Dual behavior of histidine during sensitized photo-oxidation of model compounds and proteins.

Histidine (His) photo-oxidation has been widely investigated with several transient and stable products characterized, especially for aerobic conditions. Due to its role and structure, His-side chain can be a key player in the quenching of excited states such as the triplet state of the photosensitizer 3-carboxybenzophenone (3CB*). The capacity of His and its derivatives to quench 3CB* under anaerobic conditions are characterized in the current study by laser flash photolysis, with the resulting oxidation products examined by mass spectrometry to determine the reaction mechanism. The latter include adducts of the 3-carboxybenzophenone ketyl radical (CBH•) to the imidazole ring (Imid-CH2-CBH), His-His dimers, and other products with lower yields. The data obtained with model compounds are compared to those obtained with more complicated systems, including the peptide Exendin-4, and the protein MtHpt1. The data obtained from transient spectroscopy and product analyses indicate that two CB* quenching mechanisms occur: (i) proton-coupled electron transfer (as reported previously) yielding radicals that can recombine to give His-His dimers and CBH-adducts, and (ii) energy transfer yielding 3His* undergoing further reaction leading to formation of Imidazyl-CH2-CBH adduct. The latter, unexpected process only occurs when His and its derivatives have a free α-amino group. This process yielded a novel adduct between the imidazole ring and the CBH• formed by sensitizer reduction.

Impact of weight loss and weight gain trajectories on body composition in a population at high risk of type 2 diabetes: A prospective cohort analysis.

AIM: In a primary care population at high risk of type 2 diabetes, 24-month weight change trajectories were used to investigate the impact of weight cycling on fat mass (FM) and fat-free mass (FFM). MATERIALS AND METHODS: Cohort data from the Walking Away from Type 2 Diabetes trial was used, which recruited adults at-risk of type 2 diabetes from primary care in 2009/10. Annual weight change trajectories based on weight loss/gain of ≥5% were assessed over two 24-month periods. Body composition was measured by bioelectrical impedance analysis. Repeated measures were analysed using generalized estimating equations with participants contributing up to two 24-month observation periods. RESULTS: In total, 622 participants were included (average age = 63.6 years, body mass index = 32.0 kg/m2 , 35.4% women), contributing 1163 observations. Most observations (69.2%) were from those that maintained their body weight, with no change to FM or FFM. A minority (4.6% of observations) lost over 5% of body weight between baseline and 12 months, which was then regained between 12 and 24 months. These individuals regained FM to baseline levels, but lost 1.50 (0.66, 2.35) kg FFM, adjusted for confounders. In contrast, those that gained weight between baseline and 12 months but lost weight between 12 and 24 months (5.5% of observations) had a net gain in FM of 1.70 (0.27, 3.12) kg with no change to FFM. CONCLUSION: Weight cycling may be associated with a progressive loss in FFM and/or gain in FM in those with overweight and obesity at-risk of type 2 diabetes.

Moderate-intensity stepping in older adults: insights from treadmill walking and daily living.

BACKGROUND: A step cadence of 100 steps/minute is widely used to define moderate-intensity walking. However, the generalizability of this threshold to different populations needs further research. We investigate moderate-intensity step cadence values during treadmill walking and daily living in older adults. METHODS: Older adults (≥ 60 years) were recruited from urban community venues. Data collection included 7 days of physical activity measured by an activPAL3™ thigh worn device, followed by a laboratory visit involving a 60-min assessment of resting metabolic rate, then a treadmill assessment with expired gas measured using a breath-by-breath analyser and steps measured by an activPAL3™. Treadmill stages were undertaken in a random order and lasted 5 min each at speeds of 1, 2, 3, 4 and 5 km/h. Metabolic equivalent values were determined for each stage as standardised values (METSstandard) and as multiples of resting metabolic rate (METSrelative). A value of 3 METSstandard defined moderate-intensity stepping. Segmented generalised estimating equations modelled the association between step cadence and MET values. RESULTS: The study included 53 participants (median age = 75, years, BMI = 28.0 kg/m2, 45.3% women). At 2 km/h, the median METSstandard and METSrelative values were above 3 with a median cadence of 81.00 (IQR 72.00, 88.67) steps/minute. The predicted cadence at 3 METSstandard was 70.3 (95% CI 61.4, 75.8) steps/minute. During free-living, participants undertook median (IQR) of 6988 (5933, 9211) steps/day, of which 2554 (1297, 4456) steps/day were undertaken in continuous stepping bouts lasting ≥ 1 min. For bouted daily steps, 96.4% (90.7%, 98.9%) were undertaken at ≥ 70 steps/minute. CONCLUSION: A threshold as low as 70 steps/minute may be reflective of moderate-intensity stepping in older adults, with the vast majority of all bouted free-living stepping occurring above this threshold.

