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Summary Background Diabetes prevalence is increasing in most places in the world, but prevalence is affected by both risk of developing diabetes and survival of those with diabetes. Diabetes incidence is a better metric to understand the trends in population risk of diabetes. Using a multicountry analysis, we aimed to ascertain whether the incidence of clinically diagnosed diabetes has changed over time. Methods In this multicountry data analysis, we assembled aggregated data describing trends in diagnosed total or type 2 diabetes incidence from 24 population-based data sources in 21 countries or jurisdictions. Data were from administrative sources, health insurance records, registries, and a health survey. We modelled incidence rates with Poisson regression, using age and calendar time (1995–2018) as variables, describing the effects with restricted cubic splines with six knots for age and calendar time. Findings Our data included about 22 million diabetes diagnoses from 5 billion person-years of follow-up. Data were from 19 high-income and two middle-income countries or jurisdictions. 23 data sources had data from 2010 onwards, among which 19 had a downward or stable trend, with an annual estimated change in incidence ranging from −1·1% to −10·8%. Among the four data sources with an increasing trend from 2010 onwards, the annual estimated change ranged from 0·9% to 5·6%. The findings were robust to sensitivity analyses excluding data sources in which the data quality was lower and were consistent in analyses stratified by different diabetes definitions. Interpretation The incidence of diagnosed diabetes is stabilising or declining in many high-income countries. The reasons for the declines in the incidence of diagnosed diabetes warrant further investigation with appropriate data sources. Funding US Centers for Disease Control and Prevention, Diabetes Australia Research Program, and Victoria State Government Operational Infrastructure Support Program.

OBJECTIVE To investigate trends in the prevalence of hypertension and dyslipidaemia in incident type 2 diabetes (T2DM), time to antihypertensive (AHT) and lipid-lowering therapy (LLT), and the association with systolic blood pressure (SBP) and lipid control. RESEARCH DESIGN AND METHODS Using The Health Improvement Network UK primary care database, 254 925 people with incident T2DM and existing dyslipidaemia or hypertension were identified. Among those without atherosclerotic cardiovascular disease (ASCVD) history and not on AHT or LLT at diagnosis, the adjusted median months to initiating an AHT or an LLT, and the probabilities of high SBP or lipid levels over 2 years in people initiating therapy within or after 1 year were evaluated according to high and low ASCVD risk status. RESULTS At diabetes diagnosis, 66% and 66% had dyslipidaemia and hypertension, respectively. During 2005 to 2016, dyslipidaemia prevalence increased by 10% in people aged

AIM: To evaluate temporal patterns in co-morbidities, cardiometabolic risk factors and a high atherosclerotic cardiovascular disease (ASCVD) risk population at type 2 diabetes (T2D) diagnosis by age groups and sex. MATERIALS AND METHODS: From the UK primary care database, 248,619 people with a new diagnosis of T2D during 2005-2016 were identified. Among people without ASCVD, high ASCVD risk was defined as two or more of current smoker, grade 2+ obesity, hypertension, dyslipidaemia or microvascular disease. Cardiometabolic multimorbidity (CMM) was defined as two or more of cardiovascular disease, microvascular disease, hypertension, dyslipidaemia, grade 2+ obesity or cancer. Temporal patterns in the distribution of cardiometabolic risk factors were evaluated. RESULTS: While the prevalence of ASCVD was stable over time (approximately 18%), 50% were identified to have a high ASCVD risk (26% and 38% in the 18-39 and 40-49 years age groups, respectively), with an increasing trend across all age groups. Overall, 51% had CMM at diagnosis, increasing during 2005-2016 for the 18-39 years age group by 14%-17%, for the 40-49 years age group by 27%-33%, for the 50-59 years age group by 41%-50%, for the 60-69 years age group by 56%-65%, and for the 70-79 years age group by 65%-80%. People with young-onset T2D had significantly higher HbA1c, body mass index and lipids at diagnosis (all p

Aims To explore cardiometabolic risk profiles, the probability of sustainable control, and the effectiveness of treatment with sodium-glucose co-transporter-2 (SGLT2) inhibitors in black and white adults in the United States with type 2 diabetes. Materials and methods Using nationally representative US electronic medical records, 72 690 white and 10 004 black adults diagnosed with type 2 diabetes initiating SGLT2 inhibitors during the period 2013 to 2018, continuing it for ≥6 months, and with follow-up of ≥12 months, were identified. Glycated haemoglobin (HbA1c), body weight, systolic blood pressure (SBP) and lipid changes at 6 months, and sustainability of control over 18 months post SGLT2 inhibitor initiation were explored, separately in those with and without atherosclerotic cardiovascular disease (ASCVD). Results The white group was older (58 years) with lower mean HbA1c (8.5%), compared to the black group (age 54 years, HbA1c 9.0%). Body mass index distribution was similar. The proportions of people with uncontrolled SBP, LDL cholesterol, non-HDL cholesterol and triglyceride levels were 24%, 42%, 51% and 62%, respectively, in white patients, and 31%, 51%, 49% and 32%, respectively, in black patients. At 6-month follow-up white and black patients had similar adjusted reductions in HbA1c (1.1%), SBP (8-10 mmHg), LDL cholesterol (0.26 - 0.34 mmol / L) and body weight (1.1-1.4 kg). However, over 18 months' follow-up, compared to white patients, black patients were significantly less likely to achieve sustainable control in HbA1c (odds ratio [OR] 0.67, 95% confidence interval [CI] 0.63-0.72), body weight (OR 0.81, 95% CI 0.72-0.91), SBP (OR 0.67, 95% CI 0.61-0.74) and LDL cholesterol (OR 0.77, 95% CI 0.67-0.89). Triglyceride control was significantly better among black patients. Black patients had a significantly higher risk factor burden, irrespective of ASCVD status. Conclusions While the effectiveness of SGLT2 inhibitors was similar among black and white patients, irrespective of ASCVD status, black patients continued to have worse cardiometabolic risk factor burden after SGLT2 inhibitor initiation.

OBJECTIVE To evaluate temporal prevalence trend, cardiometabolic risk factors, and the risk of atherosclerotic cardiovascular disease (ASCVD) and all-cause mortality (ACM) in incident young- and usual-onset type 2 diabetes. RESEARCH DESIGN AND METHODS From the U.K. primary care database, 370,854 people with a new diagnosis of type 2 diabetes from 2000 to 2017 were identified. Analyses were conducted by age- group (18–39, 40–49, 50–59, 60–69, 70–79 years) and high-/low-risk status without history of ASCVD at diagnosis, with subjects with two or more of current smoking, high systolic blood pressure, high LDL cholesterol (LDL-C), or chronic kidney disease classified as high risk. RESULTS The proportion of people aged CONCLUSIONS Unlike usual-onset, young-onset type 2 diabetes has similar cardiovascular and mortality risk irrespective of cardiometabolic risk factor status at diagnosis. The guidelines on the management of young-onset type 2 diabetes for intensive risk factor management and cardioprotective therapies need to be urgently reevaluated through prospective studies.

Third-line antidiabetic drug (ADD) intensification patterns and glycemic control post intensification in type 2 diabetes mellitus (T2DM) have not been thoroughly explored in a real-world setting. This study explored the patterns and risks of third-line ADD intensification post second-line ADDs and the probability of desirable glucose control over 12 months by third-line ADD classes at the population level. We used the electronic medical records of 255,236 patients with T2DM in the USA initiating a second-line ADD post metformin from January 2013 to evaluate the rates and risks of third-line intensification and the probability of desirable glycemic control with different ADDs after addressing inherent heterogeneity using appropriate methodologies. Patients had a mean age of 60 years and glycated hemoglobin (HbA1c) of 8.5% at second-line ADD. Over 209,136 person-years (PY) of follow-up, 40% had initiated a third-line ADD at HbA1c of 8.8%. Patients receiving dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as the second-line ADD had a 7% (95% hazard ratio [HR] confidence interval [CI] 1.05–1.10) and 28% (95% HR CI 1.24–1.33) higher adjusted risk of intensifying with a third-line ADD than did those receiving sulfonylureas as the second-line ADD. Those receiving sodium-glucose cotransporter-2 inhibitors (SGLT-2i) as second-line ADD had a 17% (95% HR CI 0.80–0.87) lower risk. The adjusted probability of reducing HbA1c by ≥ 1% was similar in those receiving third-line sulfonylureas, thiazolidinediones, GLP-1 RAs, SGLT-2i, and insulin (minimum, maximum 95% CI of probability 0.61, 0.68), whereas those receiving DPP-4i had a significantly lower probability (0.58; 95% CI 0.56–0.59). Similarly, the probability of reducing HbA1c

Background Many people with advanced dementia live in residential aged care homes. Care home staff need the knowledge and skills to provide high-quality end-of-life (EOL) dementia care. However, several studies have found EOL dementia care to be suboptimal, and care staff have reported they would benefit from training in palliative care and dementia. Simulation offers an immersive learning environment and has been shown to improve learners’ knowledge and skills. However, there is little research on simulation training for residential care staff. This article presents the development and evaluation protocol of IMproving Palliative care Education and Training Using Simulation in Dementia (IMPETUS-D) - a screen-based simulation training program on palliative dementia care, targeted at residential care staff. IMPETUS-D aims to improve the quality of palliative care provided to people living with dementia in residential care homes, including avoiding unnecessary transfers to hospital. Methods A cluster RCT will assess the effect of IMPETUS-D. Twenty-four care homes (clusters) in three Australian cities will be randomised to receive either the IMPETUS-D intervention or usual training opportunities (control). The primary outcome is to reduce transfers to hospital and deaths in hospital by 20% over 6-months in the intervention compared to the control group. Secondary outcomes include uptake of goals of care plans over 6 and 12 months, change in staff knowledge and attitudes towards palliative dementia care over 6 months, change in transfers to hospital and deaths in hospital over 12 months. For the primary analysis logistic regression models will be used with standard errors weighted by the cluster effects. A mixed methods process evaluation will be conducted alongside the cluster RCT to assess the mechanisms of impact, the implementation processes and contextual factors that may influence the delivery and effects of the intervention. Discussion In Australia, the need for high-quality advanced dementia care delivered in residential aged care is growing. This study will assess the effect of IMPETUS-D a new simulation-based training program on dementia palliative and EOL care. This large multisite trial will provide robust evidence about the impact of the intervention. If successful, it will be distributed to the broader residential care sector. Trial registration ANZCTR, ACTRN12618002012257. Registered 14 December 2018.

