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Background: GLP-1 RA (glucagon-like peptide-1 receptor agonists), including semaglutide, may reduce stroke risk in people with type 2 diabetes. This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk. Methods: SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and PIONEER 6 (Peptide Innovation for Early Diabetes Treatment) were randomized cardiovascular outcome trials of subcutaneous and oral semaglutide in people with type 2 diabetes at high cardiovascular risk, respectively. Time to first stroke and stroke subtypes were analyzed using a Cox proportional hazards model stratified by trial with pooled treatment as a factor. The impact of prior stroke, prior myocardial infarction or stroke, age, sex, systolic blood pressure, estimated glomerular filtration rate, and prior atrial fibrillation on treatment effects was assessed using interaction P values. Risk of major adverse cardiovascular event was analyzed according to prior stroke. Results: A total of 106/6480 participants had a stroke (1.0 event/100 patient-years of observation [PYO]). Semaglutide reduced incidence of any stroke versus placebo (0.8 versus 1.1 events/100 PYO; hazard ratio, 0.68 [95% CI, 0.46–1.00]; P =0.048), driven by significant reductions in risk of small-vessel occlusion (0.3 versus 0.7 events/100 PYO; hazard ratio, 0.51 [95% CI, 0.29–0.89]; P =0.017). Hazard ratios for risk of any stroke with semaglutide versus placebo were 0.60 (95% CI, 0.37–0.99; 0.5 versus 0.9 events/100 PYO) and 0.89 (95% CI, 0.47–1.69; 2.7 versus 3.0 events/100 PYO) in those without and with prior stroke, respectively. Except for prior atrial fibrillation ( P interaction =0.025), no significant interactions were observed between treatment effects on risk of any stroke and subgroups investigated, or between treatment effects on risk of major adverse cardiovascular event and prior stroke ( P interaction >0.05 for all). Conclusions: Semaglutide reduced incidence of any first stroke during the trials versus placebo in people with type 2 diabetes at high cardiovascular risk, primarily driven by small-vessel occlusion prevention. Semaglutide treatment, versus placebo, lowered the risk of stroke irrespective of prior stroke at baseline. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01720446 and NCT02692716.

Chronic kidney disease (CKD) is a serious, progressive condition associated with significant patient morbidity. Hypertension control and use of renin-angiotensin system blockers are the cornerstones of treatment for CKD. However, even with these treatment strategies, many individuals will progress towards kidney failure. Recently, sodium-glucose cotransporter 2 (SGLT2) inhibitor clinical trials with primary renal endpoints have firmly established SGLT2 inhibition, in addition to standard of care, as an effective strategy to slow down the progression of CKD and reduce some of its associated complications. The emergence of this new clinical evidence supports the use of SGLT2 inhibitors in the management of CKD in people with and without diabetes. As licensing and guidelines for SGLT2 inhibitors are updated, there is a need to adapt CKD treatment pathways and for this class of drugs to be included as part of standard care for CKD management. In this article, we have used consensus opinion alongside the available evidence to provide support for the healthcare community involved in CKD management, regarding the role of SGLT2 inhibitors in clinical practice. By highlighting appropriate prescribing and practical considerations, we aim to encourage greater and safe use of SGLT2 inhibitors for people with CKD, both with and without diabetes.

Different methods to measure carotid-femoral pulse wave velocity (CFPWV) may affect the measurements obtained and influence the association between CFPWV, cardiovascular risk factors and biomarkers of subclinical vascular health. The estimation of distance between the carotid and femoral artery measurement sites (the arterial path length) is particularly problematic.We determined if CFPWV and equation-based estimates of CFPWV were influenced by arterial path length and if this affected the association of CFPWV with cardiovascular risk factors and subclinical vascular biomarkers. The CFPWV derived from the measurement of surface distance (CFPWV-D), arterial path length formula (CFPWV-F), and estimated CFPWV (ePWV) were obtained from 489 older adults (67.2 ± 8.8 years). Macrovascular [carotid artery: lumen diameter (LD), inter-adventitial diameter (IAD), intima-media thickness (IMT) and total plaque area (TPA)] and microvascular [reactive hyperaemia index and urinary albumin-creatinine ratio (UACR)] biomarkers were also measured.CFPWV-D was significantly greater than CFPWV-F [9.6 (8.0-11.2) vs. 8.9 (7.6-10.5) m/s, P 0.001], because of estimated path length being longer in CFPWV-D than CFPWV-F (495.4 ± 44.8 vs. 465.3 ± 20.6 mm, P 0.001). ePWV was significantly greater than both CFPWV-F and CFPWV-D [11.0 (10.0-12.2) m/s, P 0.001]. The three CFPWV methods were similarly associated with LD, IAD, IMT, TPA and UACR but not with cardiovascular risk factors.Different methods to measure CFPWV affect the derived measurement values and the association with cardiovascular risk factors but not the association with subclinical biomarkers of vascular health. These hitherto unreported observations are important considerations in experimental design, data interpretation and of particular importance, comparison between studies where CFPWV is measured.

Chronic kidney disease (CKD) is a complex disease which affects approximately 13% of the world’s population. Over time, CKD can cause renal dysfunction and progression to end-stage kidney disease and cardiovascular disease. Complications associated with CKD may contribute to the acceleration of disease progression and the risk of cardiovascular-related morbidities. Early CKD is asymptomatic, and symptoms only present at later stages when complications of the disease arise, such as a decline in kidney function and the presence of other comorbidities associated with the disease. In advanced stages of the disease, when kidney function is significantly impaired, patients can only be treated with dialysis or a transplant. With limited treatment options available, an increasing prevalence of both the elderly population and comorbidities associated with the disease, the prevalence of CKD is set to rise. This review discusses the current challenges and the unmet patient need in CKD.

