Cardiovasc Diabetol [JOURNAL]
Sun
200 papers
Single-cell insights into maladaptive endothelial plasticity and therapeutic targets in diabetic vascular complications.
Alnuaimi NS, Lößlein L, Mousa M … +7 more , Khader TA, Alkhaaldi A, Azzam SK, Van Craenenbroeck AH, Ashraf SS, Carmeliet P, Alsafar H
Cardiovasc Diabetol · 2026 May · PMID 42092877 · Full text
Endothelial plasticity, the capacity of endothelial cells (ECs) to reversibly alter their phenotype in response to environmental cues, typically enables adaptive vascular remodeling and tissue homeostasis. In diabetes, t...
Endothelial plasticity, the capacity of endothelial cells (ECs) to reversibly alter their phenotype in response to environmental cues, typically enables adaptive vascular remodeling and tissue homeostasis. In diabetes, this plasticity becomes maladaptive, driving pathological transitions across interconnected axes: dysregulated angiogenesis with barrier destabilization, inflammatory reprogramming through immune-endothelial crosstalk, metabolic dysfunction spanning mitochondrial stress to senescence, and endothelial-to-mesenchymal transition with fibrosis. In this review, we synthesize mechanistic insights across endothelial state transitions and highlight how single-cell approaches have reframed diabetic vascular disease as a disorder of maladaptive endothelial plasticity. By integrating single-cell insights from diabetic mouse models and human patient samples, we demonstrate that restoring adaptive endothelial plasticity requires coordinated multi-dimensional intervention targeting the intersecting pathways that perpetuate pathological transitions, timed to disease stage and calibrated to vascular bed-specific context. For example, combining metabolic therapies such as GLP-1 receptor agonists or SGLT2 inhibitors with anti-inflammatory agents targeting IL-17A or IL-1β, pairing anti-VEGF treatments with inhibitors of MFAP4 or ANGPTL4 to overcome angiogenic bypass pathways, or coupling senolytics, such as UBX1325, with anti-fibrotic strategies like TGF-β or SETD7 inhibition to prevent irreversible EndoMT. We identify candidate therapeutic targets across angiogenic, inflammatory, metabolic, and fibrotic domains, and highlight critical knowledge gaps, most notably the limited characterization of human diabetic ECs, that must be addressed to translate these insights into effective clinical strategies for preventing diabetic vascular complications.
Phenotypic clustering of newly diagnosed type 2 diabetes in a Mediterranean cohort.
Fernandez-Camins B, Vlacho B, Rojo-López MI … +9 more , Granado-Casas M, Gratacòs M, Ortega-Bravo M, Cendros-Massioui M, Palmieri F, Perera-LLuna A, Franch-Nadal J, Mauricio D, COPERNICAN Research Group
Cardiovasc Diabetol · 2026 May · PMID 42083025 · Full text
BACKGROUND: Current diagnostic criteria for type 2 diabetes (T2D) capture disease heterogeneity poorly, and do not reliably predict progression, complications, or treatment response. The phenotypic clustering model propo...
