥50 % of chemotherapy treatments and local treatment of metastases were associated with better survival. PR improved outcome compared to NC, whereas PD was prognostic of increased mortality.