Device-measured physical activity and cardiac structure by magnetic resonance.

BACKGROUND AND AIMS: Although extreme cardiac adaptions mirroring phenotypes of cardiomyopathy have been observed in endurance athletes, adaptions to high levels of physical activity within the wider population are under-explored. Therefore, in this study, associations between device-measured physical activity and clinically relevant cardiac magnetic resonance volumetric indices were investigated. METHODS: Individuals without known cardiovascular disease or hypertension were included from the UK Biobank. Cardiac magnetic resonance data were collected between 2015 and 2019, and measures of end-diastolic chamber volume, left ventricular (LV) wall thickness, and LV ejection fraction were extracted. Moderate-to-vigorous-intensity physical activity (MVPA), vigorous-intensity physical activity (VPA), and total physical activity were assessed via wrist-worn accelerometers. RESULTS: A total of 5977 women (median age and MVPA: 62 years and 46.8 min/day, respectively) and 4134 men (64 years and 49.8 min/day, respectively) were included. Each additional 10 min/day of MVPA was associated with a 0.70 [95% confidence interval (CI): 0.62, 0.79] mL/m2 higher indexed LV end-diastolic volume (LVEDVi) in women and a 1.08 (95% CI: 0.95, 1.20) mL/m2 higher LVEDVi in men. However, even within the top decile of MVPA, LVEDVi values remained within the normal ranges [79.1 (95% CI: 78.3, 80.0) mL/m2 in women and 91.4 (95% CI: 90.1, 92.7) mL/m2 in men]. Associations with MVPA were also observed for the right ventricle and the left/right atria, with an inverse association observed for LV ejection fraction. Associations of MVPA with maximum or average LV wall thickness were not clinically meaningful. Results for total physical activity and VPA mirrored those for MVPA. CONCLUSIONS: High levels of device-measured physical activity were associated with cardiac remodelling within normal ranges.

Glycaemic control is still central in the hierarchy of priorities in type 2 diabetes management.

A panel of primary care and diabetes specialists conducted focused literature searches on the current role of glycaemic control in the management of type 2 diabetes and revisited the evolution of evidence supporting the importance of early and intensive blood glucose control as a central strategy to reduce the risk of adverse long-term outcomes. The optimal approach to type 2 diabetes management has evolved over time as the evidence base has expanded from data from trials that established the role of optimising glycaemic control to recent data from cardiovascular outcomes trials (CVOTs) demonstrating organ-protective effects of newer glucose-lowering drugs (GLDs). The results from these CVOTs were derived mainly from people with type 2 diabetes and prior cardiovascular and kidney disease or multiple risk factors. In more recent years, earlier diagnosis in high-risk individuals has contributed to the large proportion of people with type 2 diabetes who do not have complications. In these individuals, a legacy effect of early and optimal control of blood glucose and cardiometabolic risk factors has been proven to reduce cardiovascular and kidney disease events and all-cause mortality. As there is a lack of RCTs investigating the potential synergistic effects of intensive glucose control and organ-protective effects of newer GLDs, this article re-evaluates the evolution of the scientific evidence and highlights the importance of integrating glycaemic control as a pivotal early therapeutic goal in most people with type 2 diabetes, while targeting existing cardiovascular and kidney disease. We also emphasise the importance of implementing multifactorial management using a multidisciplinary approach to facilitate regular review, patient empowerment and the possibility of tailoring interventions to account for the heterogeneity of type 2 diabetes.

Diabetic foot disease carries an intrinsic high risk of mortality and other severe outcomes in type 2 diabetes: a propensity score-matched retrospective population-based study.

BACKGROUND: To evaluate the association between diabetic foot disease (DFD) and the incidence of fatal and non-fatal events in individuals with type 2 diabetes (T2DM) from primary-care settings. METHODS: We built a cohort of people with a first DFD episode during 2010-2015, followed up until 2018. These subjects were 1 to 1 propensity score matched to subjects with T2DM without DFD. The incidence of all-cause mortality, the occurrence of new DFD, amputations, cardiovascular diseases, or composite outcome, including all-cause mortality and/or cardiovascular events during the follow-up period, were calculated. A Cox proportional hazard analysis was conducted to evaluate the hazard ratios (HR) for different events. RESULTS: Overall, 11,117 subjects with T2DM with a first episode of DFD were compared with subjects without DFD. We observed higher incidence rates (IRs) for composite outcome (33.9 vs. 14.5 IR per 100 person-years) and a new DFD episode event (22.2 vs. 1.1 IR per 100 person-years) in the DFD group. Compared to those without DFD, those with a first episode of DFD had a higher HR for all events, with excess rates particularly for amputation and new DFD occurrence (HR: 19.4, 95% CI: 16.7-22.6, HR: 15.1, 95% CI: 13.8-16.5, respectively) was found. CONCLUSIONS: Although DFD often coexists with other risk factors, it carries an intrinsic high risk of morbidity and mortality in individuals with T2DM. DFD should be regarded as a severe complication already at its onset, as it carries a poor clinical prognosis.

