Prospective studies have demonstrated an inverse association between lipoprotein(a) [Lp(a)] levels and the risk for type 2 diabetes, although the mechanisms underlying this relationship remain unclear. We examined the associations of Lp(a) with incident type 2 diabetes, fasting serum insulin, and fasting plasma glucose, in the prospective Young Finns Study cohort. Lp(a) measurements were first available in Young Finns Study participants in 1986 (N = 2 464). For type 2 diabetes analyses, the baseline was defined as the 2001 follow-up study (participants aged 24–39 years) when data on both Lp(a) and diabetes status were available (N = 2 263). The association between Lp(a) levels and incident type 2 diabetes was examined using the Fine-Gray model. Associations with fasting insulin and glucose were analyzed using repeated-measures linear regression, utilizing data from 1986, 2001, 2007, 2011, and 2018. During the mean follow-up period of 16.6 years from 2001, 144 participants (6.4
Insulin resistance and frailty are closely related to cardiometabolic deterioration, yet their joint contribution to the development of cardiometabolic multimorbidity (CMM) among individuals with early-to-intermediate cardiovascular–kidney–metabolic (CKM) syndrome remains unclear. This study examined the associations of five insulin resistance-frailty composite indices and the joint status of insulin resistance indices and frailty index with incident CMM in Chinese middle-aged and older adults with CKM stages 0–3. This prospective cohort study included 6023 participants from the China Health and Retirement Longitudinal Study who had CKM stages 0–3 and were free of CMM at baseline. Insulin resistance was assessed using the triglyceride–glucose index (TyG), C-reactive protein-triglyceride glucose index (CTI), cholesterol, high-density lipoprotein, and glucose index (CHG), stress hyperglycemia ratio (SHR), and estimated glucose disposal rate (eGDR). Frailty was evaluated using a 32-item frailty index (FI). Composite indices included TyG-FI, CTI-FI, CHG-FI, SHR-FI, and eGDR/FI. Participants were also cross-classified into joint exposure groups according to baseline median-derived cutoff values of each insulin resistance index and FI. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95
Gestational diabetes mellitus (GDM) is the most common complication during pregnancy and early prediction for high-risk gravidas is crucial to facilitate timely intervention. However, most newly discovered biomarkers require additional blood sampling and high costs, which limits their feasibility in routine clinical practice. This study aimed to assess whether noninvasive retinal parameters could enhance the predictive performance of established models for GDM. This prospective cohort study collected demographic characteristics, glycolipid metabolism indices, and retinal images at 11–13+6 weeks of gestation. The primary outcome was GDM based on oral glucose tolerance test at 24–28 weeks. Variables were selected via least absolute shrinkage and selection operator (LASSO) regression. Six machine learning algorithms (logistic regression, random forest, extreme gradient boosting, categorical boosting [CatBoost], adaptive boosting, and support vector machine) were employed to develop the LIGHT (LIpid+Glucose+opHthalmic+maTernal factors) model incorporating baseline, glycolipid metabolism and retinal features. Model performance was assessed by the area under the receiver-operating-characteristic curve (AUC) and interpreted by the Shapley Additive Explanation method (SHAP). The incremental value of retinal features was evaluated by net reclassification improvement (NRI) and integrated discrimination improvement (IDI). We compared LIGHT model with (1) Baseline model based on demographic characteristics, (2) Glycolipid model including baseline and glycolipid metabolism features, and (3) Eye model using baseline and retinal features. Of the 2114 participants, 1774 pregnancies were included in the final analysis, of which 324 (18.3
Rapid progression of coronary atherosclerosis is associated with an increased risk of future adverse cardiovascular events. However, evidence regarding the association between glycemic status and rapid plaque progression (RPP) in the major epicardial coronary arteries remains limited. A total of 1296 subjects (mean age, 61 ± 9 years; 56.9