BACKGROUND: Current diagnostic criteria for type 2 diabetes (T2D) capture disease heterogeneity poorly, and do not reliably predict progression, complications, or treatment response. The phenotypic clustering model proposed by Ahlqvist et al. identified five T2D subtypes using six clinical variables at diagnosis, each associated with distinct metabolic profiles and complication risks. Although this framework has been replicated in several cohorts, evidence in Mediterranean populations is lacking. METHODS: We conducted a prospective cohort study in Catalonia (Northeast Spain) including adults with newly diagnosed T2D recruited between March 2022 and January 2026. Using baseline data, we evaluated the Ahlqvist clustering approach. Autoantibody-positive individuals were classified as severe autoimmune diabetes (SAID), and sex-stratified k-means clustering (k = 4) was applied to autoantibody-negative participants. Cluster separation and stability were assessed using principal component analysis and silhouette analyses. RESULTS: A final total number of 991 individuals with newly diagnosed T2D were included in the analysis. Autoantibodies were present in 67 subjects (6.8%), thereby being classified as SAID. Among the remaining 924 participants, sex-stratified k-means clustering (k = 4) identified clusters with metabolic profiles consistent with the classical subtypes: mild age-related diabetes (MARD, n = 326), severe insulin-resistant diabetes (SIRD, n = 241), mild obesity-related diabetes (MOD, n = 206), and severe insulin-deficient diabetes (SIDD, n = 151). However, cluster separation was modest, and bootstrap stability was limited (Jaccard 0.555-0.718). In an unconstrained analysis, apart from the autoimmune diabetes group, silhouette optimisation identified three clusters as the most internally optimal structure, corresponding broadly to obesity/insulin-resistant (C1, n = 347), insulin-deficient (C2, n = 186), and age-related (C3, n = 391) phenotypes. Stability was substantially higher for the three-cluster solution (Jaccard 0.799-0.863). Concordance between the Ahlqvist and data-driven models was moderate (ARI = 0.473), with MOD individuals distributed across the other clusters. CONCLUSIONS: The Ahlqvist clustering architecture could be approximated in this Mediterranean cohort at diagnosis, but internal stability of the five-cluster solution was limited. In this population, a four-cluster structure showed substantially better internal validity. These findings support the feasibility of phenotypic subclassification of T2D while underscoring the importance of evaluating population-specific cluster structures and their clinical relevance in longitudinal studies. TRIAL REGISTRATION: NCT05333718.
The role of bempedoic acid in the management of dyslipidaemia in people with diabetes: an expert opinion of Italian diabetologists.
Federici M, Buzzetti R, Candido R … +5 more , De Cosmo S, Pirillo A, Russo G, Sesti G, Avogaro A
Cardiovasc Diabetol · 2026 May · PMID 42071223 · Full text
Diabetes mellitus is a rapidly growing global health challenge and a major driver of atherosclerotic cardiovascular disease (ASCVD). Dyslipidaemia, highly prevalent in both type 1 and type 2 diabetes, plays a central rol...
Diabetes mellitus is a rapidly growing global health challenge and a major driver of atherosclerotic cardiovascular disease (ASCVD). Dyslipidaemia, highly prevalent in both type 1 and type 2 diabetes, plays a central role in this excess cardiovascular risk and often persists despite statin therapy. Although statins remain the cornerstone of lipid management, many patients with diabetes do not achieve recommended low-density lipoprotein cholesterol (LDL-C) goals. Therefore, there is a need for effective, safe, and practical adjunctive therapies. Bempedoic acid is a first-in-class oral ATP-citrate lyase inhibitor with liver-specific activation, resulting in significant LDL-C reduction without relevant muscle-related adverse effects. Across clinical trials, including the CLEAR programme, bempedoic acid has demonstrated consistent LDL-C lowering, as well as reductions in apolipoprotein B and non-HDL-C, and favourable effects on the inflammatory marker high-sensitivity C-reactive protein (hs-CRP), with similar efficacy in patients with and without diabetes. Importantly, the CLEAR Outcomes trial showed a significant reduction in major adverse cardiovascular events in statin-intolerant patients, almost half of whom had diabetes, without adverse effects on glycaemic control. This article summarises the evidence supporting the use of bempedoic acid in people with diabetes, proposes its therapeutic positioning within contemporary lipid-lowering algorithms, and highlights its role as an effective oral option, aiming to provide practical and nationally relevant guidance for lipid management in people with diabetes. By helping to reduce residual cardiovascular risk and bridge treatment gaps in patients who may not be eligible for or have access to PCSK9 inhibitors, bempedoic acid represents a valuable addition to personalised lipid management strategies aimed at lowering cardiovascular morbidity and mortality in this high-risk population.
Correction: Sirtuins and regulatory miRNAs as epigenetic determinants of empagliflozin-mediated recovery after acute myocardial infarction.