Glycaemic control and macrovascular and microvascular outcomes: A systematic review and meta-analysis of trials investigating intensive glucose-lowering strategies in people with type 2 diabetes.

AIM: We aimed to determine the macrovascular and microvascular outcomes of intensive versus standard glucose-lowering strategies in type 2 diabetes (T2D) and investigate the relationships between these outcomes and trial arm glycated haemoglobin (HbA1c) reduction. MATERIALS AND METHODS: In this systematic review and meta-analysis, we identified relevant trials from MEDLINE, Embase, the Cochrane Library, and bibliographies up to August 2023. Macrovascular and microvascular outcomes, along with safety outcomes, were evaluated. Pooled study-specific hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated, and meta-regression was employed to analyse the relationships between outcomes and HbA1c reduction. RESULTS: We included 11 unique RCTs involving 51 469 patients with T2D (intensive therapy, N = 26 691; standard therapy, N = 24 778). Intensive versus standard therapy reduced the risk of non-fatal myocardial infarction (MI) (HR 0.84; 95% CI 0.75-0.94) with no difference in the risk of major adverse cardiovascular events (HR 0.97; 95% CI 0.92-1.03) and other adverse cardiovascular outcomes. Intensive versus standard therapy reduced the risk of retinopathy (HR 0.85; 0.78-0.93), nephropathy (HR 0.71; 0.58-0.87) and composite microvascular outcomes (HR 0.88; 0.77-1.00). Meta-regression analyses showed modest evidence of inverse linear relationships between HbA1c reduction and the outcomes of major adverse cardiovascular events, non-fatal MI, stroke and retinopathy, but these were not statistically significant. CONCLUSIONS: In people with T2D, intensive glucose control was associated with a reduced risk of non-fatal MI and several microvascular outcomes, particularly retinopathy and nephropathy. The lack of an effect of intensive glucose-lowering on most macrovascular outcomes calls for a more comprehensive approach to managing cardiovascular risk factors alongside glycaemic control.

Differential associations of risk factors with severe and non-severe hypoglycaemia: the Hypoglycaemia Assessment Tool prospective observational study in people with insulin-treated type 1 diabetes and type 2 diabetes.

AIM: To assess the differential association of risk factors with severe and non-severe hypoglycaemia. MATERIALS AND METHODS: The Hypoglycaemia Assessment Tool study evaluated the risk of hypoglycaemia over a 4-week period in patients with type 1 diabetes (T1D) and type 2 diabetes (T2D) on insulin in 24 countries. Negative binomial regressions were applied to examine the associations of several risk factors with severe and non-severe hypoglycaemia. RESULTS: The median age was 41 years in 5949 patients with T1D and 62 years in 12 914 patients with T2D. The 4-week rates of non-severe hypoglycaemic were 5.57 and 1.40 episodes per person in T1D and T2D, respectively; the corresponding rates for severe hypoglycaemia were 0.94 and 0.30. The excess risk was 42% higher for severe than non-severe hypoglycaemia in females versus males with T2D; 27% higher in patients with T2D with versus without a continuous glucose monitoring (CGM); and 47% lower in patients with T1D with versus without an insulin pump. The excess risk also differed across geographical areas and was marginally lower for severe than non-severe hypoglycaemia for higher values of HbA1c in patients with T2D. Associations with severity of hypoglycaemia were not different for age, diabetes and insulin therapy duration, previous hypoglycaemic episodes and insulin regimen. CONCLUSIONS: The risk of severe versus non-severe hypoglycaemia differs in patients with T1D and T2D; sex, the use of a CGM and insulin pump, and geographical areas were differently associated with one type of hypoglycaemia than the other.

Effect of delay in treatment intensification in people with type 2 diabetes and suboptimal glycaemia after basal insulin initiation: A real-world observational study.

