Long COVID and cardiovascular disease: a prospective cohort study.

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.

Empagliflozin to prevent progressive adverse remodelling after myocardial infarction (EMPRESS-MI): rationale and design.

AIMS: Patients with a reduced left ventricular ejection fraction (LVEF) following an acute myocardial infarction (MI) are at risk of progressive adverse cardiac remodelling that can lead to the development of heart failure and death. The early addition of a sodium-glucose cotransporter 2 (SGLT2) inhibitor to standard treatment may delay or prevent progressive adverse remodelling in these patients. METHODS AND RESULTS: EMpagliflozin to PREvent worSening of left ventricular volumes and Systolic function after Myocardial Infarction (EMPRESS-MI) is a randomized, double-blind, placebo-controlled, multi-centre trial designed to assess the effect of empagliflozin on cardiac remodelling evaluated using cardiovascular magnetic resonance (CMR) in 100 patients with left ventricular systolic dysfunction following MI. Eligible patients were those ≥12 h and ≤14 days following acute MI, with an LVEF <45% by CMR. Patients were randomized to empagliflozin 10 mg once a day or matching placebo. The primary outcome will be change in left ventricular end-systolic volume indexed to body surface area over 24 weeks from randomization. Secondary endpoints include measures of left ventricular and atrial volumes, left ventricular mass, LVEF, and circulating cardiac biomarkers. CONCLUSIONS: EMPRESS-MI will assess the effect of the SGLT2 inhibitor empagliflozin on cardiac remodelling in patients with left ventricular systolic dysfunction after an acute MI.

Adipose Tissue Insulin Resistance in South Asian and Nordic Women after Gestational Diabetes Mellitus.

South Asians (SAs) have a higher risk of developing type 2 diabetes (T2D) than white Europeans, especially following gestational diabetes mellitus (GDM). Despite similar blood glucose levels post-GDM, SAs exhibit more insulin resistance (IR) than Nordics, though the underlying mechanisms are unclear. This study aimed to assess markers of adipose tissue (AT) IR and liver fat in SA and Nordic women post-GDM. A total of 179 SA and 108 Nordic women in Norway underwent oral glucose tolerance tests 1-3 years post-GDM. We measured metabolic markers and calculated the AT IR index and non-alcoholic fatty liver disease liver fat (NAFLD-LFS) scores. Results showed that normoglycaemic SAs had less non-esterified fatty acid (NEFA) suppression during the test, resembling prediabetes/T2D responses, and higher levels of plasma fetuin-A, CRP, and IL-6 but lower adiponectin, indicating AT inflammation. Furthermore, normoglycaemic SAs had higher NAFLD-LFS scores, lower insulin clearance, and higher peripheral insulin than Nordics, indicating increased AT IR, inflammation, and liver fat in SAs. Higher liver fat markers significantly contributed to the ethnic disparities in glucose metabolism, suggesting a key area for intervention to reduce T2D risk post-GDM in SAs.

Blood-based epigenome-wide analyses of chronic low-grade inflammation across diverse population cohorts.

Chronic inflammation is a hallmark of age-related disease states. The effectiveness of inflammatory proteins including C-reactive protein (CRP) in assessing long-term inflammation is hindered by their phasic nature. DNA methylation (DNAm) signatures of CRP may act as more reliable markers of chronic inflammation. We show that inter-individual differences in DNAm capture 50% of the variance in circulating CRP (N = 17,936, Generation Scotland). We develop a series of DNAm predictors of CRP using state-of-the-art algorithms. An elastic-net-regression-based predictor outperformed competing methods and explained 18% of phenotypic variance in the Lothian Birth Cohort of 1936 (LBC1936) cohort, doubling that of existing DNAm predictors. DNAm predictors performed comparably in four additional test cohorts (Avon Longitudinal Study of Parents and Children, Health for Life in Singapore, Southall and Brent Revisited, and LBC1921), including for individuals of diverse genetic ancestry and different age groups. The best-performing predictor surpassed assay-measured CRP and a genetic score in its associations with 26 health outcomes. Our findings forge new avenues for assessing chronic low-grade inflammation in diverse populations.