Individuals with the metabolic syndrome have elevated remnant cholesterol and increased cardiovascular risk. We tested the hypothesis that elevated remnant cholesterol mediates part of the excess risk of myocardial infarction, atherosclerotic cardiovascular disease (ASCVD), and all-cause mortality in the metabolic syndrome. We included 117,108 and 420,777 individuals from the 2003–2015 Copenhagen General Population Study and the 2006–2010 UK Biobank, of which 35,050 and 143,909 had the metabolic syndrome. All individuals were followed in national health registers until December 2021, during which time 3,187 and 9,166 developed myocardial infarctions and 11,275 and 39,860 ASCVD in the two studies, respectively. The main statistical analyses were Cox regression and mediation analysis, multivariable adjusted and stratified on lipid-lowering therapy use. In both studies, individuals with versus without the metabolic syndrome had higher remnant cholesterol. In individuals with the metabolic syndrome from the Copenhagen General Population Study, a 1 mmol/L (39 mg/dL) higher remnant cholesterol conferred a hazard ratio for myocardial infarction of 1.39 (95
Cardiovascular-kidney-metabolic (CKM) syndrome and cardiometabolic multimorbidity (CMM) carry substantial mortality, yet whether a composite index integrating insulin resistance and frailty shows stronger associations with advanced CKM syndrome, CMM, and mortality than conventional metabolic markers remains unclear. This study evaluated the associations of the triglyceride-glucose-frailty index (TyG-FI) with CKM, CMM, and all-cause and cardiovascular mortality, and explored the role of baseline estimated glomerular filtration rate (eGFR). The analysis included 11,228 adults aged 20–79 years from the National Health and Nutrition Examination Survey 2001–2018. TyG-FI was calculated as the TyG index multiplied by the frailty index. Survey-weighted logistic and Cox proportional-hazards models were used to estimate odds and hazard ratios, with sequential adjustment for demographic, socioeconomic, and behavioral confounders. Restricted cubic splines examined non-linear relationships. Overall model performance was assessed using receiver operating characteristic curves with DeLong’s test, time-dependent AUC, Harrell’s C-index, calibration, and decision curve analysis. Exploratory mediation analyses quantified the proportion of mortality associations accounted for by baseline eGFR. Robustness was verified through multiple sensitivity and subgroup analyses. Over a median follow-up of 90 months (1,220 all-cause and 379 cardiovascular deaths), higher TyG-FI quartiles were associated with graded decreases in survival. Compared with the lowest TyG-FI quartile, the highest quartile yielded markedly elevated odds for advanced CKM syndrome (OR = 4.57, 95
Family history is a well-established predictor of cardiometabolic risk; however, the independent prognostic contribution of sibling disease history, beyond parental history, remains to be elucidated. Using data from the prospective population-based Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort, we investigated the associations between family history of six common cardiometabolic disorders and incident cardiovascular disease (CVD), diabetes mellitus (DM), chronic kidney disease (CKD), and heart failure (HF). Primary family history was categorized into three groups: no family history, parental history only, or any sibling history. To further disentangle the distinct familial contributions, parental history was additionally stratified as no parent affected, father only affected, mother only affected, or both parents affected. The sibling disease score was calculated from reported sibling disease history across six cardiometabolic conditions and categorized as 0, 1, or ≥ 2 entries. Fine-Gray competing-risk models were employed to estimate subdistribution hazard ratios (SHRs), with death accounted for as a competing event. Among 8,592 participants (mean age, 49.8 ± 12.7 years; 49.9
Obesity is increasingly recognized as a risk factor not only for type 2 diabetes but also for type 1 diabetes. We assessed its interaction with genetic susceptibility in the risk for adult-onset type 1 diabetes. We conducted a population-based retrospective cohort study of 604,968 Israeli adolescents (aged 16–19 years; 44
