Search

Remote ischaemic per-conditioning (RIC) is neuroprotective in experimental ischaemic stroke. Several neurohumoral, vascular and inflammatory mediators are implicated. The effect of RIC on plasma biomarkers was assessed using clinical data from the REmote ischaemic Conditioning After Stroke Trial (RECAST-1).RECAST-1 was a pilot sham-controlled blinded trial in 26 patients with ischaemic stroke, randomized to receive four 5-min cycles of RIC within 24 h of ictus. Plasma taken pre-intervention, immediately post-intervention and on day 4 was analysed for nitric oxide (nitrate/nitrite) using chemiluminescence and all other biomarkers by multiplex analysis. Biomarkers were correlated with clinical outcome (day 90 National Institutes of Health Stroke Scale, modified Rankin Scale, Barthel index).Remote ischaemic per-conditioning reduced serum amyloid protein (SAP) and tissue necrosis factor α (TNF-α) levels from pre- to post-intervention (n = 13, two-way ANOVA, p 0.05). Overall (n = 26), increases in SAP pre- to post-intervention and pre-intervention to day 4 were moderately correlated with worse day 90 clinical outcomes. No consistent significant changes over time, or by treatment, or correlations with outcome were seen for other biomarkers.Remote ischaemic per-conditioning reduced SAP and TNF-α levels from pre- to post-intervention. Increases in plasma levels of SAP were associated with worse clinical outcomes after ischaemic stroke. Larger studies assessing biomarkers and the safety and efficacy of RIC in acute ischaemic stroke are warranted to further understand these relationships.

The purpose of this study was to explore self-reported physical health and achievement motives in a sample of adult cannabis consumers. An online target sample ( n = 181) of adult cannabis consumers ( M = 38 yoa) was obtained from a cannabis tourism company in Colorado. Physical health and the primary benefit of cannabis use were self-reported and achievement motives were measured using the revised 10-item version of the Achievement Motives Scale (AMS). Results revealed five categories of benefit from cannabis consumption: stress/anxiety reduction (40%), pain/disease management (38.5%), thinking/introspection (11%), alternative drug (7.1%), and enhanced sociability (3%). t test results revealed no significant differences between the stress/anxiety and pain/disease groups in self-reported health (SRH), AMS dimensions, or cannabis consumption preferences. Regression results revealed that AMS factor fear of failure ( b = −0.224, p = .003), followed by cannabis spending per week ( b = −0.217, p = .024) best predicted SRH.

Aims To compare the effect of bariatric surgery on renal, chronic kidney disease (CKD) and cardiovascular (CV) outcomes among obese patients with insulin-treated type 2 diabetes (T2D) with and without microalbuminuria (i.e., uACR > 3.0 mg/mmol). Methods A retrospective cohort study was conducted among 11,125 active patients with T2D from The Health Improvement Network (THIN) database. Propensity score matching (up to 1:6 ratio) was used to identify patients who underwent bariatric surgery (N = 131) with a non-bariatric cohort (N = 579). Follow-up was undertaken for 10 years (6487 person-years) to compare differences in risk of cardiovascular events and in renal outcomes. Results For the matched cohort at baseline: mean age 52 ± 13 years (60% female); weight 116 ± 25 kg, body mass index (BMI) 41 ± 9kg/m2, estimated glomerular filtration rate (eGFR); 70.4 ± 20 mL/min/1.73 m2, and median albumin-creatinine ratio (uACR) 2.0 mg/mmol (interquartile range (IQR): 0.9–5.2 mg/mmol). Bariatric surgery was associated with a 54% reduction in developing CKD compared to their matched non-bariatric cohort (adjusted hazard ratio [aHR]: 0.46; 95%CI: 0.24–0.85, P = 0.02). Among patients with microalbuminuria at baseline, bariatric surgery was protective against CKD (aHR: 0.42, 95%CI: 0.18–0.99, P = 0.050). eGFR was significantly increased from baseline favouring the bariatric group during 75% of the follow-up time (calculated mean difference between groups: 4.1 mL/min/1.73 m2; P < 0.05), especially at 5-year point (74.2 vs 67.8 mL/min/1.73 m2; P < 0.001). However, no significant change was observed with non-fatal CVD episodes (aHR: 0.36, 95%CI: 0.11–1.13, P = 0.079). Albumin levels were significantly reduced throughout the 2 years following the surgery (3.9 vs 4.1 g/dL, P < 0.001). uACR and total protein levels had little or no statistical association to the intervention. Conclusion Bariatric surgery may protect patients with diabetes with or without microalbuminuria against the risk of CKD and with a modest protective effect on non-fatal CVD risk. Bariatric surgery is also associated with improvements in overall renal outcomes such as eGFR.

our aim was to study the relationship between HbA1c and cardiovascular morbidity and all-cause mortality among older insulin-treated patients with type 2 diabetes (T2D) after adjustment for multiple confounders.data for 4589 adults with T2D (65 years) on insulin treatment were sourced from 532 UK General Practices via the Health Improvement Network (THIN) database. Cox proportional hazard models and Kaplan-Meier estimators were fitted to derive the hazards of all-cause mortality by HbA1c categories (6.5, 6.5-7.4, 7.5-8.4, 8.5-9.4, 9.5-10.4, 10.5-11.4%; and 11.5% and above) after 5 years of follow-up following insulin initiation.we observed a U-shaped relationship between all-cause mortality and HbA1c, with the lowest risk seen in the HbA1c range of 6.5-7.4% and marked increased in risk with HbA1c11%. The highest mortality risks of 31 and 40% were significantly associated with the lowest (6.5%) and highest (11.5% and above) HbA1c categories: aHR: 1.31; (95%CI: 1.10-1.56; P = 0.002) and aHR: 1.40; (95%CI: 1.01-1.96; P = 0.039), respectively.both low and high HbA1c were associated with increased all-cause mortality, among older patients with insulin-treated T2D. This cohort study supports the need for individualisation of care and suggests better outcomes with HbA1c levels around 6.5-7.4% and markedly excess risk with HbA1c11.

The purpose of this study was to explore the cannabis consumption preferences, leisure interests and leisure motivations of cannabis consumers in the context of legalized recreational marij...