Indirect effects of the COVID-19 pandemic on diagnosing, monitoring, and prescribing in people with diabetes and strategies for diabetes service recovery internationally.

The COVID-19 pandemic has caused major disruptions in clinical services for people with chronic long-term conditions. In this narrative review, we assess the indirect impacts of the COVID-19 pandemic on diabetes services globally and the resulting adverse effects on rates of diagnosing, monitoring, and prescribing in people with type 2 diabetes. We summarise potential practical approaches that could address these issues and improve clinical services and outcomes for people living with diabetes during the recovery phase of the pandemic.

Non-coronary arterial outcomes in people with type 1 diabetes mellitus: a Swedish retrospective cohort study.

Background: Observational studies on long-term trends, risk factor association and importance are scarce for type 1 diabetes mellitus and peripheral arterial outcomes. We set out to investigate trends in non-coronary complications and their relationships with cardiovascular risk factors in persons with type 1 diabetes mellitus compared to matched controls. Methods: 34,263 persons with type 1 diabetes mellitus from the Swedish National Diabetes Register and 164,063 matched controls were included. Incidence rates of extracranial large artery disease, aortic aneurysm, aortic dissection, lower extremity artery disease, and diabetic foot syndrome were analyzed using standardized incidence rates and Cox regression. Findings: Between 2001 and 2019, type 1 diabetes mellitus incidence rates per 100,000 person-years were as follows: extracranial large artery disease 296.5-84.3, aortic aneurysm 0-9.2, aortic dissection remained at 0, lower extremity artery disease 456.6-311.1, and diabetic foot disease 814.7-77.6. Persons with type 1 diabetes mellitus with cardiometabolic risk factors at target range did not exhibit excess risk of extracranial large artery disease [HR 0.83 (95% CI, 0.20-3.36)] or lower extremity artery disease [HR 0.94 (95% CI, 0.30-2.93)], compared to controls. Persons with type 1 diabetes with all risk factors at baseline, had substantially elevated risk for diabetic foot disease [HR 29.44 (95% CI, 3.83-226.04)], compared to persons with type 1 diabetes with no risk factors. Persons with type 1 diabetes mellitus continued to display a lower risk for aortic aneurysm, even with three cardiovascular risk factors at baseline [HR 0.31 (95% CI, 0.15-0.67)]. Relative importance analyses demonstrated that education, glycated hemoglobin (HbA1c), duration of diabetes and lipids explained 54% of extracranial large artery disease, while HbA1c, smoking and systolic blood pressure explained 50% of lower extremity artery disease and HbA1c alone contributed to 41% of diabetic foot disease. Income, duration of diabetes and body mass index explained 66% of the contribution to aortic aneurysm. Interpretation: Peripheral arterial complications decreased in persons with type 1 diabetes mellitus, except for aortic aneurysm which remained low. Besides glycemic control, traditional cardiovascular risk factors were associated with incident outcomes. Risk of these outcomes increased with additional risk factors present. Persons with type 1 diabetes mellitus exhibited a lower risk of aortic aneurysm compared to controls, despite presence of cardiovascular risk factors. Funding: Swedish Governmental and the county support of research and education of doctors, the Swedish Heart and Lung Foundation, Sweden and Åke-Wibergs grant.

Non-coronary peripheral arterial complications in people with type 2 diabetes: a Swedish retrospective cohort study.