The feasibility of a self-management programme (My Life After Stroke; MLAS) for stroke survivors.

PURPOSE: An evidence-based, theory-driven self-management programme "My Life After Stroke" (MLAS) was developed to address the longer-term unmet needs of stroke survivors.This study's aim was to test the acceptability and feasibility of MLAS as well as exploring what outcomes measures to include as part of further testing. METHODS: Stroke registers in four GP practices across Leicester and Cambridge were screened, invite letters sent to eligible stroke survivors and written, informed consent gained. Questionnaires including Southampton Stroke Self-Management Questionnaire (SSSMQ) were completed before and after MLAS.Participants (and carers) attended MLAS (consisting of two individual appointments and four group sessions) over nine weeks, delivered by two trained facilitators. Feedback was gained from participants (after the final group session and final individual appointment) and facilitators. RESULTS: Seventeen of 36 interested stroke survivors participated alongside seven associated carers. 15/17 completed the programme and attendance ranged from 13-17 per session. A positive change of 3.5 of the SSSMQ was observed. Positive feedback was gained from facilitators and 14/15 participants recommended MLAS (one did not respond). CONCLUSIONS: MLAS was a feasible self-management programme for stroke survivors and warrants further testing as part of the Improving Primary Care After Stroke (IPCAS) cluster randomised controlled trial.IMPLICATIONS FOR REHABILITATIONMy Life After Stroke is a self-management programme developed for stroke survivors living in the community.MLAS is feasible and acceptable to stroke survivors.MLAS could be considered to help address the unmet educational and psychological needs of stroke survivors.

Self-reported walking pace, polygenic risk scores and risk of coronary artery disease in UK biobank.

BACKGROUND AND AIMS: Both polygenic risk scores (PGS) and self-reported walking pace have been shown to predict cardiovascular disease; whether combining both factors produces greater risk differentiation is, however, unknown. METHODS AND RESULTS: We estimated the 10-year absolute risk of coronary artery disease (CAD), adjusted for traditional risk factors, and the C-index across nine PGS and self-reported walking pace in UK Biobank study participants between Mar/2006-Feb/2021. In 380,693 individuals (54.8% women), over a median (5th, 95th percentile) of 11.9 (8.3, 13.4) years, 2,603 (1.2%) CAD events occurred in women and 8,259 (4.8%) in men. Both walking pace and genetic risk were strongly associated with CAD. The absolute 10-year risk of CAD was highest in slow walkers at high genetic risk (top 20% of PGS): 2.72% (95% CI: 2.30-3.13) in women; 9.60% (8.62-10.57) in men. The risk difference between slow and brisk walkers was greater at higher [1.26% (0.81-1.71) in women; 3.63% (2.58-4.67) in men] than lower [0.76% (0.59-0.93) and 2.37% (1.96-2.78), respectively] genetic risk. Brisk walkers at high genetic risk had equivalent (women) or higher (men) risk than slow walkers at moderate-to-low genetic risk (bottom 80% of PGS). When added to a model containing traditional risk factors, both factors separately improved risk discrimination; combining them resulted in the greatest discrimination: C-index of 0.801 (0.793-0.808) in women; 0.732 (0.728-0.737) in men. CONCLUSION: Self-reported slow walkers at high genetic risk had the greatest risk of CAD, identifying a potentially important population for intervention. Both PGS and walking pace contributed to risk discrimination.

The importance of physical activity in management of type 2 diabetes and COVID-19.

Over time, various guidelines have emphasised the importance of physical activity and exercise training in the management of type 2 diabetes, chronic diseases, including cardiovascular disease and musculoskeletal disorders. The aim of this review is to evaluate the effectiveness of physical activity in people with type 2 diabetes and COVID-19. Most research to date indicates that people with type 2 diabetes who engage in both aerobic and resistance exercise see the greatest improvements in insulin sensitivity. Physical activity is now also known to be effective at reducing hospitalisation rates of respiratory viral diseases, such as COVID-19, due to the beneficial impacts of exercise on the immune system. Preliminary result indicates that home-based exercise may be an essential component in future physical activity recommendations given the current COVID-19 pandemic and the need for social distancing. This home-based physical exercise can be easily regulated and monitored using step counters and activity trackers, enabling individuals to manage health issues that benefit from physical exercise.