Background Combining a GLP-1 receptor agonist (GLP-1RA) with insulin is often an effective treatment strategy for overweight patients with type 2 diabetes (T2D), but little is known about the longer-term effects on cardiovascular and mortality outcomes in routine clinical practice in the United Kingdom. We therefore compared the times to a major nonfatal cardiovascular (CV) event and all-cause mortality among overweight patients with T2D treated with insulin alone versus insulin + GLP-1RA in a large UK database. Methods A retrospective cohort study was conducted in 18,227 patients with insulin-treated T2D from UK General Practices using The Health Improvement Network database. The 5-year risk of mortality and a 3-point composite of all-cause mortality and nonfatal CV outcomes (myocardial infarction or stroke) was compared between a propensity score–matched cohort of those on insulin alone (n = 1,793) and insulin + GLP-1RA (n = 1,793), irrespective of other diabetes therapies, providing a total of 12,682 person-years of follow-up. Cox proportional hazard models were used to estimate the hazard ratios of the outcomes. Results Hemoglobin A1c reduction was similar between both groups (−0.42 vs −0.33%, P = .089 at 12 months). Overall, 3-point composite events of all-cause mortality and CV events (major adverse cardiovascular even) were 98 versus 55 for the insulin alone versus insulin + GLP-1RA groups, respectively (14.7 vs 9.2 per 1,000 person-years; adjusted hazard ratio [aHR]: 0.64; 95% CI: 0.42-0.98; P = .038). Corresponding composite nonfatal CV events were 33 versus 28 (6.0 vs 5.6 per 1,000 person-years; aHR: 0.76; 95% CI: 0.41-1.42; P = .393), whereas all-cause mortality events were 49 versus 13 (6.9 vs 2.0 per 1,000 person-years; aHR: 0.35; 95% CI: 0.17-0.73; P = .005). Conclusion Based on a large UK cohort in routine clinical practice, adding a GLP-1RA to insulin therapy is associated with a reduction in risk of composite CV events and all-cause mortality but a nonsignificant higher risk of hospitalization for heart failure in overweight patients with T2D.

Under India’s DRIP program over 5,000 large dams are to be rehabilitated in accordance with modern dam safety standards. In order to prioritize the rehabilitation works for such a large number of dams, India’s Central Water Commission, needed a risk screening tool to allow for a portfolio risk screening. The tool was developed by simplifying sound principles of risk analysis followed by a comprehensive validation process. The application of the tool is relatively easy and the process of generating risk index for a single dam may take as little as few hours to 1-2 days, depending on the availability of data and personnel familiar with the dam making the tool ideal for helping to prioritize dam safety remedial projects for India’s dam safety program and for other large portfolio’s around the world.

Summary Objectives Insulin therapy induces weight gain but whether it causes long term adverse metabolic and CV outcomes in obese patients remains unclear. Methods A retrospective cohort study of 12,725 insulin initiators with T2D derived from UK General Practices. Multivariate linear, logistic regression analyses and Cox proportional hazard models were used to estimate HbA1c, BMI, risk of composite CV events between baseline BMI categories at 5 years. Results Mean age was 58.6 ± 13.8 years. The proportion of patients achieving HbA1c targets decreased across increasing BMI categories at 6 and at 12 months; p = 0.0001, but not significant beyond 24 months. 1095 composite events of all-cause mortality, non-fatal stroke and MI occurred with an adjusted hazard risk (aHR) relative to normal of: (1.10; 95%CI: 0.90–1.35) in the overweight, (1.05; 95%CI: 0.86–1.29) in the obese class I, (1.03; 95%CI: 0.83–1.29) in the obese class II and (1.30; 95%CI: 1.02–1.66) in the obese class III BMI categories. Conclusion Among patients with T2D insulin initiators, obesity adversely influences HbA1c up to 12 months, but not beyond 24 months and is associated with a decrease in BMI compared to non-obese groups. Morbidly obese patients initiating insulin have 30% increased risk of composite CV events after 5 years.

The use of risk informed decision making in the dam safety industry has been growing since the introduction of a formal (albeit simplified) risk assessment process by the US Federal Energy Regulatory Commission (FERC) in 2000. This Probable Failure Modes Analysis (PFMA) technique is widely used throughout the United States and elsewhere but recently has come under some criticism. However, despite the shortcomings with this, and other, simplified risk assessment methodologies, when used in conjunction with standards-based analyses and sound engineering judgement the qualitative approach to risk informed dam safety management and prioritization offers great value. These approaches can be further enhanced through the use of a semi-quantitative approach that makes use of a new risk screening tool to assess the probability of failure of potential failure modes in a transparent and scientific manner.

Background: Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy.Methods: RESTART was a prospective, randomised, open-label, blinded-endpoint, parallel-group trial at 122 hospitals in the UK that assessed whether starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. For this prespecified subgroup analysis, consultant neuroradiologists masked to treatment allocation reviewed brain CT or MRI scans performed before randomisation to confirm participant eligibility and rate features of the intracerebral haemorrhage and surrounding brain. We followed participants for primary (recurrent symptomatic intracerebral haemorrhage) and secondary (ischaemic stroke) outcomes for up to 5 years (reported elsewhere). For this report, we analysed eligible participants with intracerebral haemorrhage according to their treatment allocation in primary subgroup analyses of cerebral microbleeds on MRI and in exploratory subgroup analyses of other features on CT or MRI. The trial is registered with the ISRCTN registry, number ISRCTN71907627.Findings: Between May 22, 2013, and May 31, 2018, 537 participants were enrolled, of whom 525 (98%) had intracerebral haemorrhage: 507 (97%) were diagnosed on CT (252 assigned to start antiplatelet therapy and 255 assigned to avoid antiplatelet therapy, of whom one withdrew and was not analysed) and 254 (48%) underwent the required brain MRI protocol (122 in the start antiplatelet therapy group and 132 in the avoid antiplatelet therapy group). There were no clinically or statistically significant hazards of antiplatelet therapy on recurrent intracerebral haemorrhage in primary subgroup analyses of cerebral microbleed presence (2 or more) versus absence (0 or 1) (adjusted hazard ratio [HR] 0·30 [95% CI 0·08–1·13] vs 0·77 [0·13–4·61]; pinteraction=0·41), cerebral microbleed number 0–1 versus 2–4 versus 5 or more (HR 0·77 [0·13–4·62] vs 0·32 [0·03–3·66] vs 0·33 [0·07–1·60]; pinteraction=0·75), or cerebral microbleed strictly lobar versus other location (HR 0·52 [0·004–6·79] vs 0·37 [0·09–1·28]; pinteraction=0·85). There was no evidence of heterogeneity in the effects of antiplatelet therapy in any exploratory subgroup analyses (all pinteraction>0·05).Interpretation: Our findings exclude all but a very modest harmful effect of antiplatelet therapy on recurrent intracerebral haemorrhage in the presence of cerebral microbleeds. Further randomised trials are needed to replicate these findings and investigate them with greater precision.Funding: British Heart Foundation.

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. Aims: To compare non-fatal cardiovascular (CV) events and metabolic outcomes, among obese patients with insulin-treated type 2 diabetes who underwent bariatric surgery compared with a propensity-matched non-bariatric cohort. Methods: A retrospective cohort study was conducted among 11,125 active patients with type 2 diabetes from The Health Improvement Network (THIN) database. Propensity score matching (up to 1:6 ratio) was used to identify patients who underwent bariatric surgery (N = 131) with a non-bariatric cohort (N = 579). Follow-up was undertaken for 10years (9686 person-years) to compare differences in metabolic outcomes and CV risk events that included the following: acute myocardial infarction (AMI), stroke, coronary heart disease (CHD), heart failure (HF) and peripheral artery disease (PAD). Cox proportional regression was used to compute the outcomes between groups. Results: The mean age was 52 (SD 13) years (60% female); the baseline weight and BMI were 116 (SD 25) kg and 41 (SD 9) kg/m2, respectively. Significant reductions in weight and BMI were observed in bariatric group during 10years of follow-up. Bariatric surgery had a significant cardioprotective effect by reducing the risk of non-fatal CHD (adjusted hazard ratio [aHR] 0.29, 95% CI 0.16–0.52, p < 0.001) and PAD events (aHR 0.31, 95% CI 0.11–0.89, p = 0.03). However, the surgery had no significant effect on AMI (aHR 0.98, p = 0.95), stroke (HR 0.87, p = 0.76) and HF (HR 0.89, p = 0.73) risks. Bariatric surgery had favourable effects on insulin independence, HbA1c and BP. Conclusion: Among obese insulin-treated patients with type 2 diabetes, bariatric surgery is associated with significant reductions in non-fatal CHD and PAD events, lower body weight, HbA1c, BP and a greater likelihood of insulin independency during 10years of follow-up.

