Long-term exposure to ambient air pollution and risk of microvascular complications among patients with type 2 diabetes: a prospective study.

BACKGROUND: Patients with type 2 diabetes (T2D) may disproportionately suffer the adverse cardiovascular effects of air pollution, but relevant evidence on microvascular outcome is lacking. We aimed to examine the association between air pollution exposure and the risk of microvascular complications among patients with T2D. METHODS: This prospective study included 17 995 participants with T2D who were free of macro- and micro-vascular complications at baseline from the UK Biobank. Annual average concentrations of particulate matter (PM) with diameters <2.5 µm (PM2.5), <10 µm (PM10), nitrogen dioxide (NO2) and nitrogen oxides (NOx) were assessed using land use regression models. Cox proportional hazards regression was used to estimate the associations of air pollution exposure with incident diabetic microvascular complications. The joint effects of the air pollutant mixture were examined using quantile-based g-computation in a survival setting. RESULTS: In single-pollutant models, the adjusted hazard ratios (95% confidence intervals) for composite diabetic microvascular complications per interquartile range increase in PM2.5, PM10, NO2 and NOx were 1.09 (1.04-1.14), 1.06 (1.01-1.11), 1.07 (1.02-1.12) and 1.04 (1.00-1.08), respectively. Similar significant results were found for diabetic nephropathy and diabetic neuropathy, but not for diabetic retinopathy. The associations of certain air pollutants with composite microvascular complications and diabetic nephropathy were present even at concentrations below the World Health Organization limit values. Multi-pollutant analyses demonstrated that PM2.5 contributed most to the elevated risk associated with the air pollutant mixture. In addition, we found no interactions between air pollution and metabolic risk factor control on the risk of diabetic microvascular complications. CONCLUSIONS: Long-term individual and joint exposure to PM2.5, PM10, NO2 and NOx, even at low levels, was associated with an increased risk of diabetic microvascular complications, with PM2.5 potentially being the main contributor.

Associations Between Antidepressant Use and Advanced Diabetes Outcomes in Patients with Depression and Diabetes Mellitus.

CONTEXT: Comorbid depression in patients with diabetes deteriorates the prognosis. Antidepressants might attenuate the adverse effects of depression; however, they are associated with cardiometabolic adverse effects. OBJECTIVE: This study aimed to explore the association between antidepressant treatment and advanced diabetic complications and mortality among patients with depression and diabetes mellitus. METHODS: We conducted a nationwide retrospective cohort study of 36 276 patients with depression and newly treated diabetes mellitus using Taiwan's universal health insurance database. Antidepressant treatment patterns within a 6-month window were classified into none, poor, partial, and regular use, and we accounted for time-dependent variables in the Cox proportional hazards regression analysis with adjustment for time-dependent comorbidity and concomitant use of medications. Different classes of antidepressants were compared. Macro- and microvascular complications, as well as all-cause mortality, were the main outcomes. Benzodiazepines were chosen as negative control exposure. RESULTS: Compared with poor use of antidepressants, regular use was associated with a 0.92-fold decreased risk of macrovascular complications and a 0.86-fold decreased risk of all-cause mortality but not associated with microvascular complications. Regular use of selective serotonin reuptake inhibitors was associated with a 0.83- and 0.75-fold decreased risk of macrovascular complications and all-cause mortality, respectively. Regular use of tricyclic or tetracyclic antidepressants was associated with a 0.78-fold decreased risk of all-cause mortality. Regular use of benzodiazepine showed no association with diabetic outcomes. CONCLUSION: Regular antidepressant use was associated with lower risk of advanced diabetic complications compared with poor adherence. Clinicians should emphasize antidepressant treatment adherence among patients with depression and diabetes mellitus.

Improved Endothelium-Dependent Relaxation of Thoracic Aorta in Niclosamide-Treated Diabetic Rats.