Aim: Complex associations between T2DM, CKD and HF challenge treatment strategies and results in significant life years loss. Risk of CKD and HF in young- and usual-onset T2DM among White Caucasian (WC) and African American (AA) were explored. Methods: From nationally representative EMRs of USA, 1491672 WC and 31133 AA diagnosed with T2DM from 2000-2018 within age 18-39 /40-49/50-59/ 60-69 yrs were identified. The restricted mean time (RMT) to CKD and HF in AA and WC were compared, adjusting for anthropometric and time-varying disease confounders. Results: At T2DM Dx, 10 /12% and 2 /4% of WC /AA had existing CKD and HF; 48 /57% and 39 /32% had hypertension and dyslipidaemia. With mean 5 yrs follow-up, 95% CIs of CKD+HF incidence rates/1000PY were: (23-24) /(37-38) /(53-54) /(82-83) in 18-39 /40-49 /50-59/ 60-69 yrs grps for WC and (30-31) /(47-49) /(66-68) /(93-95) for AA. Compared to WC, AA had significantly higher risk of CKD and HF across all age groups (HR CI range: 1.1-2.4). In AA/WC aged 18-39 yrs, RMT (CI) in yrs to CKD [8.3 (7.8-8.7) /8.9 (8.5-9.2)] and HF [9.4 (8.6-10.3) /11.4 (9.8-12.9)] was on average only 3.2 /3.2 yrs and 2.7 /3.3 longer compared to those aged 60-69 yrs at Dx (Fig). Conclusion: Developing cardio-renal complications within 10 yrs of young-onset T2DM and significant higher risk among AA compared to WC call for more intense prevention strategies in young-onset population, particularly in AA. Disclosure S. K. Paul: Advisory Panel; Self; Sanofi, Consultant; Self; Roche Pharma. O. Montvida: None.

We determined the efficacy of tocilizumab (TCZ) in preventing grade 2-4 acute graft-versus-host disease (aGVHD) in patients with acute leukemia or myelodysplasia undergoing matched sibling donor (MSD) or volunteer unrelated donor (VUD) allogeneic stem cell transplantation after myeloablative or reduced-intensity conditioning across 5 Australian centers. A total of 145 patients (50 MSD, 95 VUD) were randomly assigned to placebo or TCZ on day −1. All patients received T-cell–replete peripheral blood stem cell grafts and graft-versus-host disease (GVHD) prophylaxis with cyclosporin/methotrexate. A planned substudy analyzed the VUD cohort. With a median follow-up of 746 days, the incidence of grade 2-4 aGVHD at day 100 for the entire cohort was 36% for placebo vs 27% for TCZ (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.38-1.26; P = .23) and 45% vs 32% (HR, 0.61; 95% CI, 0.31-1.22; P = .16) for the VUD subgroup. The incidence of grade 2-4 aGVHD at day 180 for the entire cohort was 40% for placebo vs 29% for TCZ (HR, 0.68; 95% CI, 0.38-1.22; P = .19) and 48% vs 32% (HR, 0.59; 95% CI, 0.30-1.16; P = .13) for the VUD subgroup. Reductions in aGVHD were predominantly in grade 2 disease. For the entire cohort, transplant-related mortality occurred in 8% vs 11% of placebo-treated vs TCZ-treated patients, respectively (P = .56), and overall survival was 79% vs 71% (P = .27). Median day to neutrophil and platelet engraftment was delayed by 2 to 3 days in TCZ-treated patients, whereas liver toxicity and infectious complications were similar between groups. In this phase 3 randomized double-blind trial, TCZ showed nonsignificant trends toward reduced incidence of grade 2-4 aGVHD in recipients from HLA-matched VUDs but no improvements in long term-survival.

OBJECTIVE To evaluate the temporal patterns of cardiometabolic multimorbidity (CM) and depression in White Caucasians (WCs) and African Americans (AAs) with early-onset type 2 diabetes and their impact on long-term atherosclerotic cardiovascular disease (ASCVD). RESEARCH DESIGN AND METHODS From U.S. electronic medical records, 101,104 AA and 505,336 WC subjects with type 2 diabetes diagnosed between 2000 and 2017 were identified (mean follow-up 5.3 years). Among those without ASCVD at diagnosis, risk of ASCVD and three-point major adverse cardiovascular events (MACE-3) (heart failure, myocardial infarction, or stroke) was evaluated between ethnicities by age-groups. RESULTS The proportion of patients diagnosed at CONCLUSIONS AAs have higher cardiovascular risk compared with WCs, particularly in early-onset type 2 diabetes. CM and depression at diabetes diagnosis have been increasing over the past two decades in both ethnic groups. Strategies for screening and optimal management of CM and depression, particularly in early-onset type 2 diabetes, may result in a lower cardiovascular risk.

Aims The aim of this study was to evaluate the temporal pattern of amputations in patients with type 2 diabetes mellitus (T2DM), the risk of amputations by new and older anti-diabetic drugs (ADDs), and the interplay of peripheral artery disease (PAD) with therapy and amputation risk. Methods and results Using Centricity Electronic Medical Records from USA, 3 293 983 patients with T2DM were identified: 169 739 received sodium-glucose cotransporter type-2 inhibitors (SGLT-2i; no exposure to incretins); 149 826 received glucagon-like peptide 1 receptor agonists [GLP-1RA, no SGLT-2i or dipeptidyl peptidase-4 inhibitor (DPP-4i) exposure]; 448 225 received DPP-4i (no exposure to GLP-1RA or SGLT-2i); and 1 954 353 received other ADDs. The proportion of incident amputations per 10 000 adults ranged between 4.7 and 6.8 during 2000–08 and significantly increased to 12.3 in 2017. Over 17 211 719 person-years follow-up post T2DM diagnosis, the rates per 1000 person-years of any and lower limb amputations (LLAs) were similar between SGLT-2i and incretins [95% confidence interval (CI) range: 1.06–1.67], and significantly higher in other groups (95% CI range: 1.96–2.29). In propensity score-adjusted pairwise analyses, the risk of LLA was not higher in SGLT-2i vs. GLP1-RA [hazard ratio (HR) (95% CI): 0.88 (0.73, 1.05)], and lower in SGLT-2i vs. DPP-4i/other ADD [HR (95% CI): 0.65 (0.56, 0.75)/0.43 (0.37, 0.49)]. The rate of LLA was similar in patients treated with canagliflozin, empagliflozin, or dapagliflozin. Patients with PAD had more than four-fold higher LLA risk (range of 95% CI of HR: 3.6–6.0). Conclusion The risk of amputation in patients treated with SGLT-2i and incretins was not higher compared with other ADDs. Pre-existing PAD was the greatest driver of amputation risk.

OBJECTIVE Individualized treatment of patients with diabetes requires detailed evaluation of risk factor dynamics at the population level. This study evaluated the persistent glycemic and cardiovascular (CV) risk factor burden over 2 years after treatment intensification (TI). RESEARCH DESIGN AND METHODS From U.S. Centricity Electronic Medical Records, 276,884 patients with incident type 2 diabetes who intensified metformin were selected. Systolic blood pressure (SBP) ≥130/140 mmHg and LDL ≥70/100 mg/dL were defined as uncontrolled for those with/without a history of CV disease at TI. Triglycerides ≥150 mg/dL and HbA1c ≥7.5% (58 mmol/mol) were defined as uncontrolled. Longitudinal measures over 2 years after TI were used to define risk factor burden. RESULTS With 3.7 years’ mean follow-up, patients were 59 years; 70% were obese; 22% had a history of CV disease; 60, 30, 50, and 48% had uncontrolled HbA1c, SBP, LDL, and triglycerides, respectively, at TI; and 81% and 69% were receiving antihypertensive and lipid-modifying therapies, respectively. The proportion of patients with consistently uncontrolled HbA1c increased from 31% in 2005 to 41% in 2014. Among those on lipid-modifying drugs, 41% and 37% had consistently high LDL and triglycerides over 2 years, respectively. Being on antihypertensive therapies, 29% had consistently uncontrolled SBP. Among patients receiving cardioprotective therapies, 63% failed to achieve control in HbA1c + LDL, 57% in HbA1c + SBP, 55% in LDL + SBP, and 63% in HbA1c + triglycerides over 2 years after TI. CONCLUSIONS Among patients on multiple therapies for risk factor control, more than one-third had uncontrolled HbA1c, lipid, and SBP levels, and more than one-half had two CV risk factors that were simultaneously uncontrolled after TI.