Pioglitazone, the only thiazolidinedione drug in clinical practice is under scrutiny due to reported adverse effects, it’s unique insulin sensitising action provides rationale to remain as a therapeutic option for managing type 2 diabetes mellitus (T2DM). We conducted a systematic review and meta-analysis comparing pioglitazone monotherapy with monotherapies of other oral antidiabetic drugs for assessing its efficacy and safety in T2DM patients. Mean changes in glycated haemoglobin (HbA1c), and mean changes in fasting blood sugar (FBS) level, body weight (BW) and homeostasis model assessment-insulin resistance (HOMA-IR) were primary and secondary outcomes, respectively. Safety outcomes were changes in lipid parameters, blood pressure and incidences of adverse events. Metafor package of R software and RevMan software based on random-effects model were used for analyses. We included 16 randomised controlled trials. Pioglitazone monotherapy showed equivalent efficacy as comparators in reducing HbA1c by 0.05% (95% CI: −0.21 to 0.11) and greater efficacy in reducing FBS level by 0.24 mmol/l (95% CI: −0.48 to −0.01). Pioglitazone showed similar efficacy as comparators in reducing HOMA-IR (WMD: 0.05, 95% CI: −0.49 to 0.59) and increasing high-density lipoprotein level (WMD: 0.02 mmol/l, 95% CI: −0.06 to 0.10). Improved blood pressure (WMD: −1.05 mmHg, 95% CI: −4.29 to 2.19) and triglycerides level (WMD: −0.71 mmol/l, 95% CI: −1.70 to 0.28) were also observed with pioglitazone monotherapy. There was a significant association of pioglitazone with increased BW (WMD: 2.06 kg, 95% CI: 1.11 to 3.01) and risk of oedema (RR: 2.21, 95% CI: 1.48 to 3.31), though the risk of hypoglycaemia was absolutely lower (RR: 0.51, 95% CI: 0.33 to 0.80). Meta-analysis supported pioglitazone as an effective treatment option for T2DM patients to ameliorate hyperglycaemia, adverse lipid metabolism and blood pressure. Pioglitazone is suggested to prescribe following individual patient’s needs. It can be a choice of drug for insulin resistant T2DM patients having dyslipidaemia, hypertension or history of cardiovascular disease.

Human sex hormone-binding globulin (SHBG) is a glycoprotein produced by the liver that binds sex steroids with high affinity and specificity. Clinical observations and reports in the literature have suggested a negative correlation between circulating SHBG levels and markers of non-alcoholic fatty liver disease (NAFLD) and insulin resistance. Decreased SHBG levels increase the bioavailability of androgens, which in turn leads to progression of ovarian pathology, anovulation and the phenotypic characteristics of polycystic ovarian syndrome (PCOS). This review will use a case report to illustrate the inter-relationships between SHBG, NAFLD and PCOS. In particular, we will review the evidence that low hepatic SHBG production may be a key step in the pathogenesis of PCOS. Furthermore, there is emerging evidence that serum SHBG levels may be useful as a diagnostic biomarker and therapeutic target for managing women with PCOS.

Background: Overt albuminuria (urinary albumin-creatinine ratio [ACR] > 300 mg/g) is an established risk factor for progression of nephropathy and total mortality. However, whether a reduction in ACR translates into a reduction in mortality and/or cardiovascular (CV) events among insulin-treated patients with type 2 diabetes (T2D) in routine practice is currently not known. Methods: We obtained data on a large cohort of insulin users with T2D and nephropathy (baseline ACR ≥300 mg/g) from UK general practices between 2007 and 2014. Their corresponding ACR values after 1year of follow-up were thereafter categorized into: (1) 300 mg/g (i.e., nonregression of albuminuria), and the cohort was followed-up for 5 years for all-cause mortality and CV events. Cox proportional hazard models were fitted to estimate the risk of all-cause death. Results: A total of 11,074 patients with insulin-treated T2D met the inclusion criteria. Their mean age was 62.3 (13.6) years; mean HbA1c: 8.7 (1.8) and 53% were male. A total of 682 deaths occurred after a follow-up period of 43,393 person-years with a mortality rate of 16 per 1,000 person-years. Five-year survival was markedly reduced in the group whose proteinuria persisted or progressed (91 vs. 95%; log-rank p value < 0.001). Compared to patients whose ACR levels remained above 300 mg/g, all-cause mortality and CV events were 31 and 27% lower in those whose albuminuria regressed to < 300 mg/g (adjusted hazard ratio [aHR] 0.69; 95% CI 0.52–0.91; p = 0.008 and aHR 0. 73; 95% CI 0.54–0.98; p = 0.041), respectively. Conclusion: In patients with insulin-treated T2D and nephropathy in routine practice, a regression in albuminuria (e.g., via better BP or glycemic control) is associated with a significant reduction in all-cause mortality. Thus, albuminuria is not only simply a risk marker of renal and CV disease but also an independent target for therapy. Albuminuria reduction should be viewed as a goal for renal and CV protection.

Summary Background NHS England has recommended a multidisciplinary weight management services (MWMS—Tier 3 services) for patients requiring specialized management of obesity, including bariatric surgery, but clinical and measurable health‐related outcomes from these services remains fragmented. We therefore undertook a systematic review to explore the evidence base of effect on body weight loss and comorbidities outcomes of Tier 3 or UK pre‐bariatric MWMPs. Methods AMED, CINAHL, EMBASE, HMIC, MEDLINE, PsycINFO, PubMed, HDAS search and Google Scholar were searched from January 2000 to September 2017 in a free‐text fashion and crossed‐references of included studies to identify potential illegibility. Inclusion criteria were as follows: (a) published Tier 3 original study abstracts/articles; (b) intervention studies with before and after data; (c) studies that included any sort of MWMPs conducted on British residents with obesity; and (d) studies included T2DM measurements in a MWMPs. Results In total, 19 studies met the inclusion criteria. The total number of participants analysed was N = 11,735. Baseline accumulative average BMI was calculated at 42.54 kg/m2, weight 117.88 kg and waist circumference 126.9 cm. And at 6 months, 40.73 kg/m2, 112.17 kg and 120.3 cm, respectively. Secondary outcome variables were as improved with reduction in HbA1c, fasting blood sugars, insulin usage and blood pressure. Physical activity increased at 3 months then declined after 6 months with no significant changes in cholesterol levels. Conclusion Tier 3 and MWMPs have a short to mid‐ranged positive effect on obese patients (BMI ≥30 kg/m2) living in the UK regarding accumulated reduction in weight, glycaemic control, blood pressure and with subtle improvements in physical activity.

