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Background: As future cardiovascular disease mortality trends have public health implications, we aimed to project ischemic heart disease (IHD), cerebrovascular disease (CeVD), and heart failure (HF) mortality rates for adults (40-79 years)., Methods and Results: In this population-level study, we linked the yearly mortality rates (per 100 000 US residents) (2000-2019) with IHD, CeVD, or HF as the primary cause of death from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research with the midyear US population estimates (2000-2035) for adults (40-79 years). We calculated the observed age-standardized mortality rates (2000-2019) (per 100 000 residents) (aSMR) and fitted Bayesian age-period-cohort models to project aSMR for IHD, CeVD, and HF up to 2035 in the United States. Between 2019 (last year of observed data) and 2035 (last year of projected results), the US population (40-79 years) will increase by 16% and age. The IHD aSMR will reduce from 111.9 (in 2019) to 81.8 (66.7-96.9) in 2035, an effect observed for all age groups. The CeVD aSMR will remain comparable between 2019 (37.4) and 2035 (38.6 [30.7-46.5]). The HF aSMR will increase from 16.5 in 2019 to reach 30.9 (13-48.8) in 2035; such increases were observed in all age groups., Conclusions: In the United States, between 2020 and 2035, the aSMR for IHD is expected to decrease, for CeVD will remain stable, and for HF will increase substantially. These data can inform resource allocation for future public health initiatives.

Cardio-kidney-metabolic (CKM) syndrome is defined by the American Heart Association as the intersection between metabolic, renal and cardiovascular disease. Understanding the contemporary estimates of CKM related mortality and recent trends in the US is essential for developing targeted public interventions. We collected state-level and county-level CKM-associated age-adjusted premature cardiovascular mortality (aaCVM) (2010-2019) rates from the CDC Wide-ranging Online Data for Epidemiologic Research (WONDER). We linked the county-level aaCVM with a multi-component social deprivation metric: the Social Deprivation Index (SDI: range 0-100) and grouped them as follows: I: 0-25, II: 26-50, III: 51-75, and IV: 76-100. We conducted pair-wise comparison of aaCVM between SDI groups with the multiplicity adjusted Wilcoxon test; we compared aaCVM in men versus women, metropolitan versus nonmetropolitan counties, and non-hispanic white versus non-hispanic black residents. In 3101 analyzed counties in the US, the median CKM associated aaCVM was 61 [interquartile range (IQR): 45, 82]/100 000. Mississippi (99/100 000) and Minnesota (33/100 000) had the highest and lowest values respectively. CKM associated aaMR increased across SDI groups [I - 45 (IQR: 36, 55)/100 000, II- 61 (IQR: 49, 77)/100 000, III- 77 (IQR: 61, 94)/100 000, IV- 89 (IQR: 70, 110)/100 000; all pair-wise p-values < 0.001]. Men had higher rates [85 (64, 91)/100 000] than women [41 (28, 58)/100 000](p-value < 0.001), metropolitan counties [54 (40, 72)/100 000] had lower rates than non-metropolitan counties [66 (49, 90)/100 000](p-value < 0.001), and non-Hispanic Black [110 (86, 137)/100 000] had higher aaMR than non-Hispanic White residents [59 (44, 78)/100 000](p-value < 0.001). In the US, CKM mortality remains high and disproportionately occurs in more socially deprived counties and non-metropolitan counties. Our inability to reduce CKM mortality rates over the study period highlights the need for targeted policy interventions to curb the ongoing high burden., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Aims: The 2021 European Society of Cardiology prevention guidelines recommend the use of (lifetime) risk prediction models to aid decisions regarding initiation of prevention. We aimed to update and systematically recalibrate the LIFEtime-perspective CardioVascular Disease (LIFE-CVD) model to four European risk regions for the estimation of lifetime CVD risk for apparently healthy individuals., Methods and Results: The updated LIFE-CVD (i.e. LIFE-CVD2) models were derived using individual participant data from 44 cohorts in 13 countries (687 135 individuals without established CVD, 30 939 CVD events in median 10.7 years of follow-up). LIFE-CVD2 uses sex-specific functions to estimate the lifetime risk of fatal and non-fatal CVD events with adjustment for the competing risk of non-CVD death and is systematically recalibrated to four distinct European risk regions. The updated models showed good discrimination in external validation among 1 657 707 individuals (61 311 CVD events) from eight additional European cohorts in seven countries, with a pooled C-index of 0.795 (95% confidence interval 0.767-0.822). Predicted and observed CVD event risks were well calibrated in population-wide electronic health records data in the UK (Clinical Practice Research Datalink) and the Netherlands (Extramural LUMC Academic Network). When using LIFE-CVD2 to estimate potential gain in CVD-free life expectancy from preventive therapy, projections varied by risk region reflecting important regional differences in absolute lifetime risk. For example, a 50-year-old smoking woman with a systolic blood pressure (SBP) of 140 mmHg was estimated to gain 0.9 years in the low-risk region vs. 1.6 years in the very high-risk region from lifelong 10 mmHg SBP reduction. The benefit of smoking cessation for this individual ranged from 3.6 years in the low-risk region to 4.8 years in the very high-risk region., Conclusion: By taking into account geographical differences in CVD incidence using contemporary representative data sources, the recalibrated LIFE-CVD2 model provides a more accurate tool for the prediction of lifetime risk and CVD-free life expectancy for individuals without previous CVD, facilitating shared decision-making for cardiovascular prevention as recommended by 2021 European guidelines., Competing Interests: Conflict of interest: Due to the very long author list, these will be provided per author using ICMJE forms at the revision stage, if applicable., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aim: To assess mortality and complication trends in people with type 1 diabetes during the 11 years before the SARS-CoV2 pandemic (2009-2019)., Materials and Methods: Sequential cohorts of people in England with type 1 diabetes aged ≥20 years from the National Diabetes Audit (2006/2007 to 2016/2017) were analysed. Discretized Poisson regression models, adjusted for age, sex, ethnicity, socioeconomic deprivation and duration of diabetes, were used to calculate mortality and hospitalization rates., Results: Demographic characteristics changed little; average diabetes duration increased. All-cause mortality was unchanged. Cardiovascular and kidney disease mortality declined. Mortality from respiratory disease, diabetes and dementia increased in younger people (aged 20-74 years) as did mortality from liver disease and dementia in the elderly (aged ≥75 years). Younger Asian and Black people had lower all-cause mortality than those of White ethnicity; elderly Mixed, Asian and Black people had lower all-cause mortality. People from more deprived areas had higher all-cause mortality. The deprivation gradient for mortality was steeper at younger ages. In younger people, rates of hospitalization increased for myocardial infarction, stroke, heart failure and kidney disease but only for kidney disease in the elderly. Rates of a composite measure of cardiovascular hospitalizations increased in younger people (rate ratio [RR] 1.07, 95% confidence interval [CI] 1.03-1.11) but declined in the elderly (RR 0.91, 95% CI 0.86-0.95)., Conclusion: Between 2009 and 2019, hospitalizations for cardiovascular disease increased at younger ages (20-74 years) and hospitalizations for kidney disease increased at all ages, but mortality from cardiovascular and kidney disease declined. All-cause mortality rates were unchanged., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: To estimate the incidence of major adverse cardiovascular events (MACE), expanded MACE, and MACE or Death across Fibrosis- 4 score (FIB-4) categories in people with type 2 diabetes and to determine whether efpeglenatide's effect varies with increasing FIB-4 severity., Materials and Methods: AMPLITUDE-O trial data were used to estimate the relationship of FIB-4 score categories to the hazard of MACE, expanded MACE, and MACE or death. Interactions on these outcomes between baseline FIB-4 score, and between FIB-4 score and efpeglenatide were also assessed., Results: Baseline FIB-4 score was available for 4059 participants (99.6%) allowing subdivision of the population in tertiles. During a median follow-up of 1.8 years, numerical increases in the incidence of all 3 outcomes did not change significantly across tertiles of FIB-4 score (P for trend ≥ 0.25) with negligible relationship of the score to incident outcomes (MACE HR, per 1 SD higher score, 95% CI: 1.00, 0.89-1.13). Efpeglenatide's effect on all MACE outcomes did not vary across FIB-4 tertiles (all interaction p values ≥ 0.64)., Conclusions: In high-risk people with type 2 diabetes, the degree of liver fibrosis, as estimated by FIB-4 score, was not related to incident cardiovascular outcomes. The beneficial effect of efpeglenatide on these outcomes is independent of FIB-4 category., (© 2024. The Author(s).)

Objective: In this study we examine whether hospitalized coronavirus disease 2019 (COVID-19) pneumonia increases long-term cardiovascular mortality more than other hospitalized pneumonias in people with type 2 diabetes and aim to quantify the relative cardiovascular disease (CVD) mortality risks associated with COVID-19 versus non-COVID-19 pneumonia., Research Design and Methods: With use of the SCI-Diabetes register, two cohorts were identified: individuals with type 2 diabetes in 2016 and at the 2020 pandemic onset. Hospital and death records were linked for determination of pneumonia exposure and CVD deaths. Poisson regression estimated rate ratios (RRs) for CVD death associated with both pneumonia types, with adjustment for confounders. Median follow-up durations were 1,461 days (2016 cohort) and 700 days (2020 cohort)., Results: The adjusted RR for CVD death following non-COVID-19 pneumonia was 5.51 (95% CI 5.31-5.71) prepandemic and 7.3 (6.86-7.76) during the pandemic. For COVID-19 pneumonia, the RR was 9.13 (8.55-9.75). Beyond 30 days post pneumonia, the RRs converged, to 4.24 (3.90-4.60) for non-COVID-19 and 3.35 (3.00-3.74) for COVID-19 pneumonia, consistent even with exclusion of prior CVD cases., Conclusions: Hospitalized pneumonia, irrespective of causal agent, marks an increased risk for CVD death immediately and over the long-term. COVID-19 pneumonia poses a higher CVD death risk than other pneumonias in the short-term, but this distinction diminishes over time. These insights underscore the need for including pneumonia in CVD risk assessments, with particular attention to the acute impact of COVID-19 pneumonia., (© 2024 by the American Diabetes Association.)