Use of the socio-ecological model to explore factors that influence the implementation of a diabetes structured education programme (EXTEND project) inLilongwe, Malawi and Maputo, Mozambique: a qualitative study.

BACKGROUND: Diabetes Self-Management Education and Support (DSMES) programmes are vital for type 2 diabetes mellitus (T2DM) management. However, they are limited in Sub-Saharan Africa (SSA). To address this gap, a DSMES, namedEXTEND was developed in Lilongwe (Malawi) and Maputo (Mozambique). This qualitative study aimed to explore factors that influence the implementation of DSMES in these settings. METHODS: The Socio-ecological model was applied to explore factors influencing the implementation of DSMES in SSA. Data was analysed using the Framework method and constant comparative techniques. Sixty-six people participated in the study: people with T2DM who participated in the EXTEND programme; healthcare professionals (HCPs), EXTEND educators, EXTEND trainers, and stakeholders. RESULTS: Our findings indicate that there is a need to develop an integrated and dedicated diabetes services in SSA healthcare systems, incorporating culturally adapted DSMES and tailored diabetes training to all professions involved in diabetes management. Traditional media and the involvement of community leaders were proposed as important elements to help engage and promote DSMES programmes in local communities. During the design and implementation of DSMES, it is important to consider individual and societal barriers to self-care. CONCLUSION: Findings from this study suggest that multi-faceted factors play a significant role to the implementation of DSMES programmes in LICs. In the future, EXTEND could be incorporated in the development of diabetes training and dedicated diabetes services in SSA healthcare systems, acting as an educational tool for both people with T2DM and HCPs. This project was supported by the Medical Research Council GCRF NCDs Foundation Awards 2016 Development Pathway Funding.

Association of working shifts, inside and outside of healthcare, with severe COVID-19: an observational study.

BACKGROUND: Health and key workers have elevated odds of developing severe COVID-19; it is not known, however, if this is exacerbated in those with irregular work patterns. We aimed to investigate the odds of developing severe COVID-19 in health and shift workers. METHODS: We included UK Biobank participants in employment or self-employed at baseline (2006-2010) and with linked COVID-19 data to 31st August 2020. Participants were grouped as neither a health worker nor shift worker (reference category) at baseline, health worker only, shift worker only, or both, and associations with severe COVID-19 investigated in logistic regressions. RESULTS: Of 235,685 participants (81·5% neither health nor shift worker, 1·4% health worker only, 16·9% shift worker only, and 0·3% both), there were 580 (0·25%) cases of severe COVID-19. The odds of severe COVID-19 was higher in health workers (adjusted odds ratio: 2·32 [95% CI: 1·33, 4·05]; shift workers (2·06 [1·72, 2·47]); and in health workers who worked shifts (7·56 [3·86, 14·79]). Being both a health worker and a shift worker had a possible greater impact on the odds of severe COVID-19 in South Asian and Black and African Caribbean ethnicities compared to White individuals. CONCLUSIONS: Both health and shift work (measured at baseline, 2006-2010) were independently associated with over twice the odds of severe COVID-19 in 2020; the odds were over seven times higher in health workers who work shifts. Vaccinations, therapeutic and preventative options should take into consideration not only health and key worker status but also shift worker status.

Device-measured physical activity and its association with physical function in adults with type 2 diabetes mellitus.