AIM: Despite global recommendations for type 2 diabetes mellitus treatment to maintain optimal glycaemic targets, a significant proportion of people remain in suboptimal glycaemic control. Our objective was to investigate the impact of intensification delay after basal insulin (BI) initiation on long-term complications in people with suboptimal glycaemia. MATERIALS AND METHODS: We conducted a retrospective cohort study in individuals with type 2 diabetes mellitus initiated on BI. Those with suboptimal glycaemia (glycated haemoglobin ≥7% or ≥53 mmol/mol) within 12 months of BI initiation were divided into early (treatment intensified within 5 years), or late (≥5 years) intensification groups. We estimated the age-stratified risks of micro- and macrovascular complications among these groups compared with those with optimal glycaemia (glycated haemoglobin <7%). RESULTS: Of the 13 916 people with suboptimal glycaemia, 52.5% (n = 7304) did not receive any treatment intensification. In those aged <65 years, compared with the optimal glycaemia group late intensification was associated with a 56% higher risk of macrovascular complications (adjusted hazard ratio 1.56; 95% confidence intervals 1.08, 2.26). In elderly people (≥65 years), late intensification was associated with a higher risk of cardiovascular-related death (1.62; 1.03, 2.54) and a lower risk of microvascular complications (0.26; 0.08, 0.83). CONCLUSIONS: Those who had late intensification were at an increased risk of cardiovascular death if they were ≥65 years and an increased risk of macrovascular complications if they were <65 years. These findings highlight the critical need for earlier intensification of treatment and adopting personalized treatment strategies to improve patient outcomes.

Glycaemic control and macrovascular and microvascular outcomes in type 2 diabetes: Systematic review and meta-analysis of cardiovascular outcome trials of novel glucose-lowering agents.

AIM: Using a systematic review and meta-analysis of placebo-controlled cardiovascular outcome trials (CVOTs) of newer glucose-lowering agents [sodium-glucose cotransporter-2 inhibitors (SGLT-2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4is)] in type 2 diabetes (T2D), we aimed to determine the macrovascular and microvascular outcomes of these agents and clarify the relationships between glycated haemoglobin (HbA1c) reduction and risk of these outcomes. MATERIALS AND METHODS: Randomized controlled trials were identified from MEDLINE, Embase and the Cochrane Library until September 2023. Study-specific hazard ratios with 95% confidence intervals (CIs) were pooled, and meta-regression was used to assess the relationships between outcomes and between trial arm HbA1c reductions. RESULTS: Twenty unique CVOTs (six SGLT-2is, nine GLP-1RAs, five DPP-4is), based on 169 513 participants with T2D, were eligible. Comparing SGLT-2is, GLP-1RAs and DPP-4is with placebo, the hazard ratios (95% CIs) for 3-point major adverse cardiovascular events were 0.88 (0.82-0.94), 0.85 (0.79-0.92) and 1.00 (0.94-1.06), respectively. SGLT-2is and GLP-1RAs consistently reduced the risk of several macrovascular and microvascular complications, particularly kidney events. DPP-4is showed no macrovascular benefits. There was potential evidence of an inverse linear relationship between HbA1c reduction and 3-point major adverse cardiovascular event risk (estimated risk per 1% reduction in HbA1c: 0.84, 95% CI 0.67-1.06; p = .14; R2 = 14.2%), which was driven by the component of non-fatal stroke (R2 = 100.0%; p = .094). There were non-significant inverse linear relationships between HbA1c reduction and the risk of several vascular outcomes. CONCLUSIONS: SGLT-2is and GLP-1RAs showed consistent risk reductions in macrovascular and microvascular outcomes. The vascular benefits of SGLT-2is and GLP-1RAs in patients with T2D extend beyond mere glycaemic control.

Translating trial results into interpretable risk estimates: Systematic analysis of cardiorenal outcome trials of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors.

BACKGROUND AND AIMS: In a randomised controlled trial (RCT), the between-arm difference in the average probability of an event per unit of time (i.e., yearly incidence risk difference, YIRD) is an easy-to-interpret treatment effect metric. We aimed to quantify the YIRD in cardiorenal RCTs of GLP-1RAs or SGLT-2is. METHODS AND RESULTS: We digitally searched for RCTs published up to March 1st, 2023, including subjects with type 2 diabetes randomised to GLP-1RAs or SGLT-2is and investigating cardiorenal outcomes or death. We extracted information from Kaplan-Meier (KM) plots to obtain time-to-event individual data and estimate within-arm yearly incidence risk and YIRD. Data from 19 RCTs (28 kM plots) were analysed: comparing treatment to placebo, in GLP-1RA RCTs the YIRD ranged from 0.2 % (95 % CI: -0.7 %, 1.1 %) to -1.9 % (-3.1, -0.7), for primary outcome; and from -0.2 % (-0.5, 0.2) to -0.4 % (-0.7 %, -0.0 %), for mortality. With the exception of SOLOIST-WHF (YIRD 11.9 % for primary outcome), corresponding estimates in SGLT-2is RCTs were: from -0.1 % (-0.4, 0.1) to -5.0 % (-7.7, -2.6), for primary outcome; and from -0.1 % (-0.2, 0.1) to -1.9 % (-4.4 %, 0.6 %), for mortality. CONCLUSION: The YIRD metric complements other relative treatment effect estimates and helps quantify the absolute benefit of GLP-1RAs and SGLT-2is.