Insulin represents a mainstay of glucose-lowering therapy for many adults with type 2 diabetes mellitus (T2DM). Insulin treatments prescribed as standard care for the majority of people with T2DM, such as basal human insulin, may not be optimal in the treatment of frail older adults because of the increased demand on health care staff to administer multiple daily injections and monitor the patient. When choosing an insulin regimen for a frail older person with T2DM, predictability of glucose lowering effect, risk of hypoglycaemia, ease of administration, and simplicity and flexibility of dosing are major determining factors. Multiple daily injections may be too complex for older frail adults, whilst providing an unnecessary degree of tight glycaemic control and low doses of once-daily basal insulin analogues such as insulin degludec may be a reasonable option as cognitive decline or functional disability increases. Although insulin degludec has a substantially higher acquisition cost than routinely used basal human insulin, it has a longer, more predictable pharmacological profile and is more amenable to once-daily administration, translating into a reduced burden of care and potential cost savings for insulin-treated frail older adults. Insulin acquisition cost represents only a small proportion of the total cost of treatment, and it is important to consider the value perspective of insulin therapy in frail older adults from all stakeholders in the health care system.

Prognosis and appropriate treatment goals for older adults with diabetes vary greatly according to frailty. It is now recognised that changes may be needed to diabetes management in some older people. Whilst there is clear guidance on the evaluation of frailty and subsequent target setting for people living with frailty, there remains a lack of formal guidance for healthcare professionals in how to achieve these targets. The management of older adults with type 2 diabetes is complicated by comorbidities, shortened life expectancy and exaggerated consequences of adverse effects from treatment. In particular, older adults are more prone to hypoglycaemia and are more vulnerable to its consequences, including falls, fractures, hospitalisation, cardiovascular events and all-cause mortality. Thus, assessment of frailty should be a routine component of a diabetes review for all older adults, and glycaemic targets and therapeutic choices should be modified accordingly. Evidence suggests that over-treatment of older adults with type 2 diabetes is common, with many having had their regimens intensified over preceding years when they were in better health, or during more recent acute hospital admissions when their blood glucose levels might have been atypically high, and nutritional intake may vary. In addition, assistance in taking medications, as often occurs in later life following implementation of community care strategies or admittance to a care home, may dramatically improve treatment adherence, leading to a fall in glycated haemoglobin (HbA1c) levels. As a person with diabetes gets older, simplification, switching or de-escalation of the therapeutic regimen may be necessary, depending on their level of frailty and HbA1c levels. Consideration should be given, in particular, to de-escalation of therapies that may induce hypoglycaemia, such as sulphonylureas and shorter-acting insulins. We discuss the use of available glucose-lowering therapies in older adults and recommend simple glycaemic management algorithms according to their level of frailty.

Disease burden in people with diabetes is mainly driven by long-term complications such as cardiovascular disease, heart failure and chronic kidney disease. This is a consequence of the interconnection between the cardiovascular, renal and metabolic systems, through a continuous chain of events referred to as 'the cardiorenal metabolic continuum'. Increasing evidence suggests that sodium-glucose cotransporter 2 inhibitors (SGLT2is) have beneficial effects across all stages of the cardiorenal metabolic continuum, reducing morbidity and mortality in a wide range of individuals, from those with diabetes and multiple risk factors to those with established heart failure and chronic kidney disease, regardless of the presence of diabetes. Despite this robust evidence base, the complexity of label indications and misconceptions concerning potential side effects have resulted in a lack of clear understanding in primary care regarding the implementation of SGLT2is in clinical practice. With this in mind, we provide an overview of the clinical and economic benefits of SGLT2is across the cardiorenal metabolic continuum together with practical considerations in order to help address some of these concerns and clearly define the role of SGLT2is in primary care as a holistic outcomes-driven treatment with the potential to reduce disease burden across the cardiorenal metabolic spectrum.

Introduction Metformin is the recommended initial treatment in type 2 diabetes mellitus (T2DM), but when this does not give adequate glucose control the choice of which second-line drug to use is uncertain as none have been found to have a better overall glycaemic response. In this real-world study dipeptidyl peptidase 4 inhibitors (DPP4i), sulphonylureas (SU), thiazolidinediones (TZD) and sodium glucose co-transporter 2 inhibitors (SGLT2i) were compared for their effectiveness in lowering glycated haemoglobin (HbA1c) levels for a particular individual based on their clinical characteristics. Methods A retrospective analysis was undertaken of electronic health records of people with T2DM prescribed metformin alongside a DPP4i, SU, TZD or SGLT2i at second-line. Regression modelling was used to model the changes in HbA1c from baseline at month 6 and month 12 for the individual therapies, adjusting for demographic and clinical characteristics. Results There were 7170 people included in the study. Treatment at second-line with SUs, DPP4i, TZDs and SGLT2i resulted in similar percentages of people achieving the recommended HbA1c target of

Urinary albumin-to-creatinine ratio (ACR) is a marker of diabetic nephropathy and microvascular damage. Metabolic-related traits are observationally associated with ACR, but their causal role is uncertain. Here, we confirmed ACR as a marker of microvascular damage and tested whether metabolic-related traits have causal relationships with ACR. The association between ACR and microvascular function (responses to acetylcholine [ACH] and sodium nitroprusside) was tested in the SUMMIT study. Two-sample Mendelian randomization (MR) was used to infer the causal effects of 11 metabolic risk factors, including glycemic, lipid, and adiposity traits, on ACR. MR was performed in up to 440,000 UK Biobank and 54,451 CKDGen participants. ACR was robustly associated with microvascular function measures in SUMMIT. Using MR, we inferred that higher triglyceride (TG) and LDL cholesterol (LDL-C) levels caused elevated ACR. A 1 SD higher TG and LDL-C level caused a 0.062 (95% CI 0.040, 0.083) and a 0.026 (95% CI 0.008, 0.044) SD higher ACR, respectively. There was evidence that higher body fat and visceral body fat distribution caused elevated ACR, while a metabolically “favorable adiposity” phenotype lowered ACR. ACR is a valid marker for microvascular function. MR suggested that seven traits have causal effects on ACR, highlighting the role of adiposity-related traits in causing lower microvascular function.

Acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. Timely reperfusion with primary percutaneous coronary intervention (PPCI) remains the gold standard in patients presenting with ST-segment elevation myocardial infarction (STEMI), limiting infarct size, preserving left ventricular ejection fraction (LVEF), and improving clinical outcomes. Despite this, a significant proportion of STEMI patients develop post-infarct heart failure. We review the current understanding and up-to-date evidence base for therapeutic intervention of ischaemia-reperfusion injury (IRI), a combination of myocardial ischaemia secondary to acute coronary occlusion and reperfusion injury leading to further myocardial injury and cell death. Multiple treatment modalities have been shown to be cardioprotective and reduce IRI in experimental animal models. Recent phase II/III randomised controlled trials (RCT) have assessed multiple cardioprotective strategies ranging from ischaemic conditioning, therapeutic hypothermia and hyperoxaemia to pharmacological therapies. While several therapies have been shown to reduce infarct size in animal models or proof-of-concept studies, many larger scale trial results have proven inconsistent and disappointing. Hard clinical outcomes remain elusive. We discuss potential reasons for the difficulties in translation to clinical practice.

Heart failure with preserved ejection fraction (HFpEF) is a condition with increasing disease burden. Prevalence of HFpEF is increasing, reflecting an increasingly elderly and comorbid population, as well as reinforcing the need for more treatments for this disease. The pathophysiology of HFpEF is complex. Some inflammatory processes seen in HFpEF are shared with diabetes mellitus (DM) and there is an association seen between the two conditions. It is therefore no wonder that treatments for diabetes may have some effect on heart failure outcomes. Current treatment strategies in HFpEF are limited, with treatments focusing on symptom control rather than morbidity or mortality benefit. However, there are now promising results from the EMPEROR-Preserved study that show significantly reduced cardiovascular death or hospitalisation for heart failure (HHF) in patients taking empagliflozin, compared to those taking placebo. These results indicate a promising future for sodium-glucose co-transporter 2 (SGLT2) inhibitors in HFpEF. The ongoing DELIVER trial (investigating the use of dapagliflozin in HFpEF) is awaited but could provide further evidence of support for SGLT2 inhibitors in HFpEF. With hospital admissions for HFpEF increasing in the UK, the economic impact of treatments that reduce HHF is vast. The European Society of Cardiology (ESC) recently added SGLT2 inhibitors to their guidelines for treatment of heart failure with reduced ejection fraction (HFrEF) following DAPA-HF and EMPEROR-Reduced trials and we suggest that similar changes be made to guidelines to support the use of SGLT2 inhibitors in the management of HFpEF in upcoming months.

While glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, are among the most effective drugs for treating people with type 2 diabetes (T2D), they are clinically under-utilised. Until recently, the only route for semaglutide administration was via subcutaneous injection. However, an oral formulation of semaglutide was recently licensed, with the potential to address therapy inertia and increase patient adherence to treatment, which is essential in controlling blood glucose and reducing complications. The availability of oral semaglutide provides a new option for both clinicians and patients who are reluctant to use an injectable agent. This has been of particular importance in addressing the challenge of virtual diabetes care during the COVID-19 pandemic, circumventing the logistical problems that are often associated with subcutaneous medication administration. However, there remains limited awareness of the clinical and economic value of oral semaglutide in routine clinical practice. In this article, we present our consensus opinion on the role of oral semaglutide in routine clinical practice and discuss its value in reducing the burden of delivering diabetes care in the post-COVID-19 pandemic period of chronic disease management.

ObjectivesHealthcare workers have greater exposure to SARS-CoV-2 and an estimated 2.5-fold increased risk of contracting COVID-19 than the general population. We wished to explore the predictive role of basic demographics to establish a simple tool that could help risk stratify healthcare workers.SettingWe undertook a review of the published literature (including multiple search strategies in MEDLINE with PubMed interface) and critically assessed early reports on preprint servers. We explored the relative risk of mortality from readily available demographics to identify the population at the highest risk.ResultsThe published studies specifically assessing the risk of healthcare workers had limited demographics available; therefore, we explored the general population in the literature. Clinician demographics: Mortality increased with increasing age from 50 years onwards. Male sex at birth, and people of black and minority ethnicity groups had higher susceptibility to both hospitalisation and mortality. Comorbid disease. Vascular disease, renal disease, diabetes and chronic pulmonary disease further increased risk. Risk stratification tool: A risk stratification tool was compiled using a white female aged ConclusionsWe generated a tool that provides a framework for objective risk stratification of doctors and healthcare professionals during the COVID-19 pandemic, without requiring disclosure of information that an individual may not wish to share with their direct line manager during the risk assessment process. This tool has been made freely available through the British Medical Association website and is widely used in the National Health Service and other external organisations.

ObjectiveTransient ischaemic attacks (TIA) and minor strokes are important risk factors for further vascular events. We explored the role of albumin creatinine ratio (ACR) in improving risk prediction after a first event.SettingRapid access stroke clinics in the UK.Participants2202 patients attending with TIA or minor stroke diagnosed by the attending stroke physician, able to provide a urine sample to evaluate ACR using a near-patient testing device.Primary and secondary outcomesPrimary outcome was major adverse cardiac events (MACE: recurrent stroke, myocardial infarction or cardiovascular death) at 90 days. The key secondary outcome was to determine whether urinary ACR could contribute to a risk prediction tool for use in a clinic setting.Results151 MACE occurred in 144 participants within 90 days. Participants with MACE had higher ACR than those without. A composite score awarding a point each for age >80 years, previous stroke/TIA and presence of microalbuminuria identified those at low risk and high risk. 90% of patients were at low risk (scoring 0 or 1). Their 90-day risk of MACE was 5.7%. Of the remaining ‘high-risk’ population (scoring 2 or 3) 12.4% experienced MACE over 90 days (pConclusionA risk score comprising age, previous stroke/TIA and microalbuminuria predicts future MACE while identifying those at low risk of a recurrent event. This tool shows promise in the risk stratification of patients to avoid the admission of low-risk patients.