Diabetes-induced endothelial dysfunction is critical for the development of diabetic cardiovascular complications. The aim of this study was to investigate the effect of niclosamide (Nic) on vascular endothelial dysfunction in streptozotocin (STZ)-induced diabetic rats. Male Sprague-Dawley rats were injected with a single intraperitoneal injection of STZ (75 mg/kg) to induce type 1 diabetes, and Nic (10 mg/kg) was intraperitoneally administered per day for 4 weeks. Endothelial function was evaluated as carbachol (CCh, an endothelium-dependent vasodilator)-evoked relaxation in the experiments performed on isolated thoracic aortas. The changes in the protein expressions of phosphorylated eNOS at serine 1177 (p-eNOSSer1177) and phosphorylated VASP at serine 239 (p-VASPSer239) of the rat aortas were analyzed by western blotting to determine whether NO/cGMP signaling is involved in the mechanism of Nic. STZ-injected rats had higher fasting blood glucose and less body weight compared to control rats (p < 0.05). Nic treatment did not affect blood glucose levels or body weights of the rats. CCh-induced endothelium-dependent relaxation of the aortic rings was significantly decreased in diabetic rats compared to control (Emax = 66.79 ± 7.41% and 90.28 ± 5.55%, respectively; p < 0.05). CCh-induced relaxation response was greater in Nic-treated diabetic rats compared to diabetic rats (Emax = 91.56 ± 1.20% and 66.79 ± 7.41%, respectively; p < 0.05). Phosphorylation of eNOS and VASP in aortic tissues was significantly reduced in diabetic rats, which were markedly increased by Nic treatment (p < 0.05). We demonstrated that Nic improved endothelial dysfunction possibly through the activation of NO/cGMP signaling without affecting hyperglycemia in diabetic rats. Our results suggesting that Nic has potential of repurposing for diabetic cardiovascular complications.

MiR-20a ameliorates diabetic angiopathy in streptozotocin-induced diabetic rats by regulating intracellular antioxidant enzymes and VEGF.

OBJECTIVE: We evaluated the beneficial effect of miR-20a mimic against diabetic angiopathy (DA) in rats by regulating intracellular antioxidant enzymes and vascular endothelial growth factor (VEGF). MATERIALS AND METHODS: Diabetes was induced by intraperitoneal administration of streptozotocin (STZ; 65 mg/kg). Rats were then treated with miR-20a mimic (250 nmol/kg orally) for 8 weeks after STZ administration. The effect of miR-20a mimic against DA in rats was evaluated by estimating serum glucose concentration, lipid profile, Lp-a, kidney function test, inflammatory mediators, and markers of endothelial cell function. Markers of oxidative stress in the aortic tissue were estimated in rats treated with miR-20a mimic. Western blot assay, RT-PCR, and histopathology of kidney and myocardial tissues were also performed. RESULTS: Serum levels of blood glucose and markers of renal function were significantly lower, and the lipid profile improved in the miR-20a mimic group compared to the DA group. Treatment with miR-20a mimic ameliorated the altered markers of endothelial function and oxidative stress, as well as mediators of inflammation, in the DA rats. Protein expressions of ERK1/2, JNK, and p38 MAPK, as well as mRNA expressions of TLR-4 and NF-κB, in aortic tissues were lower in the miR-20a mimic group than in the DA group. The miR-20a mimic group had fewer histopathological changes in kidney and myocardial tissues than the DA group. CONCLUSIONS: MiR-20a mimic can protect against DA in rats by regulating vascular endothelial function and oxidative stress.

Polysaccharide peptide (PsP) Ganoderma lucidum: a potential inducer for vascular repair in type 2 diabetes mellitus model.

INTRODUCTION: The increasing blood glucose level due to insulin resistance which occurs in diabetes mellitus (DM) may cause vascular damage. This study aims to prove the effect of the polysaccharide peptide (PsP) Ganoderma lucidum on improving vascular damage through an increase of circulating endothelial cells and circulating endothelial cells (CEC) ratio, decreased H2O2, triglyceride (TG), total cholesterol (TC) and insulin resistance in type 2 DM. METHODS: Our study is a true experimental study with randomized posttest control group design that used 35 Wistar rats divided into five groups: normal, control (+) and three groups of different variant PsP doses 50, 150 and 300 mg/kg BW (n=7). RESULTS: By using one-way ANOVA and post-hoc Duncan test, the results show a significant increase of endothelial progenitor cell (EPC) concentration (p=0.000) and ratio EPC:CEC (0.000) by dose-dependent fashion and also reduced CEC concentration (p=0.001), H2O2 (p=0.03), TG (p=0.001), TC (p=0.01) and insulin resistance (p=0.003). CONCLUSION: In this study, PsP induced endothelial repairing process and reduced the risk factor with 300 mg/kg BW as optimum dose. However, further research on EPC and CEC detection markers is important. Further research on PsP and clinical trial for commercial uses is also needed.