Employment outcomes of people with Long Covid symptoms: community-based cohort study.

BACKGROUND: Evidence on the long-term employment consequences of SARS-CoV-2 infection is lacking. We used data from a large, community-based sample in the UK to estimate associations between Long Covid and employment outcomes. METHODS: This was an observational, longitudinal study using a pre-post design. We included survey participants from 3 February 2021 to 30 September 2022 when they were aged 16-64 years and not in education. Using conditional logit modelling, we explored the time-varying relationship between Long Covid status ≥12 weeks after a first test-confirmed SARS-CoV-2 infection (reference: pre-infection) and labour market inactivity (neither working nor looking for work) or workplace absence lasting ≥4 weeks. RESULTS: Of 206 299 participants (mean age 45 years, 54% female, 92% white), 15% were ever labour market inactive and 10% were ever long-term absent during follow-up. Compared with pre-infection, inactivity was higher in participants reporting Long Covid 30 to <40 weeks [adjusted odds ratio (aOR): 1.45; 95% CI: 1.17-1.81] or 40 to <52 weeks (aOR: 1.34; 95% CI: 1.05-1.72) post-infection. Combining with official statistics on Long Covid prevalence, and assuming a correct statistical model, our estimates translate to 27 000 (95% CI: 6000-47 000) working-age adults in the UK being inactive because of Long Covid in July 2022. CONCLUSIONS: Long Covid is likely to have contributed to reduced participation in the UK labour market, though it is unlikely to be the sole driver. Further research is required to quantify the contribution of other factors, such as indirect health effects of the pandemic.

Capturing How the Accelerometer Measured Physical Activity Profile Differs in People with Diabetic Foot Ulceration.

Diabetic Foot Ulcers (DFUs) are a major complication of diabetes, with treatment requiring offloading. This study aimed to capture how the accelerometer-assessed physical activity profile differs in those with DFUs compared to those with diabetes but without ulceration (non-DFU). Participants were requested to wear an accelerometer on their non-dominant wrist for up to 8days. Physical activity outcomes included average acceleration (volume), intensity gradient (intensity distribution), the intensity of the most active sustained (continuous) 5-120 min of activity (MXCONT), and accumulated 5-120 min of activity (MXACC). A total of 595 participants (non-DFU = 561, DFU = 34) were included in the analysis. Average acceleration was lower in DFU participants compared to non-DFU participants (21.9 mg [95%CI:21.2, 22.7] vs. 16.9 mg [15.3, 18.8], p < 0.001). DFU participants also had a lower intensity gradient, indicating proportionally less time spent in higher-intensity activities. The relative difference between DFU and non-DFU participants was greater for sustained activity (MXCONT) than for accumulated (MXACC) activity. In conclusion, physical activity, particularly the intensity of sustained activity, is lower in those with DFUs compared to non-DFUs. This highlights the need for safe, offloaded modes of activity that contribute to an active lifestyle for people with DFUs.

Inequalities in cancer mortality trends in people with type 2 diabetes: 20 year population-based study in England.

AIMS/HYPOTHESIS: The aim of this study was to describe the long-term trends in cancer mortality rates in people with type 2 diabetes based on subgroups defined by sociodemographic characteristics and risk factors. METHODS: We defined a cohort of individuals aged ≥35 years who had newly diagnosed type 2 diabetes in the Clinical Practice Research Datalink between 1 January 1998 and 30 November 2018. We assessed trends in all-cause, all-cancer and cancer-specific mortality rates by age, gender, ethnicity, socioeconomic status, obesity and smoking status. We used Poisson regression to calculate age- and calendar year-specific mortality rates and Joinpoint regression to assess trends for each outcome. We estimated standardised mortality ratios comparing mortality rates in people with type 2 diabetes with those in the general population. RESULTS: Among 137,804 individuals, during a median follow-up of 8.4 years, all-cause mortality rates decreased at all ages between 1998 and 2018; cancer mortality rates also decreased for 55- and 65-year-olds but increased for 75- and 85-year-olds, with average annual percentage changes (AAPCs) of -1.4% (95% CI -1.5, -1.3), -0.2% (-0.3, -0.1), 1.2% (0.8, 1.6) and 1.6% (1.5, 1.7), respectively. Higher AAPCs were observed in women than men (1.5% vs 0.5%), in the least deprived than the most deprived (1.5% vs 1.0%) and in people with morbid obesity than those with normal body weight (5.8% vs 0.7%), although all these stratified subgroups showed upward trends in cancer mortality rates. Increasing cancer mortality rates were also observed in people of White ethnicity and former/current smokers, but downward trends were observed in other ethnic groups and non-smokers. These results have led to persistent inequalities by gender and deprivation but widening disparities by smoking status. Constant upward trends in mortality rates were also observed for pancreatic, liver and lung cancer at all ages, colorectal cancer at most ages, breast cancer at younger ages, and prostate and endometrial cancer at older ages. Compared with the general population, people with type 2 diabetes had a more than 1.5-fold increased risk of colorectal, pancreatic, liver and endometrial cancer mortality during the whole study period. CONCLUSIONS/INTERPRETATION: In contrast to the declines in all-cause mortality rates at all ages, the cancer burden has increased in older people with type 2 diabetes, especially for colorectal, pancreatic, liver and endometrial cancer. Tailored cancer prevention and early detection strategies are needed to address persistent inequalities in the older population, the most deprived and smokers.

Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex.

BACKGROUND: Myocarditis is more common after severe acute respiratory syndrome coronavirus 2 infection than after COVID-19 vaccination, but the risks in younger people and after sequential vaccine doses are less certain. METHODS: A self-controlled case series study of people ages 13 years or older vaccinated for COVID-19 in England between December 1, 2020, and December 15, 2021, evaluated the association between vaccination and myocarditis, stratified by age and sex. The incidence rate ratio and excess number of hospital admissions or deaths from myocarditis per million people were estimated for the 1 to 28 days after sequential doses of adenovirus (ChAdOx1) or mRNA-based (BNT162b2, mRNA-1273) vaccines, or after a positive SARS-CoV-2 test. RESULTS: In 42 842 345 people receiving at least 1 dose of vaccine, 21 242 629 received 3 doses, and 5 934 153 had SARS-CoV-2 infection before or after vaccination. Myocarditis occurred in 2861 (0.007%) people, with 617 events 1 to 28 days after vaccination. Risk of myocarditis was increased in the 1 to 28 days after a first dose of ChAdOx1 (incidence rate ratio, 1.33 [95% CI, 1.09-1.62]) and a first, second, and booster dose of BNT162b2 (1.52 [95% CI, 1.24-1.85]; 1.57 [95% CI, 1.28-1.92], and 1.72 [95% CI, 1.33-2.22], respectively) but was lower than the risks after a positive SARS-CoV-2 test before or after vaccination (11.14 [95% CI, 8.64-14.36] and 5.97 [95% CI, 4.54-7.87], respectively). The risk of myocarditis was higher 1 to 28 days after a second dose of mRNA-1273 (11.76 [95% CI, 7.25-19.08]) and persisted after a booster dose (2.64 [95% CI, 1.25-5.58]). Associations were stronger in men younger than 40 years for all vaccines. In men younger than 40 years old, the number of excess myocarditis events per million people was higher after a second dose of mRNA-1273 than after a positive SARS-CoV-2 test (97 [95% CI, 91-99] versus 16 [95% CI, 12-18]). In women younger than 40 years, the number of excess events per million was similar after a second dose of mRNA-1273 and a positive test (7 [95% CI, 1-9] versus 8 [95% CI, 6-8]). CONCLUSIONS: Overall, the risk of myocarditis is greater after SARS-CoV-2 infection than after COVID-19 vaccination and remains modest after sequential doses including a booster dose of BNT162b2 mRNA vaccine. However, the risk of myocarditis after vaccination is higher in younger men, particularly after a second dose of the mRNA-1273 vaccine.

Ethnic minority representation in UK COVID-19 trials: systematic review and meta-analysis.