As the UK, together with numerous countries in the world, moves towards a new phase of the COVID-19 pandemic, there is a need to be able to predict trends in sufficient time to limit the pressure faced by the National Health Service (NHS) and maintain low hospitalisation levels. In this study, we explore the use of an epidemiological compartmental model to devise a periodic adaptive suppression/intervention policy to alleviate the pressure on the NHS. The proposed model facilitates the understanding of the progression of the specific stages of COVID-19 in communities in the UK including: the susceptible population, the infected population, the hospitalised population, the recovered population, the deceased population, and the vaccinated population. We identify the parameters of the model by relying on past data within the period from 1 October 2020 to 1 June 2021. We use the total number of hospitalised patients and the fraction of those infected who are being admitted to hospital to develop adaptive policies: these modulate the recommended level of social restriction measures and realisable vaccination target adjustments. The analysis over the period 1 October 2020 to 1 June 2021 demonstrates our periodic adaptive policies have the potential to reduce the hospitalisation by 58% on average per month. In a further prospective analysis over the period August 2021 to May 2022, we analyse several future scenarios, characterised by the relaxation of restrictions, the vaccination ineffectiveness and the gradual decay of the vaccination-induced immunity within the population. In addition, we simulate the surge of plausible variants characterised by an higher transmission rate. In such scenarios, we show that our periodic intervention is effective and able to maintain the hospitalisation rate to a manageable level.

Cardiovascular disease (CVD) is the leading cause of mortality in people with type 2 diabetes mellitus (T2DM), yet a significant proportion of the disease burden cannot be accounted for by conventional cardiovascular risk factors. Hypertension occurs in majority of people with T2DM, which is substantially more frequent than would be anticipated based on general population samples. The impact of hypertension is considerably higher in people with diabetes than it is in the general population, suggesting either an increased sensitivity to its effect or a confounding underlying aetiopathogenic mechanism of hypertension associated with CVD within diabetes. In this contribution, we aim to review the changes observed in the vascular tree in people with T2DM compared to the general population, the effects of established anti-diabetes drugs on microvascular outcomes, and explore the hypotheses to account for common causalities of the increased prevalence of CVD and hypertension in people with T2DM.

The parameters derived from reservoir-excess pressure analysis have prognostic utility in several populations. However, evidence in type 2 diabetes (T2DM) remains scarce. We determined if these parameters were associated with T2DM and whether they would predict cardiovascular events in individuals with T2DM. We studied 306 people with T2DM with cardiovascular disease (CVD; DMCVD, 70.4±7.8 years), 348 people with T2DM but without CVD (diabetes mellitus, 67.7±8.4 years), and 178 people without T2DM or CVD (control group [CTRL], 67.2±8.9 years). Reservoir-excess pressure analysis–derived parameters, including reservoir pressure integral, peak reservoir pressure, excess pressure integral, systolic rate constant, and diastolic rate constant, were obtained by radial artery tonometry. Reservoir pressure integral was lower in DMCVD and diabetes mellitus than CTRL. Peak reservoir pressure was lower, and excess pressure integral was greater in DMCVD than diabetes mellitus and CTRL. Systolic rate constant was lower in a stepwise manner among groups (DMCVD< diabetes mellitus P

Introduction Although some differences between individual dipeptidyl peptidase-4 (DPP-4) inhibitors may exist, the National Institute for Health and Clinical Excellence (NICE) have recommended that ‘prescribers should be encouraged to select the individual DPP-4 inhibitor with the lowest acquisition cost available to them, where all other factors are equal’. We aimed to determine whether or not ‘within class’ switching to alogliptin, the DPP-4 inhibitor with lowest acquisition cost, is a clinically appropriate strategy. Methods This study evaluated people with type 2 diabetes taking DPP-4 inhibitor therapy in addition to at least one other diabetes therapy. Primary care records were reviewed from six clinical commissioning groups (CCGs). For people who had been switched from other DPP-4 inhibitors to alogliptin, an assessment of the impact of switch on both absolute haemoglobin A1c (HbA1c) levels and on HbA1c trajectory was undertaken. Persistence on alogliptin and the need for therapy intensification was also assessed. Results Overall, 865 people with diabetes met the eligibility criteria for the study. There was no significant difference between pre- and post-switch mean HbA1c level [8.44% (SD 1.52%) vs 8.42% (1.62%), p = 0.6]. Similarly, for patients where there was sufficient data to assess the impact of switching on HbA1c trajectory (n = 319) minimal impact was identified (actual HbA1c at 3 months 8.33% vs projected 8.31%). The majority of people with diabetes (80.76%) remained on alogliptin treatment at 6 months and only 4.54% required additional diabetes therapies. Switching to alogliptin resulted in a median saving of £7.24 per patient-month. Conclusion Switching United Kingdom (UK) primary care patients from other DPP-4 inhibitors to alogliptin did not result in a statistically significant or clinically meaningful change in HbA1c level and few required the addition of further diabetes therapies, suggesting that therapy change or intensification was not considered necessary in most patients who were switched to alogliptin. Trial Registration ENCePP clinical trial registration number EUPAS29153. Funding Takeda UK Ltd. Electronic Supplementary Material The online version of this article (10.1007/s13300-019-0662-y) contains supplementary material, which is available to authorized users.