Real-world evidence of glycemic control among patients with type 2 diabetes mellitus in India: the TIGHT study.

Objective: To determine glycemic control in adult patients with type 2 diabetes receiving antidiabetic therapy as part of routine healthcare in India. Research design and methods: This was a retrospective analysis of cross-sectional data of patients with type 2 diabetes receiving oral hypoglycemic agents (OHAs) with or without insulin between 2015 and 2017. We assessed proportion of patients with uncontrolled glycemia and performed logistic regression to evaluate its association with various risk factors and microvascular complications. Results: A total of 55 639 eligible records were identified; mean age of patients was 54.31 (±11.11) years. One-third of the study population had microvascular complications, predominantly neuropathy. Nearly 76.6% of patients had uncontrolled glycated hemoglobin (HbA1c) ≥7% (53 mmol/mol); 62% of these patients had HbA1c between 7% and 8% (53-64 mmol/mol). Glycemic control from combination of OHAs with or without insulin varied between 14.2% and 24.8%. In multivariate analysis, factors statistically associated with uncontrolled glycemia were obesity (OR: 1.15), hypertension (stage I OR: 1.65 and stage II OR: 2.73) and diabetes duration >5 years (OR: 1.19) (p<0.001). Similarly, the odds of having any microvascular complication increased with duration of diabetes (past 1-2 years, OR: 1.67; 2-5 years, OR: 2.53; >5 years, OR: 4.01; p<0.0001), hypertension (stage I, OR: 1.18 and stage II, OR: 1.34; p<0.05) and uncontrolled HbA1c (OR: 1.28; p<0.0001). Conclusions: Indian population with type 2 diabetes has a high burden (76.6%) of poor glycemic control. This study highlights the need for early implementation of optimum diabetes pharmacotherapy to maintain recommended glycemic control, thereby reducing burden of microvascular complications.

Comparison of mortality and cardiovascular event risk associated with various insulin secretagogues: A nationwide real-world analysis.

AIMS: Several insulin secretagogues are widely used to treat diabetes; however, few outcome-based comparative studies have clarified which one of these should be used when indicated. We investigated mortality and cardiovascular event risk associated with optimal forms of insulin secretagogues. METHODS: In this cohort study using real-world data from the diabetes database of Taiwan's National Health Insurance program, patients with diabetes were enrolled if their initial treatment was glimepiride, gliclazide, glipizide, glyburide, or repaglinide from 1999 to 2013. Each group was propensity score-matched to the glimepiride group before comparison. Primary outcomes were all-cause mortality and the combined cardiovascular event risk of acute myocardial infarction and ischemic stroke. Hazard ratios were calculated by Cox proportional hazard regression models. RESULTS: There were 66,790, 97,426, 38,806, 92,970, and 11,468 participants in the glimepiride, gliclazide, glipizide, glyburide, and repaglinide groups, respectively. The median follow-up time was 8 years. Glimepiride was associated with the best clinical outcome, showing the lowest mortality and lowest cardiovascular event risk of the five insulin secretagogues. Using patients on glimepiride as the reference group, the adjusted hazard ratios of all-cause mortality and cardiovascular event risk were 1.52 (p < 0.001) and 1.22 (p = 0.005) for gliclazide, 1.42 (p < 0.001) and 1.19 (p = 0.073) for glipizide, 1.43 (p < 0.001) and 1.32 (p < 0.001) for glyburide, and 1.88 (p < 0.001) and 1.69 (p = 0.001) for repaglinide. CONCLUSIONS: For patients with diabetes taking an insulin secretagogue, glimepiride was associated with the best clinical outcome, showing the lowest mortality and cardiovascular event risk.

Augmented contractility of murine femoral arteries in a streptozotocin diabetes model is related to increased phosphorylation of MYPT1.