Background Albuminuria is a recognized diagnostic and prognostic marker of chronic kidney disease and cardiovascular (CV) risk but the well-known relationship between increments in urinary albumin:creatinine ratio (UACR) and CV outcomes and mortality has not been fully explored in insulin-treated patients with type 2 diabetes (T2D) in routine clinical care. Methods We investigated data for insulin users with T2D from UK general practices between 2007 and 2014. The UACR at the time of insulin initiation was measured and categorized as 300 mg/g. Patients were followed up for 5 years or the earliest occurrence of all-cause mortality, non-fatal myocardial infarction or stroke. Cox proportional hazards models were fitted to estimate the risk of a composite of these events. Results A total of 12 725 patients with T2D (mean age 58.6 ± 13.8 years, mean haemoglobin A1c 8.7 ± 1.8%) initiating insulin therapy between 2007 and 2014 met the inclusion criteria. Compared with patients whose ACR levels at insulin initiation were 300 mg/g, respectively, after a follow-up period of 5 years. The ACR category on its own did not predict risk of all-cause mortality. Conclusions This study shows that in patients with T2D on insulin therapy, increased urinary ACR is independently associated with an increased risk of major adverse CV events and all-cause mortality.

Abnormalities of glucose metabolism and glucose tolerance, either because of a reduction in tissue sensitivity to insulin (e.g., in liver, skeletal muscle, and adipose tissues) and/or a reduction in pancreatic insulin secretion, are associated with a number of unwanted health outcomes. Even small increases in circulating glucose levels (often described as dysglycemia or prediabetes) may confer an increased risk of cardiovascular (CV) disease and progression to overt type 2 diabetes. A number of drug therapies, many of them used long term in chronic disease management, have adverse effects on glucose metabolism, diabetes risk, and glycemic control among patients with preexisting diabetes. In this study, we review the evidence, underlying mechanisms, and the clinical significance of drug-related adverse effects on glucose metabolism.

Introduction The aim of this study was to assess the efficacy of co-administering sitagliptin to patients with inadequate glycemic control following treatment with metformin (MET), sulfonylurea (SU), or MET + SU. Methods A cohort of 25,386 patients with type 2 diabetes mellitus (hemoglobin A1c [HbA1C] >53 mmol/mol or 7%), newly treated with sitagliptin between 2007 and 2013, was sourced from UK general practices via The Health Improvement Network database. Among these, eligible patients were segregated into three groups: MET (n = 3364), SU (n = 509), or MET + SU therapy (n = 5929). The relative efficacy of sitagliptin added to SU or MET + SU compared with sitagliptin added to MET monotherapy was assessed with regards to HbA1c and body weight changes from baseline up to 52 weeks. The glycemic efficacy was a measure of average treatment effects obtained from multivariable linear regression models and propensity score-matching analysis. Results A total of 9802 patients were included in the study. Overall, addition of sitagliptin 100 mg once daily resulted in 5.5 mmol/mol (0.5%) HbA1c reduction (P 9% receiving MET + SU therapy, adding sitagliptin, as a third agent, conferred minimal benefit. Electronic supplementary material The online version of this article (doi:10.1007/s13300-015-0110-6) contains supplementary material, which is available to authorized users.

Summary Background Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. Methods We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. Findings 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p Interpretation Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice. Funding National Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation.

AIM: To evaluate the concordance between data derived from randomized controlled trial (RCT) and real-world estimates of HbA1c and weight change after 24 weeks of initiation of a basal-bolus compared with a premixed insulin regimen in people with Type 2 diabetes. METHODS: Data eight RCTs were pooled after a systematic review of studies examining basal-bolus (n = 1893) or premixed (n = 1517) regimens. Real-world data were extracted from the UK primary care dataset for people on basal-bolus (n = 7483) or premixed insulin regimens (n=10 744). The mean differences between HbA1c and weight from baseline were calculated using t-tests, while analysis of variance was used to compare the two treatment regimens. Linear regression analyses were used to determine the predictors of this change. RESULTS: Both insulin regimens were associated with HbA1c reductions (real-world data -0.28%; RCT data, -1.4%) and weight gain (real-world data, +0.27 kg; RCT data, +2.96 kg) but there were no significant differences between basal-bolus and premixed insulin. Discordances in the pattern of treatment response were observed, however, between real-world and RCT data for both insulin regimens. For any given baseline HbA1c concentration, the change in HbA1c in the RCTs was greater than in real-world conditions and for those with baseline weight above ~60 kg, RCT data showed overall weight gain in contrast to slight weight loss in the real-world population. Lastly, for both randomized controlled trial and real-world populations, while greater baseline weight was associated with reduced response to treatment, the association was much steeper in the RCT than in the real-world population. In addition, greater baseline weight was associated with greater weight reductions in both premixed insulin and basal-bolus insulin regimens, although to a lesser extent with the latter. CONCLUSION: These results highlight specific discrepancies in the HbA1c reduction and weight change in insulin regimen between real world versus RCT populations; with greater reduction in HbA1c and greater increase in weight observed in the RCT population than in the real-world population. Also, the basal-bolus regimens in both real-world and RCT populations showed greater reduction in HbA1c compared to the premix regimen (though more marked in RCTs), while the premix regimen showed greater increase in weight in real-world, as against basal-bolus in the RCT population.

Aim Statins may increase the risk of new-onset diabetes and adversely affect glycaemic control, but their effects on the glycemic response and mortality outcomes following commencement of insulin therapy in patients with Type 2 Diabetes (T2D) are unclear. Methods A retrospective cohort study was conducted in 12,725 insulin initiators with T2D using The Health Improvement Network (THIN) UK database. Changes in HbA1c at 6, 12, 24 and 36 months, and the 5-year risk of mortality and (3-point) major adverse cardiovascular events (MACE), were compared between prior users (n = 10,682) and non-users (n = 2043) of statin therapy who were newly commenced on insulin treatment. Cox proportional hazard models were used to estimate the hazard ratios of the different outcomes. Results Mean age of the cohort was 58.7 ± 14.0 years (51% male) and mean baseline HbA1c was 8.7 ± 1.8%. A greater initial reduction in HbA1c was observed following insulin initiation in the non-users of statins compared with the users, which was significant in the short term (−0.34% vs −0.26% at 6 months; mean diff = −0.09%, p = 0.004) but not in the long term: −0.31% versus −0.35% at 3 years (mean diff = 0.05%, p = 0.344). CV events (3-point MACE) were 878 versus 217 in statin users versus non-users (20.7 vs 30.9 per 1000 person-years; adjusted Hazard Ratio (aHR) 1.36 (95% CI 1.15–1.62; p