Nowak-Szwed A, Eyileten C, Wicik Z … +6 more , Ahmadova S, Palatini J, Siller-Matula J, von Lewinski D, Sourij H, Postula M
Cardiovasc Diabetol · 2026 May · PMID 42071215 · Full text
Abstract loading — click title to view on PubMed.
The association between triglyceride glucose-frailty index and cardiometabolic multimorbidity among Chinese middle-aged and older adults: a national prospective cohort study.
Hou X, Wang G, Gao Y
Cardiovasc Diabetol · 2026 May · PMID 42071205 · Full text
BACKGROUND: Cardiometabolic multimorbidity (CMM) poses a growing global health burden, yet few studies have combined the Triglyceride-Glucose (TyG) index, which reflects metabolic dysfunction, with the Frailty Index (FI)...
BACKGROUND: Cardiometabolic multimorbidity (CMM) poses a growing global health burden, yet few studies have combined the Triglyceride-Glucose (TyG) index, which reflects metabolic dysfunction, with the Frailty Index (FI), which captures physiological reserve and aging-related vulnerability, to assess CMM risk. Given their complementary biological information, this study examines whether a composite TyG-FI index is associated with incident CMM and whether it improves risk stratification beyond established factors. METHODS: This prospective cohort study analyzed data from Chinese adults aged ≥ 45 years in the 2011-2020 waves of the China Health and Retirement Longitudinal Study (CHARLS). To assess the association between the TyG-FI index and incident CMM, we used Kaplan-Meier survival curves and multivariable Cox proportional-hazards models adjusted for potential confounders; restricted cubic spline analyses were employed to explore non-linear relationships. Predictive performance was evaluated using eight machine-learning algorithms: CatBoost, Extra Trees, Random Forest (RANGER), XGBoost, Recursive Partitioning (RPART), k-Nearest Neighbors (KKNN), Neural Network (NNET), and Support Vector Machine (SVM). Subgroup and sensitivity analyses were conducted to test the robustness of the results across population subgroups and modeling choices. RESULTS: The analytic cohort comprised 2961 adults. Kaplan-Meier curves showed a graded, significant increase in cumulative CMM incidence across TyG‑FI quartiles (log‑rank P < 0.001). In multivariable Cox models, each unit increase in TyG‑FI was associated with a 1.80-fold higher CMM risk (HR = 1.80, 95% CI 1.57-2.05; P < 0.001); participants in the highest quartile had markedly elevated risk versus the lowest (Q4 vs. Q1 HR = 7.86, 95% CI 4.16-14.86). Restricted cubic spline analyses revealed significant non-linear relationships (P for non-linearity < 0.001), showing a J-shaped association between TyG-FI and CMM with threshold effects at TyG-FI ≈ 0.7 and cumulative TyG-FI ≈ 2.7. Subgroup analyses indicated stronger associations in participants < 60 years and in normotensive individuals. TyG-FI demonstrated better predictive performance for CMM than TyG index or FI alone, with improved C-statistic, Integrated Discrimination Improvement (IDI), and Net Reclassification Improvement (NRI). Among machine-learning models, RANGER performed best (AUC ≈ 0.81), and SHAP analysis identified cumulative and baseline TyG-FI as the primary predictors. Findings were robust in sensitivity analyses. CONCLUSIONS: TyG-FI exhibits non‑linear, threshold-defined associations with incident CMM and age‑dependent effect modification. Machine‑learning models incorporating TyG-FI show strong predictive performance. TyG-FI assessment may facilitate cost‑effective risk stratification for CMM and guide targeted prevention.
Joint association of atherogenic index of plasma and estimated glucose disposal rate with new-onset cardiovascular disease risk in individuals with cardiovascular-kidney-metabolic syndrome stages 0-3: a 9-year nationwide prospective cohort study.