Type 2 diabetes (T2D) is associated with atherosclerotic cardiovascular disease (ASCVD). We aimed to compare the cardiovascular effectiveness and musculoskeletal safety of tirzepatide, glucagon-like peptide−1 receptor agonists (GLP-1 RAs), and sodium–glucose cotransporter 2 (SGLT2) inhibitors among normal-weight adults with T2D and established ASCVD. We conducted an active-comparator, retrospective cohort study using the TriNetX Analytics Network (data extracted on February 16, 2026). Adults (≥ 18 years) with T2D, ASCVD, and a baseline body mass index between 18.5 and 24.9 kg/m2 were included. Three prespecified pairwise comparisons were performed (tirzepatide vs. GLP-1 RAs, tirzepatide vs. SGLT2 inhibitors, and GLP-1 RAs vs. SGLT2 inhibitors). Cohorts were propensity score matched 1:1. The primary endpoint was three-point major adverse cardiovascular events (MACE) including all-cause mortality, acute myocardial infarction, and ischemic stroke. The secondary cardiovascular outcome was the occurrence of each MACE component. The safety outcomes included composites for sarcopenia, osteoporosis, and falls/fractures. After matching, the cohort sizes were 634 pairs (tirzepatide vs. GLP-1 RAs), 4,438 pairs (GLP-1 RAs vs. SGLT2 inhibitors), and 545 pairs (tirzepatide vs. SGLT2 inhibitors). The hazard of three-point MACE was lower with tirzepatide than with GLP-1 RAs (14.2
Metabolic dysfunction-associated steatotic liver disease (MASLD) carries a predisposition to cardiometabolic multimorbidity (CMM). The C-reactive protein-triglyceride-glucose index (CTI) captures inflammatory and metabolic derangements in a single metric, though whether its cumulative exposure or longitudinal change patterns predict CMM in MASLD has not been investigated. We therefore examined how cumulative CTI, CTI change cluster, and single-timepoint indices (CTI and TyG) relate to incident CMM in middle-aged and older Chinese adults with MASLD. We drew on 2,165 MASLD participants from the China Health and Retirement Longitudinal Study (2011–2020). CTI was derived at baseline (2012) and follow-up (2015); cumulative CTI was computed as the product of mean CTI and exposure duration. Three change phenotypes were identified through K-means clustering. Cox regression, restricted cubic splines, and Kaplan–Meier methods were applied to assess associations. Time-dependent AUC, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) served to compare predictive utility. During a mean follow-up of 102.2 months, 350 participants developed CMM (16.2
Cardiovascular-kidney-metabolic (CKM) syndrome integrates metabolic abnormalities, chronic kidney disease, and cardiovascular disease (CVD), with stages 0–3 representing a critical window for primary prevention. Whether the Chinese visceral adiposity index (CVAI) adds predictive value for CVD in this population remains uncertain. Using data from the China Health and Retirement Longitudinal Study (CHARLS), a nationwide prospective cohort, we included 7,539 participants with CKM stages 0–3. Incident CVD (heart disease or stroke) was the primary outcome. Cox proportional hazards models and restricted cubic splines assessed the association and dose-response relationship, and discrimination was evaluated with the AUC and censoring-adjusted time-dependent AUC, with comparisons against BMI, waist circumference, VAI, and TyG. Over a median follow-up of 8.0 years, 1,718 incident CVD events were recorded. Each SD increase in CVAI was associated with a 19.5
The estimated glucose disposal rate (eGDR), an insulin-resistance surrogate derived from routine clinical variables, has been associated with cardiovascular disease (CVD). We examined its association with incident CVD, cross-national transportability, and incremental discrimination across ageing populations in China, England, and the United States. We analysed harmonized prospective cohort data from the China Health and Retirement Longitudinal Study (CHARLS), the English Longitudinal Study of Ageing (ELSA), and the Health and Retirement Study (HRS). Primary analyses included participants free of diabetes, heart disease, and stroke at baseline; incident CVD was defined as new-onset heart disease or stroke. Associations per 1-SD decrease in eGDR were estimated using attained-age Cox models and pooled by random-effects meta-analysis. Frozen-coefficient models assessed transportability across cohorts, and incremental discrimination was evaluated against established risk factors, HbA1c, and eGDR’s constituent variables. The analytic samples comprised 6,059 CHARLS participants (1,219 incident CVD events), 4,061 ELSA participants (865 events), and 4,299 HRS participants (809 events). Hazard ratios per 1-SD lower eGDR were 1.24 (95