IMPORTANCE: There is limited information about the durability of glycaemic control when different oral glucose-lowering therapies (GLTs) are used as add-on treatments to metformin (MET) in patients with type 2 diabetes mellitus (T2DM). OBJECTIVE: To compare time to treatment failure between different classes of oral GLT when used as second line (add-on) treatments to MET monotherapy at HbA1c ≥ 7.5%. DESIGN, SETTING AND PARTICIPANTS: A retrospective cohort study on 20,070 patients who were newly treated with a sulphonylurea (SU), dipeptidyl-peptidase-4 (DPP-4) inhibitor or thiazolidinedione (TZD) following MET therapy failure (2007-2014). Patients' data was sourced from UK General Practices via The Health Improvement Network (THIN) database. The risk of dual therapy failure was compared between three treatment groups: MET + SU (reference group, n = 15,508), MET + DPP-4 inhibitor (n = 3,080) and MET + TZD (n = 1,482). Follow-up was until treatment substitution or intensification with a 3rd GLT, or for up to 5 years (totalling 46,430 person-years). Propensity score weighting and Cox proportional hazard regression analyses were employed. MAIN OUTCOMES AND MEASURES: Risk of dual therapy failure was compared between treatment groups while adjusting for baseline covariates. RESULTS: Unadjusted survival analysis showed the incidence of dual therapy failure at 1 year was 15% with SU, 23% with DPP-4 inhibitor and 8% with TZD. Corresponding failure rates at 2 years were 26, 38 and 12%, respectively. Adjusted multivariate models showed that, compared to the SU group, adding a DPP-4 inhibitor was associated with an increased risk of treatment failure (adjusted hazard ratio, aHR, 1.58; 95% CI: 1.48-1.68), while adding a TZD was associated with a reduced hazard (aHR, 0.45; 95% CI: 0.41-0.50). Baseline parameters associated with an increased hazard of intensification included HbA1c, diabetes duration, gender, smoking status and the use of statins. CONCLUSIONS AND RELEVANCE: In routine clinical practice, adding a DPP-4 inhibitor to MET is associated with an increased, earlier requirement for treatment intensification compared to adding an SU or TZD. Adding a TZD to MET resulted in the most durable glycaemic response. Key messages The Agency for Healthcare Research and Quality has suggested that the durability of glycaemic response after treatment intensification is best investigated using well-designed long-term observational studies. In routine clinical practice, among patients with T2DM receiving a second line glucose lowering treatment as add-on to MET, the addition of a Thiazolidinediones is associated with the most durable glycaemic response, followed by a Sulfonylurea and then a DPP-4 inhibitor. Factors associated with earlier dual therapy failure included concomitant use of statin therapy, being female, a smoker, those with longer diabetes duration and higher baseline HbA1c levels. The addition of a Thiazolidinediones was associated with significant weight gain (1.8 kg, p

Aim: To conduct a systematic review and meta-analysis to determine the risk of cardiovascular events and all-cause mortality associated with sulphonylureas (SUs) vs other glucose lowering drugs in patients with T2DM (T2DM. Materials and methods: A systematic review of Medline, Embase, Cochrane and clinicaltrials.gov was conducted for studies comparing SUs with placebo or other antihyperglycaemic drugs in patients with T2DM. A cloglog model was used in the Bayesian framework to obtain comparative hazard ratios (HRs) for the different interventions. For the analysis of observational data, conventional fixed-effect pairwise meta-analyses were used. Results: The systematic review identified 82 randomized controlled trials (RCTs) and 26 observational studies. Meta-analyses of RCT data showed an increased risk of all-cause mortality and cardiovascular-related mortality for SUs compared with all other treatments combined (HR 1.26, 95% confidence interval [CI] 1.10-1.44 and HR 1.46, 95% CI 1.21-1.77, respectively). The risk of myocardial infarction was significantly higher for SUs compared with dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose co-transporter-2 inhibitors (HR 2.54, 95% CI 1.14-6.57 and HR 41.80, 95% CI 1.64-360.4, respectively). The risk of stroke was significantly higher for SUs than for DPP-4 inhibitors, glucagon-like peptide-1 agonists, thiazolidinediones and insulin. Conclusions: The present meta-analysis showed an association between SU therapy and a higher risk of major cardiovascular disease-related events compared with other glucose lowering drugs. Results of ongoing RCTs, which should be available in 2018, will provide definitive results on the risk of cardiovascular events and all-cause mortality associated with SUs vs other antihyperglycaemic drugs.

Background This study explores the association of insulin-induced weight (wt) gain on cardiovascular outcomes and mortality among patients with type 2 diabetes (T2D) following insulin initiation using real-world data. Methods A historical cohort study was performed in 18,814 adults with insulin-treated T2D derived from the UK The Health Improvement Network database. Based on the average weight change of 5 kg, 1 year postinsulin initiation, patients were grouped into 5 categories (>5 kg wt loss; 1.0-5.0 kg wt loss; no wt change; 1.0-5.0 kg wt gain; >5.0 kg wt gain) and followed-up for 5 years. Cox proportional hazard models and Kaplan-Meier estimators were fitted to estimate the hazards of a 3-point composite of nonfatal myocardial infarction, stroke, and all-cause mortality between categories. Results The median age was 62.8 (IQR: 52.3-71.8) years, HbA1c : 8.6% (IQR: 7.4-9.8) and mean BMI: 31.8 (6.5) kg/m2 . The 5 year probability of survival differed significantly within the wt-change categories (log-rank test P value = .0005). Only 1963 composite events occurred. Compared with the weight-neutral group, the risk of composite events was 31% greater in the >5 kg wt-loss group (aHR: 1.31; 95% CI: 1.02, 1.68), the same in the 1.0 to 5.0 kg wt-gain category, but nonsignificantly increased in the 1.0 to 5.0 kg wt loss (15%) and >5.0 kg wt gain (13%) categories, respectively. In the obese subgroup, this risk was 50% (aHR: 1.50, 95% CI: 1.08-2.08) more in the >5 kg weight-loss group compared with the weight-neutral group. Conclusion Insulin-induced weight gain did not translate to adverse cardiovascular outcomes and mortality in patients with T2D. These data provide reassurance on the cardiovascular safety of insulin patients with T2D.

Background and Purpose— Repeated episodes of limb ischemia and reperfusion (remote ischemic conditioning [RIC]) may improve outcome after acute stroke. Methods— We performed a pilot blinded placebo-controlled trial in patients with acute ischemic stroke, randomized 1:1 to receive 4 cycles of RIC within 24 hours of ictus. The primary outcome was tolerability and feasibility. Secondary outcomes included safety, clinical efficacy (day 90), putative biomarkers (pre- and post-intervention, day 4), and exploratory hemodynamic measures. Results— Twenty-six patients (13 RIC and 13 sham) were recruited 15.8 hours (SD 6.2) post-onset, age 76.2 years (SD 10.5), blood pressure 159/83 mm Hg (SD 25/11), and National Institutes of Health Stroke Scale (NIHSS) score 5 (interquartile range, 3.75–9.25). RIC was well tolerated with 49 out of 52 cycles completed in full. Three patients experienced vascular events in the sham group: 2 ischemic strokes and 2 myocardial infarcts versus none in the RIC group ( P =0.076, log-rank test). Compared with sham, there was a significant decrease in day 90 NIHSS score in the RIC group, median NIHSS score 1 (interquartile range, 0.5–5) versus 3 (interquartile range, 2–9.5; P =0.04); RIC augmented plasma HSP27 (heat shock protein 27; P P Conclusions— RIC after acute stroke is well tolerated and appears safe and feasible. RIC may improve neurological outcome, and protective mechanisms may be mediated through HSP27. A larger trial is warranted. Clinical Trial Registration— URL: http://www.isrctn.com . Unique identifier: ISRCTN86672015.