Objective: To investigate the incidence of cardiovascular disease (CVD) overall and by age, sex, and socioeconomic status, and its variation over time, in the UK during 2000-19., Design: Population based study., Setting: UK., Participants: 1 650 052 individuals registered with a general practice contributing to Clinical Practice Research Datalink and newly diagnosed with at least one CVD from 1 January 2000 to 30 June 2019., Main Outcome Measures: The primary outcome was incident diagnosis of CVD, comprising acute coronary syndrome, aortic aneurysm, aortic stenosis, atrial fibrillation or flutter, chronic ischaemic heart disease, heart failure, peripheral artery disease, second or third degree heart block, stroke (ischaemic, haemorrhagic, and unspecified), and venous thromboembolism (deep vein thrombosis or pulmonary embolism). Disease incidence rates were calculated individually and as a composite outcome of all 10 CVDs combined and were standardised for age and sex using the 2013 European standard population. Negative binomial regression models investigated temporal trends and variation by age, sex, and socioeconomic status., Results: The mean age of the population was 70.5 years and 47.6% (n=784 904) were women. The age and sex standardised incidence of all 10 prespecified CVDs declined by 19% during 2000-19 (incidence rate ratio 2017-19 v 2000-02: 0.80, 95% confidence interval 0.73 to 0.88). The incidence of coronary heart disease and stroke decreased by about 30% (incidence rate ratios for acute coronary syndrome, chronic ischaemic heart disease, and stroke were 0.70 (0.69 to 0.70), 0.67 (0.66 to 0.67), and 0.75 (0.67 to 0.83), respectively). In parallel, an increasing number of diagnoses of cardiac arrhythmias, valve disease, and thromboembolic diseases were observed. As a result, the overall incidence of CVDs across the 10 conditions remained relatively stable from the mid-2000s. Age stratified analyses further showed that the observed decline in coronary heart disease incidence was largely restricted to age groups older than 60 years, with little or no improvement in younger age groups. Trends were generally similar between men and women. A socioeconomic gradient was observed for almost every CVD investigated. The gradient did not decrease over time and was most noticeable for peripheral artery disease (incidence rate ratio most deprived v least deprived: 1.98 (1.87 to 2.09)), acute coronary syndrome (1.55 (1.54 to 1.57)), and heart failure (1.50 (1.41 to 1.59))., Conclusions: Despite substantial improvements in the prevention of atherosclerotic diseases in the UK, the overall burden of CVDs remained high during 2000-19. For CVDs to decrease further, future prevention strategies might need to consider a broader spectrum of conditions, including arrhythmias, valve diseases, and thromboembolism, and examine the specific needs of younger age groups and socioeconomically deprived populations., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: NC is funded by a personal fellowship from the Research Foundation Flanders and a research grant from the European Society of Cardiology. JMF, PSJ, JGC, NS, and JJVM are supported by British Heart Foundation Centre of Research Excellence. PSJ and JJVM are further supported by the Vera Melrose Heart Failure Research Fund. JJVM has received funding to his institution from Amgen and Cytokinetics for his participation in the steering sommittee for the ATOMIC-HF, COSMIC-HF, and GALACTIC-HF trials and meetings and other activities related to these trials; has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; and has received personal lecture fees from the Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Alkem Metabolics, Eris Lifesciences, Lupin, ProAdWise Communications, Servier Director, and Global Clinical Trial Partners. NS declares consulting fees or speaker honorariums, or both, from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; and grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics. KK has acted as a consultant or speaker or received grants for investigator initiated studies for Astra Zeneca, Bayer, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, Oramed Pharmaceuticals, Roche, and Applied Therapeutics. KK is supported by the National Institute for Health and Care Research (NIHR) Applied Research Collaboration East Midlands (ARC EM) and the NIHR Leicester Biomedical Research Centre (BRC). CL is funded by an NIHR Advanced Research Fellowship (NIHR-300111) and supported by the Leicester BRC. PSJ has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals, and Intas Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices; his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer, Novartis, and Novo Nordisk; and is the Director of Global Clinical Trial Partners. HS is supported by the China Scholarship Council. Other authors report no support from any organisation for the submitted work, no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Clinical guidelines often recommend treating individuals based on their cardiovascular risk. We revisit this paradigm and quantify the efficacy of three treatment strategies: (i) overall prescription, i.e. treatment to all individuals sharing the eligibility criteria of a trial; (ii) risk-stratified prescription, i.e. treatment only to those at an elevated outcome risk; and (iii) prescription based on predicted treatment responsiveness., Methods and Results: We reanalysed the PROSPER randomized controlled trial, which included individuals aged 70-82 years with a history of, or risk factors for, vascular diseases. We conducted the derivation and internal-external validation of a model predicting treatment responsiveness. We compared with placebo (n = 2913): (i) pravastatin (n = 2891); (ii) pravastatin in the presence of previous vascular diseases and placebo in the absence thereof (n = 2925); and (iii) pravastatin in the presence of a favourable prediction of treatment response and placebo in the absence thereof (n = 2890). We found an absolute difference in primary outcome events composed of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke, per 10 000 person-years equal to: -78 events (95% CI, -144 to -12) when prescribing pravastatin to all participants; -66 events (95% CI, -114 to -18) when treating only individuals with an elevated vascular risk; and -103 events (95% CI, -162 to -44) when restricting pravastatin to individuals with a favourable prediction of treatment response., Conclusion: Pravastatin prescription based on predicted responsiveness may have an encouraging potential for cardiovascular prevention. Further external validation of our results and clinical experiments are needed., Trial Registration: ISRCTN40976937., Competing Interests: Conflict of interest: N.S. has consulted for Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi and received grant support paid to his University from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside the submitted work. All the other authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: To develop and externally validate the LIFE-T1D model for the estimation of lifetime and 10-year risk of cardiovascular disease (CVD) in individuals with type 1 diabetes., Materials and Methods: A sex-specific competing risk-adjusted Cox proportional hazards model was derived in individuals with type 1 diabetes without prior CVD from the Swedish National Diabetes Register (NDR), using age as the time axis. Predictors included age at diabetes onset, smoking status, body mass index, systolic blood pressure, glycated haemoglobin level, estimated glomerular filtration rate, non-high-density lipoprotein cholesterol, albuminuria and retinopathy. The model was externally validated in the Danish Funen Diabetes Database (FDDB) and the UK Biobank., Results: During a median follow-up of 11.8 years (interquartile interval 6.1-17.1 years), 4608 CVD events and 1316 non-CVD deaths were observed in the NDR (n = 39 756). The internal validation c-statistic was 0.85 (95% confidence interval [CI] 0.84-0.85) and the external validation c-statistics were 0.77 (95% CI 0.74-0.81) for the FDDB (n = 2709) and 0.73 (95% CI 0.70-0.77) for the UK Biobank (n = 1022). Predicted risks were consistent with the observed incidence in the derivation and both validation cohorts., Conclusions: The LIFE-T1D model can estimate lifetime risk of CVD and CVD-free life expectancy in individuals with type 1 diabetes without previous CVD. This model can facilitate individualized CVD prevention among individuals with type 1 diabetes. Validation in additional cohorts will improve future clinical implementation., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known., Objectives: To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors., Methods: In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health., Results: From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86)., Conclusion: Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need., Trail Registration Number: ISRCTN10980107., Competing Interests: Competing interests: KK is chair of the ethnicity subgroup of the UK Scientific Advisory Group for Emergencies (SAGE) and is a member of SAGE. KK (Chair) and RE are members of the Long COVID Epidemiological Research Group that reports to the CMO. CB is an author of the COVID-19 rapid guideline: managing the long-term effects of COVID-19 NICE guideline (NG188) https://www.nice.org.uk/guidance/ng188/history. CB is a member of the NHS National Services Scotland Long COVID group and his employer, the University of Glasgow, holds a research agreement with AstraZeneca and Somalogic for research in COVID-19. AJM is an employee of AstraZeneca., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Competing Interests: Disclosures N. Sattar has consulted for and/or received speaker honoraria from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Menarini-Ricerche, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; he has received grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside the submitted work. Dr Neeland has consulted for and/or received speaker honoraria from Boehringer Ingelheim, Eli Lilly and Co, Novo Nordisk, Bayer Pharmaceuticals, and Nestle Health Sciences outside the submitted work. Dr McGuire reports research support for Clinical Trials Leadership from Boehringer Ingelheim, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, and CSL Behring, as well as honoraria for consultancy from Lilly USA, Pfizer, Boehringer Ingelheim, Lexicon, Novo Nordisk, Applied Therapeutics, Altimmune, CSL Behring, Bayer, Intercept, and New Amsterdam.

Background: Circulating concentrations of vascular endothelial growth factor (VEGF) family members may be abnormally elevated in type 2 diabetes (T2D). The roles of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFLT-1), and VEGF-A in cardio-renal complications of T2D are not established., Method: The 2602 individuals with diabetic kidney disease (DKD) from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial were randomized to receive canagliflozin or placebo and followed for incident cardio-renal outcomes. PlGF, sFLT-1, and VEGF-A were measured at baseline, year 1, and year 3. Primary outcome was a composite of end-stage kidney disease, doubling of the serum creatinine, or renal/cardiovascular death. Cox proportional hazard regression was used to investigate the association between biomarkers with adverse clinical events., Results: At baseline, individuals with higher PlGF levels had more prevalent cardiovascular disease compared to those with lower values. Treatment with canagliflozin did not meaningfully change PlGF, sFLT-1, and VEGF-A concentrations at years 1 and 3. In a multivariable model, 1 unit increases in baseline log PlGF (hazard ratio [HR]: 1.76, 95% confidence interval [CI]: 1.23, 2.54, P-value = .002), sFLT-1 (HR: 3.34, [95% CI: 1.71, 6.52], P-value < .001), and PlGF/sFLT-1 ratio (HR: 4.83, [95% CI: 0.86, 27.01], P-value = .07) were associated with primary composite outcome, while 1 unit increase in log VEGF-A did not increase the risk of primary outcome (HR: 0.96 [95% CI: 0.81, 1.07]). Change by 1 year of each biomarker was also assessed: HR (95% CI) of primary composite outcome was 2.45 (1.70, 3.54) for 1 unit increase in 1-year concentration of log PlGF, 4.19 (2.18, 8.03) for 1 unit increase in 1-year concentration of log sFLT-1, and 21.08 (3.79, 117.4) for 1 unit increase in 1-year concentration of log PlGF/sFLT-1. Increase in 1-year concentrations of log VEGF-A was not associated with primary composite outcome (HR: 1.08, [95% CI: 0.93, 1.24], P-value = .30)., Conclusions: People with T2D and DKD with elevated levels of PlGF, sFLT-1, and PlGF/sFLT-1 ratio were at a higher risk for cardiorenal events. Canagliflozin did not meaningfully decrease concentrations of PlGF, sFLT-1, and VEGF-A., Clinical Trial: CREDENCE, https://clinicaltrials.gov/ct2/show/NCT02065791., Competing Interests: Disclosures Dr. Januzzi is a trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; is a director at Jana Care; has received grant support from Abbott, Applied Therapeutics, HeartFlow, Innolife, and Roche Diagnostics; has received consulting income from Abbott, Beckman, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Merck, Novartis, Pfizer, Roche Diagnostics, and Siemens; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, CVRx, Intercept, and Takeda. Drs. Tefera, Yavin, and Hansen are full-time employees of Jansen Research & Development, LLC. All other authors report no relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In high-income countries, rates of atherosclerotic complications in type 2 diabetes have declined markedly over time due to better management of traditional risk factors including lipids, blood pressure, and glycemia levels. Population-wide reductions in smoking have also helped lower atherosclerotic complications and so reduce premature mortality in type 2 diabetes. However, as excess adiposity is a stronger driver for heart failure (HF), and obesity levels have remained largely unchanged, HF risks have not declined as much and may even be rising in the increasing number of people developing type 2 diabetes at younger ages. Excess weight is also an underrecognized risk factor for chronic kidney disease (CKD). Based on evidence from a range of sources, we explain how excess adiposity must be influencing most risks well before diabetes develops, particularly in younger-onset diabetes, which is linked to greater excess adiposity. We also review potential mechanisms linking excess adiposity to HF and CKD and speculate on how some of the responsible pathways-e.g., hemodynamic, cellular overnutrition, and inflammatory-could be favorably influenced by intentional weight loss (via lifestyle or drugs). On the basis of available evidence, we suggest that the cardiorenal outcome benefits seen with sodium-glucose cotransporter 2 inhibitors may partially derive from their interference of some of these same pathways. We also note that many other complications common in diabetes (e.g., hepatic, joint disease, perhaps mental health) are also variably linked to excess adiposity, the aggregated exposure to which has now increased in type 2 diabetes. All such observations suggest a greater need to tackle excess adiposity earlier in type 2 diabetes., (© 2024 by the American Diabetes Association.)