This article was migrated. The article was marked as recommended. The defining feature of 2020 will be the early and mid-stages of the covid-19 pandemic, declared by the World Health Organisation on 11th March. Rapid worldwide exponential spread continues and by 15 April, more than 1 900 000 cases and 123 000 deaths had been reported worldwide (WHO, 2020).Health services have coped to varying degrees. One common feature has been the withdrawal of routine care (Iacobucci, 2020a) and 'non-essential' staff including learners, although many have returned to undertake care roles. As the likely timeframe for stabilisation of health services becomes clearer, certainly in the United Kingdom (UK) (Iacobucci, 2020b), medical educators need to rapidly get the teaching of the next generation of health care workers back on track if they are to enter health services as confident and competent practitioners in 2020 and 2021.Although a 'whole world' experience, the effects of covid-19 sit in national contexts. We detail the issues for the UK in re-starting and re-inventing medical education, noting that the principles, if not necessarily the detail, will be common across the world.

Obesity is a chronic condition that requires long-term management and is associated with unprecedented stigma in different settings, including during interactions with the health-care system. This stigma has a negative effect on the mental and physical health of people with obesity and can lead to avoidance of health care and disruption of the doctor–patient relationship. Considerable evidence exists to suggest that simply having a conversation about obesity can lead to weight loss, which translates into health benefits. However, both health-care practitioners and people living with obesity report apprehension in initiating this conversation. We have collaborated with stakeholders from Obesity UK, physicians, dieticians, clinical psychologists, obesity researchers, conversation analysts, nurses, and representatives from National Health Service England Diabetes and Obesity. This group has contributed to the production of this consensus statement, which addresses how people living with obesity wish to have their condition referred to and provides practical guidance for health-care professionals to facilitate collaborative and supportive discussions about obesity. Expert stakeholders consider that changes to language used at the point of care can alleviate the stigma of obesity within the health-care system and support improved outcomes for both people living with obesity and for the health-care system.

Additional file 2. MEDLINE search strategy.

Additional file 3. Data extraction form for delirium and thiamine in the ICU SR (DELTA-ICU).

Additional file 1. PRISMA-P statement.

Background Delirium is an acute confusional state, common in critical illness and associated with cognitive decline. There is no effective pharmacotherapy to prevent or treat delirium, although it is scientifically plausible that thiamine could be effective. Thiamine studies in dementia patients are inconclusive. Aside from small numbers, all used oral administration: bioavailability of thiamine is poor; parenteral thiamine bypasses this. In the UK, parenteral thiamine is administered as a compound vitamin B and C solution (Pabrinex®). The aim of this review is to evaluate the effectiveness of parenteral thiamine (alone or in a compound solution) in preventing or treating delirium in critical illness. Methods We will search for studies in electronic databases (MEDLINE (Pro-Quest), EMBASE, CINAHL, LILACS, CNKI, AMED, and Cochrane CENTRAL), clinical trials registries (WHO International Clinical Trials Registry, ClinicalTrials.gov, and Controlled-trials.com), and grey literature (Google Scholar, conference proceedings, and Index to Theses). We will perform complementary searches of reference lists of included studies, relevant reviews, clinical practice guidelines, or other pertinent documents (e.g. official documents and government reports). We will consider quasi-randomised or randomised controlled trials in critically ill adults. We will include studies that evaluate parenteral thiamine versus standard of care, placebo, or any other non-pharmacological or pharmacological interventions. The primary outcomes will be the delirium core outcome set, including incidence and severity of delirium and cognition. Secondary outcomes are adapted from the ventilation core outcome set: duration of mechanical ventilation, length of stay, and adverse events incidence. Screening, data extraction, and risk of bias assessment will be undertaken independently by two reviewers. If data permits, we will conduct meta-analyses using a random effects model and, where appropriate, sensitivity and subgroup analyses to explore sources of heterogeneity. Discussion This review will provide evidence for the effectiveness of parental thiamine in the prevention or treatment of delirium in critical care. Findings will contribute to establishing the need for a multicentre study of parenteral thiamine in the prevention and treatment of critical care delirium. Systematic review registration PROSPERO CRD42019118808

Objectives To estimate associations between long-term use of proton pump inhibitors (PPIs) and pneumonia incidence in older adults in primary care. Design Longitudinal analyses of electronic medical records. Setting England PARTICIPANTS: Individuals aged 60 and older in primary care receiving PPIs for 1 year or longer (N=75,050) and age- and sex-matched controls (N=75,050). Measurements Net hazard ratios for pneumonia incidence in Year 2 of treatment were estimated using the prior event rate ratio (PERR), which adjusts for pneumonia incidence differences before initiation of treatment. Inverse probability weighted models adjusted for 78 demographic, disease, medication, and healthcare usage measures. Results During the second year after initiating treatment, PPIs were associated with greater hazard of incident pneumonia (PERR-adjusted hazard ratio=1.82, 95% confidence interval=1.27-2.54), accounting for pretreatment pneumonia rates. Estimates were similar across age and comorbidity subgroups. Similar results were also obtained from propensity score- and inverse probability-weighted models. Conclusion In a large cohort of older adults in primary care, PPI prescription was associated with greater risk of pneumonia in the second year of treatment. Results were robust across alternative analysis approaches. Controversies about the validity of reported short-term harms of PPIs should not divert attention from potential long-term effects of PPI prescriptions on older adults.

Diabetes is a growing worldwide epidemic and a leading cause of blindness in working-age people around the world. Diabetic retinopathy (DR) and diabetic macular edema (DME) are common causes of visual impairment in people with diabetes and often indicate the presence of diabetes-associated preclinical micro- and macrovascular complications. As such, patients with DR and DME often display complex, highly comorbid profiles. Several treatments are currently available for the treatment of DME, including anti-vascular endothelial growth factor (VEGF) agents, which are administered via intravitreal injection. While the safety profiles of approved ocular anti-VEGF therapies have been reassuring, the high-risk nature of the DME patient population means that treatment must be carefully considered and a holistic approach to disease management should be taken. This requires multidisciplinary, collaborative care involving all relevant specialties to ensure that patients not only receive prompt treatment for DME but also appropriate consideration is taken of any systemic comorbidities to evaluate and minimize potentially serious safety issues.