Fan Y, Si Z, Wei M … +2 more , Gu Y, Li X
Cardiovasc Diabetol · 2026 May · PMID 42069607 · Full text
BACKGROUND: The atherogenic index of plasma (AIP) and estimated glucose disposal rate (eGDR) are two composite indices derived from routine metabolic measurements and are associated with cardiocerebrovascular disease ris...
BACKGROUND: The atherogenic index of plasma (AIP) and estimated glucose disposal rate (eGDR) are two composite indices derived from routine metabolic measurements and are associated with cardiocerebrovascular disease risk. In individuals with Cardiovascular-Kidney-Metabolic (CKM) syndrome stages 0-3, however, it remains unclear whether joint stratification by these markers helps summarize gradients of cardiovascular disease, heart disease, and stroke risk beyond single-marker assessment. METHODS: Using data from the China Health and Retirement Longitudinal Study (CHARLS), 5,925 participants without CVD at the start and in CKM stages 0-3 were analyzed. Participants were grouped by median AIP and/or eGDR values. Kaplan-Meier curves and Cox models assessed the link between these indicators and new CVD, heart disease, and stroke cases. Furthermore, both multiplicative and additive interactions between AIP and eGDR were assessed. The predictive value was assessed using the time-dependent Harrell's C index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI). RESULTS: A cohort of 5,925 participants aged 45 years and older (mean age: 57.92 ± 8.52 years) was analyzed, with 54.65% of the cohort being female. During the nine-year follow-up period, 1,467 (24.76%) participants developed incident CVD, including 1,106 (18.67%) with heart disease and 525 (8.86%) with stroke. The high AIP and low eGDR group had the highest risk, with CVD hazard ratios (HRs) of 1.35 (95% CI 1.14-1.59), heart disease HRs of 1.32 (95% CI 1.08-1.62), and stroke HRs of 1.59 (95% CI 1.19-2.12), using the low AIP and high eGDR group as the reference. Neither multiplicative nor additive interaction was statistically significant. The combined application of AIP and eGDR provided a modest improvement in predictive capability for cardiovascular disease, heart disease, and stroke. CONCLUSION: In individuals with CKM stages 0-3, combined AIP and eGDR stratification captured gradients of cardiovascular risk. The combined application of these indicators may provide modest incremental value for risk stratification within CKM stages, thereby aiding in the identification of high-risk individuals during the early stages of CKM.
Metabolomic signatures of hepatic steatosis reveal heterogeneity in cardiometabolic risk and responses to lifestyle interventions in type 2 diabetes: a post hoc analysis.
Wu X, Ding Y, Shao F … +18 more , Cao Q, Jiang Y, Li X, Xu Y, Zhao Z, Xu M, Lu J, Wang T, Wang S, Lin H, Li J, Liu Y, Gao J, Ning G, Wang W, Wang B, Bi Y, Li M
Cardiovasc Diabetol · 2026 Apr · PMID 42057080 · Full text
BACKGROUND: Hepatic steatosis measured by imaging fails to capture the variation in cardiometabolic risk and intervention response, which may be better characterized by metabolomic profiles. We aimed to construct metabol...
BACKGROUND: Hepatic steatosis measured by imaging fails to capture the variation in cardiometabolic risk and intervention response, which may be better characterized by metabolomic profiles. We aimed to construct metabolomics-based indices to define this variation. METHODS: Using data from a three-arm lifestyle intervention randomized trial in adults with type 2 diabetes (T2D) and overweight/obesity, we constructed two novel indices from untargeted plasma metabolomics and MRI-measured liver fat: a metabolomics-based liver fat score (mliver fat), and the discordance between mliver fat and MRI-measured liver fat (Δliver fat). We examined their associations with cardiometabolic traits and intervention response. RESULTS: Both mliver fat and Δliver fat were associated with body composition, glucose indices, insulin sensitivity, and triglyceride, but only Δliver fat was independent of MRI-measured liver fat. Despite having comparable MRI-measured liver fat, compared with the participants with a high Δliver fat (mliver fat > MRI-measured liver fat), those with a low Δliver fat (mliver fat < MRI-measured liver fat) had a more favorable cardiometabolic profile and derived greater benefits and more sustained benefits from diet intervention, with more pronounced long-term improvements in weight, insulin sensitivity, and β-cell function. CONCLUSIONS: Among individuals with T2D, a metabolomics-based liver fat score, particularly the discordance between metabolomic and imaging assessments, identifies systemic metabolic heterogeneity and differential responsiveness to lifestyle interventions. Future research is warranted to evaluate its performance in improving risk stratification and personalizing lifestyle intervention. TRIAL REGISTRATION: NCT03839667.