Background: Diabetic peripheral neuropathy (DPN) is a common complication in patients (pts) with diabetes. However, multinational data do not support any convincing efficacy of the current therapies for treating DPN. This necessitated the evaluation of safety and efficacy of alternative medicine to tackle DPN. Methods: A double-blinded RCT was conducted in 8 Chinese medicine hospitals in China, evaluating the safety and efficacy of 190 g Tangbi Waixi decoction (TW, intervention (Int)) compared with 19 g TW (control (Cont)). Change in Toronto Clinical Scoring System - Total Score (TCSS-TS) at 12 and 24 weeks follow-up was the primary outcome, with treatment ceasing at 12 weeks. Secondary outcomes included change in bilateral motor velocity (BMV) and sensory nerve conduction velocity (SNCV) of the common peroneal nerve (CPN). All pts received standard care for glycaemic management. The pts in the Int (n=317) and Cont (n=315) groups were analysed on ITT principle. All adverse events (AEs) were recorded. Results: The pts were mean 60 years old with median 10 yrs and 2 yrs of diabetes and DPN duration respectively at randomisation. With median TCSS-TS of 10 at randomisation in both groups, the median (95% CI) reduction in Int and Cont: at 12 weeks 2 (1.7, 2.3) and 3 (2.7, 3.3) respectively (median between group difference (MBGD): 1.0, p=0.011); at 24 weeks 3 (2.6, 3.4) in both groups. At 12 weeks, median (95% CI) CPN velocity increased in both Int and Cont - BMV Int vs. Cont: 2.7 (1.9, 4.9) m/s vs. 4.9 (2.7, 5.5) m/s, MBGD - 2.5 m/s (p=0.044); SNCV Int vs. Cont: 1.4 (0, 2) m/s vs. 2.7 (1.9, 4.9) m/s, MBGD - 0.7 m/s (p=0.26). Similar increase in CPN velocity was observed at 24 weeks in both groups. Overall 12% pts experienced at least one AE, with no difference between groups. Conclusion: Treatment of DPN with TW decoction significantly benefitted the pts and is safe, while lower dose of TW appears to be more effective than the higher does. Disclosure F. Guanjie: None. Y. Lin: None. S.K. Paul: Advisory Panel; Self; Sanofi. Research Support; Self; AstraZeneca, Genentech, Inc. H. Huang: None. T. Xianyu: None. Z. Yuehong: None. F. Zhaohui: None. Q. Xiaotang: None. D. Fang: None. S. Wang: None. M. Wang: None. H. Wei: None. Z. Ling: None. L. Zhenjie: None. Y. Fu: None. M. Wu: None. L. Anxiang: None. H. Jinzhu: None. Q. Li: None. Funding National Science and Technology Support Program (2015BAI04B09)

Current approaches to antibiotic dose determination in critically ill patients requiring renal replacement therapy are primarily based on the assessment of highly heterogeneous data from small number of patients. The standard modelling approaches limit the scope of constructing robust confidence boundaries of the distribution of pharmacokinetics (PK) parameters, especially when the evaluation of possible association of demographic and clinical factors at different levels of the distribution of drug clearance is of interest. Commonly used compartmental models generally construct the inferences through a linear or non-linear mean regression, which is inadequate when the distribution is skewed, multi-modal or effected by atypical observation. In this study, we discuss the statistical challenges in robust estimation of the confidence boundaries of the PK parameters in the presence of highly heterogenous patient characteristics. A novel stepwise approach to evaluate the confidence boundaries of PK parameters is proposed by combining PK modelling with mixed-effects quantile regression (MEQR) methods. This method allows the assessment demographic and clinical factors’ effects at any arbitrary quantiles of the outcome of interest, without restricting assumptions on the distributions. The MEQR approach allows us to investigate if the levels of association of the covariates are different at low, medium or high concentration. This methodological assessment is deemed as a background initial approach to support the development of a class of statistical algorithm in constructing robust confidence intervals of PK parameters which can be used for developing an optimised antibiotic dosing guideline for critically ill patients requiring renal replacement therapy.

Aims To estimate the risk of developing long-term major cardiovascular and renal complications in relation to levels of body mass index (BMI) in a population of White European (WE), African-Caribbean (AC), and South Asian (SA) patients with type 2 diabetes mellitus (T2DM). Materials and methods Patients with new diagnosis of T2DM, aged ≥ 18 years from January 2000 (n = 69,436) and their age-sex-ethnicity matched non-diabetic controls (n = 272,190) were identified from UK primary care database. Incidence rates ratios (IRRs) for non-fatal major cardiovascular events (MACE) and chronic kidney disease (CKD) in patients with T2DM compared to controls were estimated using multivariate Mantel-Cox model. Results Among normal weight patients with T2DM, WEs had significantly higher prevalence of cardiovascular multi-morbidity (95% CI 9.5, 11.3), compared to SAs (95% CI 4.8, 9.5). AC and SA overweight and obese patients had similar prevalence, while obese WEs had significantly higher prevalence. During a median 7 years of follow-up, risk of MACE was significantly higher for overweight (95% CI of IRR 1.50, 2.46) and obese (95% CI of IRR 1.49, 2.43) SAs compared to their WE counterparts. However, similar risk levels were observed for normal weight WEs and SAs, respectively. Risk of CKD was higher and uniform for BMI ≥ 25 kg/m2 amongst WEs and ACs, whereas only overweight patients had significantly higher risk of CKD amongst SA [IRR 2.08 (95% CI 1.49, 2.93)]. Conclusion Risk of MACE/CKD varies over levels of BMI within each ethnic group, with overweight SAs having a disproportionate risk of CKD. Electronic supplementary material The online version of this article (10.1186/s12933-018-0712-1) contains supplementary material, which is available to authorized users.

AIMS To inform patients and their carers about both the probability of reducing glycated haemoglobin (HbA1c) to clinically desirable levels and the sustainability of such control over 2 years with major second-line antidiabetic therapies, in individual risk scenarios, with and without third-line intensification. MATERIALS AND METHODS From US Centricity Electronic Medical Records, 163 081 patients with type 2 diabetes aged 18 to 80 years, who had initiated metformin, intensified their treatment with dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), sulphonylureas (SUs), insulin or thiazolidinediones (TZDs), and continued second-line treatment for ≥6 months, were selected. Treatment groups were balanced with regard to baseline characteristics, and glycaemic achievements were estimated using logistic regression analysis. RESULTS With HbA1c concentrations of 58-63.9 mmol/mol (7.5-7.9%) at second-line treatment initiation, the adjusted probabilities of achieving HbA1c

Background:Identification of diseased patients from primary care based electronic medical records (EMRs) has methodological challenges that may impact epidemiologic inferences.Objective:To compare deterministic clinically guided selection algorithms with probabilistic machine learning (ML) methodologies for their ability to identify patients with type 2 diabetes mellitus (T2DM) from large population based EMRs from nationally representative primary care database.Methods:Four cohorts of patients with T2DM were defined by deterministic approach based on disease codes. The database was mined for a set of best predictors of T2DM and the performance of six ML algorithms were compared based on cross-validated true positive rate, true negative rate, and area under receiver operating characteristic curve.Results:In the database of 11,018,025 research suitable individuals, 379 657 (3.4%) were coded to have T2DM. Logistic Regression classifier was selected as best ML algorithm and resulted in a cohort of 383,330 patients with potential T2DM. Eighty-three percent (83%) of this cohort had a T2DM code, and 16% of the patients with T2DM code were not included in this ML cohort. Of those in the ML cohort without disease code, 52% had at least one measure of elevated glucose level and 22% had received at least one prescription for antidiabetic medication.Conclusion:Deterministic cohort selection based on disease coding potentially introduces significant mis-classification problem. ML techniques allow testing for potential disease predictors, and under meaningful data input, are able to identify diseased cohorts in a holistic way.

OJBECTIVE To explore temporal trends in antidiabetes drug (ADD) prescribing and intensification patterns, along with glycemic levels and comorbidities, and possible benefits of novel ADDs in delaying the need for insulin initiation in patients diagnosed with type 2 diabetes. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes aged 18–80 years, who initiated any ADD, were selected (n = 1,023,340) from the U.S. Centricity Electronic Medical Records. Those who initiated second-line ADD after first-line metformin were identified (subcohort 1, n = 357,482); the third-line therapy choices were further explored. RESULTS From 2005 to 2016, first-line use increased for metformin (60–77%) and decreased for sulfonylureas (20–8%). During a mean follow-up of 3.4 years post metformin, 48% initiated a second ADD at a mean HbA1c of 8.4%. In subcohort 1, although sulfonylurea usage as second-line treatment decreased (60–46%), it remained the most popular second ADD choice. Use increased for insulin (7–17%) and dipeptidyl peptidase-4 inhibitors (DPP-4i) (0.4–21%). The rates of intensification with insulin and sulfonylureas did not decline over the last 10 years. The restricted mean time to insulin initiation was marginally longer in second-line DPP-4i (7.1 years) and in the glucagon-like peptide 1 receptor agonist group (6.6 years) compared with sulfonylurea (6.3 years, P < 0.05). CONCLUSIONS Most patients initiate second-line therapy at elevated HbA1c levels, with highly heterogeneous clinical characteristics across ADD classes. Despite the introduction of newer therapies, sulfonylureas remained the most popular second-line agent, and the rates of intensification with sulfonylureas and insulin remained consistent over time. The incretin-based therapies were associated with a small delay in the need for therapy intensification compared with sulfonylureas.

Background: Electronic Medical Records (EMRs) from primary/ ambulatory care systems present a new and promising source of information for conducting clinical and translational research. Objectives: To address the methodological and computational challenges in order to extract reliable medication information from raw data which is often complex, incomplete and erroneous. To assess whether the use of specific chaining fields of medication information may additionally improve the data quality. Methods: Guided by a range of challenges associated with missing and internally inconsistent data, we introduce two methods for the robust extraction of patient-level medication data. First method relies on chaining fields to estimate duration of treatment (“chaining”), while second disregards chaining fields and relies on the chronology of records (“continuous”). Centricity EMR database was used to estimate treatment duration with both methods for two widely prescribed drugs among type 2 diabetes patients: insulin and glucagon-like peptide-1 receptor agonists. Results: At individual patient level the “chaining” approach could identify the treatment alterations longitudinally and produced more robust estimates of treatment duration for individual drugs, while the “continuous” method was unable to capture that dynamics. At population level, both methods produced similar estimates of average treatment duration, however, notable differences were observed at individual-patient level. Conclusion: The proposed algorithms explicitly identify and handle longitudinal erroneous or missing entries and estimate treatment duration with specific drug(s) of interest, which makes them a valuable tool for future EMR based clinical and pharmaco-epidemiological studies. To improve accuracy of real-world based studies, implementing chaining fields of medication information is recommended.