Laser Doppler Fluximetry (LDF) and iontophoresis of vasodilators have been combined to assess microvascular flow and vasodilator reactivity in humans for many years and their use established. However, traditional data analysis methods measure the magnitude of flux change but not its time-course, a factor that may be of importance in defining vascular health. The aim of this study was to develop and utilise a novel data analysis method using a standardised LDF and iontophoresis protocol, assessing time to peak vasodilation (Tmax). Methods: Endothelial-dependent and -independent vasodilator responses (using acetylcholine and sodium nitroprusside respectively) were measured in the perimalleolar region both supine and standing in patients with isolated superficial venous insufficiency (ISVI) (n=24) and controls (n=20), on two occasions. Tmax was measured at each post-iontophoretic period. Results: Tmax was slower while standing and in patients with ISVI. There was no statistical difference in Tmax between visits for both groups (p

Objective: Angiogenesis occurs within atherosclerotic plaques, and thrombin has been implicated in plaque progression by increasing smooth muscle cell proliferation and upregulating Vascular Endothelial Growth Factor (VEGF) receptor expression. This study investigated the effects of thrombin on key aspects of angiogenesis and expression of pro- and anti-angiogenic regulators: VEGF and Pigment Epithelial Derived Factor. Research Design and Methods: Human umbilical smooth muscle cells (HUASMC) were exposed to vehicle or thrombin at 10 U/ml. To quantify cell proliferation, methyl tetrazolium salt (MTS) solution was added after exposure to thrombin for 24, 48 and 72 hours and the absorbance at 490nm recorded using a plate reader. For Real-time RT-PCR cells were exposed to thrombin for 24hr before analysis of VEGF and PEDF mRNA. A commercial Angiokit was used to construct an in vitro angiogenesis model to measure tubule formation and branching. After 12 days treatment with thrombin 10 U/ml, cells were fixed and the AngioSys 1.0 software was used to analyse tubule morphology. Results: In comparison with controls, thrombin significantly increased HUASMC proliferation (p = 0.002, n = 11) and VEGF mRNA expression by 93% (n = 4, p = 0.024). However in the HUVEC/fibroblast co-cultures it decreased the number of junctions [132(9) vs 196(18), n = 6, p = 0.017] and tubules [537 (17) vs 589 (26), n = 6, p = 0.049], and tubule length [11393 (1601) vs 12195 (1014), n = 6, p = 0.044], indicating an anti-angiogenic effect. Conclusions: Thrombin stimulates vascular smooth muscle cell proliferation and VEGF expression, but attenuates endothelial cell-mediated growth of vascular tubules and branching of new vascular structures.

The sodium-glucose co-transporter-2 (SGLT2) is a low-affinity transport system that is specifically expressed in the kidney and plays an important role in renal glucose reabsorption in the proximal tubule. Competitive inhibition of SGLT2 therefore represents an innovative therapeutic strategy for the treatment of hyperglycaemia and/or obesity in patients with type 1 or type 2 diabetes by enhancing glucose and energy loss through the urine. The observation that individuals with familial renal glycosuria maintain normal long-term kidney function provides some reassurance that this mode of action will not adversely affect renal function. Intense research in this therapeutic area has led to the discovery of novel SGLT2 inhibitors, each with different chemical, pharmacodynamic and pharmacokinetic profiles. This review outlines the biology, expression and pleotropic activity of the SGLT system and the pharmacological profile of SGLT2 inhibitors and provides a summary of preclinical and limited clinical data available to characterize the efficacy, safety and potential clinical utility of SGLT2 inhibitors in the management of diabetes.

Aim: The Helping Evaluate Exenatide in overweight patients with diabetes compared with Long-Acting insulin (HEELA) study was designed to examine whether the glucagon-like peptide-1 (GLP-1) receptor agonist, exenatide, could improve HbA1c (≤7.4%) with minimal weight gain (≤1 kg) compared with insulin glargine. Methods: Patients [body mass index (BMI) >27 kg/m2] with elevated cardiovascular risk and type 2 diabetes inadequately controlled on two or three oral antidiabetes drugs (OADs) were randomized to add-on exenatide 5–10 μg b.i.d. (n = 118) or insulin glargine o.d. (titrated to target fasting plasma glucose ≤5.6 mmol/l; n = 117) for 26 weeks. Results: The study population had baseline mean (s.d.) age of 56.5 (9.1) years and BMI of 34.1 (5.3) kg/m2, and 58.5% of patients were taking two OADs. Mean baseline HbA1c was 8.65 (0.68)% in the exenatide group and 8.48 (0.66)% in the insulin glargine group. The proportions of patients achieving the composite endpoint of HbA1c ≤7.4% with weight gain ≤1 kg were 53.4% for the exenatide group and 19.8% for the insulin glargine group (p < 0.001 for exenatide vs. insulin glargine). Exenatide and insulin glargine did not demonstrate a significant difference in HbA1c improvements [least square (LS) mean [s.e.m.]: −1.25 [0.09]% and −1.26 [0.09]% respectively; p = 0.924], but had divergent effects on body weight (−2.73 [0.31] vs. +2.98 [0.31] kg respectively, p < 0.001) after 26 weeks. There were more treatment-related adverse events with exenatide but a lower incidence of nocturnal hypoglycaemia, with no differences in overall or severe hypoglycaemia. Conclusions: Additional treatment with exenatide resulted in significantly more overweight and obese patients with an elevated cardiovascular risk and type 2 diabetes achieving better glycaemic control with minimal weight gain compared with insulin glargine.

BACKGROUND: Apart from baseline glycated hemoglobin (HbA1c), little is known about clinical parameters that affect glycemic response to a dipeptidyl peptidase-4 (DPP4) inhibitor when used in routine clinical practice. We aimed to use a large primary care database to assess the variability in response to a DPP4 inhibitor when used as add-on therapy. MATERIALS AND METHODS: Data on 25,386 patients with type 2 diabetes, newly treated with a DPP4 inhibitor (2007-2013), were sourced from a United Kingdom general practice database via the Health Improvement Network database. Baseline clinical parameters of patients (n = 13,525) for whom a DPP4 inhibitor was added because of suboptimal glucose control (HbA1c >7%) were compared with 12-month follow-up data. An optimum response to the DPP4 inhibitor was defined as an HbA1c level of

The prevalence of type 2 diabetes and its associated mortality and morbidity are continuing to increase across the world. People with type 2 diabetes typically have a cluster of risk factors for cardiovascular disease, including hyperglycaemia, hypertension and lipid abnormalities, which contribute to the high cardiovascular morbidity and mortality in these patients. Targets for glycosylated haemoglobin, lipids and blood pressure are becoming more stringent, and most patients will require multiple therapies to maximally reduce cardiovascular risk. In a large randomised, controlled, long-term cardiovascular outcomes study pioglitazone showed durable glycaemic control, a powerful insulin-sparing effect and changes in the lipid profile associated with reduced cardiovascular risk. This article reviews these metabolic findings in the context of previous randomised, controlled studies for pioglitazone and discusses whether the integration of this agent into the treatment regimen of appropriate patient groups has the potential to improve cardiovascular outcomes in type 2 diabetes.