Background: Few studies have explored long-term trends and risk factors for peripheral arterial complications in type 2 diabetes compared to the general population. Our research focuses on identifying optimal risk factors, their significance, risk associated with multifactorial risk factor control, and trends for these complications in diabetic patients versus general controls. Methods: This study included persons with type 2 diabetes mellitus entered into the Swedish National Diabetes Register 2001-2019 and controls matched for age-, sex- and county of residence. Outcomes comprised of extracranial large artery disease, aortic aneurysm, aortic dissection, lower extremity arterial disease and diabetes foot disease. Standardized incidence rates and Cox regression were used for analyses. Findings: The study comprises 655,250 persons with type 2 diabetes mellitus; average age 64.2; 43.8% women. Among persons with type 2 diabetes mellitus, the incidence rates per 100,000 person years for each non-coronary peripheral arterial complication event changed between 2001 and 2019 as follows: extracranial large artery disease 170.0-84.9; aortic aneurysm 40.6-69.2; aortic dissection 9.3 to 5.6; lower extremity artery disease from 338.8 to 190.8; and diabetic foot disease from 309.8 to 226.8. Baseline hemoglobin A1c (HbA1c), systolic blood pressure (SBP), smoking status and lipid levels were independently associated with all outcomes in the type 2 diabetes mellitus cohort. Within the cohort with type 2 diabetes mellitus, the risk for extracranial large artery disease and lower extremity artery disease increased in a stepwise fashion for each risk factor not within target. Excess risk for non-coronary peripheral arterial complications in the entire cohort for persons with type 2 diabetes mellitus, compared to matched controls, were as follows: extracranial large artery disease adjusted hazard ratio (HR) 1.69 (95% confidence interval (CI), 1.65-1.73), aortic aneurysm HR 0.89 (95% CI, 0.87-0.92), aortic dissection HR 0.51 (95% CI, 0.46-0.57) and lower extremity artery disease HR 2.59 (95% CI, 2.55-2.64). Interpretation: The incidence of non-coronary peripheral arterial complications has declined significantly among persons with type 2 diabetes mellitus, with the exception of aortic aneurysm. HbA1c, smoking and blood pressure demonstrated greatest relative contribution for outcomes and lower levels of cardiometabolic risk factors are associated with reduced relative risk of outcomes. Funding: Swedish Governmental and the County support of research and education of doctors, the Swedish Heart-Lung Foundation and Åke-Wibergs grant.

Natriuretic Peptides and Prognosis in Patients With Type 2 Diabetes Mellitus and High Risk for Cardiovascular Events.

BACKGROUND: The prognosis of individuals with and without an established heart failure (HF) diagnosis and similarly elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels is not well-known. METHODS AND RESULTS: CANVAS (Canagliflozin Cardiovascular Assessment Study) trial participants were stratified according to baseline NT-proBNP quartiles and history of HF at baseline. Adjusted event rates per 1000 patient-years of follow-up for hospitalizations for HF, cardiovascular mortality, and kidney events were assessed, and hazard ratios (HR) were calculated using Cox proportional hazard models. Of the 3507 participants with available NT-proBNP concentrations, 471 (13.4%) had history of HF. The incidence rate per 1000 patient-years for hospitalizations for HF increased across the NT-proBNP quartiles in patients with (0, 2.8, 13.4, and 40.1; P < .001) and without (1.8, 3.1, 6.0, and 19.1; P < .001) HF, with a significantly higher risk in patients with HF compared with those without (with HF, quartile 3 HR 9.28 [interquartile range (IQR) 1.15-75.05]; P = .04; without HF, quartile 4 HR 4.86 [95% CI, 2.08-11.35]; P < .001). A similar higher risk for kidney events was seen in HF patients (with HF, quartile 4 HR 6.94 [95% CI, 2.66-18.08]; P = .001; without HF, quartile 4 HR 4.85 [95% CI, 3.02-7.80]; P = .001). Similar trends were seen for cardiovascular mortality. CONCLUSIONS: Among patients with type 2 diabetes and cardiovascular risk, an elevated NT-proBNP level was associated with worse HF and kidney outcomes in general, regardless of history of HF; however, the presence of a clinical diagnosis of HF at baseline was associated with an incrementally higher risk, particularly in higher NT-proBNP quartiles.

Body mass index and cardiorenal outcomes in the EMPEROR-Preserved trial: Principal findings and meta-analysis with the DELIVER trial.