Aim The Xiaoke Pill containing Chinese herb extracts and Glibenclamide, is used in therapy for type 2 diabetes mellitus (T2DM), and is effective in reducing the risk of hypoglycemia and improving diabetes symptoms compared with Glibenclamide. We describe a quantitative proteomics project to measure the T2DM serum proteome response to the Xiaoke Pill and Glibenclamide. Methods Based on a recently conducted 48-week clinical trial comparing the safety and efficacy of Glibenclamide (n = 400) and Xiaoke Pill (n = 400), after matching for age, sex, BMI, drug dose and whether hypoglycemia occurred, 32 patients were selected for the serum based proteomic analysis and divided into four groups (with/without hypoglycemia treated with Xiaoke Pill or Glibenclamide, n = 8 for each group). We screened the differential serum proteins related to treatments and the onset of hypoglycemia using the iTRAQ labeling quantitative proteomics technique. Baseline and follow-up samples were used. Results The quantitative proteomics experiments demonstrated that 25 and 21 proteins differed upon treatment with the Xiaoke Pill in patients without and with hypoglycemia, respectively, while 24 and 25 proteins differed upon treatment with Glibenclamide in patients without and with hypoglycemia, respectively. The overlap of different proteins between the patients with and without hypoglycemia given the same drug treatment was much greater than between the patients given different drug treatments. Conclusions We conclude that the serum proteins response to the two different anti-diabetic drug treatments may serve as a sensitive biomarker for evaluation of the therapeutic effects and continue investigations into the mechanism. Electronic supplementary material The online version of this article (doi:10.1186/s12014-017-9154-0) contains supplementary material, which is available to authorized users.

Augmented renal clearance (ARC) is known to influence β-lactam antibiotic pharmacokinetics. This substudy of the BLING-II trial aimed to explore the association between ARC and patient outcomes in a large randomised clinical trial. BLING-II enrolled 432 participants with severe sepsis randomised to receive β-lactam therapy by continuous or intermittent infusion. An 8-h creatinine clearance (CLCr) measured on Day 1 was used to identify ARC, defined as CLCr ≥ 130 mL/min. Patients receiving any form of renal replacement therapy were excluded. Primary outcome was alive ICU-free days at Day 28. Secondary outcomes included 90-day mortality and clinical cure at 14 days following antibiotic cessation. A total of 254 patients were included, among which 45 (17.7%) manifested ARC [median (IQR) CLCr 165 (144–198) mL/min]. ARC patients were younger (P

Aims: To compare glucose control and safety of different basal insulin therapies (BI, including Insulin NPH, glargine and detemir) in real-world clinical settings based on a large-scale registry study.Methods: In this multi-center 6-month prospective observational study, patients with type 2 diabetes (HbA1c >= 7%) who were uncontrolled by oral anti-diabetic drugs (OADs) and were willing to initiate BI therapy were enrolled from 209 hospitals within 8 regions of China. Type and dose of BI were at the physician's discretion and the patients' willingness. Interviews were conducted at 0 months (visit 1), 3 months (visit 2) and 6 months (visit 3). Outcomes included change in HbA1c, hypoglycemia rate and body weight from baseline at 6 months.Results: A total of 16 341 and 9002 subjects were involved in Intention-To-Treat (ITT) and per-protocol (PP) analysis, respectively. After PS regression adjustment, ITT analysis showed that reduction in HbA1c in glargine (2.2% +/- 2.1%) and detemir groups (2.2% +/- 2.1%) was higher than that in the NPH group (2.0% +/- 2.2%) (P < .01). The detemir group had the lowest weight gain (-0.1 +/- 2.9 kg) compared with the glargine (+0.1 +/- 3.0 kg) and NPH (+0.3 +/- 3.1 kg) groups (P < .05). The glargine group had the lowest rate of minor hypoglycaemia, while there was no difference in severe hypoglycaemia among the 3 groups. The results observed in PP analyses were consistent with those in ITT analysis.Conclusion: In a real-world clinical setting in China, treatment with long-acting insulin analogues was associated with better glycaemic control, as well as less hypoglycaemia and weight gain than treatment with NPH insulin in type 2 diabetes patients. However, the clinical relevance of these observations must be interpreted with caution.

There is increasing interest in gait training devices to improve walking ability in people following stroke. This randomised controlled trial aimed to compare the effectiveness of the Robowalk, a novel cable-driven gait trainer combined with conventional physiotherapy to conventional physiotherapy alone in improving walking speed, endurance, balance, functional outcomes, and quality of life in people following stroke. Rehabilitation inpatients within 3 months following stroke (n = 40) were randomised to standard care with conventional physiotherapy ('control,' n = 20) and cable-driven gait trainer combined with conventional physiotherapy ('intervention,' n = 20). All participants received 1 hour of physiotherapy a day, 5 days a week. The control group received conventional physiotherapy only; the intervention group received a combination of 30 minutes of conventional physiotherapy and 30 minutes of cable-driven gait trainer consecutively. Outcome measures were 10-metre walk test (primary outcome), 6-minute walk test, timed up and go, step test, Functional Independence Measure, and EuroQol five-dimension scale. Evaluation timepoints were on admission (T0), discharge (T1), and 4 weeks post discharge (T2). There were no differences between groups at T0, T1, and T2 in all outcome measures although there was a trend towards a larger and more sustained improvement in 10-metre walk test in favour of the intervention group and in Functional Independence Measure motor and self-care in favour of the control group, both at T2. The combination of cable-driven gait trainer with conventional physiotherapy appears as effective as conventional physiotherapy alone in improving gait outcomes in people following a recent stroke. Further studies are required to confirm these findings and determine optimal dosing regimens and long-term outcomes.

Aim: Temporal trend in the prevalence and incidence of depression (DP), any mental illness (AMI) and use of anti-depressants (ADM) in incident T2DM pts is not well known. We evaluate these trends and the risk of developing DP in young pts in real world settings from U.S. and UK. Method: Adults with diagnosis (Dx) of T2DM from 2000 from Centricity Electronic Medical Records of U.S. and The Health Improvement Network (THIN) database of UK were examined. Results: In U.S. (n= 1,395,572)/UK (n= 343,714) cohorts, the age at T2DM Dx was 59/58 years, 2/8% had Dx of DP but were not on ADM, 16/10% were on ADM without DP or AMI Dx, 9/15% were using ADM with Dx of DP. The prevalence of DP, AMI and ADM use increased exponentially in UK since 2000 (Figure B), while an increasing prevalence in AMI and ADM use was seen in U.S. (Figure A). Between 2000-2016, the use of ADM without Dx of DP or AMI increased from 16-26%/5-41% in U.S./UK cohort. Incidence rates of DP and ADM use were significantly higher in the U.S. cohort compared to UK (Figures C and D). Among pts without a co-morbid condition at T2DM Dx, younger U.S./UK pts (≤ 50 years) had 28%/18% significantly higher risks of developing DP compared to older pts (≥ 60 years); among pts with existing co-morbidity, the risks were higher by 46%/33%. Conclusion: In incident T2DM pts in UK and U.S., a striking rise in the prevalence of DP and the ADP use without Dx of AMI is seen, with younger pts having higher risk of developing DP. Disclosure J. Dibato: None. D. Koye: None. W. Polonsky: Consultant; Self; Abbott, Bigfoot Biomedical, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Johnson & Johnson Diabetes Institute, Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. O. Montvida: None. S.K. Paul: Consultant; Self; AstraZeneca, Roche Pharma. Research Support; Self; Roche Pharma.

Aim: Benefits of early initiation of SGLT2 and GLP-1RA for glucose and cardiovascular (CV) risk factor control at population level real-world setting is not known. Association of early (≤ 6 months) vs. late (>6 months) initiation of these drugs in the antidiabetic therapy management pathway on sustainable HbA1c, body weight, blood pressure and lipid control was evaluated. Method: U.S. Centricity Electronic Medical Records of 21,897/28,266 pts with T2DM receiving SGLT2/GLP-1RA post 2013 without therapy overlap with min of 1 year follow-up was used. Odds of reducing CV risk factors within 6 month and maintaining the control over 1 year was estimated by timeline of these antidiabetes drug (ADD) initiation (first prescription date of SGLT2 or GLP-1RA - first prescription date of any first line ADD): HbA1c < 7.5%, body weight reduction > 5%, SBP < 130/140 mmHg and LDL-C 70/100 mg/dL for patients with/without CVD history. Propensity score based balanced analyses were conducted. Results: At SGLT2/GLP-1RA initiation, patients were 57/58 years old, mean HbA1c 8.7/8.8%, 79/76% had HbA1c ≥ 7.5%, body weight 102/107 Kg, 26/28% and 45/45% had uncontrolled SBP and LDL-C respectively, 22/22% had existing CVD, 80/78% and 84/86% were on lipid lowering and anti-hypertensive drugs respectively. Compared to late initiators, the early initiation of SGLT2/GLP-1RA was significantly associated with 47% (CI of OR: 1.27, 1.71)/23% (CI of OR: 1.07, 1.42) higher odds for longer term HbA1c control, and 58% (CI of OR: 1.31, 1.91)/52% (CI of OR: 1.28, 1.83) higher odds for at least two of the CV risk factors control simultaneously. The odds for risk factor control was similar for the two drugs, and similar for those with and without history of CVD. Conclusion: This study based on large representative U.S. data suggests significant benefits of initiating SGLT2 or GLP-1RA early on the antidiabetes therapy management pathway for holistic glycaemic and cardiovascular risk factor control in patients with and without existing CVD. Disclosure S.K. Paul: Consultant; Self; AstraZeneca, Roche Pharma. Research Support; Self; Roche Pharma. D. Koye: None. K. Khunti: Advisory Panel; Self; Amgen Inc., AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Servier, Takeda Pharmaceutical Company Limited. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. Speaker's Bureau; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Menarini Group, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi, Servier, Takeda Pharmaceutical Company Limited. O. Montvida: None.