Exploiting the incretin effect to develop new glucose-lowering treatments has become the focus of intense research. One successful approach has been the development of oral inhibitors of dipeptidyl peptidase-IV (DPP-IV). These drugs reversibly block DPP-IV-mediated inactivation of incretin hormones, for example, glucagon-like peptide 1 (GLP-1) and also other peptides that have alanine or proline as the penultimate N-terminal amino acid. DPP-IV inhibitors, therefore, increase circulating levels and prolong the biological activity of endogenous GLP-1, but whether this is sufficient to fully explain the substantial reduction in haemoglobin A(1c) (HbA(1c)) and associated metabolic profile remains open to further investigation. DPP-IV inhibitors such as vildagliptin and sitagliptin have been shown to be highly effective antihyperglycaemic agents that augment insulin secretion and reduce glucagon secretion via glucose-dependent mechanisms. This review summarizes the major clinical trials with DPP-IV inhibitors as monotherapy and as add-on therapy in patients with type 2 diabetes. The magnitude of HbA(1c) reduction with DPP-IV inhibitors depends upon the pretreatment HbA(1c) values, but there seems to be no change in body weight, and very low rates of hypoglycaemia and gastrointestinal disturbance with these agents. DPP-IV inhibitors represent a major new class of oral antidiabetic drug and their metabolic profile offers a number of unique clinical advantages for the management of type 2 diabetes.

A number of large randomised controlled trials have shown that angiotensin-converting enzyme (ACE) inhibitors, compared with placebo or other blood pressure-lowering drugs, improve coronary heart disease outcomes (fatal and non-fatal myocardial infarction, and coronary revascularisation) in diverse patient groups, e.g. in primary and secondary prevention, those with and without left ventricular dysfunction, and among hypertensive and non-hypertensive subjects. An updated meta-regression analysis which included five major trials in patients with established coronary artery disease (CAD) (EUROPA, INVEST, ACTION, PEACE and CAMELOT) concluded that ACE inhibitor (ACE-I) therapy has clear benefits in secondary prevention, but there are important and unexplained differences between trials in clinical outcome, baseline cardiovascular risk, blood pressure changes and trial design which deserve further discussion of the underlying mechanisms and clinical interpretation. For example, in placebo-controlled trials the biggest (20—22%) reductions in primary end points (including mortality) have been observed with perindopril and ramipril, whereas trials using trandolapril and quinapril had no effect on survival or recurrent CAD events. This review summarises and compares the major findings of these recent trials, and provides further analysis of the underlying mechanisms and clinical significance of secondary CAD prevention with ACE-I therapy.

Sustainable development is a fundamentally different challenge for the engineering profession, and engineers must evolve to meet this challenge. Unfortunately, the profession is caught in a number of difficult Catch-22 situations, which constrain the ability of engineers to tackle sustainability issues in their work. These situations can be described as: the problem of existing paradigms of development; the problem of scope; the problem of framing versus solving; the problem of context; and the problem of conventional education. This paper provides a comprehensive overview of these problems and suggests what could be done to overcome them. Engineers must understand the concept of sustainability and its implications, as well as the urgency to start making the necessary changes now. Engineers must also adopt new ways of thinking and become leaders of change. To do this, they must be given the tools they need to see and address the barriers to their efforts.

Protein kinase C (PKC) is a family of multifunctional isozymes that plays an important role in the regulation of intracellular insulin signal transduction in various insulin-sensitive tissues. This article highlights current understanding on the mechanism of PKC-induced insulin resistance in skeletal muscle, a major target site for insulin-mediated glucose disposal. Initial, apparently contradictory findings on the role of PKC on insulin action can be explained on the basis that certain PKC isoforms (e.g., -zeta and -lambda) have been identified as downstream targets of PI3-kinase activation, while DAG-sensitive PKCs (e.g., -theta; and -epsilon) have negative regulatory effects on insulin signaling. Hence, pharmacological therapies targeting specific PKC isoforms could enhance insulin action and improve glycemic control in patients with impaired glucose tolerance and overt diabetes.

Background Temporal arteritis (TA) is the commonest form of primary vasculitis. Symptoms are variable, and therefore the diagnosis (or exclusion) of TA is often difficult. Surgeons are frequently asked to perform a temporal artery biopsy (TAB), but whether the histological result actually influences clinical management is unclear. Aim To assess whether, in routine clinical practice, a TAB affects clinical decision-making in patients with suspected TA. Design Retrospective audit. Methods All patients who underwent a TAB in a single hospital over a 2-year period were identified. This included patients referred from different specialist departments. Individual patient records were examined to document the TAB result, and in particular, the timings of commencement and discontinuation of corticosteroid therapy. Results A total of 44 patients were included. TAB was positive in seven patients and negative in 37. In 31, there was no change in their clinical management despite a negative biopsy result: 18 continued with corticosteroids for >6 months with a clinical diagnosis of TA, and in 13 patients a decision to stop steroids, or an alternative diagnosis, was made before the biopsy result was known. Discussion In this retrospective study, only a small number of TABs provided positive histological confirmation of TA, and in most patients undergoing TAB, there was little evidence that clinical decision-making with respect to corticosteroid therapy was influenced by the TAB result.

Purpose of review Use of home blood-pressure monitoring is increasing but the technique and the equipment have limitations. We provide an overview of recent evidence in this rapidly evolving field. Recent findings Home blood-pressure monitoring is an acceptable method for screening patients for hypertension. There is increasing evidence supporting the predictive power of home blood pressure for stroke risk even in the general population. The identification of white-coat and masked hypertension remains an important role for home blood-pressure monitoring. Unvalidated equipment and poor patient technique are major concerns. The purchase of devices needs to be linked to a simple patient-education programme, which is perhaps an opportunity for collaboration between healthcare providers and commercial companies. Devices that store the blood-pressure measurements in the memory are preferred to ensure accuracy of reporting. Data-transmission systems providing automatic storage, transmission and reporting of blood pressure, direct involvement of the patient and potentially a reduced number of hospital/general practitioner visits, offer significant advantages. To reduce patient anxiety, overuse of home blood-pressure monitoring should be avoided but there is the potential for self-modification of treatment, subject to certain safeguards. Summary Self-monitoring of blood pressure is developing rapidly, linked to increasing awareness of the impact of reducing high blood pressure on public health and the marketing/advertising strategies used to sell automatic devices. Home blood-pressure monitoring has a role in the detection and management of blood pressure, but not at the expense of careful blood-pressure measurement in the office and adherence to national guidelines.