BACKGROUND: The COVID-19 pandemic has highlighted health disparities affecting ethnic minority communities. There is growing concern about the lack of diversity in clinical trials. This study aimed to assess the representation of ethnic groups in UK-based COVID-19 randomised controlled trials (RCTs). METHODS: A systematic review and meta-analysis were undertaken. A search strategy was developed for MEDLINE (Ovid) and Google Scholar (1st January 2020-4th May 2022). Prospective COVID-19 RCTs for vaccines or therapeutics that reported UK data separately with a minimum of 50 participants were eligible. Search results were independently screened, and data extracted into proforma. Percentage of ethnic groups at all trial stages was mapped against Office of National Statistics (ONS) statistics. Post hoc DerSimonian-Laird random-effects meta-analysis of percentages and a meta-regression assessing recruitment over time were conducted. Due to the nature of the review question, risk of bias was not assessed. Data analysis was conducted in Stata v17.0. A protocol was registered (PROSPERO CRD42021244185). RESULTS: In total, 5319 articles were identified; 30 studies were included, with 118,912 participants. Enrolment to trials was the only stage consistently reported (17 trials). Meta-analysis showed significant heterogeneity across studies, in relation to census-expected proportions at study enrolment. All ethnic groups, apart from Other (1.7% [95% CI 1.1-2.8%] vs ONS 1%) were represented to a lesser extent than ONS statistics, most marked in Black (1% [0.6-1.5%] vs 3.3%) and Asian (5.8% [4.4-7.6%] vs 7.5%) groups, but also apparent in White (84.8% [81.6-87.5%] vs 86%) and Mixed 1.6% [1.2-2.1%] vs 2.2%) groups. Meta-regression showed recruitment of Black participants increased over time (p = 0.009). CONCLUSIONS: Asian, Black and Mixed ethnic groups are under-represented or incorrectly classified in UK COVID-19 RCTs. Reporting by ethnicity lacks consistency and transparency. Under-representation in clinical trials occurs at multiple levels and requires complex solutions, which should be considered throughout trial conduct. These findings may not apply outside of the UK setting.

Empagliflozin is associated with lower cardiovascular risk compared with dipeptidyl peptidase-4 inhibitors in adults with and without cardiovascular disease: EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study results from Europe and Asia.

BACKGROUND: Studies that have reported lower risk for cardiovascular outcomes in users of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) are limited by residual cofounding and lack of information on prior cardiovascular disease (CVD). This study compared risk of cardiovascular events in patients within routine care settings in Europe and Asia with type 2 diabetes (T2D) initiating empagliflozin compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) stratified by pre-existing CVD and history of heart failure (HF). METHODS AND RESULTS: Adults initiating empagliflozin and DPP-4i in 2014-2018/19 from 11 countries in Europe and Asia were compared using propensity score matching and Cox proportional hazards regression to assess differences in rates of primary outcomes: hospitalisation for heart failure (HHF), myocardial infarction (MI), stroke; and secondary outcomes: cardiovascular mortality (CVM), coronary revascularisation procedure, composite outcome including HHF or CVM, and 3-point major adverse cardiovascular events (MACE: MI, stroke and CVM). Country-specific results were meta-analysed and pooled hazard ratios (HR) with 95% confidence intervals (CI) from random-effects models are presented. In total, 85,244 empagliflozin/DPP4i PS-matched patient pairs were included with overall mean follow-up of 0.7 years. Among those with pre-existing CVD, lower risk was observed for HHF (HR 0.74; 95% CI 0.64-0.86), CVM (HR 0.55; 95% CI 0.38-0.80), HHF or CVM (HR 0.57; 95% CI 0.48-0.67) and stroke (HR 0.79; 95% CI 0.67-0.94) in patients initiating empagliflozin vs DPP-4i. Similar patterns were observed among patients without pre-existing CVD and those with and without pre-existing HF. CONCLUSION: These results from diverse patient populations in routine care settings across Europe and Asia demonstrate that initiation of empagliflozin compared to DPP-4i results in favourable cardioprotective effects regardless of pre-existing CVD or HF status.

Intensive glucose control and recurrent cardiovascular events: 14-year follow-up investigation of the ACCORDION study.

AIMS: While cardiovascular disease in patients with type 2 diabetes commonly progresses with the occurrence of repeated events, most trials consider the effect of glucose-lowering strategies only on the first event. We examined the Action to Control Cardiovascular Risk in Diabetes trial and its observational follow-up study (ACCORDION) to investigate the effect of intensive glucose control on multiple events and further identify any subgroup effects. MATERIALS AND METHODS: A recurrent events analysis, using a negative binomial regression model, was applied to estimate the treatment effect on different consecutive cardiovascular disease events, including non-fatal myocardial infarction, non-fatal stroke, hospitalisation from heart failure, and cardiovascular death. Interaction terms were used to identify potential effect modifiers. The robustness of the results was confirmed in sensitivity analyses using alternative models. RESULTS: The median duration of follow-up was 7.7 years. Of the 5128 participants in the intensive and 5123 in the standard glucose control arm, respectively, 822 (16.0%) and 840 (16.4%) participants experienced a single event; 189 (3.7%) and 214 (4.2%) participants experienced two events; 52 (1.0%) and 40 (0.8%) experienced three events; and 1 (0.02%) and 1 (0.02%) experienced four events. There was no evidence of a treatment effect, with a rate difference of 0.0 (-0.3, 0.3) per 100 person-years comparing intensive versus standard intervention, although with non-significantly lower event rates in younger patients with HbA1c < 7% and higher event rates in older patients with HbA1c ≥ 9%. DISCUSSION: Intensive glucose control may not affect cardiovascular disease progression except in select subgroups. Since time-to-first event analysis may miss beneficial or harmful effects of glucose control on the risk of cardiovascular disease, recurrent events analysis should be routinely analysed in cardiovascular outcome trials, particularly when investigating long-term treatment effects. CLINICAL TRIAL REG NO: NCT00000620, clinicaltrials.gov.