Aims: To estimate the incidence of a major adverse cardiovascular event (MACE) and a composite kidney outcome across estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) levels, and to determine whether efpeglenatide's effect varies with these indices., Materials and Methods: AMPLITUDE-O trial data were used to estimate the relationship of eGFR, UACR, and Kidney Disease Improving Global Outcomes (KDIGO) category to the hazard of MACE and the kidney composite. Interactions on these outcomes between eGFR and the UACR, and between each of these variables and efpeglenatide were also assessed., Results: Baseline eGFR and UACR were available for 3983 participants (mean age 64.5 years). During a median follow-up of 1.8 years, the hazards of MACE and the kidney composite for the lowest versus highest eGFR third were 1.6 (95% confidence interval [CI] 1.2, 2.2) and 2.3 (95% CI 1.9, 2.8), respectively. The hazards for the highest versus the lowest UACR third were 2.3 (95% CI 1.8, 3.1) and 18.0 (95% CI 12.7, 25.5), respectively, and for the high- versus low-risk KDIGO categories the hazards were 2.4 (95% CI 1.8, 3.1) and 16.0 (95% CI 11.6, 22.0), respectively. eGFR and UACR were independent determinants of both outcomes, but negatively interacted with each other for the kidney outcome. Efpeglenatide's effect on both outcomes did not vary with any kidney disease measure (all interaction p values ≥0.26)., Conclusions: In high-risk people with diabetes, eGFR, UACR, and KDIGO category have different relationships to incident cardiovascular and kidney outcomes. The beneficial effect of efpeglenatide on these outcomes is independent of kidney-related risk category., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Gout, a common crystal arthropathy, is associated with increased risk of cardiovascular disease. We aimed to identify how this risk varies by individual cardiovascular disease across a broad spectrum of conditions., Methods: In this matched case-control study, we used linked primary and secondary electronic health records from the UK Clinical Practice Research Datalink to assemble a cohort of individuals with a first-time diagnosis of gout between Jan 1, 2000 and Dec 31, 2017, who were aged 80 years or younger at diagnosis, and free of cardiovascular diseases up to 12 months after diagnosis. The control cohort comprised up to five control individuals per patient with gout, matched on age, sex, socioeconomic status, geographical region, and calendar time, randomly selected among individuals free of gout at any time before and during the study period. The cohorts were followed up until June 30, 2019. We investigated the incidence of 12 cardiovascular diseases and used Cox proportional hazards models to examine differences in people with and without gout, overall and by subgroups of sex, age, socioeconomic status, and year of study inclusion. We further adjusted models for known cardiovascular risk factors (blood pressure, BMI, smoking status, cholesterol, type 2 diabetes, chronic kidney disease, and history of hypertension)., Findings: We identified 152 663 individuals with gout (mean age 56·2 years [SD 13·3]; 120 324 [78·8%] men and 32 339 [21·2%] women) and 709 981 matched controls (mean age 56·5 years [13·2]; 561 002 [79·0%] men and 148 979 [21·0%] women). Of these individuals, 31 479 (20·6%) with gout and 106 520 (15·0%) without gout developed cardiovascular disease during a median follow-up of 6·5 years (IQR 3·1-10·5). Patients with gout had higher risk of cardiovascular diseases than matched controls (hazard ratio [HR] 1·58 [95% CI 1·52-1·63]). Excess risk of cardiovascular disease in gout was greater in women than men (women: HR 1·88 [1·75-2·02]; men: HR 1·49 [1·43-1·56]), and, among all age groups, was highest in younger individuals (HR in people aged <45 years: 2·22 [1·92-2·57]). Excess risk was observed across all 12 cardiovascular diseases investigated. Patients with gout had higher BMI than matched controls (mean difference 2·90 kg/m 2 [95% CI 2·87-2·93]) and higher prevalence of chronic kidney disease, dyslipidaemia, history of hypertension, obesity, and type 2 diabetes. Adjusting for known cardiovascular risk factors attenuated but did not eliminate the excess risk of cardiovascular disease related to gout (adjusted HR 1·31 [1·27-1·36])., Interpretation: Patients with gout had an excess risk of developing a broad range of cardiovascular diseases that extend beyond atherosclerotic diseases and include heart failure, arrhythmias, valve disease, and thromboembolic diseases. Excess risk was highest in women and younger individuals. These findings suggest that strategies to reduce cardiovascular risk in patients with gout need to evolve and be implemented in clinical practice., Funding: Research Foundation Flanders., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Competing Interests: Conflict of interest: N.S. declares consulting fees or speaker honoraria from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; and grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics, outside the submitted work. J.D. received consulting fees from GENinCode UK Ltd; received CME honoraria and/or consulting fees from Aegerion, Amgen, Bayer, Boehringer Ingelheim, Merck, Novartis, Novo Nordisk A/S, Pfizer, Sanofi, and Takeda; and holds the following unpaid positions: Chief Medical Advisor for Our Future Health, senior advisor for Cardiovascular Disease Prevention for Public Health England, and Chair of the NHS Healthcheck Expert Scientific and Clinical Advisory Panel (ESCAP) and Review of the National Health Check Programme for Public Health England. C.D. and N.S. are supported by the British Heart Foundation (Centre of Research Excellence, reference RE/18/6/34217).

Background: Many studies have investigated whether single cardiac biomarkers improve cardiovascular risk prediction for primary prevention but whether a combined approach could further improve risk prediction is unclear. We aimed to test a sex-specific, combined cardiac biomarker approach for cardiovascular risk prediction., Methods: In the Generation Scotland Scottish Family Health Study, N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor-15 (GDF-15), cardiac troponin I (cTnI), cardiac troponin T (cTnT), and C-reactive protein (CRP) were measured in stored serum using automated immunoassays. Sex-specific Cox models that included SCORE2 risk factors evaluated addition of single and combined biomarkers for prediction of major adverse cardiovascular events (MACE). Combined biomarker models were compared to a baseline model that included SCORE2 risk factors., Results: The study population comprised 18 383 individuals (58.9% women, median age of 48 years [25th-75th percentile, 35-58 years]). During the median follow up of 11.6 (25th-75th percentile, 10.8-13.0) years, MACE occurred in 942 (5.1%) individuals. The greatest increase in discrimination with addition of individual biomarkers to the base model was for women GDF-15 and for men NT-proBNP (change in c-index: + 0.010 for women and +0.005 for men). For women, combined biomarker models that included GDF-15 and NT-proBNP (+0.012) or GDF-15 and cTnI (+0.013), but not CRP or cTnT, further improved discrimination. For men, combined biomarker models that included NT-proBNP and GDF-15 (+0.007), NT-proBNP and cTnI (+0.006), or NT-proBNP and CRP (+0.008), but not cTnT, further improved discrimination., Conclusions: A combined biomarker approach, particularly the use of GDF-15, NT-proBNP and cTnI, further refined cardiovascular risk estimates., (© The Author(s) 2023. Published by Oxford University Press on behalf of Association for Diagnostics & Laboratory Medicine.)

Background and Aims: Elevated lipoprotein(a) [Lp(a)] is a genetic driver for atherosclerotic cardiovascular disease (ASCVD). We aimed to provide novel insights into the associated risk of elevated versus normal Lp(a) levels on major adverse cardiovascular events (MACE) in an incident ASCVD cohort., Methods: This was an observational cohort study of incident ASCVD patients. MACE counts and incidence rates (IRs) per 100-person-years were reported for patients with normal (<65 nmol/L) and elevated (>150 nmol/L) Lp(a) within the first year after incident ASCVD diagnosis and overall follow-up. Cox proportional hazard models quantified the risk of MACE associated with a 100 nmol/L increase in Lp(a)., Results: The study cohort included 32,537 incident ASCVD patients; 5204 with elevated and 22,257 with normal Lp(a). Of those with elevated Lp(a), 41.2% had a subsequent MACE, versus 35.61% with normal Lp(a). Within the first year of follow-up, the IRs of composite MACE and coronary revascularisation were significantly higher (p < 0.001) in patients with elevated versus normal Lp(a) (IR difference 6.79 and 4.66). This trend was also observed in the overall follow-up (median 4.7 years). Using time to first subsequent MACE, a 100 nmol/L increase in Lp(a) was associated with an 8.0% increased risk of composite MACE, and 18.6% increased risk of coronary revascularisation during the overall follow-up period., Conclusions: The association of elevated Lp(a) with increased risk of subsequent MACE and coronary revascularisation highlights a population who may benefit from earlier and more targeted intervention for cardiovascular risk including Lp(a), particularly within the first year after ASCVD diagnosis. Proactive Lp(a) testing as part of routine clinical practice can help identify and better manage these higher-risk individuals., Competing Interests: Declaration of competing interest Paul Welsh reports grants from Novartis Pharma AG, Basel, Switzerland during the conduct of the study, grants from Boehringer Ingelheim, Roche Diagnostics, Astrazeneca, and personal fees from Novo Nordisk, and Raisio, outside the submitted work. Naveed Sattar reports grants and personal fees from Novartis Pharma AG, Basel, Switzerland, consulted for and/or received speaker honoraria from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; and received grant support paid to his University from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside the submitted work. Rosemary Brown reports grant from Novartis Pharma AG, Basel, Switzerland during the conduct of the study. Anas Al Zabiby was an employee of Novartis, Kuala Lumpur, Malaysia at time of study. Hannah Byrne, Harriet R. Benbow and Gabriella Farries are employees of Novartis Pharma AG, Dublin, Ireland. Ana Filipa Fonseca and Philippe Ferber are employees of Novartis Pharma AG, Basel, Switzerland. Madlaina Costa-Scharplatz is an employee of Novartis Sweden AB, Stockholm, Sweden. Lorraine Martin is an employee of Novartis Pharmaceuticals UK Limited, United Kingdom. Taha Itani was an employee of Novartis Pharma AG, Basel, Switzerland at the time of conduct of this study., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cardiovascular disease (CVD) is among the leading causes of death worldwide. The discovery of new omics biomarkers could help to improve risk stratification algorithms and expand our understanding of molecular pathways contributing to the disease. Here, ASSIGN-a cardiovascular risk prediction tool recommended for use in Scotland-was examined in tandem with epigenetic and proteomic features in risk prediction models in ≥12 657 participants from the Generation Scotland cohort., Methods: Previously generated DNA methylation-derived epigenetic scores (EpiScores) for 109 protein levels were considered, in addition to both measured levels and an EpiScore for cTnI (cardiac troponin I). The associations between individual protein EpiScores and the CVD risk were examined using Cox regression (n cases ≥1274; n controls ≥11 383) and visualized in a tailored R application. Splitting the cohort into independent training (n=6880) and test (n=3659) subsets, a composite CVD EpiScore was then developed., Results: Sixty-five protein EpiScores were associated with incident CVD independently of ASSIGN and the measured concentration of cTnI ( P <0.05), over a follow-up of up to 16 years of electronic health record linkage. The most significant EpiScores were for proteins involved in metabolic, immune response, and tissue development/regeneration pathways. A composite CVD EpiScore (based on 45 protein EpiScores) was a significant predictor of CVD risk independent of ASSIGN and the concentration of cTnI (hazard ratio, 1.32; P =3.7×10 -3 ; 0.3% increase in C-statistic)., Conclusions: EpiScores for circulating protein levels are associated with CVD risk independent of traditional risk factors and may increase our understanding of the etiology of the disease., Competing Interests: Disclosures L. Murphy and Dr Marioni received a speaker fee from Illumina. Dr Marioni is an advisor to the Epigenetic Clock Development Foundation. D.A. Gadd and Dr Marioni received consultancy fees from Optima Partners. The other authors report no conflicts.