We tested the feasibility of setting individualized glycemic goals and factors influencing targets set in a clinical trial in elderly patients with type 2 diabetes. A 24-week, randomized, double-blind, placebo-controlled study was conducted in 45 outpatient centers in seven European countries. 278 drug-naïve or inadequately controlled (mean HbA1c 7.9%) patients with type 2 diabetes aged ≥70 years with HbA1c levels ≥7.0% and ≤10.0% were enrolled. Investigator-defined individualized HbA1c targets and the impact of baseline characteristics on individualized treatment targets was evaluated. The average individualized HbA1c target was set at 7.0%. HbA1c at baseline predicted a target setting such that higher the HbA1c, more aggressive was the target (P

Aims/hypothesis Although cardiovascular disease is the biggest cause of death in people with diabetes, microvascular complications have a significant impact on quality of life and financial burden of the disease. Little is known about the progression of microvascular dysfunction in the early stages of type 2 diabetes before the occurrence of clinically apparent complications. We aimed to explore the determinants of endothelial-dependent and -independent microvascular function progression over a 3 year period, in people with and without both diabetes and few clinical microvascular complications. Methods Demographics were collected in 154 participants with type 2 diabetes and in a further 99 participants without type 2 diabetes. Skin microvascular endothelium-dependent response to iontophoresis of acetylcholine and endothelium-independent responses to sodium nitroprusside were measured using laser Doppler fluximetry. All assessments were repeated 3 years later. Results People with type 2 diabetes had impaired endothelial-dependent microvascular response compared with those without (AUC 93.9 [95% CI 88.1, 99.4] vs 111.9 [102.3, 121.4] arbitrary units [AU] × min, p p = 0.002). Mean microvascular function declined over 3 years in both groups to a similar degree (pinteraction 0.74 for response to acetylcholine and 0.69 for response to sodium nitroprusside). In those with diabetes, use of sulfonylurea was associated with greater decline (p = 0.022 after adjustment for co-prescriptions, change in HbA1c and weight), whereas improving glycaemic control was associated with less decline of endothelial-dependent microvascular function (p = 0.03). Otherwise, the determinants of microvascular decline were similar in those with and without diabetes. The principal determinant of change in microvascular function in the whole population was weight change over 3 years, such that those that lost ≥5% weight had very little decline in either endothelial-dependent or -independent function compared with those that were weight stable, whereas those who gained weight had a greater decline in function (change in endothelial-dependent function was 1.2 [95% CI −13.2, 15.7] AU × min in those who lost weight; −15.8 [−10.5, −21.0] AU × min in those with stable weight; and −37.8 [−19.4, −56.2] AU × min in those with weight gain; ptrend Conclusions/interpretation Over 3 years, physiological change in weight was the greatest predictor of change in microvascular function.

Background in chronic kidney disease (CKD), hypertension is associated with poor outcomes at ages 60. In the 70 plus group with SBPs 140–169 mmHg, there was no increase in mortality, versus SBP 130–139. Similarly, SBPs 140–169 mmHg were not associated with increased incident heart failure, stroke or myocardial infarctions. SBPs 150 mmHg. Results were little altered after excluding those with declining SBPs during 5 years before baseline, or for longer-term outcomes (5–10 years after baseline). Conclusions in older primary care patients, CKD3 or 4 was the dominant outcome predictor. SBP 140–169 mmHg having little additional predictive value

Background Type 2 diabetes mellitus (T2DM) is a complex disease, particularly in a continental country like Brazil. We attempted to understand and evaluate the perceptions and routines of Brazilians with T2DM and physicians, compared with other countries. Methods We compared the results from a 20-min online survey in Brazil with simultaneously collated data from India, Japan, Spain, UK and USA. Results In total, 652 adults with T2DM and 337 treating physicians were enrolled, of whom 100 patients and 55 physicians were from Brazil. The numbers of primary care physicians from the five countries were 221 versus 43 in Brazil, diabetes specialists were 61 versus 12. There was disconnect between the opinions of physicians and people with diabetes globally. Further, there were differences between clinical practices in Brazil versus the rest of the world, in many areas Brazilians were performing better. Conclusions Communication between patients and physicians should be clearer. There is an urgent need to identify the deficits in education, in order to address the clinical inertia within the diabetes management team. There is a necessity to understand the specific requirements of the Brazilian population in order to contextualise international guidelines and implement local changes in practice.

Aims/hypothesis The aim of this study was to determine whether random non-fasting C-peptide (rCP) measurement can be used to assess hypoglycaemia risk in insulin-treated type 2 diabetes. Methods We compared continuous glucose monitoring-assessed SD of blood glucose and hypoglycaemia duration in 17 patients with insulin-treated type 2 diabetes and severe insulin deficiency (rCP 600 pmol/l). We then assessed the relationship between rCP and questionnaire-based measures of hypoglycaemia in 256 patients with insulin-treated type 2 diabetes and a comparison group of 209 individuals with type 1 diabetes. Results Continuous glucose monitoring (CGM)-assessed glucose variability and hypoglycaemia was greater in individuals with rCP

Introduction Refractory angina is the occurrence of clinical symptoms despite maximal therapy. We investigated associations between microvascular function, atherosclerotic burden, and clinical symptoms in subjects with CAD. Methods Skin microvascular response to heating and ischemia was assessed in 167 male volunteers by laser Doppler fluximetry; 82 with CAD on maximal therapy and 85 with no known CAD (noCAD). CAC scores, carotid IMT, and femoral IMT were measured and symptoms were scored using the Rose angina questionnaire. Results Patients with CAD had poorer microvascular response to heating (114[95% CI 106–122]au CAD vs. 143[134–153]au no CAD; p