Hepatic steatosis and prediabetes are increasingly prevalent among older adults; however, their respective impacts on cardiometabolic outcomes remain unclear. We aimed to evaluate the associations of hepatic steatosis and prediabetes with incident diabetes and cardiovascular outcomes in this population. This nationwide cohort study included 142,518 adults aged ≥ 65 years without diabetes. Hepatic steatosis was defined using the fatty liver index (FLI ≥ 60), and impaired fasting glucose (IFG) was defined by fasting glucose levels of 100–125 mg/dL. Outcomes included incident diabetes and composite major adverse cardiovascular events (MACE), comprising myocardial infarction, stroke, heart failure, or cardiovascular death, which were analyzed using multivariable Cox proportional hazards models and Fine–Gray subdistribution hazard models. At baseline, FLI-defined hepatic steatosis was identified in 6.6
Diabetes is associated with sudden cardiac death (SCD), but evidence in patients without coronary artery disease (CAD) remains limited. SCD risk may vary by revascularisation strategy in diabetic patients with CAD. We retrospectively analysed 22,395 consecutive patients undergoing coronary angiography from 2007 to 2018, either electively for suspected or known CAD or for acute coronary syndrome. Follow-up ended 31 December 2022. Sudden cardiac arrest (SCA), SCD and SCD-equivalent events were adjudicated using medical records, death certificates, and nationwide mortality data. Among 22,395 patients, 5,804 had diabetes. Over a median follow-up of 8.1 years (IQR 5.1–11.6), 1,710 experienced SCA, including 1,046 SCD or SCD-equivalent events. After multivariable adjustment including left ventricular ejection fraction (LVEF), diabetes showed similar associations with SCD or SCD-equivalent event (subdistribution hazard ratio [SHR] 1.38, 1.21–1.58; P < 0.001) and non-SCD death (SHR 1.37, 1.30–1.44; P < 0.001). Yet, among patients with diabetes, the 10-year cumulative incidence of non-SCA death was more than three times that of SCA. Diabetes was associated with SCD or SCD-equivalent event even without obstructive CAD (SHR 1.53, 1.11–2.12; P = 0.010). In patients with diabetes and CAD, lower SCD risk was observed in revascularized patients than in those receiving medical therapy (SHR 0.77, 0.60–0.99; P = 0.039). The diabetes–SCD association appeared stronger at age < 70 years, with LVEF ≥ 40
Patients with acute myocardial infarction (AMI) continue to face a considerable risk of death, even in the era of contemporary reperfusion and secondary prevention. Metabolic abnormalities may partly explain this residual risk. The cholesterol, high-density lipoprotein, and glucose (CHG) index, calculated as Ln[total cholesterol (TC, mg/dL) × fasting blood glucose (FBG, mg/dL)]/[2 × high-density lipoprotein cholesterol (HDL-C, mg/dL)], is a recently proposed marker integrating lipid and glucose metabolism. We primarily aimed to examine the association between the CHG index and mortality in patients with AMI. We analyzed two prospective cohorts, including 8,782 patients with AMI from the China Acute Myocardial Infarction (CAMI) registry and 3,466 AMI patients undergoing percutaneous coronary intervention at Fuwai Hospital. Outcomes included in-hospital, 1-year, and 2-year all-cause mortality in the CAMI cohort, and all-cause mortality in the Fuwai Hospital cohort. Associations between the CHG index and mortality were assessed using Cox proportional hazards models and restricted cubic splines. Discrimination, reclassification, and decision curve analyses were performed as secondary exploratory analyses. In the CAMI cohort, higher CHG levels were associated with a graded increase in mortality risk. After multivariable adjustment, patients in the highest CHG tertile had higher risks of in-hospital mortality [hazard ratio (HR): 2.66, 95