Cardiovascular-kidney-metabolic syndrome: a comprehensive review of pathophysiology, epidemiology, diagnosis, and management.
Jankauskas SS, Komici K, Varzideh F … +6 more , Aversa LS, Kansakar U, D'Onghia ML, Pande S, Mone P, Santulli G
Cardiovasc Diabetol · 2026 Apr · PMID 42057054 · Full text
Cardiovascular-kidney-metabolic (CKM) syndrome is a multisystem condition integrating metabolic dysfunction, chronic kidney disease (CKD), and cardiovascular disease into a unified framework. CKM syndrome encompasses pro...
Cardiovascular-kidney-metabolic (CKM) syndrome is a multisystem condition integrating metabolic dysfunction, chronic kidney disease (CKD), and cardiovascular disease into a unified framework. CKM syndrome encompasses progressive metabolic derangements, renal injury, and cardiovascular remodeling, which interact to amplify morbidity and mortality. Lifestyle interventions (including structured weight loss, dietary modification, physical activity, and sleep optimization) form a cornerstone of prevention and management. Pharmacologic strategies targeting the renin-angiotensin-aldosterone system, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and lipid-lowering therapies provide additional multisystem benefits. In this comprehensive review, we systematically examine the most updated evidence on CKM syndrome, in terms of pathophysiology, epidemiology, clinical manifestations, diagnostic evaluation, and therapeutic strategies. We also highlight future research directions and precision medicine approaches.
Synergistic effects of insulin resistance and revascularization completeness on prognosis in patients with coronary artery calcification.
Lin Z, Song Y, Yuan S … +3 more , Li B, He J, Dou K
Cardiovasc Diabetol · 2026 Apr · PMID 42050529 · Full text
BACKGROUND: The association between percutaneous coronary intervention (PCI) outcomes for moderate-to-severe coronary artery calcification (MSCAC) lesions and long-term clinical outcomes in individuals with varying level...
BACKGROUND: The association between percutaneous coronary intervention (PCI) outcomes for moderate-to-severe coronary artery calcification (MSCAC) lesions and long-term clinical outcomes in individuals with varying levels of insulin resistance is not well-defined. This study aims to examine the relationship between MSCAC-PCI outcomes and long-term poor clinical outcomes in individuals with varying insulin resistance statuses. METHODS: This prospective cohort research comprised 4,087 patients who received MSCAC-PCI at Fuwai Hospital from January 2017 to December 2018. Patients were classified according to MSCAC-PCI outcomes: failure (device uncrossable or no change in lesion stenosis severity), suboptimal revascularization (meeting neither the criteria for optimal revascularization nor procedural failure), and optimal revascularization (post-PCI TIMI grade = 3 and residual stenosis < 30%). The insulin resistance status was assessed utilizing the triglyceride-glucose (TyG) index, and patients were classified based on baseline TyG tertiles (tertile 1 [T1]: <8.66; T2: 8.66–9.14; T3: ≥9.14). The primary outcome was the composite of cardiovascular (CV) death and target-vessel myocardial infarction (TVMI). RESULTS: During the median follow-up period of 3 years, 154 (3.77%) patients with primary outcomes were recorded. There were 267 instances of MSCAC-PCI failure, 274 instances of suboptimal revascularization, and 3546 instances of optimal revascularization. Patients who underwent optimal revascularization exhibited markedly reduced risks of CV death/TVMI (adjusted hazard ratio [aHR], 0.53; 95% confidence interval [CI], 0.32–0.87) in comparison to those experiencing MSCAC-PCI failure. No significant difference was observed between patients who got suboptimal revascularization and those with MSCAC-PCI failure. Subgroup analysis indicated that patients in the TyG T3 subgroup have a diminished risk of CV death/TVMI (aHR, 0.45; 95% CI, 0.21–0.97) following optimal revascularization, mostly attributable to a decreased risk of CV death (aHR, 0.29; 95% CI, 0.10–0.78) after optimal revascularization. No substantial variations were observed in PCI outcomes between the TyG T1 and T2 subgroups of patients. CONCLUSIONS: Our findings suggest that optimal revascularization during PCI is associated with improved long-term clinical outcomes in patients with MSCAC, particularly in those with a high level of insulin resistance.