The increasingly large number of patients with diabetes in the UK are at greatly increased risk of cardiovascular disease, including coronary heart disease and stroke, compared to the general population. Many diabetes patients exhibit metabolic syndrome and these additional risk factors, such as raised hypertension and cholesterol, multiply the overall risk. Reducing these risk factors to target levels is essential and requires a multifactorial approach. Lifestyle changes, tight glycaemic control, antiplatelet drugs (aspirin) and control of lipid levels, e.g. using statins, can all have significant beneficial effects. Blood pressure control is another vital aspect in reducing risk and a number of recent studies have provided evidence supporting the use of angiotensin-converting enzyme inhibitors as first-line treatment in patients with diabetes.

The long-term administration of clopidogrel to patients with atherosclerotic vascular disease – manifested as either recent ischaemic stroke, recent myocardial infarction (MI) or symptomatic peripheral arterial disease (PAD) – is more effective than the use of aspirin in reducing the combined risk of ischaemic stroke, MI and vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin.

Canagliflozin is a sodium-glucose transporter protein inhibitor under development for the treatment of type 2 diabetes mellitus; it reduces circulatory glucose by facilitating its urinary excretion. In this Drug profile, Richard Donnelly discusses the need for drugs with a mode of action independent of insulin and considers the efficacy and tolerability of canagliflozin in clinical trials, to date, as well as its potential place in management. Copyright © 2013 John Wiley & Sons, Ltd.

The incidence of type 2 diabetes is increasing at an alarming rate; epidemiological studies indicate that by the year 2010 there will be 300 million people with type 2 diabetes worldwide. The rate of increase is highest in Asia and among young adults with obesity. On average, patients with diabetes live 5 10 years less than their non-diabetic counterparts, mainly because of accelerated atherosclerotic disease. A diagnosis of diabetes confers a twoto fourfold increased risk of intermittent claudication and a 10 16-fold increase in the lifetime risk of a lower limb amputation. Furthermore, the incidence and outcomes from critical limb ischaemia are significantly worse among patients with diabetes; for example, higher amputation rates and less successful outcomes from revascularization procedures (angioplasty or bypass grafting). These observations are due in part to the effects of diabetes on the distribution and morphology of occlusive atherosclerotic lesions in the lower limb. Specifically, diabetes tends to cause more diffuse andmoredistal (i.e. infrapopliteal and tibial) atherosclerotic disease, often associated with vascular calcification. It is important to recognize that diabetes is a syndrome in which a cluster of haemodynamic and metabolic abnormalities interact to cause macroand microvascular complications. Although the diagnosis and symptoms of diabetes are defined by hyperglycaemia, other features of the syndrome (e.g. hypertension and dyslipidaemia), are equally if not more important in the pathogenesis of diabetes-related cardiovascular complications. In general, small vessel disease (e.g. diabetic retinopathy) is closely related to hyperglycaemia, but the development of atherothrombotic complications in larger arteries (e.g. in the lower limb), is multifactorial, reflecting interactions between high glucose, lipids and blood pressure. For example, there is evidence that dyslipidaemia in type 2 diabetes is strongly associated with the development of intermittent claudication, and that hypertension also affects the development of PAD in the diabetic population. Recent studies have highlighted that type 2 diabetes is associated with chronic low-grade inflammation, endothelial dysfunction and insulin resistance, which has led to new hypotheses about the pathogenesis of macrovascular complications and the interactions between metabolic, endocrine and haemodynamic mechanisms.

This paper represents a review, by experts, of current opinion and information on intermittent claudication (IC) and the role that cilostazol plays in its treatment. IC is a common and debilitating condition that has a significant adverse impact on health-related quality of life (HR-QoL). It is currently under-recognised as a powerful marker of increased cardiovascular (CV) risk. The clinical priority is secondary prevention -- sometimes referred to as best medical therapy aimed at reducing CV risk. However, the priority for most patients (often overlooked by clinicians) is symptom relief: an increase in walking distance leading to an improvement in HR-QoL. The symptoms of IC may be improved by exercise, pharmacotherapy, and when these are unsuitable or unsuccessful, endovascular or surgical intervention. Cilostazol is indicated for the improvement of maximal and pain-free walking distance in patients with IC who do not have rest pain or tissue necrosis. In clinical trials, cilostazol improved symptoms both objectively and subjectively, and also improved HR-QoL. Cilostazol is usually well tolerated, with adverse events being generally mild to moderate in intensity, and transient or resolved after symptomatic treatment (e.g. non-prescription analgesics). Such events only infrequently require permanent drug withdrawal. There are no interactions with other drugs commonly prescribed in patients with IC, such as statins and anti-platelet agents. Cilostazol also has a range of potentially beneficial effects that may in the future be proven to decrease CV risk and modify the underlying process of atherosclerosis. Cilostazol represents the best evidence-based pharmacological therapy available for the symptoms of IC and should be the first-line treatment for symptom improvement in appropriate patients. Based on the available treatment strategies, the paper presents a suggested algorithm for the management of IC highlighting the role of cilostazol.

The physiological processes of angiogenesis, vasculogenesis and arteriogenesis contribute to the growth of collateral vessels in response to obstructive arterial disease causing lower limb or myocardial ischaemia, but in clinical practice the endogenous angiogenic response is often suboptimal or impaired, e.g. by factors such as ageing, diabetes or drug therapies. Therapeutic angiogenesis is an application of biotechnology to stimulate new vessel formation via local administration of pro-angiogenic growth factors in the form of recombinant protein or gene therapy, or by implantation of endothelial progenitor cells that will synthesize multiple angiogenic cytokines. Numerous experimental and clinical studies have sought to establish ‘proof of concept’ for therapeutic angiogenesis in PAD and myocardial ischaemia using different treatment modalities, but the results have been inconsistent. This review summarises the mechanisms of angiogenesis and the results of recent trials evaluating the efficacy and safety of different gene therapy, recombinant protein and cellular-based treatment approaches to enhance collateral vessel formation.

BACKGROUND Increases in PKC-theta (the major isoenzymic form of PKC in skeletal muscle) protein and isozyme activity have been reported in skeletal muscle from patients with type 2 diabetes mellitus (T2DM) and dietary-induced rodent models of insulin resistance, but the underlying biochemical mechanism is unclear and muscle PKC-theta mRNA expression has not been previously reported in patients with T2DM or in relation to in-vivo measurements of insulin sensitivity. METHODS Diet-only treated patients with T2DM (n=7) and healthy nondiabetic controls (n=7) of similar BMI attended the clinical research unit on two occasions, 1 week apart, for a skeletal muscle biopsy 2 h after a 75-g oral glucose load and measurement of whole-body insulin sensitivity using the euglycaemic hyperinsulinaemic clamp. RESULTS Type 2 DM patients were insulin resistant (M-value 3.0 +/- 0.4 vs. 8.6 +/- 0.8 mg glucose kg(-1) min(-1)) with fasting hyperinsulinaemia (306 +/- 116 vs. 34 +/- 9 pmol L(-1), P