Diabetes mellitus (DM) is a metabolic disorder with high prevalence, and a major risk factor for macro- and microvascular abnormalities. This study was undertaken to explore the mechanisms of hypercontractility of murine femoral arteries (FA) obtained from mice with streptozotocin (STZ)-induced diabetes and its relation to the phosphorylation profile of the myosin phosphatase target subunit 1, MYPT1. The immunoreactivity of MYPT1 toward phospho-MYPT1-T696, MYPT1-T853, or MYPT1-S695, used as a read out for MYPT1 phosphorylation, has been studied by Western Blotting. Contractile activity of FA from control and STZ mice has been studied by wire myography. At basal conditions (no treatment), the immunoreactivity of MYPT1-T696/T853 was ~2-fold higher in the STZ arteries compared with controls. No changes in MYPT1-T696/853 phosphorylation were observed after stimulation with the Thromboxan-A2 analog, U46619. Neither basal nor U46619-stimulated phosphorylation of MYPT1 at S695 was affected by STZ treatment. Mechanical distensibility and basal tone of FA obtained from STZ animals were similar to controls. Maximal force after treatment of FA with the contractile agonists phenylephrine (10 µmol/L) or U46619 (1 µmol/L) was augmented in the arteries of STZ mice by ~2- and ~1.5-fold, respectively. In summary, our study suggests that development of a hypercontractile phenotype in murine FA in STZ diabetes is at least partially related to an increase in phosphorylation of MLCP at MYPT1-T696/853. Interestingly, the phosphorylation at S695 site was not altered in STZ-induced diabetes, supporting the view that S695 may serve as a sensor for mechanical activity which is not directly involved in tone regulation.

Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: A systematic review and meta-analysis.

AIM: The use of sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) has been limited, primarily because glycaemic efficacy is dependent on kidney function. We performed a systematic review and meta-analysis to assess the efficacy and safety of SGLT2 inhibitors in patients with T2DM and CKD, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 . MATERIALS AND METHODS: We searched MEDLINE, EMBASE and the Cochrane Library until 7 August 2018 and websites of the US, European and Japanese regulatory authorities until 27 July 2018 for data from randomized controlled trials of SGLT2 inhibitors that included reporting of effects on biomarkers, cardiovascular, renal or safety outcomes in individuals with T2DM and CKD. Random effects models and inverse variance weighting were used to calculate relative risks with 95% confidence intervals. RESULTS: Data were obtained from 27 studies with up to 7363 participants involved. In patients with T2DM and CKD, SGLT2 inhibitors lowered glycated haemoglobin (-0.29%; 95% CI, -0.39 to -0.19) as well as blood pressure, body weight and albuminuria. SGLT2 inhibition reduced the risk of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (RR, 0.81; 95% CI, 0.70-0.94) and heart failure (RR, 0.61; 95% CI, 0.48-0.78), without a clear effect on all-cause mortality (HR, 0.86; 95% CI, 0.73-1.01). These agents also attenuated the annual decline in eGFR slope (placebo-subtracted difference of 1.35 mL/1.73 m2 /y; 95% CI, 0.78-1.93) and reduced the risk of the composite renal outcome (HR, 0.71; 95% CI, 0.53-0.95). There was no evidence of additional risks with SGLT2 inhibition in CKD beyond those already known for the class, although heterogeneity was observed across individual agents for some safety outcomes. CONCLUSION: Currently available data suggest that, despite only modest reductions in glycated haemoglobin, SGLT2 inhibitors reduce the risk of cardiovascular and renal outcomes in patients with T2DM and CKD, without clear evidence of additional safety concerns.

SGLT2 inhibitors and risk of stroke in patients with type 2 diabetes: A systematic review and meta-analysis.

The effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on risk of stroke have not been conclusively established. Therefore, we conducted a meta-analysis to evaluate the effects of SGLT2 inhibitors on stroke risk in patients with type 2 diabetes mellitus (T2DM) by searching available randomized trials in PubMed, Embase, CENTRAL, Web of Science, Scopus and ClinicalTrials.gov databases. We identified 32 eligible trials involving 75 540 participants. The incidence of stroke in groups receiving SGLT2 inhibitor monotherapy or combination therapy did not differ significantly from that in control groups, with a relative risk (RR) of 1.01 and 1.0, respectively. Three SGLT2 inhibitors were tested, with similar RR values (canagliflozin [RR, 0.91], dapagliflozin [RR, 0.99] and empagliflozin [RR, 1.03]). Subgroup analyses showed that RR values were not affected by gender, age, diabetes duration, BMI or HbA1C levels, but Black patients had a lower incidence of stroke than White or Asian patients. This meta-analysis indicated that SGLT2 inhibitor therapy did not increase stroke incidence, and no significant differences in stroke risk were observed among 3 SGLT2 inhibitors (class effect). However, the small racial disparity requires further study and confirmation.

DECLARE-TIMI 58: Participants' baseline characteristics.

AIM: To describe the baseline characteristics of participants randomized in the Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58) trial, the pivotal study conducted to assess cardiovascular (CV) outcomes with dapagliflozin. METHODS: The DECLARE-TIMI 58 trial will analyse 17 160 patients with type 2 diabetes randomized to treatment with dapagliflozin (10 mg/d) or matching placebo. We analysed their baseline characteristics. RESULTS: The participants' mean ± SD age was 63.8 ± 6.8 years, 62.6% were male, and their mean ± SD diabetes duration was 11.8 ± 7.8 years, glycated haemoglobin 8.3% ± 1.2% (67 mmol/mol ± 9.7 mmol/mol) and body mass index 32.1 ± 6.0 kg/m2 . Randomization included 6971 (40.6%) patients with atherosclerotic CV disease (CVD), and 10 189 (59.4%) patients with multiple risk factors (MRF) for CVD (defined as men age ≥ 55 years or women ≥60 years, with at least one of dyslipidaemia, hypertension or smoking). Patients with CVD compared with patients with MRF were younger (62.5 ± 8.1 vs 64.7 ± 5.6 years), more frequently male (72.1% vs 56.1%), less often used metformin (74.6% vs 81.2%), more often used insulin (44.2% vs 36.4%), and more frequently used statins, aspirin, clopidogrel and ß-blockers (82.2%, 71.1%, 24.7% and 66.6% vs 63.7%, 39.1%, 1.5% and 32.3%, respectively). CONCLUSION: The DECLARE-TIMI 58 trial is expected to provide conclusive data on the effect of treatment with dapagliflozin in addition to standard of care, on CV outcomes in a broad patient population with type 2 diabetes and CVD or MRF for CVD.

Have we really demonstrated the cardiovascular safety of anti-hyperglycaemic drugs? Rethinking the concepts of macrovascular and microvascular disease in type 2 diabetes.

A primary goal of the treatment of type 2 mellitus is the prevention of morbidity and mortality associated with cardiovascular disease; however, anti-hyperglycaemic drugs have the capacity to cause deleterious effects on the circulation, a risk that is not adequately reflected by the endpoints selected for emphasis in large-scale clinical trials that are designed to evaluate cardiovascular safety. The primary endpoint of the large-scale studies mandated by regulatory authorities focuses only on 3 to 4 events that depict only a limited view of the circulatory system. One of the most serious adverse effects of many glucose-lowering drugs is new-onset or worsening heart failure. Most antidiabetic drugs can aggravate heart failure because they exert anti-natriuretic actions, and possibly, adverse effects on the myocardium. In addition, certain anti-hyperglycaemic agents may worsen peripheral vascular disease and trigger cardiac arrhythmias that may lead to sudden death. Initiation of treatment with antidiabetic medications may also cause deterioration of the function of the kidneys, retina and peripheral nerves, which are typically regarded as reflecting microvascular disease. The current confusion about the cardiovascular effects of glucose-lowering drugs may be exacerbated by conceptual uncertainties about the classification of large and small vessel disease in determining the clinical course of diabetes. Physicians should not be falsely reassured by claims that a new treatment appears to have passed a narrowly defined regulatory test. The management of people with diabetes often carries with it the risk of important cardiovascular consequences, even for drugs that do not overtly increase the risk of myocardial infarction or stroke.

TRAF3IP2 mediates high glucose-induced endothelin-1 production as well as endothelin-1-induced inflammation in endothelial cells.