Background: Tirzepatide, a once-weekly GIP/GLP-1 receptor agonist, reduces blood glucose and body weight in people with type 2 diabetes. The cardiovascular (CV) safety and efficacy of tirzepatide have not been definitively assessed in a cardiovascular outcomes trial., Methods: Tirzepatide is being studied in a randomized, double-blind, active-controlled CV outcomes trial. People with type 2 diabetes aged ≥40 years, with established atherosclerotic CV disease, HbA1c ≥7% to ≤10.5%, and body mass index ≥25 kg/m 2 were randomized 1:1 to once weekly subcutaneous injection of either tirzepatide up to 15 mg or dulaglutide 1.5 mg. The primary outcome is time to first occurrence of any major adverse cardiovascular event (MACE), defined as CV death, myocardial infarction, or stroke. The trial is event-driven and planned to continue until ≥1,615 participants experience an adjudication-confirmed component of MACE. The primary analysis is noninferiority for time to first MACE of tirzepatide vs dulaglutide by demonstrating an upper confidence limit <1.05, which will also confirm superiority vs a putative placebo, and also to determine whether tirzepatide produces a greater CV benefit than dulaglutide (superiority analysis)., Results: Over 2 years, 13,299 people at 640 sites in 30 countries across all world regions were randomized. The mean age of randomized participants at baseline was 64.1 years, diabetes duration 14.7 years, HbA1c 8.4%, and BMI 32.6 kg/m 2 . Overall, 65.0% had coronary disease, of whom 47.3% reported prior myocardial infarction and 57.4% had prior coronary revascularization. 19.1% of participants had a prior stroke and 25.3% had peripheral artery disease. The trial is fully recruited and ongoing., Conclusion: SURPASS-CVOT will provide definitive evidence as to the CV safety and efficacy of tirzepatide as compared with dulaglutide, a GLP-1 receptor agonist with established CV benefit., Competing Interests: Conflict of interest SJN reports grants or contracts from Amgen, Anthera Pharmaceuticals, AstraZeneca, Cerenis Therapeutics, CSL Behring, Eli Lilly and Company, Esperion Therapeutics, Infraredx, New Amsterdam Pharma, Novartis, Resverlogix, and Sanofi Regeneron; consulting fees from Akcea Therapeutics, Amgen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly and Company, Esperion Therapeutics, Kowa, Merck, Novo Nordisk, Pfizer, Sanofi Regeneron, Takeda, Vaxxinity, Silence Therapeutics, and CSL Sequiris; is a named inventor on a patent planned, issued or pending with Amgen; and is President of Cardiac Society of Australia and New Zealand. DLB reports grants or contracts from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, Cincor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Eli Lilly and Company, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer Inc, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89bio, Otsuka, and Alnylam; royalties from Elsevier; consulting fees from Broadview Ventures, Hims, and McKinsey; payment or honoraria from American College of Cardiology, Baim Institute for Clinical Research, Belvoir Publications, Boston Scientific, Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Novartis, Population Health Research Institute, Rutgers University, Canadian Medical and Surgical Knowledge Translation Research Group, Cowen and Company, HMP Global, Journal of the American College of Cardiology, K2P, Level Ex, Medtelligence/ReachMD, MJH Life Sciences, Oakstone CME, Piper Sandler, Population Health Research Institute, Slack Publications, WebMD, Wiley, Society of Cardiovascular Patient Care, and CSL Behring; payment for expert testimony from Arnold and Porter law firm; meeting/travel support from American College of Cardiology, Society of Cardiovascular Patient Care, and American Heart Association; a pending patent for Sotagliflozin; participation on data monitoring or advisory boards for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, AngioWave, Baim Institute, Bayer, Boehringer Ingelheim, Boston Scientific, Cardax, CellProthera, Cereno Scientific, Cleveland Clinic, Contego Medical, Duke Clinical Research Institute, Elsevier Practice Update Cardiology, Janssen, Level Ex, Mayo Clinic, Medscape Cardiology, Merck, Mount Sinai School of Medicine, MyoKardia, NirvaMed, Novartis, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Population Health Research Institute, and Stasys; leadership or fiduciary roles with American College of Cardiology, AngioWave, Boston VA Research Institute, Bristol Myers Squibb, DRS.LINQ, High Enroll, Society of Cardiovascular Patient Care, TobeSoft, and AHA NYC Chapter; stock or stock options in AngioWave, Bristol Myers Squibb, DRS.LINQ, and High Enroll; and other financial or non-financial interests in Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), American Heart Association Quality Oversight Committee (Chair), VA CART Research and Publications Committee (Chair), Contego Medical (Chair, PERFORMANCE 2), conducts unfunded research with FlowCo and Takeda, and is site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Phillips SpectraWAVE, Svelte, and Vascular Solutions. JBB reports grant support from Dexcom, Insulet, MannKind, NovaTarg, Novo Nordisk, Sanofi, Tolerion, and vTv Therapeutics; consulting fees from Novo Nordisk, Alkahest, Altimmune, Anji, AstraZeneca, Bayer, Biomea Fusion Inc, Boehringer Ingelheim, CeQur, Cirius Therapeutics Inc, Corcept Therapeutics, CultHealth, Eli Lilly and Company, embecta, GentiBio, Glycadia, Glyscend, Janssen, Mellitus Health, Metsera, Moderna, Pendulum Therapeutics, Praetego, Sanofi, Stability Health, Tandem, Terns Inc, Valo, and Zealand Pharma; payment for expert testimony from Medtronic; participation on data monitoring or advisory boards for Alkahest, Altimmune, AstraZeneca, and Tandem; a leadership or fiduciary role with Association of Clinical and Translational Science; stock or stock options in Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio, Praetego and Stability Health; and other financial or other non-financial interests in Dasman Diabetes Center, Kuwait City (scientific advisory board), and ReachMD and Mediflix (audiovisual content development). SDP reports consultation for Abbott, Amarin, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Hengrui Pharmaceuticals, Menarini International, MSD, Novo Nordisk, and Sanofi; grant support from AstraZeneca and Boehringer Ingelheim; and speaker fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Laboratori Guidotti, MSD, Novartis, Novo Nordisk, and Sanofi.. SEK reports consulting fees from Anji Pharamceuticals, Eli Lilly and Company, Merck, and Novo Nordisk; and payment or honoraria from Novo Nordisk. AML reports grants or contracts from Eli Lilly and Company; consulting fees from Eli Lilly and Company, Novo Nordisk, and Novartis; and meeting/travel support from Novo Nordisk and Eli Lilly and Company. DKM reports research support for clinical trials leadership from Boehringer Ingelheim, Merck & Co, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, Lexicon, CSL Behring, and New Amsterdam; and honoraria for consultancy from Lilly USA, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Applied Therapeutics, Altimmune, CSL Behring, Bayer, and Intercept. MAN reports grants or contracts from Merck, Sharp & Dohme; consulting fees from Boehringer Ingelheim, Berlin-Chemie/Menarini, Eli Lilly and Company, Medtronic, Merck, Sharp & Dohme, Novo Nordisk, Pfizer, Regor, Structure Therapeutics (Gasherbrum), and Sun Pharma; payment or honoraria from Berlin-Chemie/Menarini, Eli Lilly and Company, Medical Learning Institute, Medscape, Merck, Sharp & Dohme, Novo Nordisk, Sanofi, and Sun Pharma; and participation on a data monitoring or advisory board with Inventiva. SEN reports that the Cleveland Clinic Center for Clinical Research has received funding to perform clinical trials from Abbvie, AstraZeneca, Arrowhead, Amgen, Bristol Myers Squibb, Eli Lilly, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics. NS reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, and Novartis; a grant from Roche Diagnostics; and personal fees from Abbott Laboratories, Amgen, Eli Lilly and Company, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi. BZ reports consulting fees from Eli Lilly and Company. SZ reports grants or contracts from NHMRC, Australian Government Department of Health and Aged Care, JDRF Centre of Excellence, and MRFF; consulting fees from Eli Lilly Australia, Boehringer-Ingelheim, MSD Australia, Astra Zeneca, Novo Nordisk, and Sanofi; payment or honoraria from Heart Foundation; meeting/travel support from Australian Diabetes Society 2022, International Diabetes Federation 2022, and KDIGO Implementation Summit on Diabetes Management in CKD; and leadership or fiduciary roles with Melanoma and Skin Cancer Trials Ltd., Australian Clinical Trials Alliance, and Victorian Institute of Forensic Medicine. JB reports consulting fees from Eli Lilly and Company, ReCor, and Medtronic; and participation on advisory boards for ReCor, Medtronic, and Eli Lilly and Company. AB, DM, HN, IP, GW, and RJW are employees and shareholders in Eli Lilly and Company. DD reports consulting fees from Eli Lilly and Company, Sun Pharmaceuticals, and Structure Therapeutics; payment or honoraria from University of Chicago, University of Iowa, and Korean Diabetes Association; meeting/travel support from American Diabetes Association; and stock or stock options in MBX Biosciences., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Disparities exist in the cardiovascular mortality rates among people with type 2 diabetes (T2D). Research has established that these disparities are often related to the environmental and social determinations of health. This study explores the spatial variation between air pollution, social determinants of health and T2D related age-adjusted cardiovascular mortality (aa-CVM) in the United States. We obtained county-level T2D related to aa-CVM (per 100,000 residents) from Centers for Disease Control and Prevention WONDER (Wide-ranging Online Data for Epidemiologic Research) (2010 to 2019). We fit a geographically weighted linear regression with aa-CVM as the outcome and the following covariates (ambient air pollution [particulate matter of 2.5 µm size], median annual household income, racial/ethnic minorities, higher education, rurality, food insecurity, and primary health care access) were included. Overall, the median aa-CVM rate was 92.9 and highest in the South (102.2). In the West, aa-CVM was significantly associated with particulate matter of 2.5 µm size, annual median household income, racial minority status and primary health care access. Food insecurity was the most significant exposure in the Midwest and Northeast, while in the South, annual median household income and food insecurity were significant. In conclusion, this study demonstrated a substantial regional variation of exposure to determinants of T2D related aa-CVM in the United States. These findings should be considered in policy frameworks and interventions as part of community-level approaches to addressing T2D related aa-CVM, and within broader state and national discussions of the importance of population health., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Published by Elsevier Inc.)

Objective: To determine the extent to which changes in plasma proteins, previously predictive of cardiometabolic outcomes, predict changes in two diabetes remission trials., Research Design and Methods: We applied SomaSignal predictive tests (each derived from ∼5,000 plasma protein measurements using aptamer-based proteomics assay) to baseline and 1-year samples of trial intervention (Diabetes Remission Clinical Trial [DiRECT], n = 118, and Diabetes Intervention Accentuating Diet and Enhancing Metabolism [DIADEM-I], n = 66) and control (DiRECT, n = 144, DIADEM-I, n = 76) group participants., Results: Mean (SD) weight loss in DiRECT (U.K.) and DIADEM-I (Qatar) was 10.2 (7.4) kg and 12.1 (9.5) kg, respectively, vs. 1.0 (3.7) kg and 4.0 (5.4) kg in control groups. Cardiometabolic SomaSignal test results showed significant improvement (Bonferroni-adjusted P < 0.05) in DiRECT and DIADEM-I (expressed as relative difference, intervention minus control) as follows, respectively: liver fat (-26.4%, -37.3%), glucose tolerance (-36.6%, -37.4%), body fat percentage (-8.6%, -8.7%), resting energy rate (-8.0%, -5.1%), visceral fat (-34.3%, -26.1%), and cardiorespiratory fitness (9.5%, 10.3%). Cardiovascular risk (measured with SomaSignal tests) also improved in intervention groups relative to control, but this was significant only in DiRECT (DiRECT, -44.2%, and DIADEM-I, -9.2%). However, weight loss >10 kg predicted significant reductions in cardiovascular risk, -19.1% (95% CI -33.4 to -4.91) in DiRECT and -33.4% (95% CI -57.3, -9.6) in DIADEM-I. DIADEM-I also demonstrated rapid emergence of metabolic improvements at 3 months., Conclusions: Intentional weight loss in recent-onset type 2 diabetes rapidly induces changes in protein-based risk models consistent with widespread cardiometabolic improvements, including cardiorespiratory fitness. Protein changes with greater (>10 kg) weight loss also predicted lower cardiovascular risk, providing a positive outlook for relevant ongoing trials., (© 2023 by the American Diabetes Association.)