AIM: To quantify how differences in metrics characterizing physical activity and sedentary behaviour in type 2 diabetes are associated with physical function. METHODS: This analysis included participants' data from the Chronotype of Patients with Type 2 Diabetes and Effect on Glycaemic Control (CODEC) cross-sectional study. Data were stratified into two groups according to their short physical performance battery (SPPB) score (impaired physical function = SPPB < 10 and normal physical function = SPPB ≥ 10). Hand-grip strength, sit-to-stand 60 (STS-60) and the Duke Activity Status Index (DASI) score were used to assess functional capacity, while physical activity metrics were measured with a wrist-worn accelerometer. The associations between physical activity metrics and measures of functional capacity were analysed using generalized linear modelling. RESULTS: Some 635 adults (median age 66 years, 34% female) were included in this analysis. Overall, 29% of the cohort scored < 10 in the SPPB test indicating impaired physical function. This group spent more time in prolonged sedentary behaviour (600.7 vs. 572.5 min) and undertook less-intense physical activity. Each sd increase in physical activity volume and intensity gradients for those with impaired physical function was associated with 17% more repetitions for STS-60 with similar associations seen for DASI score. Each sd in sedentary time was associated with 15% fewer repetitions in STS-60 and 16% lower DASI score in those with impaired physical function, whereas in normal physical function group it was 2% and 1%, respectively. CONCLUSIONS: The strength of the associations for physical activity measures and functional capacity were modified by physical function status, with the strongest association seen in those with impaired physical function.

Patient-reported outcomes after 10-year follow-up of intensive, multifactorial treatment in individuals with screen-detected type 2 diabetes: the ADDITION-Europe trial.

AIMS: To present the longer-term impact of multifactorial treatment of type 2 diabetes on self-reported health status, diabetes-specific quality of life, and diabetes treatment satisfaction at 10-year follow up of the ADDITION-Europe trial. METHODS: The ADDITION-Europe trial enrolled 3057 individuals with screen-detected type 2 diabetes from four centres [Denmark, the UK (Cambridge and Leicester) and the Netherlands], between 2001 and 2006. Participants were randomized at general practice level to intensive treatment or to routine care . The trial ended in 2009 and a 10-year follow-up was performed at the end of 2014. We measured self-reported health status (36-item Short-Form Health Survey and EQ-5D), diabetes-specific quality of life (Audit of Diabetes-Dependent Quality of Life questionnaire), and diabetes treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire) at different time points during the study period. A mixed-effects model was applied to estimate the effect of intensive treatment (intention-to-treat analyses) on patient-reported outcome measures for each centre. Centre-specific estimates were pooled using a fixed effects meta-analysis. RESULTS: There was no difference in patient-reported outcome measures between the routine care and intensive treatment arms in this 10-year follow-up study [EQ-5D: -0.01 (95% CI -0.03, 0.01); Physical Composite Score (36-item Short-Form Health Survey): -0.27 (95% CI -1.11, 0.57), Audit of Diabetes-Dependent Quality of Life questionnaire: -0.01 (95% CI -0.11, 0.10); and Diabetes Treatment Satisfaction Questionnaire: -0.20 (95% CI -0.70, 0.29)]. CONCLUSIONS: Intensive, multifactorial treatment of individuals with screen-detected type 2 diabetes did not affect self-reported health status, diabetes-specific quality of life, or diabetes treatment satisfaction at 10-year follow-up compared to routine care.

Influence of sociodemographic characteristics on the preferred format of health education delivery in individuals with type 2 diabetes mellitus and or cardiovascular disease: a questionnaire study.

AIM: To examine the influence of sociodemographic factors of interest on preference for a particular health education format among people with type 2 diabetes and/or cardiovascular disease. METHODS: A questionnaire was used to collect information on the influence of six sociodemographic factors of interest on the preference for health education formats in people with type 2 diabetes and/or cardiovascular disease. Chi-squared tests were used to examine the distribution of preferences between groups. The characteristics of the population preferring the online format were then examined in more detail using logistic regression. RESULTS: Responses were received from 1559 participants. Overall the preferred health education format was one-to-one learning from a doctor or nurse (67%). Age, gender, diagnosis and educational level all affected the preferences expressed. The characteristics showing most consistent and significant influence were age and educational level. Overall, 29% ranked the online format highly (scores 1 or 2). This group were more likely to be aged < 65 years (P < 0.001) and to have a higher level of educational attainment (upper secondary education or higher; P < 0.001). CONCLUSIONS: Significant differences between sociodemographic groups exist in preferences for health education formats among people with type 2 diabetes and/or cardiovascular disease. Preferences should be considered when designing educational interventions to ensure they are accessible to the target group and to avoid increases in health inequality.

Leisure-time physical activity and life expectancy in people with cardiometabolic multimorbidity and depression.