Hyperglycemia-induced production of endothelin (ET)-1 is a hallmark of endothelial dysfunction in diabetes. Although the detrimental vascular effects of increased ET-1 are well known, the molecular mechanisms regulating endothelial synthesis of ET-1 in the setting of diabetes remain largely unidentified. Here, we show that adapter molecule TRAF3 interacting protein 2 (TRAF3IP2) mediates high glucose-induced ET-1 production in endothelial cells and ET-1-mediated endothelial cell inflammation. Specifically, we found that high glucose upregulated TRAF3IP2 in human aortic endothelial cells, which subsequently led to activation of JNK and IKKß. shRNA-mediated silencing of TRAF3IP2, JNK1, or IKKß abrogated high-glucose-induced ET-converting enzyme 1 expression and ET-1 production. Likewise, overexpression of TRAF3IP2, in the absence of high glucose, led to activation of JNK and IKKß as well as increased ET-1 production. Furthermore, ET-1 transcriptionally upregulated TRAF3IP2, and this upregulation was prevented by pharmacological inhibition of ET-1 receptor B using BQ-788, or inhibition of NADPH oxidase-derived reactive oxygen species using gp91ds-tat and GKT137831. Notably, we found that knockdown of TRAF3IP2 abolished ET-1-induced proinflammatory and adhesion molecule (IL-1ß, TNF-α, monocyte chemoattractant protein 1, ICAM-1, VCAM-1, and E-selectin) expression and monocyte adhesion to endothelial cells. Finally, we report that TRAF3IP2 is upregulated and colocalized with CD31, an endothelial marker, in the aorta of diabetic mice. Collectively, findings from the present study identify endothelial TRAF3IP2 as a potential new therapeutic target to suppress ET-1 production and associated vascular complications in diabetes. NEW & NOTEWORTHY This study provides the first evidence that the adapter molecule TRAF3 interacting protein 2 mediates high glucose-induced production of endothelin-1 by endothelial cells as well as endothelin-1-mediated endothelial cell inflammation. The findings presented herein suggest that TRAF3 interacting protein 2 may be an important therapeutic target in diabetic vasculopathy characterized by excess endothelin-1 production.

A comprehensive review of the FDA-approved labels of diabetes drugs: Indications, safety, and emerging cardiovascular safety data.

AIMS: FDA-approved drug labels are an important source of information for clinicians who prescribe medications for treatment of diabetes. We reviewed drug labels to (1) understand the landscape of classes of medications approved for type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), (2) explore the indications and safety information and (3) examine their cardiovascular safety. METHODS: We searched four public references and reviewed all FDA-approved labels for "indication and usage," "adverse effects," "warnings and precautions," and "cardiovascular outcomes" from October 1982 to July 2016. We also reviewed FDA drug-safety communications from January 2015 to May 2017. RESULTS: The labels reveal 12 classes of medications approved for T2DM with only 2 classes approved for T1DM. There is emerging evidence about cardiovascular safety and risk reduction from diabetes medications which is now being incorporated in drug labels. CONCLUSIONS: All currently available diabetes medications are approved for adults with T2DM with a remarkably limited number for adults with T1DM and children with T1DM or T2DM. The incorporation of emerging data on cardiovascular outcomes in FDA drug labels is expected to influence the way physicians treat patients with diabetes.

Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis.

Objective To assess the impact of incretin based treatment on all cause mortality in patients with type 2 diabetes.Design Systematic review and meta-analysis of randomised trials.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov.Eligibility criteria Randomised controlled trials that compared glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors with placebo or active anti-diabetic drugs in patients with type 2 diabetes.Data collection and analysis Paired reviewers independently screened citations, assessed risk of bias of included studies, and extracted data. Peto's method was used as the primary approach to pool effect estimates from trials, sensitivity analyses were carried out with other statistical approaches, and meta-regression was applied for six prespecified hypotheses to explore heterogeneity. The GRADE approach was used to rate the quality of evidence.Results 189 randomised controlled trials (n=155 145) were included, all of which were at low to moderate risk of bias; 77 reported no events of death and 112 reported 3888 deaths among 151 614 patients. Meta-analysis of 189 trials showed no difference in all cause mortality between incretin drugs versus control (1925/84 136 v 1963/67 478; odds ratio 0.96, 95% confidence interval 0.90 to 1.02, I2=0%; risk difference 3 fewer events (95% confidence interval 7 fewer to 1 more) per 1000 patients over five years; moderate quality evidence). Results suggested the possibility of a mortality benefit with GLP-1 agonists but not DPP-4 inhibitors, but the subgroup hypothesis had low credibility. Sensitivity analyses showed no important differences in the estimates of effects.Conclusions Current evidence does not support the suggestion that incretin based treatment increases all cause mortality in patients with type 2 diabetes. Further studies are warranted to examine if the effect differs between GLP-1 agonists versus DPP-4 inhibitors.