Background: Whether frailty influences the initiation of two cardioprotective diabetes drug therapies (ie, SGLT2 inhibitors and GLP-1 receptor agonists) in people with type 2 diabetes and cardiovascular disease is unknown. We aimed to assess rates of initiation of SGLT2 inhibitors and GLP-1 receptor agonists according to frailty in people with type 2 diabetes and cardiovascular disease., Methods: For this cross-sectional, nationwide study, all people with type 2 diabetes and cardiovascular disease in Denmark between Jan 1, 2015, and Dec 31, 2021, from six Danish health-data registers were identified. People younger than 40 years, with end-stage renal disease, with registered contraindications to SGLT2 inhibitors or GLP-1 receptor agonists, or with previous use of either drug therapy were excluded. The Hospital Frailty Risk Score was used to categorise people as either non-frail, moderately frail, or severely frail. Cox proportional hazards models were used to analyse the association between frailty and initiation of an SGLT2 inhibitor or a GLP-1 receptor agonist., Findings: Of 119 390 people with type 2 diabetes and cardiovascular disease, 103 790 were included. Median follow-up time was 4·5 years (IQR 2·7-6·1) and median age across the three frailty groups was 71 years (64-79). 65 959 (63·6%) of 103 790 people were male and 37 831 (36·5%) were female. At index date, 66 910 (64·5%) people were non-frail, 29 250 (28·2%) were moderately frail, and 7630 (7·4%) were severely frail. Frailty was associated with a significantly lower probability of initiating therapy with an SGLT2 inhibitor or a GLP-1 receptor agonist than in people who were non-frail (moderately frail hazard ratio 0·91, 95% CI 0·88-0·94, p<0·0001; severely frail 0·75, 0·70-0·80, p<0·0001). This association persisted after adjustment for age, sex, socioeconomic status, year of inclusion, duration of type 2 diabetes, duration of cardiovascular disease, polypharmacy, and comorbidity., Interpretation: In people with type 2 diabetes and cardiovascular disease in Denmark, frailty was associated with a significantly lower probability of SGLT2-inhibitor or GLP-1 receptor-agonist initiation, despite their benefits. Formulating clear and updated guidelines on the use of SGLT2 inhibitors and GLP-1 receptor agonists in people who are frail with type 2 diabetes and cardiovascular disease should be a priority., Funding: Department of Cardiology, Herlev and Gentofte University Hospital., Translation: For the Danish translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests MEM receives grants from the CARDIO-HGH Foundation, Herlev and Gentofte University Hospital, and the Danish Cardiovascular Academy. MS receives lecture fees from Novartis, Boehringer Ingelheim, AstraZeneca, and Novo Nordisk. ACF receives grants from Steno Diabetes Center Sjaelland, Region Sjælland Den Sundhedsvidenskabelige Forskningsfond, and Murermester Lauritz Peter Christensen og Hustru Kirsten Sigrid Christensens Fond. JHB participates on an advisory board for Bayer. JJ receives grants from The Danish Heart Foundation and the CARDIO-HGH Foundation; receives payment and honoraria for lectures, presentations, and manuscript writing from Boehringer Ingelheim; and participates on advisory boards for AstraZeneca and Boehringer Ingelheim. JES receives grants from Herlev-Gentofte Forskningsfond, Snedkermester Sophus Jacobs; Torben og Alice Frimodts Fond; Dagmar Marshalls Fond; and Eva og Henry Frænkels Mindefond. LK receives speaker honoraria from Novo Nordisk, AstraZeneca, Novartis, and Boehringer Ingelheim. MCP receives grants and contracts from Boehringer Ingelheim, Roche, SQ Innovation, AstraZeneca, Novartis, Novo Nordisk, and Pharmacosmos; receives consulting fees from Boehringer Ingelheim, Novartis, AstraZeneca, Novo Nordisk, AbbVie, Bayer, Takeda, Corvia, Cardiorentis, Pharmacosmos, Siemens, and Vifor; receives payment or honoraria for lectures, presentations, manuscript writing, or educational events from Boehringer Ingelheim, Novartis, AstraZeneca, Novo Nordisk, AbbVie, Bayer, Takeda, Corvia, Cardiorentis, Pharmacosmos, Siemens, and Vifor; participates on a data safety monitoring board and advisory board for Takeda and Taikoku; and is the Director of Global Clinical Trials Partners. NS receives grants and contracts from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics; receives consulting fees from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; and receives fees for lectures or manuscript writing from Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, and Novo Nordisk. JJVM receives payment or honoraria for lectures, presentations, speaker bureaus, or manuscript writing from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape, Herat.org, ProAdWise, Servier, and the Corpus. JJVM receives payment for participating on advisory boards for Cytokinetics, Amgen, AstraZeneca, Theracos, Ionis Pharmaceuticals, DalCor, Cardurion, Novartis, GlaxoSmithKline, Bayer, KBP Biosciences, Boehringer Ingelheim, and Bristol Myers Squibb. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Cardiovascular diseases (CVDs) are the leading causes of morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). Secular changes in CVD outcomes have occurred over the past few decades, mainly due to a decline in the incidence of ischaemic heart disease. The onset of T2DM at a young age (<40 years), leading to a greater number of life-years lost, has also become increasingly common. Researchers are now looking beyond established risk factors in patients with T2DM towards the role of ectopic fat and, potentially, haemodynamic abnormalities in mediating important outcomes (such as heart failure). T2DM confers a wide spectrum of risk and is not necessarily a CVD risk equivalent, indicating the importance of risk assessment strategies (such as global risk scoring, consideration of risk-enhancing factors and assessment of subclinical atherosclerosis) to inform treatment. Data from epidemiological studies and clinical trials demonstrate that successful control of multiple risk factors can reduce the risk of CVD events by ≥50%; however, only ≤20% of patients achieve targets for risk factor reduction (plasma lipid levels, blood pressure, glycaemic control, body weight and non-smoking status). Improvements in composite risk factor control with lifestyle management (including a greater emphasis on weight loss interventions) and evidence-based generic and novel pharmacological therapies are therefore needed when the risk of CVD is high., (© 2023. Springer Nature Limited.)

Objective: To investigate the causal association of type 2 diabetes and its components with risk of vascular complications independent of shared risk factors obesity and hypertension and to identify the main driver of this risk., Research Design and Methods: We conducted Mendelian randomization (MR) using independent genetic variants previously associated with type 2 diabetes, fasting glucose, HbA1c, fasting insulin, BMI, and systolic blood pressure as instrumental variables. We obtained summary-level data for 18 vascular diseases (15 for type 2 diabetes) from FinnGen and publicly available genome-wide association studies as our outcomes. We conducted univariable and multivariable MR, in addition to sensitivity tests to detect and minimize pleiotropic effects., Results: Univariable MR analysis showed that type 2 diabetes was associated with 9 of 15 outcomes; BMI and systolic blood pressure were associated with 13 and 15 of 18 vascular outcomes, respectively; and fasting insulin was associated with 4 and fasting glucose with 2. No robust association was found for HbA1c instruments. With adjustment for correlated traits in the multivariable test, BMI and systolic blood pressure, consistent causal effects were maintained, while five associations with type 2 diabetes (chronic kidney disease, ischemic heart disease, heart failure, subarachnoid hemorrhage, and intracerebral hemorrhage) were attenuated to null., Conclusions: Our findings add strong evidence to support the importance of BMI and systolic blood pressure in the development of vascular complications in people with type 2 diabetes. Such findings strongly support the need for better weight and blood pressure management in type 2 diabetes, independent of glucose lowering, to limit important complications., (© 2023 by the American Diabetes Association.)

Metabolic mechanisms underlying the heterogeneity of major adverse cardiovascular (CV) event (MACE) risk in individuals with type 2 diabetes mellitus (T2D) remain unclear. We hypothesized that circulating metabolites reflecting mitochondrial dysfunction predict incident MACE in T2D. Targeted mass-spectrometry profiling of 60 metabolites was performed on baseline plasma samples from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS; discovery cohort) and Exenatide Study of Cardiovascular Event Lowering (EXSCEL; validation cohort) biomarker substudy cohorts. A principal components analysis metabolite factor comprising medium-chain acylcarnitines (MCACs) was associated with MACE in TECOS and validated in EXSCEL, with higher levels associated with higher MACE risk. Meta-analysis showed that long-chain acylcarnitines (LCACs) and dicarboxylacylcarnitines were also associated with MACE. Metabolites remained associated with MACE in multivariate models and favorably changed with exenatide therapy. A third cohort (Cardiac Catheterization Genetics [CATHGEN]) with T2D was assessed to determine whether these metabolites improved discriminative capability of multivariate models for MACE. Nine metabolites (MCACs and LCACs and 1 dicarboxylacylcarnitine) were associated with time to MACE in the CATHGEN cohort. Addition of these metabolites to clinical models minimally improved the discriminative capability for MACE but did significantly down reclassify risk. Thus, metabolites reporting on dysregulated mitochondrial fatty acid oxidation are present in higher levels in individuals with T2D who experience subsequent MACE. These biomarkers may improve CV risk prediction models, be therapy responsive, and highlight emerging risk mechanisms.

Obesity is causally associated with multiple cardiovascular outcomes but effective population measure to control obesity is limited. This study aims to decipher to which extent excess atherosclerotic cardiovascular diseases (ASCVD) and heart failure (HF) risk due to obesity can be explained by conventional risk factors. This is a prospective cohort study of 404,332 White UK Biobank participants. Participants with prior CVDs or other chronic diseases at baseline, or body mass index <18.5 kg/m 2 were excluded. Data were collected at the baseline assessment between 2006 and 2010. Linkage to death registrations and hospital admission records was used to ascertain ASCVD and HF outcomes up to late 2021. Obesity was defined as body mass index ≥30 kg/m 2 . Candidate mediators included lipids, blood pressure (BP), glycated hemoglobin (HbA1c), and liver and kidney function markers, which were chosen based on clinical trials and Mendelian randomization studies. Cox proportional hazard models were used to estimate hazard ratios (HR) and their 95% confidence intervals (CIs). Mediation analysis based on g-formula was used to separately estimate the relative importance of mediators for ASCVD and HF. Compared with people without obesity, obese people had an increased risk of ASCVD (HR 1.30, 95% CI, 1.26-1.35) and HF (HR 2.04, 95% CI, 1.96-2.13) after adjusting for sociodemographic and lifestyle factors and medications for cholesterol, BP and insulin. The strongest mediators for ASCVD were renal function (eGFR: mediation proportion: 44.6%), BP (SBP: 24.4%; DBP: 31.1%), triglycerides (19.6%), and hyperglycemia (HbA1c 18.9%). These mediators collectively explained more excess risk of ASCVD than that of HF. Interventions that help obese individuals to maintain healthy lipid concentrations, BP, glycemic control, and kidney function could potentially alleviate a sizable proportion of the ASCVD burden. However, HF burden could not be meaningfully reduced without weight management., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Randomized trials suggest moderate-intensity statins increase type 2 diabetes risk by around 11% with a potential further 12% moving to high-intensity statins, such that high intensity may increase risk by 20% or more relative to placebo. These data translate into one extra diabetes case per 100-200 statin recipients over 5 years, with ∼10-fold greater benefits on major vascular outcomes. The underlying mechanisms for diabetes harm are not clear but could include modest weight gain (noted in randomized trials), or, speculatively, beta cell harm. Concordant genetic studies link HMG CoA Reductase inhibition to diabetes risk and weight gain. Patients should be warned about a slight diabetes risk when prescribed statin and told that modest lifestyle improvements can i) nullify diabetes risk, and ii) improve cardiovascular risks beyond statins. Doctors should also measure glycemia status post statin commencement, most commonly with HbA1c, and tailor lifestyle advice and care dependent on the results., Competing Interests: Conflict of interest statement NS has consulted for and/or received speaker honoraria from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; and received grant support paid to his University from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside the submitted work., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Competing interests: NC declares support from European Union’s Horizon 2020 under the Marie Sklodowska-Curie Actions programme (grant agreement No 843267) and from European Society of Cardiology (grant number App000037070); grant funding paid to her institution from Research Foundation Flanders (FWO) (grant number 12ZU922N); and royalties on the intellectual property of a home-monitoring system for patients with heart failure paid to Oxford University Innovation. IBM declares honoraria from AbbVie; grant support paid to his university from AstraZeneca and Eli Lilly; participation on data safety monitoring boards/advisory boards of AstraZeneca, BMS, Eli Lilly, Novartis, Janssen, GSK, AbbVie, Cabaletta, Compugen, Causeway, Gilead, Moonlake, Reflexion, UCB, XinThera; patents from Novartis; leadership roles with Evelo, Versus Arthritis, and Greater Glasgow and Clyde Health Board; and stock or stock options with Evelo, Compugen, and Cabaletta. JJVM has received funding to his institution from Amgen and Cytokinetics for his participation in the Steering Committee for the ATOMIC-HF, COSMIC-HF, and GALACTIC-HF trials and meetings and other activities related to these trials; has received payments through Glasgow University from work on clinical trials, consulting and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; has received personal lecture fees from the Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Servier Director, and Global Clinical Trial Partners (GCTP). NS declares consulting fees and/or speaker honoraria from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; and grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics. The views expressed are those of the authors and not necessarily those of the funders.