ObjectiveTo explore possible associations of treatment with biological disease-modifying antirheumatic drugs (bDMARDs), including T-cell-based and interleukin-6 inhibition (IL-6i)-based therapies, and the risk for type 2 diabetes mellitus (T2DM) in patients with rheumatoid arthritis (RA).Study design, setting and participantsFive treatment groups were selected from a United States Electronic Medical Records database of 283 756 patients with RA (mean follow-up, 5 years): never received bDMARD (No bDMARD, n=125 337), tumour necrosis factor inhibitors (TNFi, n=34 873), IL-6i (n=1884), T-cell inhibitors (n=5935) and IL-6i+T cell inhibitor abatacept (n=1213). Probability and risk for T2DM were estimated with adjustment for relevant confounders.ResultsIn the cohort of 169 242 patients with a mean 4.5 years of follow-up and a mean 641 200 person years of follow-up, the adjusted probability of developing T2DM was significantly lower in the IL-6i (probability, 1%; 95% CI 0.6 to 2.0), T-cell inhibitor (probability, 3%; 95% CI 2.3 to 3.3) and IL-6i+T cell inhibitor (probability, 2%; 95% CI 0.1 to 2.9) groups than in the No bDMARD (probability, 5%; 95% CI 4.6 to 4.9) and TNFi (probability, 4%; 95% CI 3.7 to 4.7) groups. Compared with No bDMARD, the IL-6i and IL-6i+T cell inhibitor groups had 37% (95% CI of HR 0.42 to 0.96) and 34% (95% CI of HR 0.46 to 0.93) significantly lower risk for T2DM, respectively; there was no significant difference in risk in the TNFi (HR 0.99; 95% CI 0.93 to 1.06) and T-cell inhibitor (HR 0.96; 95% CI 0.82 to 1.12) groups.ConclusionsTreatment with IL-6i, with or without T-cell inhibitors, was associated with reduced risk for T2DM compared with TNFi or No bDMARDs; a less pronounced association was observed for the T-cell inhibitor abatacept.

Aims To investigate the probability of developing type 2 diabetes mellitus (T2DM) at different body mass index levels compared to matched non-diabetic controls in a multi-ethnic population. Materials and methods This was a case-control study of 90 367 patients with incident diabetes and 362 548 age-sex-ethnicity matched controls from UK primary care. The probability of developing T2DM was estimated. Results Case and control patients were 56 years old at index and 56% were male. Patients with T2DM had significantly higher mean BMI levels by about 5 kg/m2 at diagnosis (32.2 kg/m2) compared to the matched controls (27.4 kg/m2). White Europeans (n = 79 270), African-Caribbeans (n = 4115) and South Asians (n = 7252) were 58, 48 and 46 years old with a mean BMI of 32.5, 31.1 and 29.2 kg/m2, respectively, at diagnosis. More South Asians developed T2DM at BMI below 30 kg/m2 (38%) than White Europeans (26%) and African-Caribbeans (29%) (all P

BackgroundThe need for healthcare workers (HCWs) to have skills and knowledge in non-cancer palliative care has been recognised. Simulation is increasingly being used for palliative care training, offering participants the opportunity to learn in a realistic environment and fully interactive way.ObjectiveThe aim of this systematic review was to summarise and critically appraise controlled studies on simulation training in non-cancer palliative care for HCWs.SelectionMedline, CINAHL, PubMed and Cochrane Library databases were searched using palliative care and simulation terms. Randomised controlled trials (RCTs), non-randomised RCTs and controlled before-and-after (CBA) studies were included. Two reviewers independently screened titles and abstracts and undertook full article review using predefined selection criteria. Studies that met the inclusion criteria had data extracted and risk of bias assessed using the Cochrane Effective Practice and Organisation of Care risk of bias criteria.FindingsFive articles were included: three RCTs and two CBA studies. All studies assessed learners’ palliative care communication skills, most studies evaluated learners’ perception of change in skills and one study assessed impact on patient outcomes and learners’ change in behaviour when applied in practice. There was variation in intervention content, intensity and duration, outcome measures and study design, making it difficult to compare and synthesise results.ConclusionThere is a paucity of evidence to support simulation training to improve non-cancer palliative care. This review highlights the need for more robust research, including multicentre studies that use standardised outcome measures to assess clinician skills, changes in clinical practice and patient-related outcomes.

Background and aims The association of beta-blockers and their selectivity with mortality and cardiovascular events in patients with and without hypoglycaemia is unknown. Methods and results Insulin-treated patients with diabetes were identified within the UK CPRD database. All-cause deaths, cardiovascular events, and hypoglycaemic episodes were captured to assess the interaction between beta-blocker therapy and selectivity with hypoglycaemia. 13,682 patients, of which 2036 (14.9%) with at least one hypoglycaemic episode, were included; 3148 deaths and 1235 cardiovascular events were recorded during a median of 2.3 and 4.7 years in patients with and without incident hypoglycaemia, respectively. Treatment with any beta-blocker was not associated with risk of death in both patients with and without hypoglycaemia, without significant interaction. Compared to no therapy, non-selective beta-blockers were associated with higher risk of death in patients without hypoglycaemia (hazard ratio (HR) 2.93 [1.26–6.83] in the fully adjusted model) but not in those with hypoglycaemia; interactions was not significant. For beta1-selective beta-blockers, there was no association with mortality in both patients with and without hypoglycaemia, without significant interaction. After missing data imputation, results were consistent for non-selective beta-blockers (HR in patients without hypoglycaemia 1.59 [1.22–2.08]) while indicated a reduced risk of death for beta1-selective beta-blockers in patients with hypoglycaemia (HR 0.76 [0.61–0.94]). Due to few cardiovascular events, complete-case analysis compared only any vs no beta-blocker therapy and indicated no associations with therapy or interaction by hypoglycaemia. Conclusion In patients with hypoglycaemic episodes, treatment with beta1-selective beta-blockers may potentially reduce the risk of death. These explorative findings and the potential role of confounding by indication need to be evaluated in other studies.

Aims: In people with metformin-treated diabetes, to evaluate the risk of acute pancreatitis, pancreatic cancer and other diseases of the pancreas post second-line anti-hyperglycaemic agent initiation. Methods: People with Type 2 diabetes diagnosed after 2004 who received metformin plus a dipeptidyl peptidase-4 inhibitor (DPP-4i, n = 50 095), glucagon-like peptide-1 receptor agonist (GLP-1RA, n = 12 654), sulfonylurea (n = 110 747), thiazolidinedione (n = 17 597) or insulin (n = 34 805) for at least 3 months were identified in the US Centricity Electronic Medical Records. Time to developing acute pancreatitis, other diseases of the pancreas and pancreatic cancer was estimated, balancing and adjusting anti-hyperglycaemic drug groups for appropriate confounders. Results: In the DPP-4i group, the adjusted mean time to acute pancreatitis was 2.63 [95% confidence intervals (CI) 2.38, 2.88] years; time to pancreatic cancer was 2.70 (2.19, 3.21) years; and time to other diseases of the pancreas was 2.73 (2.33, 3.12) years. Compared with DPP-4i, the insulin group developed acute pancreatitis 0.48 years (P

AIM: To evaluate the risk of CVD and all-cause mortality at different BMI levels in conjunction with weight change prior to diagnosis of T2DM in a multi-ethnic population. METHODS: Longitudinal study of 51,455 patients with T2DM and without a history of comorbid diseases at diagnosis. Weight changes prior to diagnosis of T2DM were evaluated, and the risk of CVD and all-cause mortality at different BMI levels among three ethnic groups estimated using treatment effects model. RESULTS: White Europeans (WE), African-Caribbeans (AC), and South Asians (SA) were mean 52, 49, and 47 years with a mean BMI of 33.0, 32.0, and 30.0 kg/m2 at diagnosis, respectively. Among WE, normal weight patients developed CVD significantly earlier by 0.5 years (95% CI 0.1, 0.9 years; p = 0.018) compared to obese patients. Furthermore, those with normal body weight at diagnosis were significantly more likely to die earlier by 0.6 years (95% CI 0.03, 1.2 years; p = 0.037) among WE and by 2.5 years (95% CI 0.3, 4.6 years; p = 0.023) among SA compared to their respective obese patients. However, BMI at diagnosis was not associated with increased risk of CVD and death among AC. CONCLUSIONS: This study suggests a paradoxical association of BMI with cardiovascular and mortality risks in different ethnic groups, which may partially be driven by different cardiovascular and glycaemic risk profiles at diagnosis.

A large proportion of diabetes patients do not receive a basic minimum of standard care. Telemedicine holds the promise of improving access to health care. However, the validity of remote consultation for diabetes has not been well researched. This pilot randomized control trial was designed to evaluate the agreement on prescription decisions of endocrinologists between two consultation formats: videoconferencing and face-to-face (in-person) consultation.Seventy-three patients were randomized to telemedicine (n=36) and reference group (n=37). Each study patient in the telemedicine group received one face-to-face consultation and one video consultation. The reference group received two face-to-face consultations. The paired consultations for each patient were performed by two different endocrinologists. The level of agreement between endocrinologists was evaluated by comparing their recommendations on antidiabetes and cardioprotective medications.The level of agreement between two endocrinologists on changing antidiabetes drugs was 64% in the telemedicine group and 78% in the reference group. Although the level of agreement was lower when one of the consultations was provided via videoconference, the difference was not significant. The level of agreement on changing cardiovascular drugs was 78% in the telemedicine group and 76% in the reference group, again not significantly different.The results of this study demonstrate the preliminary evidence on the validity of recommendations made by endocrinologists via video consultation. Known limitations of videoconferencing for clinical purposes did not have remarkable impact on the outcome of consultation in terms of adjustment of patient's medications. Video teleconsultation can substitute for a considerable proportion of conventional outpatient specialty consultations for people with diabetes.

Background The cardiovascular and mortality risk in patients with incident type 2 diabetes (T2D) in relation to smoking status and concurrent use of metformin is not well known. Methods A cohort study was performed in 82 205 incident T2D patients from the UK Clinical Practice Research Datalink. In the present study, the risks of myocardial infarction (MI), stroke, and mortality in incident T2D patients were evaluated in relation to their smoking status with and without concurrent use of metformin. Results Over a median 5.4 years of follow-up, of patients without a history of cardiovascular disease (CVD) before a diagnosis of diabetes (n = 63 166), current smokers with and without metformin had an 8% (hazard ratio [HR] 1.08; 95% confidence interval [CI] 0.81, 1.45) and 32% (HR 1.32; 95% CI 1.07, 1.65) increased risk of MI or stroke, respectively, compared with non-smokers without metformin treatment. The respective HRs (95% CI) for mortality in these patients were 0.96 (0.83, 1.11) and 1.86 (1.68, 2.07). The HR for mortality among ex-smokers with and without concurrent metformin treatment was 0.92 (95% CI 0.83, 1.11) and 1.19 (95% CI 1.10, 1.30), respectively. Similar beneficial modifiable effects of metformin among ex- and current smokers were observed in patients with CVD before diagnosis of diabetes (n = 19 039). Conclusions In T2D patients, concurrent treatment with metformin attenuates the observed higher cardiovascular and mortality risk in ex- and current smokers. In addition to smoking cessation support, treatment with metformin, particularly in ex- and current smokers, should be encouraged.