BACKGROUND: Whether and to what extent leisure-time physical activity at the recommended levels of 150-min moderate activity is associated with survival in people with cardiometabolic multimorbidity and depression is unknown. METHODS: UK Biobank participants were classified into groups: (i) no disease; (ii) diabetes; (iii) cardiovascular disease (CVD); (iv) depression; (v) diabetes and CVD; (vi) diabetes and depression; (vii) CVD and depression; (viii) diabetes, CVD and depression. Leisure-time physical activity was categorized as active (meeting recommendations) or inactive. Survival models were applied to estimate life expectancy. RESULTS: A total of 480 940 participants were included (median age, 58 years; 46% men; 95% white), of whom 74% with cardiometabolic multimorbidity and depression were inactive. During a mean follow-up of 7 years, 11 006 deaths occurred. At age of 45 years, being physically active was associated with 2.34 (95% confidence interval: 0.93, 3.54) additional years of life compared with being inactive in participants with diabetes; corresponding estimates were 2.28 (1.40, 3.16) for CVD; 2.15 (0.05, 4.26) for diabetes and CVD; and 1.58 (1.27, 1.89) for no disease. Participants with a combination of diabetes, CVD and depression, being active was associated with 6.81 (-1.50, 15.31) additional years compared with being inactive; corresponding estimates were 3.07 (-2.46, 8.59) for diabetes and depression; 2.34 (-1.24, 5.91) for CVD and depression; and 0.80 (-0.46, 2.05) for depression. A similar pattern was found at 65 years. CONCLUSIONS: Meeting the recommended level of physical activity was associated with a longer life expectancy in people with cardiometabolic multimorbidity but not in those with depression.

The Microalbuminuria Education Medication and Optimisation (MEMO) study: 4 years follow-up of multifactorial intervention in high-risk individuals with type 2 diabetes.

AIMS: The Microalbuminuria Education Medication and Optimisation (MEMO) study, revealed improved cardiovascular risk and glycaemic control with 18 months of intensive multifactorial intervention in high-risk people with type 2 diabetes, without any increase in severe hypoglycaemia. Our aim was to assess longer-term outcomes at 4-year follow-up in these participants. METHODS: Some 189 individuals with type 2 diabetes and microalbuminuria were recruited from a multi-ethnic population in Leicestershire, UK. The intervention group (n = 95) received multifactorial intervention with self-management education, and the control group (n = 94) received usual care. The primary outcome was change in HbA1c , and secondary outcomes were blood pressure (BP), cholesterol, microalbuminuria, estimated GFR, cardiovascular risk scores and major adverse cardiovascular events. RESULTS: Some 130 participants (68.7%), mean (sd) age 60.8 (10.4) years, duration of diabetes 11.5 (9.7) years, completed 4 years of follow-up. Mean change [95% confidence intervals (CI)] in HbA1c over 4 years was greater with intensive intervention compared with control (-3 mmol/mol, 95% CI -4.95,-1.11; -0.4%, 95% CI -0.67,-0.15; P = 0.002). Significant improvements over the 4 years were also seen in systolic BP (-7.3 mmHg, 95% CI -11.1, -3.5; P < 0.001), diastolic BP (-2.9 mmHg, 95% CI -5.4, -0.3; P = 0.026), cholesterol (-0.3 mmol/l, 95% CI -0.52,-0.12; P = 0.002), and 10-year coronary heart disease (-5.3, 95% CI -8.2,-2.3; P < 0.001) and stroke risk (-4.4, 95% CI -7.5, -1.3; P < 0.001). CONCLUSION: Multifactorial intervention with structured diabetes self-management education compared with usual diabetes care has benefits for cardio-metabolic risk factor profile. There was no increase in severe hypoglycaemia and cardiovascular mortality despite intensive glycaemic control, although the study was not powered to assess these outcomes.

Effectiveness of psychoeducational interventions for the treatment of diabetes-specific emotional distress and glycaemic control in people with type 2 diabetes: A systematic review and meta-analysis.