To investigate the association between the Life's Essential 8 (LE8) score and the incidence of four cardiovascular outcomes (ischemic heart disease, myocardial infarction, stroke, and heart failure [HF]) - separately and as a composite outcome of major adverse cardiovascular events (MACE) - in UK Biobank. 250,825 participants were included in this prospective study. Smoking, non-HDL cholesterol, blood pressure, body mass index, HbA1c, physical activity, diet, and sleep were used to create a modified version of the LE8 score. Associations between the score (both as a continuous score and as quartiles) and outcomes were investigated using adjusted Cox proportional hazard models. The potential impact fractions of two scenarios were also calculated. Over a median follow-up of 10.4 years, there were 25,068 MACE. Compared to individuals in the highest quartile of the score (healthiest), those in the lowest quartile (least healthy) had 2.07 (95% CI: 1.99; 2.16) higher risk for MACE. The highest relative risk gradient of the individual outcomes was observed for HF (HR lowest quartile : 2.67 [95% CI: 2.42; 2.94]). The magnitude of association was stronger in participants below 50 years, women, and ethnic minorities. A targeted intervention that increased, by 10-points, the score among individuals in the lowest quartile could have prevented 9.2% of MACE. Individuals with a lower LE8 score experienced more MACE, driven especially by incident HF. Our scenarios suggested that relevant interventions targeted towards those in the lowest quartile may have a greater impact than interventions producing small equal changes across all quartiles., Competing Interests: Declaration of Competing Interest N.S declares consulting fees and/or speaker honoraria from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi; and grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics. None of these disclosures are directly related to the study, nor its conception, analyses or interpretation. The other authors declare none conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: In the AMPLITUDE-O (Effect of Efpeglenatide on Cardiovascular Outcomes) cardiovascular outcomes trial, adding either 4 mg or 6 mg weekly of the glucagon-like peptide-1 receptor agonist efpeglenatide to usual care reduced major adverse cardiovascular events (MACE) in people with type 2 diabetes at high cardiovascular risk. Whether these benefits are dose related remains uncertain., Methods: Participants were randomly assigned in a 1:1:1 ratio to placebo, 4 mg or 6 mg of efpeglenatide. The effect of 6 mg versus placebo and of 4 mg versus placebo on MACE (a nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or unknown causes) and on all the secondary composite cardiovascular and kidney outcomes was assessed. A dose-response relationship was assessed using the log-rank test and χ 2 statistic for trend., Results: During a median follow-up of 1.8 years, MACE occurred in 125 (9.2%) participants assigned to placebo, 84 (6.2%) participants assigned to 6 mg of efpeglenatide (hazard ratio [HR], 0.65 [95% CI, 0.5-0.86]; P =0.0027), and 105 (7.7%) assigned to 4 mg of efpeglenatide (HR, 0.82 [95% CI, 0.63-1.06]; P =0.14). Participants receiving high-dose efpeglenatide also experienced fewer secondary outcomes, including the composite of MACE, coronary revascularization, or hospitalization for unstable angina (HR, 0.73 for 6 mg, P =0.011; HR, 0.85 for 4 mg, P =0.17), a kidney composite outcome comprising sustained new macroalbuminuria, a ≥40% decline in estimated glomerular filtration rate or renal failure (HR, 0.63 for 6 mg, P <0.0001; HR, 0.73 for 4 mg, P =0.0009), MACE or any death (HR, 0.67 for 6 mg, P =0.0021; HR, 0.81 for 4 mg, P =0.08), a kidney function outcome comprising a sustained ≥40% decline in estimated glomerular filtration rate, renal failure, or death (HR, 0.61 for 6 mg, P =0.0072; HR, 0.97 for 4 mg, P =0.83), and the composite of MACE, any death, heart failure hospitalization, or the kidney function outcome (HR, 0.63 for 6 mg, P =0.0002; HR, 0.81 for 4 mg, P =0.067). A clear dose-response was noted for all primary and secondary outcomes (all P for trend ≤0.018)., Conclusions: The graded salutary relationship between efpeglenatide dose and cardiovascular outcomes suggests that titrating efpeglenatide and potentially other glucagon-like peptide-1 receptor agonists to high doses may maximize their cardiovascular and renal benefits., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03496298.

Importance: Updated guidelines on diabetes recommend targeting sodium-glucose cotransporter-2 inhibitors (SGLT2i) at patients at risk of heart failure (HF) and glucagon-like peptide-1 receptor agonists (GLP1-RA) at those at greater risk of atherothrombotic events., Objective: We estimated the risk of different cardiovascular events in patients with type 2 diabetes (T2D) and newly established cardiovascular disease., Design, Setting and Participants: Patients with T2D and newly established cardiovascular disease from 1998 to 2016 were identified using Danish healthcare registers and divided into one of four phenotype groups: (1) HF, (2) ischemic heart disease (IHD), (3) transient ischemic stroke (TIA)/ischemic stroke, and (4) peripheral artery disease (PAD). The absolute 5-year risk of the first HF- or atherothrombotic event occurring after inclusion was calculated, along with the risk of death., Main Outcomes and Measures: The main outcome was the first event of either HF or an atherothrombotic event (IHD, TIA/ischemic stroke or PAD) in patients with T2D and  new-onset cardiovascular disease., Results: Of the 37,850 patients included, 40% were female and the median age was 70 years. Patients with HF were at higher 5-year risk of a subsequent HF event (17.9%; 95% confidence interval (CI) 17.1-18.8%) than an atherothrombotic event (15.8%; 15.0-16.6%). Patients with IHD were at higher risk of a subsequent atherothrombotic event (24.6%; 23.9-25.3%) than developing HF, although the risk of HF was still substantial (10.6%; 10.2-11.1%). Conversely, patients with PAD were at low risk of developing HF (4.4%; 3.8-5.1%) but at high risk of developing an atherothrombotic event (15.9%; 14.9-17.1%). Patients with TIA/ischemic stroke had the lowest risk of HF (3.2%; 2.9-3.6%) and the highest risk of an atherothrombotic event (20.6%; 19.8-21.4)., Conclusions: In T2D, a patient's cardiovascular phenotype can help predict the pattern of future cardiovascular events., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Aims: The 2021 European Society of Cardiology cardiovascular disease (CVD) prevention guidelines recommend the use of (lifetime) risk prediction models to aid decisions regarding intensified preventive treatment options in adults with Type 2 diabetes, e.g. the DIAbetes Lifetime perspective model (DIAL model). The aim of this study was to update the DIAL model using contemporary and representative registry data (DIAL2) and to systematically calibrate the model for use in other European countries., Methods and Results: The DIAL2 model was derived in 467 856 people with Type 2 diabetes without a history of CVD from the Swedish National Diabetes Register, with a median follow-up of 7.3 years (interquartile range: 4.0-10.6 years) and comprising 63 824 CVD (including fatal CVD, non-fatal stroke and non-fatal myocardial infarction) events and 66 048 non-CVD mortality events. The model was systematically recalibrated to Europe's low- and moderate-risk regions using contemporary incidence data and mean risk factor distributions. The recalibrated DIAL2 model was externally validated in 218 267 individuals with Type 2 diabetes from the Scottish Care Information-Diabetes (SCID) and Clinical Practice Research Datalink (CPRD). In these individuals, 43 074 CVD events and 27 115 non-CVD fatal events were observed. The DIAL2 model discriminated well, with C-indices of 0.732 [95% confidence interval (CI) 0.726-0.739] in CPRD and 0.700 (95% CI 0.691-0.709) in SCID., Conclusion: The recalibrated DIAL2 model provides a useful tool for the prediction of CVD-free life expectancy and lifetime CVD risk for people with Type 2 diabetes without previous CVD in the European low- and moderate-risk regions. These long-term individualized measures of CVD risk are well suited for shared decision-making in clinical practice as recommended by the 2021 CVD ESC prevention guidelines., Competing Interests: Conflict of interest: BE declares consulting fees and/or speaker honoraria from Eli Lilly, Sanofi, AstraZeneca, NovoNordisk, all outside the submitted work. WH reports grants or contracts from Medical Research Council UK, Kidney Research UK, Boehringer Ingelheim and EliLilly; and grant support paid to his university for the EMPA-Kidney trial, all outside the submitted work. NS declares consulting fees and/or speaker honoraria from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi; and grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics, all outside the submitted work., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: to investigate the association between variability and loss of body weight with subsequent cognitive performance and activities of daily living in older individuals., Design: cross-sectional cohort study., Setting: PROspective Study of Pravastatin in the Elderly at Risk, multicentre trial with participants from Scotland, Ireland and the Netherlands., Subjects: 4,309 participants without severe cognitive dysfunction (mean age 75.1 years, standard deviation (SD) = 3.3), at higher risk for cardiovascular disease (CVD)., Methods: body weight was measured every 3 months for 2.5 years. Weight loss was defined as an average slope across all weight measurements and as ≥5% decrease in baseline body weight during follow-up. Visit-to-visit variability was defined as the SD of weight measurements (kg) between visits. Four tests of cognitive function were examined: Stroop test, letter-digit coding test (LDCT), immediate and delayed picture-word learning tests. Two measures of daily living activities: Barthel Index (BI) and instrumental activities of daily living (IADL). All tests were examined at month 30., Results: both larger body weight variability and loss of ≥5% of baseline weight were independently associated with worse scores on all cognitive tests, but minimally with BI and IADL. Compared with participants with stable weight, participants with significant weight loss performed 5.83 seconds (95% CI 3.74; 7.92) slower on the Stroop test, coded 1.72 digits less (95% CI -2.21; -1.13) on the LDCT and remembered 0.71 pictures less (95% CI -0.93; -0.48) on the delayed picture-word learning test., Conclusion: in older people at higher risk for CVD, weight loss and variability are independent risk-factors for worse cognitive function., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

How the Coronavirus Disease 2019 (COVID-19) pandemic has affected prevention and management of cardiovascular disease (CVD) is not fully understood. In this study, we used medication data as a proxy for CVD management using routinely collected, de-identified, individual-level data comprising 1.32 billion records of community-dispensed CVD medications from England, Scotland and Wales between April 2018 and July 2021. Here we describe monthly counts of prevalent and incident medications dispensed, as well as percentage changes compared to the previous year, for several CVD-related indications, focusing on hypertension, hypercholesterolemia and diabetes. We observed a decline in the dispensing of antihypertensive medications between March 2020 and July 2021, with 491,306 fewer individuals initiating treatment than expected. This decline was predicted to result in 13,662 additional CVD events, including 2,281 cases of myocardial infarction and 3,474 cases of stroke, should individuals remain untreated over their lifecourse. Incident use of lipid-lowering medications decreased by 16,744 patients per month during the first half of 2021 as compared to 2019. By contrast, incident use of medications to treat type 2 diabetes mellitus, other than insulin, increased by approximately 623 patients per month for the same time period. In light of these results, methods to identify and treat individuals who have missed treatment for CVD risk factors and remain undiagnosed are urgently required to avoid large numbers of excess future CVD events, an indirect impact of the COVID-19 pandemic., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Patients with type 2 diabetes are at high risk for development of cardiovascular disease, including myocardial infarction, stroke, heart failure, and cardiovascular death. Multiple large cardiovascular outcome trials with novel glucose-lowering agents, namely SGLT2i (SGLT2 inhibitors) and GLP-1 RA (GLP-1 receptor agonists), have demonstrated robust and significant reductions of major adverse cardiovascular events and additional cardiovascular outcomes, such as hospitalizations for heart failure. This evidence has changed the landscape for treatment of patients with type 2 diabetes. Both diabetes and cardiology guidelines and professional societies have responded to this paradigm shift by including strong recommendations to use SGLT2i and/or GLP-1 RA, with evidence-based benefits to reduce cardiovascular risk in high-risk individuals with type 2 diabetes, independent of the need for additional glucose control. GLP-1 RA were initially developed as glucose-lowering drugs because activation of the GLP-1 receptor by these agents leads to a reduction in blood glucose and an improvement in postprandial glucose metabolism. By stimulating GLP-1R in hypothalamic neurons, GLP-1 RA additionally induce satiety and lead to weight loss. Data from cardiovascular outcome trials demonstrated a robust and consistent reduction in atherothrombotic events, particularly in patients with established atherosclerotic cardiovascular disease. Despite the consistent evidence of atherosclerotic cardiovascular disease benefit from these trials, the number of patients receiving these drugs remains low. This overview summarizes the experimental and clinical evidence of cardiovascular risk reduction offered by GLP-1 RA, and provides practical information on how these drugs should be implemented in the treatment of type 2 diabetes in the cardiology community.