Background Undiagnosed comorbid diseases that independently lead to weight loss before type 2 diabetes mellitus (T2DM) diagnosis could explain the observed increased mortality risk in T2DM patients with normal weight. Objectives To evaluate the impact of weight change patterns before the diagnosis of T2DM on the association between body mass index (BMI) at diagnosis and mortality risk. Methods This was a longitudinal cohort study using 145,058 patients from UK primary care, with newly diagnosed T2DM from January 2000. Patients aged 18–70, without established disease history at diagnosis (defined as the presence of cardiovascular diseases, cancer, and renal diseases on or before diagnosis) were followed up to 2014. Longitudinal 6-monthly measures of bodyweight three years before (used to define groups of patients who lost bodyweight or not before diagnosis) and 2 years after diagnosis were obtained. The main outcome was all-cause mortality. Results At diagnosis, mean (SD) age was 52 (12) years, 56% were male, 52% were current or ex-smokers, mean BMI was 33 kg/m2, and 66% were obese. Normal weight and overweight patients experienced a small but significant reduction in body weight 6 months before diagnosis. Among all categories of obese patients, consistently increasing body weight was observed within the same time window. Among patients who did not lose body weight pre-diagnosis (n = 117,469), compared with the grade 1 obese, normal weight patients had 35% (95% CI of HR: 1.17, 1.55) significantly higher adjusted mortality risk. However, among patients experiencing weight loss before diagnosis (n = 27,589), BMI at diagnosis was not associated with mortality risk (all p > 0.05). Conclusions Weight loss before the diagnosis of T2DM was not associated with the observed increased mortality risk in normal weight patients with T2DM. This emphasises the importance of addressing risk factors post diagnosis for excess mortality in this group.

Background Self-monitoring of blood glucose (SMBG) is used as a means to detect and prevent hypoglycemia in patients with diabetes. However, information on the longitudinal measures (trajectory) of SMBG-based pre- and postprandial glucose fluctuations over time in relation to hypoglycemia is limited. Among patients treated with exenatide once weekly (EQW) or insulin glargine (IG), this study compared SMBG profiles over 52 weeks between patients who did and did not experience hypoglycemia. Methods Pooled patient-level 52-week longitudinal data of treatment with EQW (n = 531) or IG (n = 219) from three controlled trials were analyzed. Results The proportion of patients with at least one episode of hypoglycemia in the EQW and IG groups was 23% and 54%, respectively. The preprandial glucose measures from SMBG were significantly lower among patients who experienced hypoglycemia in both treatment groups compared with those who did not. In patients who experienced hypoglycemia, the average preprandial glucose levels over 52 weeks were lower by 0.64 and 0.66 mmol/L in the EQW and IG groups, respectively (P < 0.01 in both cases) compared with those without hypoglycemia. The average postprandial levels were not significantly different between patients who did and did not experience hypoglycemia in both treatment groups. Among patients with hypoglycemia, the average prebreakfast glucose trajectory was higher by 0.48 mmol/L in the EQW compared with the IG group. Conclusions This study has revealed differential trajectories of pre- and postprandial glucose profiles between patients with and without hypoglycemia. However, the SMBG trajectories were similar between patients treated with EQW and IG.

Background While rheumatoid arthritis (RA) has been associated with the increased risk of developing type 2 diabetes mellitus (T2DM), few basic science studies have indicated the possible beneficial role of some biologic disease-modifying antirheumatic drugs (bDMARDs), including the interleukin-6 (IL-6) based DMARDs, on insulin resistance in patients with RA. Objectives To evaluate the impact of treatment with bDMARDs, including the IL-6 inhibitors, on the probability of developing T2DM in a real world setting. Methods From the Centricity Electronic Medical Records of GE Healthcare, a longitudinal cohort of 192,509 US adults (age≥18 years) with diagnosis of RA from January 2000 to April 2016 was selected. Patients were excluded if they had a prior history of diabetes, cancer and micro- or macro-vascular diseases at diagnosis of RA. Four mutually exclusive antirheumatic treatment groups (TGs) were identified by diagnosis date (Dx) and treatment initiation date (ID): tocilizumab (TCZ, n=843), TCZ+Other bDMARDs (TCZ+obDMARD, n=2489), non-TCZ other bDMARDs (obDMARD, n=45,262) and no bDMARD (n=143,915). Within the treatment groups, 142,225 patients had a minimum 6 months of exposure before development of T2DM or end of follow-up. Treatment-effects regression models were used to estimate the probabilities (95% CI) of developing T2DM during follow-up in the 4 TGs after adjusting and balancing with inverse-probability-weighted regression for various factors including age, sex, smoking status, body mass index, use of non-biologic DMARDs, use of statins, anaemia status and follow-up time post ID. Results At diagnosis, the 142,225 patients were on average 55 years old, 22% male, 71% white Caucasian, 13% with anaemia, and 32% obese with mean BMI of 29 kg/m 2 . About 28%/42% were using statins/MTX at diagnosis or during follow-up before development of T2DM. During mean 4.6 years of follow-up from Dx, 2.6%/2.6%/5.3%/5.8% developed T2DM in the TCZ/TCZ+obDMARD/obDMARD/no bDMARD TGs. The adjusted probability of developing T2DM was 0.05 (95% CI: 0.04, 0.05) in no bDMARD group; with significantly lower probability of developing T2DM in TCZ [0.02 (95% CI: 0.01, 0.04)], TCZ+obDMARD [0.03 (95% CI: 0.02, 0.04)] and obDMARD [0.01 (95% CI: 0.01, 0.02)] groups (Table). Hypertension, higher BMI and Statin use were associated with significantly higher probability of developing T2DM by 0.25 (95% CI: 0.16, 0.35), 0.08 (95% CI: 0.07, 0.08) and 0.36 (95% CI: 0.27, 0.47) respectively. Patients with anaemia had 8% higher likelihood of developing T2DM (p=0.13). Among those who received any bDMARD, those who ever received TCZ had significantly lower probability of developing T2DM (0.024, 95% CI: 0.02, 0.03), compared to those who were never exposed to TCZ therapy. Conclusions This study indicates the possible beneficial role of IL-6 inhibitors (TCZ) in reducing the likelihood of developing T2DM among adults without major co-morbidities at diagnosis of RA. Acknowledgements Funding by F. Hoffmann-La Roche/Genentech. Disclosure of Interest S. Paul Grant/research support from: Therapeutic Innovations Australia, O. Montvida: None declared, J. Best Employee of: Genentech, S. Gale Employee of: Genentech, A. Pethoe-Schramm Employee of: F. Hoffmann-La Roche, K. Sarsour Employee of: Genentech

Background To evaluate the impact of treatment with disease-modifying antirheumatic drugs (DMARDs), including IL-6 receptor inhibitor tocilizumab (TCZ), on anaemia markers in patients with rheumatoid arthritis. Methods Using the Centricity Electronic Medical Records from USA, patients with rheumatoid arthritis diagnosed between January 2000 and April 2016, who initiated TCZ ( n = 3732); tofacitinib (TOFA, n = 3126); other biologic DMARD (obDMARD, n = 55,964); or other non-biologic DMARD (onbDMARD, n = 91,236) were identified. Changes in haemoglobin (Hb) and haematocrit (Hct) over 2 years of treatment initiation were evaluated, adjusting and balancing for confounders. Results Mean (95% CI) adjusted increase in Hb and Hct levels at 24 months in TCZ group were 0.23g/dL (0.14, 0.42) and 0.96% (0.41, 1.52) respectively. Among patients with anaemia in the TCZ group, Hb and Hct increased significantly by 0.72g/dL and 2.06%, respectively. Patients in the TCZ group were 86% (95% CI of OR: 1.43, 2.00) more likely to increase Hb ≥ 1g/dL compared to the other groups combined. No clinically significant changes in Hb were observed in the other groups. The obDMARD group demonstrated lower Hct increase than TCZ group, while no significant changes were observed in the remaining groups. Compared to those who initiated TCZ therapy after 1 year of diagnosis of rheumatoid arthritis, those who initiated earlier were 95% (OR = 1.95; 95% CI: 1.19, 3.21; p Conclusions This real-world study suggests significant increase in Hb and Hct levels after TCZ therapy in anaemic and non-anaemic patients with rheumatoid arthritis, compared with other biologic and non-biologic DMARDs.

Aims To evaluate whether plasma glycated albumin, which provides an integrated measure of plasma glucose levels over the preceding 2–4 weeks, better reflects changes in postprandial glucose excursions than HbA1c. Methods People with suboptimum glycaemic control on dual oral therapy were enrolled in the Treating-to-Target-in-Type 2 diabetes (4-T) trial, in which participants were randomized to the addition of once-daily basal insulin, twice-daily biphasic insulin or thrice-daily prandial insulin. Glycated albumin levels were assayed enzymatically from baseline and 1-year fasting plasma samples. We evaluated robust correlations of glycated albumin and HbA1c both with fasting and postprandial glucose levels at these two time points, and with insulin-induced changes in the postprandial excursion. Results Requisite data were available for 625 of the participants in the 4-T trial. Their mean (±sd) age was 62 ± 10 years and body weight was 85.8 ± 15.9 kg, and their median (interquartile range) diabetes duration was 9 (6, 13) years. Partial correlations at baseline and 1 year between postprandial glucose excursions and glycated albumin/HbA1c, after adjusting for fasting glucose, were 0.27/0.15 and 0.22/0.18, respectively. Glycated albumin, compared with HbA1c, explained 66% more of the variation in postprandial glucose excursions at baseline. At 1 year, postprandial glucose excursions on basal, biphasic and prandial and insulin therapy were reduced by 0.43, 0.78 and 1.88 mmol/l, respectively. These reductions were associated with changes in both glycated albumin and HbA1c (P < 0.01), with a stronger association for glycated albumin. Conclusion Changes in glycated albumin and HbA1c reflect changes in postprandial glucose excursions to a similar extent. This article is protected by copyright. All rights reserved.