Guidelines suggest setting individualised targets for glycaemic control in elderly patients with type 2 diabetes, despite no evidence. We aimed to assess the feasibility of setting and achieving individualised targets over 24 weeks along with conventional HbA1c reduction using vildagliptin versus placebo.In this multinational, double-blind, 24 week study, we enrolled drug-naive or inadequately controlled (glycosylated haemoglobin A1c [HbA1c] ≥7·0% to ≤10·0%) patients with type 2 diabetes aged 70 years or older from 45 outpatient centres in Europe. Investigators set individualised treatment targets on the basis of age, baseline HbA1c, comorbidities, and frailty status before a validated automated system randomly assigned patients (1:1) to vildagliptin (50 mg once or twice daily as per label) or placebo. Coprimary efficacy endpoints were proportion of patients reaching their investigator-defined HbA1c target and HbA1c reduction from baseline to study end. The study is registered with ClinicalTrials.gov, number NCT01257451, and European Union Drug Regulating Authorities Clinical Trials database, number 2010-022658-18.Between Dec 22, 2010, and March 14, 2012, we randomly assigned 139 patients each to the vildagliptin and placebo groups. 37 (27%) of 137 patients in the placebo group achieved their individualised targets by education and interactions with the study team alone and 72 (52·6%) of 137 patients achieved their target in the vildagliptin group (adjusted odds ratio 3·16, 96·2% CI 1·81-5·52; p0·0001). This finding was accompanied by a clinically relevant 0·9% reduction in HbA1c from a baseline of 7·9% with vildagliptin and a between-group difference of -0·6% (98·8% CI -0·81 to -0·33; p0·0001). The overall safety and tolerability was similar in the vildagliptin and placebo groups, with low incidence of hypoglycaemia and no emergence of new safety signals.This study is the first to introduce and show the feasibility of using individualised HbA1c targets as an endpoint in any type 2 diabetes population. Individualised glycaemic target levels are achievable with vildagliptin without any tolerability issues in the elderly type 2 diabetes population.Novartis Pharma AG.

The role of microcirculatory dysfunction is increasingly being recognized in the etiopathogenesis of cardiovascular disease. Whilst the importance of detailed mechanistic studies to determine the exact nature of these disturbances is without question, it was large-scale population-based studies that first identified the associations between deranged microvascular perfusion, autoregulation or structure, and subsequent target organ damage. This is the subject of considerable studies to establish whether there is a causal effect in either direction, or simply represents shared risk factors, although it is most likely to be a complex combination of bidirectional interactions. The techniques for investigating microcirculatory function have evolved almost exponentially over the last 75 years: So too have the strategies for investigation. Current epidemiological studies are focusing on attempting to untangle the inter-relationship between risk factors and pathological mechanisms to attempt to determine whether these represent therapeutic targets or simple markers of unmeasured risk. We plan to review the techniques used for these population-based studies, the advances made, and the clinical implications derived.

Noninvasive, easy-to-use and accurate measurements of wall shear stress (WSS) in human blood vessels have always been challenging in clinical applications. Echo particle image velocimetry (Echo PIV) has shown promise for clinical measurements of local hemodynamics and wall shear rate. Thus far, however, the method has only been validated under simple flow conditions. In this study, we validated Echo PIV under in vitro and in vivo conditions. For in vitro validation, we used an anatomically correct, compliant carotid bifurcation flow phantom with pulsatile flow conditions, using optical particle image velocimetry (optical PIV) as the reference standard. For in vivo validation, we compared Echo PIV-derived 2-D velocity fields obtained at the carotid bifurcation in five normal subjects against phase-contrast magnetic resonance imaging (PC-MRI)-derived velocity measurements obtained at the same locations. For both studies, time-dependent, 2-D, two-component velocity vectors; peak/centerline velocity, flow rate and wall shear rate (WSR) waveforms at the common carotid artery (CCA), carotid bifurcation and distal internal carotid artery (ICA) were examined. Linear regression, correlation analysis and Bland-Altman analysis were used to quantify the agreement of different waveforms measured by the two techniques. In vitro results showed that Echo PIV produced good images of time-dependent velocity vector maps over the cardiac cycle with excellent temporal (up to 0.7 ms) and spatial (∼0.5 mm) resolutions and quality, comparable with optical PIV results. Further, good agreement was found between Echo PIV and optical PIV results for velocity and WSR measurements. In vivo results also showed good agreement between Echo PIV velocities and phase contrast MRI velocities. We conclude that Echo PIV provides accurate velocity vector and WSR measurements in the carotid bifurcation and has significant potential as a clinical tool for cardiovascular hemodynamics evaluation.

SummaryAs the absolute numbers and proportion of older adults increases across most of the developed world, a greater understanding of the aetiopathogenic mechanisms of the increased vascular risk and their therapeutic implications becomes essential to all clinicians assessing and managing the geriatric patient. The role of endothelial function and the microcirculation is increasingly recognized in the maintenance of adequate perfusion, and their dysfunction is thought to be an early and potentially reversible mechanism by which age acts to increase cardiovascular risk.Here we review evidence that altered microvascular function appears before other recognized predictors of vascular disease, and progresses from childhood to late adult life, preceding fulminant atherosclerotic or arteriosclerotic disease. Low birth-weight babies have reduced endothelial function in skin microvessels at 3 months, and by age ten brachial artery endothelial function is reduced in comparison with normal birth-weight babies. In overweight/obese adolescent children with clustering of traditional cardiovascular disease risk factors, endothelial function is lower compared with normal weight children and this appears to persist into early adulthood. Adult ageing is associated with impaired microvessel endothelial function and an increase in capillary blood pressure, independent of brachial artery blood pressure. Biological and lifestyle factors that influence microvessel function include body fat and visceral adiposity, sex hormone status, diet and physical activity.Exploration of the therapeutic implications for management of endothelial dysfunction remains in embryonic state. The use of ACE-inhibitors, angiotensin receptor blockers and direct renin inhibitors in patients with evidence of microvascular damage such as retinopathy and microalbuminuria has been established; however, in the general older population the benefit has yet to be established. Therefore current recommendations are to screen for microvascular damage and if present target treatments after control of other vascular risk factors such as hypertension.