All-cause and cardiorenal mortality in 6 million adults with and without type 2 diabetes: A comparative, trend analysis in Canada, Spain, and the UK.

AIMS: To understand geographical and temporal patterns in the diabetes gap, the excess mortality risk associated with type 2 diabetes (T2D), in three high-income countries. METHODS: Using databases from Canada (Ontario), Spain (Catalonia) and the UK (England), we harmonized the study design and the analytical strategy to extract information on subjects aged over 35 years with incident T2D between 1998 and 2018 matched to up to five subjects without diabetes. We used Poisson models to estimate age-specific mortality trends by diabetes status and rate ratios and rate differences associated with T2D. RESULTS: In more than 6 million people, 694 454 deaths occurred during a follow-up of 52 million person-years. Trends in all-cause mortality rates differed between Ontario and England; yet, the diabetes gaps were very similar in recent years: in 2018, we estimated 1.3 (95% confidence interval: 0.8, 1.8) and 0.8 (0.2, 1.5) more deaths per 1000 person-years in 50-year-old men with diabetes in Ontario and England, respectively, and 8.9 (6.1, 11.7) and 12.1 (9.1, 15.1) in 80-year-old men; between-country differences were small also in women. In Catalonia, rate ratios comparing T2D with no diabetes in men in 2018 were 1.53 (1.11, 2.11) at 50 years old, 0.88 (0.72, 1.06) at 60 years old, 0.74 (0.60, 0.90) at 70 years old and 0.81 (0.66, 1.00) at 80 years old, indicating lower mortality rates in men with T2D from the age of 60 years; rates were similar in women with and without diabetes at all ages. The diabetes gaps in cardiorenal mortality mirrored those of all-cause mortality: we observed consistent reductions in the proportions of cardiorenal deaths in subjects aged 80 years but variations in subjects aged ≤70 years, regardless of the presence of diabetes. CONCLUSIONS: By reducing the confounding impact of epidemiological and analytical differences, this study showed geographical similarities and differences in the diabetes gap: an excess risk of all-cause and cardiorenal mortality in subjects with T2D is still present in Ontario and England in recent years, particularly in elderly subjects. Conversely, there were very small gaps in young men with T2D or even lower mortality rates in older subjects with T2D in Catalonia.

Life expectancy following a cardiovascular event in individuals with and without type 2 diabetes: A UK multi-ethnic population-based observational study.

BACKGROUND AND AIMS: We aimed to evaluate the life expectancy following the first cardiovascular disease (CVD) event by type 2 diabetes (T2D) status and ethnicity. METHODS AND RESULTS: We used the Clinical Practice Research Datalink database in England (UK), linked to the Hospital Episode Statistics information, to identify individuals with and without T2D who survived a first CVD event between 1st Jan 2007 and 31st Dec 2017; subsequent death events were extracted from the Office for National Statistics database. Ethnicity was categorised as White, South Asian (SA), Black, or other. Flexible parametric survival models were used to estimate survival and predict life expectancy. 59,939 individuals with first CVD event were included: 7596 (12.7%) with T2D (60.9% men; mean age at event: 69.7 years [63.2 years in SA, 65.9 in Black, 70.2 in White]) and 52,343 without T2D (56.7% men; 65.9 years [54.7 in Black, 58.2 in SA, 66.3 in White]). Accounting for potential confounders (sex, deprivation, lipid-lowering medication, current smoking, and pre-existing hypertension), comparing individuals with vs without T2D the mortality rate was 53% higher in White (hazard ratio [HR]: 1.53 [95% CI: 1.44, 1.62]), corresponding to a potential loss of 3.87 (3.30, 4.44) life years at the age of 50 years in individuals with T2D. No evidence of a difference in life expectancy was observed in individuals of SA (HR: 0.82 [0.52, 1.29]; -1.36 [-4.58, 1.86] life years), Black (HR: 1.26 [0.59, 2.70]; 1.21 [-2.99, 5.41] life years); and other (HR: 1.64 [0.80, 3.39]; 3.89 [-2.28, 9.99] life years) ethnic group. CONCLUSION: Following a CVD event, T2D is associated with a different prognosis and life years lost among ethnic groups.