Background Glycemic control in patients with type 2 diabetes is a dynamic process, and changes in risk factors affecting the incidence of hypoglycemia are not well understood. This study explored the association of longitudinal interactive effects of clinical risk factors and concomitant medications on hypoglycemia risk in patients treated with insulin glargine (IG) or exenatide once weekly (EQW). Methods Pooled patient-level 52-week longitudinal data of treatment with EQW (n = 541) or IG (n = 223) from three controlled trials were analyzed. Results Proportions of patients with at least one episode of hypoglycemia in the EQW and IG groups were 23% and 54%, respectively. Compared with patients with HbA1c ≥7% (53 mmol/mol) over time, patients with HbA1c 35 kg/m2 had a 119% increased hypoglycemia risk in the EQW group, but a 57% reduced risk in the IG group. Sulfonylurea-treated patients in the EQW and IG groups had 4.7- and 3-fold additional hypoglycemia risk, respectively, versus non-sulfonylurea-treated patients. Conclusion This study revealed differential effects of tight glycemic control and itsinteraction with treatment-induced changes in BMI on hypoglycemia risk its interaction in patients treated with EQW and IG. The residual adverse effect of sulfonylurea was higher in EQW-treated patients. 摘要 背景：2型糖尿病患者的血糖控制是一个动态过程，目前还不是很清楚影响低血糖发生率的危险因素是如何变化的。本研究在每日一次使用甘精胰岛素（insulin glargine，IG）或者每周一次使用艾塞那肽（exenatide once weekly，EQW）治疗的患者中调查了临床危险因素以及伴随用药的纵向相互作用与低血糖风险之间的关系。 方法：分析了来自3项对照试验的使用EQW（n = 541）或者IG（n = 223）治疗52周的患者水平的纵向数据。 结果：在EQW组与IG组中至少出现了1次低血糖事件的患者比例分别为23%与54%。经过一段时间后，与HbA1c ≥ 7%（53 mmol/mol）的患者相比，两组中HbA1c 35 kg/m2的患者的低血糖风险增加了119%，但是IG组的低血糖的风险却减少了57%。与不使用磺脲类药物治疗的患者相比，在EQW组与IG组中使用磺脲类药物治疗的患者出现低血糖的风险分别额外增加了4.7倍与3倍。 结论：这项研究显示对EQW治疗组以及IG治疗组的患者进行严格的血糖控制具有不同的影响，并且治疗导致的BMI变化对低血糖风险影响的相互作用也不同。在使用EQW治疗的患者中，磺脲类药物残留的不良作用明显更多。

OBJECTIVE Hypoglycemia has been associated with an increased risk of cardiovascular (CV) events and all-cause mortality. This study assessed whether, in a nationally representative population, there is an association between hypoglycemia, the risk of CV events, and all-cause mortality among insulin-treated people with type 1 diabetes or type 2 diabetes. RESEARCH DESIGN AND METHODS This retrospective cohort study used data from the Clinical Practice Research Datalink database and included all insulin-treated patients (≥30 years of age) with a diagnosis of diabetes. RESULTS In patients who experienced hypoglycemia, hazard ratios (HRs) for CV events in people with type 1 diabetes were 1.51 (95% CI 0.83, 2.75; P = ns) and 1.61 (1.17, 2.22), respectively, for those with and without a history of CV disease (CVD) before the index date. In people with type 2 diabetes, the HRs for patients with and without a history of CVD were 1.60 (1.21, 2.12) and 1.49 (1.23, 1.82), respectively. For all-cause mortality, HRs in people with type 1 diabetes were 1.98 (1.25, 3.17), and 2.03 (1.66, 2.47), respectively, for those with and without a history of CVD. Among people with type 2 diabetes, HRs were 1.74 (1.39, 2.18) and 2.48 (2.21, 2.79), respectively, for those with and without a history of CVD. The median time (interquartile range) from first hypoglycemia event to first CV event was 1.5 years (0.5, 3.5 years) and 1.5 years (0.5, 3.0 years), respectively, for people with type 1 and type 2 diabetes. CONCLUSIONS Hypoglycemia is associated with an increased risk of CV events and all-cause mortality in insulin-treated patients with diabetes. The relationship between hypoglycemia and CV outcomes and mortality exists over a long period.

Background: IL-6 mediates graft-vs.-host disease (GVHD) in experimental models of allogeneic stem cell transplantation. The addition of a humanized anti-IL-6R mAb (Tocilizumab; TCZ) to standard GVHD prophylaxis has shown in promise in reducing the incidence of acute GVHD in two prospective phase I/II clinical studies. Aims: To determine the efficacy of TCZ in preventing grade II-IV acute GVHD in patients with acute leukaemia or myelodysplasia undertaking 8/8 matched related sibling (MSD) or matched unrelated donor (MUD) allogeneic HPCT after myeloablative (MAC) or reduced intensity conditioning (RIC) across five Australian transplant centers. Methods: 145 patients (50 MSD and 95 MUD) were randomly assigned to either placebo or TCZ (8mg/kg; max dose 800mg) on day-1 of conditioning. Patients and physicians were both blinded to treatment. RIC patients all received Flu/Mel (n=81, 56%) while MAC patients received Cy/TBI (n=46, 32%) or Bu/Cy (n=18, 12%). All patients received T-replete PBPC grafts, and standard GVHD prophylaxis cyclosporine and day 1 (15mg/m2), 3, 6 and 11 (10mg/m2) methotrexate. The primary endpoint was incidence of grade II-IV acute GVHD. A planned substudy analyzed the MUD cohort. Secondary endpoints included day 180 grade II-IV acute GVHD free-survival (GVHD-FS), transplant-related mortality (TRM), progression-free survival (PFS), overall survival (OS), time to engraftment and rates of infection. The study was powered to observe a 50% reduction in the incidence of grade II-IV acute GVHD at day +100 for the entire and MUD cohorts, assuming a 50-55% baseline in the control group. Competing risk (death) regression adjusted hazard ratio (HR) was estimated to evaluate the GVHD-related outcomes in TCZ vs. placebo groups. Results: With a median follow up of 746 days, the overall incidence of grade II-IV GVHD at day 100 for the entire cohort was 36% vs. 27% for placebo vs. TCZ respectively (HR: 0.69; 95% CI 0.38-1.26; p=0.23), and 45% vs. 32% (HR: 0.61; 95% CI 0.31-1.22; p=0.16) for the MUD subgroup. The incidence of grade II-IV GVHD at day 180 for the entire cohort was 40% vs. 29% for placebo vs. TCZ respectively (HR: 0.68; 95% CI 0.38-1.22; p=0.19), and 48% vs. 32% (HR: 0.59; 95% CI 0.30-1.16; p=0.13) for the MUD subgroup. The incidence of severe grade III/IV GVHD at day 100 for the entire cohort was similar, 13% vs. 14% for placebo vs. TCZ respectively (HR: 1.04; 95% CI 0.42-2.61; p=0.93), and 10% vs. 14% for the MUD subgroup (HR: 1.42; 95% CI 0.41-4.95; p=0.59). A trend to improved GVHD-FS was noted in the TCZ-treated MUD subgroup, 52% vs. 68% for placebo vs. TCZ treated (HR: 1.70; 95% CI 0.86-3.37; p=0.13). For the entire cohort, TRM occurred in 8% of placebo-treated vs. 11% of TCZ-treated patients respectively (HR: 1.37; 95% CI 0.48-3.96; p=0.56); Progressions were similar at 25% vs. 33% (HR:1.44; CI 0.78-2.63, p=0.24) and OS was 79% vs. 71% (HR: 0.69; CI 0.35-1.34, p=0.27). No significant differences were seen in these outcomes in the MUD cohort. Day to neutrophil engraftment was marginally delayed in TCZ-treated patients, with median time to neutrophil ≥0.5 of 15 days (range 11-24 days) vs. 18 days (range 9-35 days) for placebo vs. TCZ-treated patients respectively (95% CI 1.3-4.7; p=0.001). Time to platelet engraftment was also marginally delayed in TCZ-treated patients, with median time to plts≥20 of 16 days (range 9-36 days) vs. 19 days (range 11-389 days) (95% CI 0.4-5.6; p=0.022). The median time to neutrophil and platelet engraftment in TCZ-treated patients were each 2 days slower in the MUD cohort (p=0.016 and p=0.22 for neutrophils and plts respectively). Two TCZ-treated patients died beyond day 30 (at day 31 and 32) with incomplete neutrophil recovery. The incidence of 1 or more grade 3 or higher liver toxicity (LT) was similar between groups, occurring in 14% of placebo-treated patients vs. 15% of TCZ-treated patients respectively (OR: 1.14; 95% CI 0.45-2.88; p=0.79). Grade 2 or higher infection adverse events occurred in 64% of placebo-treated patients vs. 71% of TCZ-treated patients respectively (OR: 1.34; 95% CI 0.67-2.71; p=0.41). Conclusion: In a phase III randomized, double-blind trial, TCZ administered at D-1 showed non-significant trends to reduced incidence of grade II-IV GVHD and improved acute GVHD-free survival in recipients of HLA-matched MUD donors, but no improvements in long term-survival. Study power was compromised by lower rates of acute GVHD in the control group than anticipated. Disclosures Ritchie: Novartis: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Takeda: Research Funding; Beigene: Research Funding; Imago: Research Funding; Sanofi: Honoraria. Gottlieb:Novartis: Consultancy; AbbVie: Consultancy; University of Sydney: Employment; Merck: Consultancy; Gilead: Consultancy; Haemalogix P/L: Membership on an entity's Board of Directors or advisory committees, Research Funding. Paul:Novo Nordisk: Consultancy, Research Funding; Sanofi: Consultancy, Speakers Bureau; Roche: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Hill:Roche: Other: Investigator driven trial funding; Pharamcyclics: Consultancy, Research Funding; CSL: Consultancy, Research Funding; Implicit Bioscience: Consultancy, Research Funding. OffLabel Disclosure: Use of Tocilizumab for the prevention of acute GVHD

Aims: Perioperative chemotherapy has improved the prognosis for patients with operable osteosarcoma. The literature is conflicting about which regimen is optimal. The aim of this study was to evaluate the survival outcomes of two cohorts of patients with operable osteosarcoma treated with different perioperative chemotherapy regimens. Methods: This was a retrospective review of patients diagnosed with operable osteosarcoma treated at the Princess Alexandra Hospital from 1986 to 2009. The standard perioperative chemotherapy regimen changed from the modified T10 Rosen protocol to cisplatin/doxorubicin in 1997. Using the Kaplan–Meier method, overall survival (OS) and disease-free survival (DFS) curves were generated for the cisplatin/doxorubicin and the modified T10 Rosen cohorts. Results: Seventy-one patients were identified of whom 63 had potentially curable disease. Of these, 24 received the modified T10 Rosen regimen and 39 received cisplatin/doxorubicin. There was a non-significant trend toward better OS and DFS in the patients who received the modified T10 Rosen protocol. Conclusion: The trend toward poorer survival in the cisplatin/doxorubicin cohort, in combination with current evidence, has prompted our institution to change its practice.