The ongoing obesity epidemic represents a global public health crisis that contributes to poor health outcomes, reduced quality of life, and >2.8 million deaths each year. Obesity is relapsing, progressive, and heterogeneous. It is considered a chronic disease by the World Obesity Federation (WOF) and a chronic condition by the World Heart Federation (WHF). People living with overweight/obesity are at greater risk for cardiovascular (CV) morbidity and mortality. Increased adiposity (body fat), particularly visceral/abdominal fat, is linked to CV risk and CV disease (CVD) via multiple direct and indirect pathophysiological mechanisms. The development of CVD is driven, in part, by obesity-related metabolic, endocrinologic, immunologic, structural, humoral, haemodynamic, and functional alterations. The complex multifaceted nature of these mechanisms can be challenging to understand and address in clinical practice. People living with obesity and CVD often have concurrent chronic physical or psychological disorders (multimorbidity) requiring multidisciplinary care pathways and polypharmacy. Evidence indicates that intentional weight loss (particularly when substantial) lowers CVD risk among people with overweight/obesity. Long-term weight loss and maintenance require ongoing commitment from both the individual and those responsible for their care. This position paper, developed by the WOF and the WHF, aims to improve understanding of the direct and indirect links between overweight/obesity and CVD, the key controversies in this area and evidence relating to cardiometabolic outcomes with available weight management options. Finally, an action plan for clinicians provides recommendations to help in identifying and addressing the risks of obesity-related CVD (recognizing resource and support variances between countries)., Competing Interests: Conflict of interest: Professor Lopez-Jimenez has no relevant financial disclosures. Dr Wael Almahmeed has no relevant financial disclosures. Dr Harold Bays’ research site institution has received research grants from Alon Medtech/Epitomee, Amgen, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Pfizer. Dr Harold Bays has served as a speaker for Novo Nordisk. Professor Ada Cuevas has received fees relating to conference and/or advisory board activities from Abbott, TEVA, Novo Nordisk, Merck and Saval. Professor Emanuele Di Angelantonio has no relevant financial disclosures. Professor Carel le Roux reports grants from the Irish Research Council, Science Foundation Ireland, Anabio and the Health Research Board. He served on advisory boards of Novo Nordisk, Herbalife, GI Dynamics, Eli Lilly, Johnson and Johnson, Sanofi Aventis, Astra Zeneca, Janssen, Bristol-Myers Squibb, Boehringer-Ingelheim and Keyron. Professor Naveed Sattar has consulted for Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi; and received grant support paid to his University from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside the submitted work. Dr Marie Chan Sun has no relevant financial disclosures. Professor Gary Wittert has received research support from Bayer, Lilly, Lawley Pharmaceuticals, Weight Watchers, ResMed Foundation, and Phillips. Speaker honoraria from Bayer, and Besins Healthcare. He is a member of an International and National Bayer advisory board. Professor Fausto Pinto has no relevant financial disclosures. Professor John PH Wilding undertakes consultancy and speaking engagements for industry contracted via the University of Liverpool (no personal payment) in relation to obesity and type 2 diabetes; in the last 2 years this includes work for Alnylam, AstraZeneca, Boehringer Ingelheim, Janssen Pharmaceuticals, Lilly, Napp, Novo Nordisk, Mundipharma, Pfizer, Rhythm Pharmaceuticals, Saniona and Ysopia (all modest). He is a named grant holder (at University of Liverpool) for research grants for clinical trials from AstraZeneca and Novo Nordisk (significant). He has received honoraria/lecture fees from AstraZeneca, Boehringer Ingelheim, Napp, Novo Nordisk, Mundipharma, Sanofi and Takeda (all modest)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: It is unclear whether replacing oral glucose tolerance test (OGTT) with hemoglobin A1c (HbA1c) measurement for diagnosing diabetes is justified. We aimed to assess the proportion of OGTT-diagnosed diabetes cases that can be confirmed by HbA1c and to examine whether individuals with OGTT diagnosis but nondiagnostic HbA1c are at higher risk of macrovascular and microvascular disease., Methods: Participants were 5773 men and women from the population-based Whitehall II prospective cohort study in the United Kingdom. New OGTT diabetes cases diagnosed in clinical examinations in 2002 to 2004 and 2007 to 2009 were assessed for HbA1c confirmation (≥6.5%) in these and subsequent clinical examinations in 2012 to 2013 and 2015 to 2016. All participants were followed up for major cardiovascular events through linkage to electronic health records until 2017 and for incident chronic kidney disease (estimated glomerular filtration rate <60 mL·min -1 ·1.73 m -2 ) until the last clinical examination. In analysis of vascular disease risk, new OGTT-diagnosed diabetes cases with and without diagnostic HbA1c and preexisting diabetes cases were compared with diabetes-free participants., Results: Of the 378 (59.3%) participants with OGTT-diagnosed diabetes, 224 were confirmed by HbA1c during 4.1 years (SD, 4.1 years) of follow-up. We recorded 942 cardiovascular events over 12.1 years. After adjustment for nonmodifiable risk factors and compared with the 4997 diabetes-free participants, 371 participants with new HbA1c-confirmed diabetes and 405 participants with preexisting diabetes had increased risk of cardiovascular disease (hazard ratio, 1.53 [95% CI, 1.12-2.10] and 1.85 [95% CI, 1.50-2.28], respectively). The corresponding hazard ratios in the analysis of incident chronic kidney disease (487 cases; follow-up, 6.6 years) were 1.69 (95% CI, 1.09-2.62) for 282 participants with new HbA1c-confirmed diabetes and 1.67 (95% CI, 1.22-2.28) for 276 participants with preexisting diabetes. In both analyses, OGTT cases with nondiagnostic HbA1c (n=149 and 107) had a risk (hazard ratio, 0.99-1.07) similar to that of the diabetes-free population., Conclusions: More than 40% of OGTT-diagnosed diabetes cases were not confirmed by HbA1c during an extended follow-up. However, because these individuals have a risk of cardiovascular disease and chronic kidney disease similar to that of the diabetes-free population, replacement of OGTT with HbA1c-based diagnosis appears justified.

Background: Controversy exists as to whether the threshold for blood pressure-lowering treatment should differ between people with and without type 2 diabetes. We aimed to investigate the effects of blood pressure-lowering treatment on the risk of major cardiovascular events by type 2 diabetes status, as well as by baseline levels of systolic blood pressure., Methods: We conducted a one-stage individual participant-level data meta-analysis of major randomised controlled trials using the Blood Pressure Lowering Treatment Trialists' Collaboration dataset. Trials with information on type 2 diabetes status at baseline were eligible if they compared blood pressure-lowering medications versus placebo or other classes of blood pressure-lowering medications, or an intensive versus a standard blood pressure-lowering strategy, and reported at least 1000 persons-years of follow-up in each group. Trials exclusively on participants with heart failure or with short-term therapies and acute myocardial infarction or other acute settings were excluded. We expressed treatment effect per 5 mm Hg reduction in systolic blood pressure on the risk of developing a major cardiovascular event as the primary outcome, defined as the first occurrence of fatal or non-fatal stroke or cerebrovascular disease, fatal or non-fatal ischaemic heart disease, or heart failure causing death or requiring hospitalisation. Cox proportional hazard models, stratified by trial, were used to estimate hazard ratios (HRs) separately by type 2 diabetes status at baseline, with further stratification by baseline categories of systolic blood pressure (in 10 mm Hg increments from <120 mm Hg to ≥170 mm Hg). To estimate absolute risk reductions, we used a Poisson regression model over the follow-up duration. The effect of each of the five major blood pressure-lowering drug classes, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β blockers, calcium channel blockers, and thiazide diuretics, was estimated using a network meta-analysis framework. This study is registered with PROSPERO, CRD42018099283., Findings: We included data from 51 randomised clinical trials published between 1981 and 2014 involving 358 533 participants (58% men), among whom 103 325 (29%) had known type 2 diabetes at baseline. The baseline mean systolic/diastolic blood pressure of those with and without type 2 diabetes was 149/84 mm Hg (SD 19/11) and 153/88 mm Hg (SD 21/12), respectively. Over 4·2 years median follow-up (IQR 3·0-5·0), a 5 mm Hg reduction in systolic blood pressure decreased the risk of major cardiovascular events in both groups, but with a weaker relative treatment effect in participants with type 2 diabetes (HR 0·94 [95% CI 0·91-0·98]) compared with those without type 2 diabetes (0·89 [0·87-0·92]; p interaction =0·0013). However, absolute risk reductions did not differ substantially between people with and without type 2 diabetes because of the higher absolute cardiovascular risk among participants with type 2 diabetes. We found no reliable evidence for heterogeneity of treatment effects by baseline systolic blood pressure in either group. In keeping with the primary findings, analysis using stratified network meta-analysis showed no evidence that relative treatment effects differed substantially between participants with type 2 diabetes and those without for any of the drug classes investigated., Interpretation: Although the relative beneficial effects of blood pressure reduction on major cardiovascular events were weaker in participants with type 2 diabetes than in those without, absolute effects were similar. The difference in relative risk reduction was not related to the baseline blood pressure or allocation to different drug classes. Therefore, the adoption of differential blood pressure thresholds, intensities of blood pressure lowering, or drug classes used in people with and without type 2 diabetes is not warranted., Funding: British Heart Foundation, UK National Institute for Health Research, and Oxford Martin School., Competing Interests: Declaration of interests KR reports personal fees from the BMJ Heart and PLOS Medicine, outside of the submitted work. MW reports personal funding from Amgen, Kyowa Kirin, and Freeline, outside of the current work. NS has consulted for, or received lecture fees from, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, MSD, Novartis, Novo Nordisk, Pfizer, and Sanofi; and received grant support from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics through his institution, the University of Glasgow. RRH reports research support from AstraZeneca, Bayer, and MSD; and personal fees from Anji Pharmaceuticals, Bayer, Novartis, and Novo Nordisk. RJM received blood pressure monitors from Omron for research and his institution receives fees from Omron and Sensyne for blood pressure telemonitoring systems. JC reports research grants and personal fees from Servier for the ADVANCE and PROGRESS trials, and grants from the National Health and Medical Research Council of Australia for these two trials. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Aims: To evaluate the time-varying cardio-protective effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) using pooled data from eight contemporary cardiovascular outcome trials using the difference in the restricted mean survival time (ΔRMST) as the effect estimate., Material and Methods: Data from eight multinational cardiovascular outcome randomized controlled trials of GLP-1RAs for type 2 diabetes mellitus were pooled. Flexible parametric survival models were fit from published Kaplan-Meier plots. The differences between arms in RMST (ΔRMST) were calculated at 12, 24, 36 and 48 months. ΔRMST values were pooled using an inverse variance-weighted random-effects model; heterogeneity was tested with Cochran's Q statistic. The endpoints studied were: three-point major adverse cardiovascular events (MACE), all-cause mortality, stroke, cardiovascular mortality and myocardial infarction., Results: We included eight large (3183-14 752 participants, total = 60 080; median follow-up range: 1.5 to 5.4 years) GLP-1RA trials. Among GLP-1RA recipients, we observed an average delay in three-point MACE of 0.03, 0.15, 0.37 and 0.63 months at 12, 24, 36 and 48 months, respectively. At 48 months, while cardiovascular mortality was comparable in both arms (pooled ΔRMST 0.163 [-0.112, 0.437]; P = 0.24), overall survival was higher (ΔRMST = 0.261 [0.08-0.43] months) and stroke was delayed (ΔRMST 0.22 [0.15-0.33]) in patients receiving GLP-1RAs., Conclusions: Glucagon-like peptide-1 receptor agonists may delay the occurrence of MACE by an average of 0.6 months at 48 months, with meaningfully larger gains in patients with cardiovascular disease. This metric may be easier for clinicians and patients to interpret than hazard ratios, which assume a knowledge of absolute risk in the absence of treatment., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Socioeconomic deprivation is associated with higher cardiovascular morbidity and mortality. Whether deprivation status should be incorporated in more cardiovascular risk estimation scores remains unclear. This study evaluates how socioeconomic deprivation status affects the performance of 3 primary prevention cardiovascular risk scores., Methods: The Generation Scotland Scottish Family Health Study was used to evaluate the performance of 3 cardiovascular risk scores with (ASSIGN [Assessing cardiovascular risk using SIGN (Scottish Intercollegiate Guidelines Network) guidelines to ASSIGN preventive treatment]) and without (SCORE2 [Systematic Coronary Risk Evaluation 2 algorithm], Pooled Cohort Equations) socioeconomic deprivation as a covariate in the risk prediction model. Deprivation was defined by Scottish Index of Multiple Deprivation score. The predicted 10-year risk was evaluated against the observed event rate for the cardiovascular outcome of each risk score. The comparison was made across 3 groups defined by the deprivation index score consisting of group 1 defined as most deprived, group 3 defined as least deprived, and group 2, which consisted of individuals in the middle deprivation categories., Results: The study population consisted of 15 506 individuals (60.0% female, median age of 51). Across the population, 1808 (12%) individuals were assigned to group 1 (most deprived), 8119 (52%) to group 2, and 4708 (30%) to group 3 (least deprived), and 871 (6%) individuals had a missing deprivation score. Risk scores based on models that did not include deprivation status significantly under predicted risk in the most deprived (6.43% observed versus 4.63% predicted for SCORE2 [ P =0.001] and 6.69% observed versus 4.66% predicted for Pooled Cohort Equations [ P <0.001]). Both risk scores also significantly overpredicted the risk in the least deprived group (3.97% observed versus 4.72% predicted for SCORE2 [ P =0.007] and 4.22% observed versus 4.85% predicted for Pooled Cohort Equations [ P =0.028]). In contrast, no significant difference was demonstrated in the observed versus predicted risk when using the ASSIGN risk score, which included socioeconomic deprivation status in the risk model., Conclusions: Socioeconomic status is a largely unrecognized risk factor in primary prevention of cardiovascular disease. Risk scores that exclude socioeconomic deprivation as a covariate under- and overestimate the risk in the most and least deprived individuals, respectively. This study highlights the importance of incorporating socioeconomic deprivation status in risk estimation systems to ultimately reduce inequalities in health care provision for cardiovascular disease.