AIMS: Both low and high body mass index (BMI) are associated with poor heart failure outcomes. Whether BMI modifies benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in heart failure with preserved ejection fraction (HFpEF) requires further investigation. METHODS AND RESULTS: Using EMPEROR-Preserved data, the effects of empagliflozin versus placebo on the risks for the primary outcome (hospitalization for heart failure [HHF] or cardiovascular [CV] death), change in estimated glomerular filtration rate (eGFR) slopes, change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), and secondary outcomes across baseline BMI categories (<25 kg/m2, 25 to <30 kg/m2, 30 to <35 kg/m2, 35 to <40 kg/m2 and ≥40 kg/m2) were examined, and a meta-analysis conducted with DELIVER. Forty-five percent had a BMI of ≥30 kg/m2. For the primary outcome, there was a consistent treatment effect of empagliflozin versus placebo across the BMI categories with no formal interaction (p trend = 0.19) by BMI categories. There was also no difference in the effects on secondary outcomes including total HHF (p trend = 0.19), CV death (p trend = 0.20), or eGFR slope with slower declines with empagliflozin regardless of BMI (range 1.12-1.71 ml/min/1.73 m2 relative to placebo, p trend = 0.85 for interaction), though there was no overall impact on the composite renal endpoint. The difference in weight change between empagliflozin and placebo was -0.59, -1.48, -1.54, -0.87, and - 2.67 kg in the lowest to highest BMI categories (p trend = 0.016 for interaction). A meta-analysis of data from EMPEROR-Preserved and DELIVER showed a consistent effect of SGLT2i versus placebo across BMI categories for the outcome of HHF or CV death. There was a trend toward greater absolute KCCQ-CSS benefit at 32 weeks with empagliflozin at higher BMIs (p = 0.08). CONCLUSIONS: Empagliflozin treatment resulted in broadly consistent cardiac effects across the range of BMI in patients with HFpEF. SGLT2i treatment yields benefit in patients with HFpEF regardless of baseline BMI.

Insulin-like growth factor binding protein-7 concentrations in chronic heart failure: Results from the EMPEROR programme.

AIMS: Insulin-like growth factor binding protein-7 (IGFBP7) is a biomarker of tissue senescence with a role in cardio-renal pathophysiology. The role of IGFBP7 as a prognostic biomarker across the full ejection fraction (EF) spectrum of heart failure (HF) remains less well understood. We examined associations between IGFBP7 and risk of cardio-renal outcomes regardless of EF and the effect of empagliflozin treatment on IGFBP7 concentrations among individuals with HF. METHODS AND RESULTS: IGFBP7 was measured in 1125 study participants from the EMPEROR-Reduced and EMPEROR-Preserved trials. Cox regression was used to study associations with outcomes. Study participants with IGFBP7 levels in the highest tertile had a higher-risk clinical profile. In Cox proportional hazards models adjusted for clinical variables, N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T, baseline IGFBP7 values in the highest tertile predicted an increased risk of HF hospitalization or cardiovascular death (hazard ratio [HR] 2.00, 95% confidence interval [CI] 1.28-3.10, p = 0.002, p for trend <0.001) and higher risk of the renal composite endpoint (HR 4.66, 95% CI 1.61-13.53, p = 0.005, p for trend = 0.001), regardless of EF. Empagliflozin reduced risk for cardiovascular death/HF hospitalization irrespective of baseline IGFBP7 (p for trend across IGFBP7 tertiles = 0.26). Empagliflozin treatment was not associated with meaningful change in IGFBP7 at 12 or 52 weeks. CONCLUSION: Across the entire left ventricular EF spectrum in the EMPEROR Programme, concentrations of the senescence-associated biomarker IGFBP7 were associated with higher risk clinical status and predicted adverse cardio-renal outcomes even in models adjusted for conventional biomarkers. Empagliflozin did not significantly affect IGFBP7 levels over time.

Putting More Weight on Obesity Trials in Heart Failure.

PURPOSE OF REVIEW: To review ongoing and planned clinical trials of weight loss among individuals with or at high risk of heart failure. RECENT FINDINGS: Intentional weight loss via semaglutide among persons with heart failure and preserved ejection fraction and obesity significantly improves weight loss and health status as assessed by the KCCQ-CSS score and is associated with improvements in 6-min walk test. Ongoing and planned trials will explore the role of intentional weight loss with treatments such as semaglutide or tirzepatide for individuals with heart failure across the entire ejection fraction spectrum.

Lifetime and 10-year cardiovascular risk prediction in individuals with type 1 diabetes: The LIFE-T1D model.

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.