Association between highly active antiretroviral therapy and selected cardiovascular disease risk factors in sub-Saharan Africa: a systematic review and meta-analysis protocol.

INTRODUCTION: The increasing highly active antiretroviral therapy (HAART) coverage in sub-Saharan Africa (SSA) has been associated with increasing cardiovascular disease (CVD) incidence. However, the epidemiology of the association between HAART and CVD risk factors in SSA is sparse. We aim to assess the extent to which HAART is associated with selected cardiovascular risk factors (hypertension, diabetes, dyslipidaemia and metabolic syndrome) in SSA. METHODS AND ANALYSIS: This will be a systematic review and meta-analysis of published studies on the association between HAART and CVD risk factors retrieved from Medline, Embase, Popline, Africa-Wide Information, African Index Medicus and the Cochrane library databases. Studies will be screened for eligibility according to the selection criteria by two independent reviewers. Eligible studies will be assessed for the quality of their evidence and risk of bias using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies of the National Health Institute and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, with respect to the measured outcomes (hypertension, diabetes, dyslipidaemia and metabolic syndrome). A data abstraction form will be produced on Epi info V.7 and data analysis done on STATA V.14 statistical software. Summary estimates of measures of effects for the association between HAART use and the outcomes will be derived. Random effects meta-analyses will be performed and I2 statistic used to assess for heterogeneity between studies with respect to measured parameters. Qualitative synthesis will be used where data is insufficient to produce quantitative synthesis. ETHICS AND DISSEMINATION: The protocol has been reviewed by the Research Governance & Integrity Office of the Research Ethics Committee of the London School of Hygiene and Tropical Medicine and confirmed as not requiring ethical approval. The findings of this study will be made widely available especially to national HIV/AIDS committees formulating HIV/AIDS guidelines for their respective settings. TRIAL REGISTRATION NUMBER: CRD42016042306; Pre-results.

Treatment with the glucagon receptor antagonist LY2409021 increases ambulatory blood pressure in patients with type 2 diabetes.

AIMS: To assess the effect of LY2409021 on systolic blood pressure (SBP) in patients with type 2 diabetes. MATERIALS AND METHODS: This 6-week, randomized, crossover study evaluated the effects of once-daily administration of LY2409021 20 mg vs those of placebo on SBP, diastolic BP (DBP), and mean arterial pressure (MAP) using 24-hour ambulatory BP monitoring (ABPM) in 270 subjects treated with diet/exercise ± metformin. Other measures included changes in glycemic control, serum lipids, and hepatic safety markers. RESULTS: At 6 weeks of LY2409021 treatment, 24-hour mean SBP was increased, with a least squares mean (LSM) difference of 2.26 mm Hg vs placebo (95% CI: 1.11, 3.40; P < .001). The 24-hour mean DBP and MAP also increased, with LSM differences of 1.37 mm Hg (95% CI: 0.66, 2.08; P < .001) and 1.67 mm Hg (95% CI: 0.86, 2.47; P < .001) vs placebo, respectively. At week 6, LY2409021 treatment reduced glycated hemoglobin (HbA1c) levels, with an LSM difference of -0.49% (-5.4 mmol/mol) (95% CI: -0.56%, -0.42% [-6.1, -4.6 mmol/mol]; P < .001) vs placebo. Mean HbA1c at baseline was 7.3% (56 mmol/mol). Small but significant changes in serum lipid and aminotransferase levels were observed with LY2409021 treatment (all P < .05 vs placebo). CONCLUSIONS: Statistically significant increases in BP, MAP and serum lipid levels were observed with LY2409021 treatment at a dose that lowered HbA1c and glucose levels. These effects may limit the clinical utility of LY2409021 as a chronic treatment for type 2 diabetes.