To address the debate on 'obesity paradox' in patients with type 2 diabetes mellitus (T2DM) by evaluating the cardiovascular and mortality risks associated with normal and overweight patients compared to obese at diagnosis of diabetes, separately for patients with and without cardiovascular disease (CVD) before diagnosis. A retrospective study with two study cohorts with/without prior CVD (n = 10237/37272) with complete measures of body mass index (BMI) at diagnosis of T2DM from UK General Practice Research Database. Primary outcomes were long-term risks of cardiovascular events (CVEs) and all-cause mortality in patients with normal weight, overweight and obesity at diagnosis. The mortality rates per 1000 person-years in normal weight, overweight and obese patients among patients without prior CVD were 13.1, 8.6 and 6.0, respectively, during 5 years of median follow-up. For patients with prior CVD, these estimates were 30.1, 21.1 and 15.5, respectively. Among patients without and with prior CVD, normal weight patients had 47% (hazard ratio, HR CI: 1.29, 1.69) and 30% (HR CI: 1.11, 1.53) increased mortality risk respectively compared to obese patients. In the cohort without prior CVD, compared to obese patients, those with normal body weight did not have increased CVE risk. Interactions between age, HbA1c and BMI at diagnosis were observed in both cohorts. Adults with normal weight at the diagnosis of T2DM have significantly higher mortality risk compared to those who are obese, with significant interactions between age, BMI and HbA1c. Elevated cardiovascular risk was not observed in normal weight patients without prior CVD.

Aims: To report the characteristics and treatment of individuals requiring emergency ambulance services for severe hypoglycaemia and estimate associated provider costs. Methods: Retrospective analysis of routinely collected data collected by the East Midlands Ambulance Trust, UK, of episodes of severe hypoglycaemia attended by emergency ambulance services during a four-month period. Standard clinical measures, response time, on-site treatment and transportation were recorded and ambulance services costs calculated. Results: 90,435 emergency calls were recorded, 523 (0.6%) for severe hypoglycaemia, equating to an incidence of to 2.76 per 100 patient years; 74% of individuals were insulin-treated, 28% of events occurred nocturnally (00:00–07:59), and 32% were transported to hospital. Higher respiratory rate was a positive predictor (p = 0.03), whereas higher post treatment blood glucose (p = 0.05) and insulin treatment (p < 0.01) were negative predictors of trans- port to hospital. Median treatment costs for individuals transported and not transported to hospital were £92 and £176 respectively. Conclusions: Most cases of severe hypoglycaemia requiring assistance from emergency ambulance services are successfully treated at the scene. Individuals not responding to treatment or were non insulin-treated were more likely to be transported to hospital. Further studies are needed to evaluate the effect of prehospital ambulance care by treatment and diabetes type on subsequent outcomes.

BACKGROUND: Patellofemoral pain (PFP) is a prevalent, often recalcitrant and multifactorial knee pain condition. One method to optimize treatment outcome is to tailor treatments to the patient's presenting characteristics. Foot orthoses and hip exercises are two such treatments for PFP with proven efficacy yet target different ends of the lower limb with different proposed mechanisms of effect. These treatments have not been compared head-to-head, so there is a dearth of evidence for which to use clinically. Only foot orthoses have been explored for identifying patient characteristics that might predict a beneficial effect with either of these two treatments. Preliminary evidence suggests patients will do well with foot orthoses if they have a midfoot width in weight bearing that is ≥ 11 mm more than in non-weight bearing, but this has yet to be verified in a study that includes a comparator treatment and an adequate sample size. This trial will determine if: (i) hip exercises are more efficacious than foot orthoses, and (ii) greater midfoot width mobility will be associated with success with foot orthoses, when compared to hip exercises.METHODS: Two hundred and twenty participants, aged 18-40 years, with a clinical diagnosis of PFP will be randomly allocated with a 1:1 ratio to receive foot orthoses or progressive resisted hip exercises, and stratified into two subgroups based on their presenting midfoot width mobility (high mobility defined as ≥11 mm). The primary outcome will be a 7-point Likert scale for global rating of change. All analyses will be conducted on an intention-to-treat basis using regression models.DISCUSSION: This trial is designed to compare the efficacy of foot orthoses versus hip exercise, as well as to determine if high midfoot width mobility is associated with better outcomes with foot orthoses when compared to hip exercises. Results of this trial will assist clinicians in optimising the management of those with PFP by testing whether a simple measure of midfoot width mobility can help to determine which patients are most likely to benefit from foot orthoses.TRIAL REGISTRATION: This trial is registered on the Australian New Zealand Clinical Trials Register (ACTRN12614000260628).

Background\ud \ud Real world outcomes of addition or switch to insulin therapy in type 2 diabetes (T2DM) patients on glucagon-like paptide-1 receptor agonist (GLP-1RA) with inadequately controlled hyperglycaemia, are not known.\ud Materials and methods\ud \ud Patients with T2DM (n = 66 583) with a minimum of 6 months of GLP-1RA treatment and without previous insulin treatment were selected. Those who added insulin (n = 39 599) or switched to insulin after GLP-1RA cessation (n = 4706) were identified. Adjusted changes in glycated haemoglobin (HbA1c), weight, systolic blood pressure (SBP), and LDL cholesterol were estimated over 24 months follow-up.\ud Results\ud \ud Among those who continued with GLP-1RA treatment without adding or switching to insulin, the highest adjusted mean HbA1c change was achieved within 6 months, with no further glycaemic benefits observed during 24 months of follow-up. Addition of insulin within 6 months of GLP-1RA initiation was associated with 18% higher odds of achieving HbA1c

Background. Patients with prediabetes are at high risk for diabetes and cardiovascular disease (CVD). No study has explored whether intervention could revert prediabetes to normal glycemic status as the primary outcome. Beijing Prediabetes Reversion Program (BPRP) would evaluate whether intensive lifestyle modification and/or pioglitazone could revert prediabetic state to normoglycemia and improve the risk factors of CVD as well.Methods. BPRP is a randomized, multicenter, 2 × 2 factorial design study. Participants diagnosed as prediabetes were randomized into four groups (conventional/intensive lifestyle intervention and 30 mg pioglitazone/placebo) with a three-year follow-up. The primary endpoint was conversion into normal glucose tolerance. The trial would recruit 2000 participants (500 in each arm).Results. Between March 2007 and March 2011, 1945 participants were randomized. At baseline, the individuals were53±10years old, with median BMI 26.0 (23.9, 28.2) kg/m2and HbA1c 5.8 (5.6, 6.1)%. 85% of the participants had IGT and 15% had IFG. Parameters relevant to glucose, lipids, blood pressure, lifestyle, and other metabolic markers were similar between conventional and intensive lifestyle intervention group at baseline.Conclusion. BPRP was the first study to determine if lifestyle modification and/or pioglitazone could revert prediabetic state to normoglycemia in Chinese population. Major baseline parameters were balanced between two lifestyle intervention groups. This trial is registered with www.chictr.org.cn:ChiCTR-PRC-06000005.

From the Diabetes Trials Unit (R.R.H., S.K.P., M.A.B.), the Division of Public Health and Primary Health Care (H.A.W.N.), and the National Institute of Health Re- search (NIHR) School for Primary Care Research (H.A.W.N.), Oxford Centre for Diabetes, Endocrinology, and Metabo- lism (R.R.H., S.K.P., M.A.B., D.R.M., H.A.W.N.); and the NIHR Oxford Bio- medical Research Centre (R.R.H., D.R.M., H.A.W.N.) — both in Oxford, United Kingdom. Address reprint requests to Dr. Holman at the Diabetes Trials Unit, Ox- ford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Head- ington, Oxford OX3 7LJ, United Kingdom, or at rury.holman@dtu.ox.ac.uk. Background During the United Kingdom Prospective Diabetes Study (UKPDS), patients with type 2 diabetes mellitus who received intensive glucose therapy had a lower risk of microvascular complications than did those receiving conventional dietary therapy. We conducted post-trial monitoring to determine whether this improved glucose con- trol persisted and whether such therapy had a long-term effect on macrovascular outcomes. Methods Of 5102 patients with newly diagnosed type 2 diabetes, 4209 were randomly assigned to receive either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) for glucose control. In post-trial monitoring, 3277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned thera- pies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires. We examined seven prespecified aggregate clinical outcomes from the UKPDS on an intention-to-treat basis, according to previous randomization categories. Results Between-group differences in glycated hemoglobin levels were lost after the first year. In the sulfonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P = 0.04) and microvascular disease (24%, P = 0.001), and risk reductions for myocardial infarction (15%, P = 0.01) and death from any cause (13%, P = 0.007) emerged over time, as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-relat- ed end point (21%, P = 0.01), myocardial infarction (33%, P = 0.005), and death from any cause (27%, P = 0.002). Conclusions Despite an early loss of glycemic differences, a continued reduction in microvascu- lar risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of post-trial follow-up. A continued benefit after metformin therapy was evident among overweight patients. (UKPDS 80; Current Controlled Trials number, ISRCTN75451837.)