Gestational diabetes mellitus (GDM) increases offspring cardiometabolic risk, potentially through intrauterine epigenetic programming. We aimed to characterize GDM-associated DNA methylation differences in cord blood, evaluate their consistency with previously identified maternal methylation marks, and explore associations with neonatal anthropometric outcomes. An epigenome-wide association study (EWAS) was performed in cord blood DNA from 22 offspring, including 11 exposed to GDM and 11 controls, using the Infinium MethylationEPIC BeadChip. Differentially methylated positions (DMPs) and regions (DMRs) were evaluated using models adjusted for fetal sex, gestational age, maternal age, pre-pregnancy BMI, and estimated cell-type proportions. Functional enrichment analyses were conducted using Enrichr. A candidate-site analysis evaluated 272 previously identified maternal GDM-associated CpGs and their associations with neonatal anthropometric outcomes. Seventeen DMRs remained significant after FDR correction, including regions annotated to ZFP57 and HIF3A. Functional enrichment identified nominal associations with metabolic and developmental pathways, while four ClinVar terms related to neonatal and monogenic diabetes remained significant after multiple-testing correction, with ZFP57 contributing to all four. Among the 272 maternal candidate CpGs, 25 showed nominal evidence of association in cord blood and 12 displayed the same direction of effect across tissues. Effect estimates across all 272 CpGs were weakly positively correlated between maternal and cord blood. Nominal associations were also observed with birth weight and head circumference percentiles, including two associations with head circumference percentile after adjustment for GDM status. No individual DMP or neonatal association reached FDR-adjusted significance. GDM was associated with FDR-significant regional DNA methylation differences in cord blood, including biologically plausible loci related to imprinting and metabolic regulation. The observed overlap with maternal GDM-associated CpGs and the associations with neonatal anthropometric outcomes support further investigation of cross-tissue epigenetic variation in larger independent cohorts.
Diabetic Cardiomyopathy (DiabCM) develops in patients with Type-2-Diabetes Mellitus (T2D) and is characterized by cardiac dysfunction independent of ischemic heart disease or systemic hypertension. Its underlying mechanisms remain poorly defined with likely genetic and non-genetic mechanisms including epigenetic modifications. Combining T2D-derived polygenic risk scores (PRS) and methylation risk scores (MRS) with key clinical characteristics may aid risk stratification for myocardial dysfunction among patients with T2D. We analyzed 173 deeply phenotyped participants from the CARDIATEAM discovery study, grouping them by the severity of myocardial dysfunction determined by echocardiography. Both PRS and MRS show significantly different distribution between severity groups (p-value = 0.02 and 1.29e-05, respectively) with significant odds ratios (ORs) at ≥ 80th and ≥ 90th percentiles: PRS (2.23 [95
The cholesterol-high-density lipoprotein–glucose (CHG) index combines lipid and glycemic measures, but whether its adiposity- and inflammation-related derivatives add information beyond their components and established risk factors is uncertain. We compared nine CHG-related indices with incident cardiovascular disease (CVD) and mortality. We included 7516 adults aged ≥ 45 years without baseline CVD from the China Health and Retirement Longitudinal Study (CHARLS). Associations across four follow-up intervals were estimated using multivariable discrete-time complementary log–log models. False discovery rate (FDR) correction was applied within prespecified families. Component-separated analyses and internally cross-validated prediction models benchmarked derivatives against components and conventional risk models. Complementary mortality analyses used survey-weighted Cox models in the 1999–2018 National Health and Nutrition Examination Survey (NHANES); complete-case analyses included 8658 participants for eight core indices and 7059 for CHG-CRP. Over 9 years, 1849 CHARLS participants developed CVD. In fully adjusted Model 3, all nine indices were associated with incident CVD per 1-SD increment (HRs 1.077–1.213; all FDR-adjusted P ≤ 0.002), with the largest estimate for CHG-CVAI (HR 1.213, 95