Flavonoids from Litsea japonica Inhibit AGEs Formation and Rat Lense Aldose Reductase In Vitro and Vessel Dilation in Zebrafish.

In our ongoing efforts to identify effective naturally sourced agents for the treating of diabetic complications, two new (1 and 2) and 11 known phenolic compounds (3-13) were isolated from an 80 % ethanol extract of Litsea japonica leaves. The structures of the new compounds were established by spectroscopic and chemical studies. These isolates (1-13) were subjected to an in vitro bioassay evaluating their inhibitory activity on advanced glycation end products formation and rat lens aldose reductase activity. Of the compounds evaluated, the flavonoids (3, 4, 6-8, 11, and 12) markedly inhibited advanced glycation end products formation, with IC50 values of 7.4-72.0 µM, compared with the positive control, aminoguanidine (IC50 = 975.9 µM). In the rat lens aldose reductase assay, consistent with the inhibition of advanced glycation end products formation, the flavonoids (3, 4, 6-8, 11, and 12) exhibited considerable inhibition of rat lens aldose reductase activity, with IC50 values of 1.1-12.5 µM. In addition, the effects of kaempferol (4) and tiliroside (7) on the dilation of hyaloid-retinal vessels induced by high glucose in larval zebrafish were investigated. Only kaempferol significantly reduced the diameters of high glucose-induced hyaloid-retinal vessels, by 52.2 % at 10 µM, compared with those in the high glucose-treated control group.

The effects of voluntary exercise and prazosin on capillary rarefaction and metabolism in streptozotocin-induced diabetic male rats.

Type-1 diabetes mellitus (T1D) causes impairments within the skeletal muscle microvasculature. Both regular exercise and prazosin have been shown to improve skeletal muscle capillarization and metabolism in healthy rats through distinct angiogenic mechanisms. The aim of this study was to evaluate the independent and additive effects of voluntary exercise and prazosin treatment on capillary-to-fiber ratio (C:F) in streptozotocin (STZ)-treated diabetic rats. STZ (65 mg/kg) was intraperitoneally administered to male Sprague-Dawley rats (n = 36) to induce diabetes, with healthy, nondiabetic, sedentary rats (n = 10) as controls. The STZ-treated rats were then divided into sedentary (SED) or exercising (EX; 24-h access to running wheels) groups and then further subdivided into prazosin (Praz) or water (H2O) treatment groups: nondiabetic-SED-H2O, STZ-SED-H2O, STZ-EX-H2O, STZ-SED-Praz, and STZ-EX-Praz. After 3 wk, untreated diabetes significantly reduced the C:F in tibialis anterior (TA) and soleus muscles in the STZ-SED-H2O animals (both P < 0.05). Voluntary exercise and prazosin treatment independently resulted in a normalization of C:F within the TA (1.86 ± 0.12 and 2.04 ± 0.03 vs 1.71 ± 0.09, P < 0.05) and the soleus (2.36 ± 0.07 and 2.68 ± 0.14 vs 2.13 ± 0.12, P < 0.05). The combined STZ-EX-Praz group resulted in the highest C:F within the TA (2.26 ± 0.07, P < 0.05). Voluntary exercise volume was negatively correlated with fed blood glucose levels (r2 = -0.7015, P < 0.01) and, when combined with prazosin, caused further enhanced nonfasted glucose (P < 0.01). Exercise and prazosin reduced circulating nonesterified fatty acids more than either stimulus alone (P < 0.05). These results suggest that the distinct stimulation of angiogenesis, with both regular exercise and prazosin treatment, causes a cooperative improvement in the microvascular complications associated with T1D.NEW & NOTEWORTHY It is currently well established that poorly controlled diabetes reduces both skeletal muscle mass and muscle capillarization. These muscle-specific features of diabetes may, in turn, compromise insulin sensitivity and glucose control. Using a model of streptozotocin-induced diabetes, we show the vascular complications linked with disease and how chronic exposure to exercise and prazosin (an α1-adrenergic antagonist) can reduce these complications and improve glycemic control.