Background: To determine whether there were racial differences in short-term cardiometabolic responses to once-weekly exenatide (EQW) in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL)., Methods: EXSCEL enrolled 14,752 patients with type 2 diabetes (hemoglobin A 1c (HbA 1c ) 6.5-10.0% [48-86 mmol/mol]) with or without cardiovascular disease who were randomized double-blind to EQW or placebo. Background glucose-lowering/other cardiovascular therapies were unaltered for 6 months post-randomization unless clinically essential, facilitating comparison of EQW-associated effects in 14,665 evaluable participants self-identifying as White (n = 11,113), Asian (n = 1444), Black (n = 870), or Other Race (n = 1,238. Placebo-adjusted 6 month absolute changes in cardiometabolic variables were assessed using generalized linear models., Results: Mean 6-month placebo-adjusted HbA 1c reductions were similar in the four groups (range 0.54-0.67% [5.9 to 7.3 mmol/mol], P = 0.11 for race×treatment interaction), with no significant difference in Asians (reference) versus other groups after covariate adjustment (all P ≥ 0.10). Six-month placebo-adjusted mean changes in systolic (-1.8 to 0.0 mmHg) and diastolic (0.2 to 1.2 mmHg) blood pressure, serum LDL (- 0.06 to 0.02 mmol/L) and HDL (0.00 to 0.01 mmol/L) cholesterol, and serum triglycerides (-0.1 to 0.0 mmol/L) were similar in the racial groups (P ≥ 0.19 for race×treatment interaction and all P ≥ 0.13 for comparisons of Asians with other races). Resting pulse rate increased more in Asians (4 beats/min) than in other groups (≤ 3 beats/min, P = 0.016 for race×treatment interaction and all P ≤ 0.050 for comparisons of Asians with other races)., Conclusions: Short-term cardiometabolic responses to EQW were similar in the main racial groups in EXSCEL, apart from a greater pulse rate increase in Asians., Trial Registration: https://clinicaltrials.gov NCT01144338., (© 2022. The Author(s).)

Objective: To develop recommendations for cardiovascular risk (CVR) management in gout, vasculitis, systemic sclerosis (SSc), myositis, mixed connective tissue disease (MCTD), Sjögren's syndrome (SS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS)., Methods: Following European League against Rheumatism (EULAR) standardised procedures, a multidisciplinary task force formulated recommendations for CVR prediction and management based on systematic literature reviews and expert opinion., Results: Four overarching principles emphasising the need of regular screening and management of modifiable CVR factors and patient education were endorsed. Nineteen recommendations (eleven for gout, vasculitis, SSc, MCTD, myositis, SS; eight for SLE, APS) were developed covering three topics: (1) CVR prediction tools; (2) interventions on traditional CVR factors and (3) interventions on disease-related CVR factors. Several statements relied on expert opinion because high-quality evidence was lacking. Use of generic CVR prediction tools is recommended due to lack of validated rheumatic diseases-specific tools. Diuretics should be avoided in gout and beta-blockers in SSc, and a blood pressure target <130/80 mm Hg should be considered in SLE. Lipid management should follow general population guidelines, and antiplatelet use in SLE, APS and large-vessel vasculitis should follow prior EULAR recommendations. A serum uric acid level <0.36 mmol/L (<6 mg/dL) in gout, and disease activity control and glucocorticoid dose minimisation in SLE and vasculitis, are recommended. Hydroxychloroquine is recommended in SLE because it may also reduce CVR, while no particular immunosuppressive treatment in SLE or urate-lowering therapy in gout has been associated with CVR lowering., Conclusion: These recommendations can guide clinical practice and future research for improving CVR management in rheumatic and musculoskeletal diseases., Competing Interests: Competing interests: GCD, DV, EH, LB, SB, DTB, NB, GK, FM, CM, MR-C, KS, SS, VPvH, GJM, MMW and MN have nothing to declare. FA: research grants from BMS, Celgene, Novartis and Sandoz and consulting fees from AbbVie, Biogen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer and Sanofi-Aventis, all unrelated to this manuscript; INB: grant from GSK paid to institution, consulting fees from Astra Zeneca, GSK, Eli lilly, UC, MSD paid to institution, support for attending meetings and/or travel from GSK, participation on a data safety monitoring board/or advisory board from Aurinia, Astra Zeneca and ILTOO paid to institution, all unrelated to this manuscript; MÁG-G: grants/research support from AbbVie, MSD, Jansen and Roche paid to institution and personal consulting fees/participation in company sponsored speakers bureau from AbbVie, Pfizer, Roche, Celgene, MSD, Novartis, SOBI and Sanofi, all unrelated to this manuscript; SJ: grants from BMS paid to institution, personal consulting fees from Astra Zeneca, and personal fees from Danish Medicolegal Council, all unrelated to this manuscript; NS: grants paid to institution from Astrazeneca, Boehringer Ingelheim and Roche Diagnostics, personal consulting fees from Afimmune, Amgen, Astrazeneca, Boehringer Ingelheim, Eli-Lilly, Hanmi Pharamceuticals, MSD, Novartis, Novo Nordisk, Pfizer and Sanofi, all unrelated to this manuscript; ES: grant from Merck and honoraria from Janssen, all unrelated to this manuscript; ZS: research grants from Pfizer paid to institution and personal consulting fees from Pfizer, MSD, Lilly, Novartis, Roche, Gedeon Richter, Boehringer Ingelheim, Abbvie, all unrelated to this manuscript; A-KT: speakers fee from Berlin Chemie Menarini, Novarti and personal fees and non-financial support from AstraZeneca and Grünenthal, all unrelated to this manuscript; AT: consulting fees from Magenta Therapeutics and personal fees from Novartis and Idorsia for participation on a Data Safety Monitoring Board or Advisory Board, all unrelated to this manuscript; AV: personal consulting fees from Astra Zeneca and GS, all unrelated to this manuscript; MGT: research grants from Genesis, GSK, MSD, Pfizer and UCB paid to institution, and personal consulting fees from Genesis, GSK and Novartis, all unrelated to this manuscript., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: This study aimed to investigate the associations of grip strength with incidence and mortality from dementia and whether these associations differ by sociodemographic and lifestyle factors., Methods: A total of 466 788 participants of the UK Biobank (median age 56.5 years, 54.5% women). The outcome was all-cause dementia incidence and mortality and the exposure was grip strength. Grip strength was assessed using a Jamar J00105 hydraulic hand dynamometer., Results: Excluding the first 2 years of follow-up (landmark analysis), mean follow-up was 9.1 years (inter-quartile range: 8.3; 9.7) for incidence and 9.3 (inter-quartile range: 8.7; 10.0) for mortality. During this time, 4087 participants developed dementia, and 1309 died from it. Lower grip strength was associated with a higher risk of dementia incidence and mortality independent of major confounding factors (P < 0.001). Individuals in the lowest quintile of grip strength had 72% [95% confidence interval (CI): 1.55; 1.92] higher incident dementia risk and 87% [95% CI: 1.55; 2.26] higher risk of dementia mortality compared with those in the highest quintile. Our PAF analyses indicate that 30.1% of dementia cases and 32.3% of dementia deaths are attributable to having low grip strength. The association between grip strength and dementia outcomes did not differ by lifestyle or sociodemographic factors., Conclusions: Lower grip strength was associated with a higher risk of all-cause dementia incidence and mortality, independently of important confounding factors., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Aims: Empagliflozin treatment reduced liver fat in small type 2 diabetes cohorts. This post-hoc study evaluated effects of empagliflozin on risk for non-alcoholic fatty liver disease-related steatosis and fibrosis, as well as the relationship between risk categories and cardiorenal outcomes in the randomized, placebo-controlled EMPA-REG OUTCOME trial., Materials and Methods: EMPA-REG OUTCOME treated 7020 people with type 2 diabetes and cardiovascular disease with 10/25 mg/day empagliflozin or placebo. For this analysis, the Dallas steatosis index, hepatic steatosis index, non-alcoholic fatty liver disease fibrosis score and Fibrosis-4 score were calculated to assess steatosis and fibrosis risk. Changes from baseline in scores were examined by mixed model repeated measures and their associations with cardiorenal outcomes and mortality by Cox regression., Results: At baseline, 73% and 84% of participants had high steatosis risk by Dallas steatosis index and hepatic steatosis index, whereas 23% and 4% had a high risk of advanced fibrosis by non-alcoholic fatty liver disease fibrosis score and Fibrosis-4 score. Percentages of people at high steatosis risk slightly decreased with empagliflozin only, whereas empagliflozin did not improve percentages of individuals at high fibrosis risk over time compared with placebo. The high risk of advanced fibrosis at baseline related to higher risk for cardiovascular events. Effects of empagliflozin on cardiorenal and all-cause mortality outcomes were consistent across all risk groups., Conclusions: Empagliflozin may reduce steatosis but not fibrosis risk in individuals with type 2 diabetes and cardiovascular disease. The improvements in cardiorenal outcomes and mortality associated with empagliflozin therapy appear to be independent of steatosis and fibrosis risk., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: This study aimed to study the association between shift work and incident and fatal cardiovascular disease (CVD), and to explore modifying and mediating factors., Methods: This is a population-based, prospective cohort study with a median follow-up of 11 years; 238 661 UK Biobank participants who were in paid employment or self-employed at baseline assessment were included., Results: Shift workers had higher risk of incident [hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.06-1.19] and fatal (HR 1.25, 95% CI 1.08-1.44) CVD compared with non-shift workers, after adjusting for socio-economic and work-related factors. The risk was higher with longer duration of shift work, in women and in jobs with little heavy manual labour. Current smoking, short sleep duration, poor sleep quality, adiposity, higher glycated haemoglobin and higher cystatin C were identified as the main potentially modifiable mediators. Mediators collectively explained 52.3% of the associations between shift work and incident CVDs., Conclusions: Shift workers have higher risk of incident and fatal CVD, partly mediated through modifiable risk factors such as smoking, sleep duration and quality, adiposity and metabolic status. Workplace interventions targeting these mediators have the potential to alleviate shift workers' CVD risk., (© The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.)