Temporal trends in admissions for atrial fibrillation and severe bleeding in England: an 18-year longitudinal analysis.

Objective. Temporal trends in admissions for atrial fibrillation (AF) and severe bleeding associated with AF vary worldwide. We aimed to explore their temporal trends in England and their relation to the introduction of DOACs in 2014 in the UK. Design. This longitudinal ecological study utilised aggregated data that was extracted from the Hospital Episode Statistics database, which captured annual admissions for AF and severe bleeding associated with AF between 2001 and 2018. Trends in admissions over the study period and across age groups, gender and regions in England were assessed. Results. In total, there were 11,292,177 admissions for AF and 324,851 admissions for severe bleeding associated with AF. There was a steady rise in admissions for AF from 2001 to 2017 (204,808 to 1,109,295; p for trend<.001). A similar trend was observed for severe bleeding (4940 to 30,169; p for trend <.001), but the increase dropped slightly between 2013 and 2014 and continued thereafter. Conclusions. There was a rise in admissions for AF and severe bleeding in England between 2001 and 2018. There is little evidence that the slight drop in admissions for severe bleeding between 2013 and 2014 may have been caused by the introduction of DOACs in 2014. Contributors to these trends need urgent exploration.

COVID-19 vaccination uptake amongst ethnic minority communities in England: a linked study exploring the drivers of differential vaccination rates.

BACKGROUND: Despite generally high coronavirus disease 2019 (COVID-19) vaccination rates in the UK, vaccination hesitancy and lower take-up rates have been reported in certain ethnic minority communities. METHODS: We used vaccination data from the National Immunisation Management System (NIMS) linked to the 2011 Census and individual health records for subjects aged ≥40 years (n = 24 094 186). We estimated age-standardized vaccination rates, stratified by ethnic group and key sociodemographic characteristics, such as religious affiliation, deprivation, educational attainment, geography, living conditions, country of birth, language skills and health status. To understand the association of ethnicity with lower vaccination rates, we conducted a logistic regression model adjusting for differences in geographic, sociodemographic and health characteristics. ResultsAll ethnic groups had lower age-standardized rates of vaccination compared with the white British population, whose vaccination rate of at least one dose was 94% (95% CI: 94%-94%). Black communities had the lowest rates, with 75% (74-75%) of black African and 66% (66-67%) of black Caribbean individuals having received at least one dose. The drivers of these lower rates were partly explained by accounting for sociodemographic differences. However, modelled estimates showed significant differences remained for all minority ethnic groups, compared with white British individuals. CONCLUSIONS: Lower COVID-19 vaccination rates are consistently observed amongst all ethnic minorities.

Ethnic disparities in COVID-19 outcomes: a multinational cohort study of 20 million individuals from England and Canada.

BACKGROUND: Heterogeneous studies have demonstrated ethnic inequalities in the risk of SARS-CoV-2 infection and adverse COVID-19 outcomes. This study evaluates the association between ethnicity and COVID-19 outcomes in two large population-based cohorts from England and Canada and investigates potential explanatory factors for ethnic patterning of severe outcomes. METHODS: We identified adults aged 18 to 99 years in the QResearch primary care (England) and Ontario (Canada) healthcare administrative population-based datasets (start of follow-up: 24th and 25th Jan 2020 in England and Canada, respectively; end of follow-up: 31st Oct and 30th Sept 2020, respectively). We harmonised the definitions and the design of two cohorts to investigate associations between ethnicity and COVID-19-related death, hospitalisation, and intensive care (ICU) admission, adjusted for confounders, and combined the estimates obtained from survival analyses. We calculated the 'percentage of excess risk mediated' by these risk factors in the QResearch cohort. RESULTS: There were 9.83 million adults in the QResearch cohort (11,597 deaths; 21,917 hospitalisations; 2932 ICU admissions) and 10.27 million adults in the Ontario cohort (951 deaths; 5132 hospitalisations; 1191 ICU admissions). Compared to the general population, pooled random-effects estimates showed that South Asian ethnicity was associated with an increased risk of COVID-19 death (hazard ratio: 1.63, 95% CI: 1.09-2.44), hospitalisation (1.53; 1.32-1.76), and ICU admission (1.67; 1.23-2.28). Associations with ethnic groups were consistent across levels of deprivation. In QResearch, sociodemographic, lifestyle, and clinical factors accounted for 42.9% (South Asian) and 39.4% (Black) of the excess risk of COVID-19 death. CONCLUSION: International population-level analyses demonstrate clear ethnic inequalities in COVID-19 risks. Policymakers should be cognisant of the increased risks in some ethnic populations and design equitable health policy as the pandemic continues.