Ongoing burden and recent trends in severe hospitalised hypoglycaemia events in people with type 1 and type 2 diabetes in Scotland: A nationwide cohort study 2016-2022.

AIMS: We examined severe hospitalised hypoglycaemia (SHH) rates in people with type 1 and type 2 diabetes in Scotland during 2016-2022, stratifying by sociodemographics. METHODS: Using the Scottish National diabetes register (SCI-Diabetes), we identified people with type 1 and type 2 diabetes alive anytime during 2016-2022. SHH events were determined through linkage to hospital admission and death registry data. We calculated annual SHH rates overall and by age, sex, and socioeconomic status. Summary estimates of time and stratum effects were obtained by fitting adjusted generalised additive models using R package mgcv. RESULTS: Rates for those under 20 with type 1 diabetes reached their minimum at the 2020-2021 transition, 30% below the study period average. A gradual decline over time also occurred among 20-49-year-olds with type 1 diabetes. Overall, females had 15% higher rates than males with type 2 diabetes (rate ratio 1.15, 95% CI 1.08-1.22). People in the most versus least deprived quintile experienced 2.58 times higher rates (95% CI 2.27-2.93) in type 1 diabetes and 2.33 times higher (95% CI 2.08-2.62) in type 2 diabetes. CONCLUSIONS: Despite advances in care, SHH remains a significant problem in diabetes. Future efforts must address the large socioeconomic disparities in SHH risks.

Effects of long-term HbA1c variability on serious infection risks in patients with type 2 diabetes and the influence of age, sex and ethnicity: A cohort study of primary care data.

AIMS: Long-term HbA1c (glycated haemoglobin) variability is associated with micro- and macrovascular complications in Type 2 diabetes (T2D). We explored prospective associations between HbA1c variability and serious infections, and how these vary by HbA1c level, age, sex and ethnicity. METHODS: 411,963 T2D patients in England, aged 18-90, alive on 01/01/2015 in the Clinical Practice Research Datalink with ≥ 4 HbA1c measurements during 2011-14. Poisson regression estimated incidence rate ratios (IRRs) for infections requiring hospitalisation during 2015-19 by HbA1c variability score (HVS) and average level, adjusting for confounders, and stratified by age, sex, ethnicity and average level. Attributable risk fractions (AF) were calculated using reference categories for variability (HVS < 20) and average level (42-48 mmol/mol). RESULTS: An increased infection risk (IRR > 1.2) was seen with even modest variability (HVS ≥ 20, 73 % of T2D patients), but only at higher average levels (≥64 mmol/mol, 27 % patients). Estimated AFs were markedly greater for variability than average level (17.1 % vs. 4.1 %). Associations with variability were greater among older patients, and those with lower HbA1c levels, but not observed among Black ethnicities. CONCLUSIONS: HbA1c variability between T2D patients' primary care visits appears to be associated with more serious infections than average level overall. Well-designed trials could test whether these associations are causal.

Worth Their Weight? An Update on New and Emerging Pharmacologic Agents for Obesity and Their Potential Role for Persons with Cardiac Conditions.

PURPOSE OF REVIEW: Obesity is associated with cardiovascular (CV) conditions, including but not limited to atherosclerotic disease, heart failure, and atrial fibrillation. Despite this, the impact of intentional weight loss on CV outcomes for persons with obesity and established CV conditions remains poorly studied. New and emerging pharmacologic therapies for weight loss primarily targeting the incretin/nutrient sensing axes induce substantial and sustained weight loss. The glucagon-like-peptide 1 receptor agonists (GLP-1 RA) liraglutide and semaglutide have US FDA approval for the treatment of obesity, and the application for an obesity indication for the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide is presently under FDA review. Extensive phase II and IIIa randomized controlled trials are underway evaluating permutations of combined GLP-1 RA, GIP receptor agonist, GIP receptor antagonist, and glucagon receptor agonists. Clinical outcome trials of these therapies in persons with obesity at high risk of established CV conditions should make it possible to estimate the role of intentional weight loss in managing CV risk via these medications. RECENT FINDINGS: High-dose once weekly injectable semaglutide (2.4 mg/week) use among persons with obesity and heart failure with preserved ejection fraction was effective at both reducing weight and improving health status; exercise capacity was also improved. Ongoing CV outcome trials of oral semaglutide and once weekly injectable tirzepatide will help to establish the role of these therapies among persons with other CV conditions. In addition to these two therapies targeting a CV claim or indication, many other new therapeutics for weight loss, as reviewed, are currently in development. The impact of pharmacologic-induced weight loss on CV conditions for persons with obesity and established CV conditions is currently under investigation for multiple agents. These therapies may offer new avenues to manage CV risk in persons with obesity and with established or at high risk for CV disease.