Age is a primary risk factor for cardiovascular disease, and this is an increasingly important public health concern because of an increase in the absolute number and proportion of the population at an older age in many countries. A key component of cardiovascular ageing is reduced function of the vascular endothelium, and this probably contributes to the impaired microvessel function observed with ageing in multiple vascular beds. In turn, impaired microvessel function is thought to contribute to the pathophysiology of cardiovascular and metabolic diseases. Here we review evidence that the first signs of altered endothelial and microvessel function can appear in childhood and at all stages of the human lifespan; low-birth-weight babies have reduced endothelial function in skin microvessels at 3 months, and by age 10 years their brachial artery endothelial function is reduced in comparison with normal-birth-weight babies. In overweight/obese adolescent children with clustering of traditional cardiovascular disease risk factors, endothelial function is reduced compared with normal-weight children, and this appears to persist into early adulthood. Adult ageing is associated with impaired microvessel endothelial function and an increase in capillary blood pressure. Biological and lifestyle factors that influence microvessel function include body fat and visceral adiposity, sex hormone status, diet and physical activity. The mechanisms underlying age-associated changes in microvessel function are uncertain but may involve alterations in nitric oxide, prostanoid, endothelium-derived hyperpolarizing factor(s) and endothelin-1 pathways.

The grey-scale median of the common carotid artery intima-media complex (IM-GSM) characterizes arterial wall composition, and a low IM-GSM is associated with increased cardiovascular mortality in the elderly. We aimed to determine differences in the IM-GSM between a cohort with cerebrovascular disease and a healthy cohort. Eighty-two healthy individuals (control group: 63.2 ± 8.7 y) and 96 patients with either stroke or transient ischemic attacks (CRVD group: 68.6 ± 9.8 y) were studied. Common carotid artery intima-media thickness and IM-GSM obtained by ultrasound were analyzed using semi-automated edge-detection software. The IM-GSM was significantly lower in the CRVD group than in the control group (106 ± 24 vs. 124 ± 27 au, p < 0.001). The IM-GSM was similar for the infarct and non-infarct sides in CRVD. In the pooled cohort of all participants, the lower the quartile of IM-GSM, the greater were the carotid artery intima-media thickness and carotid artery remodeling. These results suggest the presence of an altered atherosclerotic phenotype in the intima-media complex of CRVD patients that can be detected by ultrasound.

Background The impact of diabetes on vascular target organ damage (TOD) is not wholly explained by conventional risk factors. African Caribbeans have a greater prevalence of diabetes and some aspects of TOD. We hypothesized that arterial stiffness, an independent cardiovascular risk factor, would be more prevalent with diabetes and in African Caribbeans with diabetes than Europeans. Methods We measured pulse wave velocity (PWV), a measure of arterial stiffness, in the carotid-to-femoral, carotid-to-radial and femoral-to-dorsalis pedis segments, of men and women aged 40 to 65 years from the general population: 49 and 100 Europeans; 66 and 88 African Caribbeans with and without diabetes, respectively. Results Carotid-to-femoral PWV was faster (ie, arteries were stiffer) in diabetes and faster in African Caribbeans with diabetes compared with Europeans. These diabetes differences in PWV persisted after adjustment for conventional cardiovascular risk factors; Europeans without diabetes (95% confidence interval [CI]) 11.8 (11.4–12.3) versus with diabetes 13.3 (12.5–14.1) m/sec, P = .005; African Caribbeans without diabetes 12.6 (12.1–13.2) versus 14.0 (13.2–14.9) m/sec with diabetes, P = .008 (all fully adjusted). The ethnic difference in diabetes was largely attenuated by multivariate adjustment (P = .4). In the carotid-to-radial segment there was no ethnic difference in those without diabetes; however, African Caribbeans with diabetes had significantly faster PWV, which was not observed in Europeans (P for diabetes:ethnicity interaction = .001). Conclusions Elastic arteries are stiffer in diabetes independent of traditional risk factors. African Caribbeans with diabetes have increased stiffness compared to Europeans, predominantly accounted for by blood pressure differences. Muscular arteries respond differently to diabetes in the two ethnic groups, which may reflect differences in remodeling.

Elevated albumin excretion rate (AER) independently predicts total and cardiovascular mortality in a variety of conditions, although the exact mechanisms are unknown. Laser Doppler fluximetry was used to study associations with risk factors and renal damage (AER calculated from a timed overnight urine collection) in 188 people without diabetes and 117 individuals with diabetes. Skin flow (flux) in response to arterial occlusion (ischemia) was measured. Three distinct patterns of postischemic peak flow were observed: 1) gradual rise to peak (normal), 2) nondominant early peak, and 3) dominant early peak. Those with a dominant early peak were more likely to have diabetes (P = 0.01), hypertension (P = 0.001), and obesity (P < 0.001) and had a higher AER (12.6 μg/min [95% CI 7.8–20.2] vs. 7.2 [5.5–9.5] nondominant early peak group and 3.7 [3.2–4.1] normal group; P < 0.001 for trend). This could not be accounted for by conventional cardiovascular risk factors (P < 0.001 after adjustment). A rapid peak flow response after ischemia is associated with an elevated AER and increased cardiovascular risk. This may represent shared mechanistic pathways and causative or con-sequential changes in the microvasculature and supports the hypothesis that microvascular dysfunction may contribute to large vessel pathophysiology.