AIMS: Psychological comorbidity, such as depression and/or diabetes-specific emotional distress (DSD), is highly prevalent in people with type 2 diabetes (T2DM) and associated with poorer treatment outcomes. While treatments for depression are well established, interventions specifically designed for DSD are sparse. The aim of this study was to determine interventions that successfully address DSD and HbA1c in people with T2DM. METHODS: Seven databases were searched to identify potentially relevant studies. Eligible studies were selected and appraised independently by two reviewers. Multiple meta-analyses and meta-regression analyses were performed to synthesise the data; the primary analyses determined the effect of interventions on DSD, with secondary analyses assessing the effect on HbA1c. RESULTS: Thirty-two studies (n = 5206) provided sufficient DSD data, of which 23 (n = 3818) reported data for HbA1c. Meta-analyses demonstrated that interventions significantly reduced DSD (p = 0.034) and HbA1c (p = 0.006) compared to controls, although subgroup meta-analyses and meta-regression to explore specific intervention characteristics that might mediate this effect yielded non-significant findings. CONCLUSIONS: The findings demonstrate that existing interventions successfully reduce DSD and HbA1c in people with T2DM. While promising, deductions should be interpreted tentatively, highlighting a stark need for further focused exploration of how best to treat psychological comorbidity in people with T2DM.

Association of depression and anxiety with clinical, sociodemographic, lifestyle and environmental factors in South Asian and white European individuals at high risk of diabetes.

AIM: To investigate the prevalence and correlates of depressive and anxiety symptoms within South Asian and white European populations at high risk of developing Type 2 diabetes. METHODS: Data were collected at baseline, and at 12, 24 and 36 months from 1429 white European individuals (age 64±7 years, 35.8% women) and 160 South Asian individuals (age 59±9 years, 30.6% women) who were at high risk of Type 2 diabetes and who took part in two Type 2 diabetes prevention trials in Leicestershire, UK. The Hospital Anxiety and Depression Scale was administered during each study visit. Clinical, sociodemographic, lifestyle and environmental data were collected. RESULTS: At baseline, the burden of depressive symptoms varied by ethnic group and gender, with 9.9% of white European men, 14.9% of white European women, 23.6% of South Asian men and 29.2% of South Asian women exceeding the cut-off score for mild-to-severe depression. During the course of the study and after adjustment for clinical, sociodemographic, lifestyle and environmental factors, depressive symptoms remained higher in the South Asian compared to the white European participants [score higher by 1.5, 95% CI 0.9-2.1]. Levels of anxiety were also higher in the South Asian participants, although associations were attenuated after adjustment. Social deprivation, BMI, proximity to fast-food outlets and physical activity were correlates for depression in both the South Asian and white European participants. CONCLUSIONS: A higher burden of depressive symptoms was consistently evident among the South Asian individuals, even after adjustment for multiple covariates. It is important to understand both the reasons why these differences are present, to help reduce health inequalities, and whether higher levels of depressive symptoms affect the uptake of and retention rates in diabetes prevention programmes in South Asian communities.

Selectivity of beta-blockers, cardiovascular and all-cause mortality in people with hypoglycaemia: An observational study.

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.

Cardiovascular efficacy and safety of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: a systematic review and network meta-analysis.

AIMS: To compare the cardiovascular efficacy and safety of sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) in adults with Type 2 diabetes. METHODS: Electronic databases were searched from inception to 22 October 2018 for randomized controlled trials designed to assess the cardiovascular efficacy of SGLT2 inhibitors or GLP-1RAs with regard to a three-point composite measure of major adverse cardiovascular events (non-fatal stroke, non-fatal myocardial infarction and cardiovascular mortality). Cardiovascular and safety data were synthesized using Bayesian network meta-analyses. RESULTS: Eight trials, including 60 082 participants, were deemed eligible for the network meta-analysis. Both SGLT2 inhibitors [hazard ratio 0.86 (95% credible interval 0.74, 1.01]) and GLP-1RAs [hazard ratio 0.88 (95% credible interval 0.78, 0.98)] reduced the three-point composite measure compared to placebo, with no evidence of differences between them [GLP-1RAs vs SGLT2 inhibitors: hazard ratio 1.02 (95% credible interval 0.83, 1.23)]. SGLT2 inhibitors reduced risk of hospital admission for heart failure compared to placebo [hazard ratio 0.67 (95% credible interval 0.53, 0.85)] and GLP-1RAs [hazard ratio 0.71 (95% credible interval 0.53, 0.93)]. No differences were found between the two drug classes in non-fatal stroke, non-fatal myocardial infarction, cardiovascular mortality, all-cause mortality or safety outcomes. CONCLUSIONS: SGLT2 inhibitors and GLP-1RAs reduced the three-point major adverse cardiovascular event risk compared to placebo, with no differences between them. Compared with GLP-1RAs and placebo, SGLT2 inhibitors led to a larger reduction in hospital admission for heart failure risk.