Genetic Evidence for Distinct Biological Mechanisms That Link Adiposity to Type 2 Diabetes: Toward Precision Medicine.

We aimed to unravel the mechanisms connecting adiposity to type 2 diabetes. We used MR-Clust to cluster independent genetic variants associated with body fat percentage (388 variants) and BMI (540 variants) based on their impact on type 2 diabetes. We identified five clusters of adiposity-increasing alleles associated with higher type 2 diabetes risk (unfavorable adiposity) and three clusters associated with lower risk (favorable adiposity). We then characterized each cluster based on various biomarkers, metabolites, and MRI-based measures of fat distribution and muscle quality. Analyzing the metabolic signatures of these clusters revealed two primary mechanisms connecting higher adiposity to reduced type 2 diabetes risk. The first involves higher adiposity in subcutaneous tissues (abdomen and thigh), lower liver fat, improved insulin sensitivity, and decreased risk of cardiometabolic diseases and diabetes complications. The second mechanism is characterized by increased body size and enhanced muscle quality, with no impact on cardiometabolic outcomes. Furthermore, our findings unveil diverse mechanisms linking higher adiposity to higher disease risk, such as cholesterol pathways or inflammation. These results reinforce the existence of adiposity-related mechanisms that may act as protective factors against type 2 diabetes and its complications, especially when accompanied by reduced ectopic liver fat.

Carbohydrate antigen 125 concentrations across the ejection fraction spectrum in chronic heart failure: The EMPEROR programme.

AIM: Vascular congestion may lead to an increase of carbohydrate antigen 125 (CA-125). The role of CA-125 as a biomarker of congestion or for prognosis across the full ejection fraction (EF) spectrum of chronic heart failure (HF) remains unknown. METHODS AND RESULTS: Serum CA-125 was measured in 1111 study participants from the EMPEROR-Reduced and EMPEROR-Preserved trials. Congestive signs and symptoms were evaluated across CA-125 tertiles. Cox regression was used to study the association with outcomes. The primary outcome was a composite of first HF hospitalization or cardiovascular (CV) death. No significant association was present between baseline CA-125 levels and congestive signs or symptoms. In the overall population, higher CA-125 levels were not associated with an increased risk of primary outcome (tertile 3 vs. tertile 1: hazard ratio [HR] 1.34; 95% confidence interval [CI] 0.91-1.96; p-trend = 0.11). However, higher CA-125 levels were associated with an increased risk of primary outcome in patients with HF and reduced EF (HFrEF; tertile 3 vs. tertile 1: HR 2.25 [95% CI 1.30-3.89]), but not among patients with preserved EF (HFpEF; tertile 3 vs. tertile 1: HR 0.68 [95% CI 0.38-1.21]); interaction-p = 0.02). Patients in the upper CA-125 tertile also showed the steepest estimated glomerular filtration rate decline over time (p-trend = 0.03). The effect of empagliflozin to reduce the risk of CV death or HF hospitalization appeared to be attenuated in those with lower baseline CA-125 levels (interaction-p-trend = 0.09). CONCLUSION: Across the range of EF in patients with chronic HF enrolled in the EMPEROR trials, the majority of whom did not have clinical evidence of congestion, CA-125 concentrations were not significantly associated with congestive signs or symptoms. CA-125 concentrations may predict HF hospitalization/CV death in patients with HFrEF, but not those with HFpEF. CLINICAL TRIAL REGISTRATION: EMPEROR-Reduced (NCT03057977), EMPEROR-Preserved (NCT03057951).