Obesity and insulin resistance trigger the early onset of adolescent-like sexually dimorphic metabotypes in middle childhood.
González-Domínguez Á, Domínguez-Riscart J, Savolainen O … +3 more , Lechuga-Sancho A, Landberg R, González-Domínguez R
Cardiovasc Diabetol · 2026 Apr · PMID 42046123 · Full text
BACKGROUND: The pathophysiology of obesity and insulin resistance are differentially affected by sexual dimorphisms along lifespan, being female children often at higher metabolic risk although presenting lower obesity r...
BACKGROUND: The pathophysiology of obesity and insulin resistance are differentially affected by sexual dimorphisms along lifespan, being female children often at higher metabolic risk although presenting lower obesity rates, whereas puberty induces a switch in their prevalence. However, scarce data is available in middle childhood, when crucial hormonal maturation processes begin. METHODS: In this study, we recruited a cohort of prepubertal children (6–12 years, Tanner I) of both sexes, comprising subjects with obesity and insulin resistance (N = 19 girls, 20 boys), children with obesity without insulin resistance (N = 10 girls, 12 boys), and healthy controls (N = 12 girls, 16 boys). Plasma and erythrocyte samples were collected for exhaustive clinical biochemistry assessment (insulin/glucose metabolism, inflammatory markers, hormonal profile) and state-of-the-art metabolomics. Then, sex-stratified multivariate and univariate statistical analyses were applied to decipher obesity- and insulin resistance-driven metabolic impairments separately in boys and girls. RESULTS: Surprisingly, we found boys to exhibit a more unfavorable metabolic profile, with exacerbated insulin resistance and raised inflammatory markers compared to girls, as expected for adolescents rather than prepubertal children. This was accompanied by a sexually dimorphic increase of steroid levels in children with obesity (i.e., androgens in boys, but also estrogens and progestogens in girls) compared to controls, as well as by male-specific alterations in metabolites associated with the pathophysiology of obesity and insulin resistance (e.g., carbohydrate, lipid, and protein metabolism, oxidative stress, phospholipid turnover). CONCLUSIONS: Altogether, we hypothesize that premature obesity-driven hormonal development may induce an adolescent-like metabotype in mid-aged children (i.e., protective estrogenic profile in girls vs. deleterious androgenic profile in boys), which could be responsible for sex differences in related metabolic complications.
Joint association of estimated glucose disposal rate and systemic inflammation response index with mortality in metabolic-dysfunction associated steatotic liver disease: evidence from two cohort studies.
Yang G, Qiu X, Shen S … +5 more , Li P, Feng Y, Zhang J, Su Z, Xiang B
Cardiovasc Diabetol · 2026 Apr · PMID 42046117 · Full text
BACKGROUND AND AIMS: Mortality in metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily driven by the synergy between insulin resistance (IR) and systemic inflammation. However, practical tools fo...
BACKGROUND AND AIMS: Mortality in metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily driven by the synergy between insulin resistance (IR) and systemic inflammation. However, practical tools for integrated risk assessment remain scarce. This study aimed to evaluate the individual and joint prognostic value of the estimated Glucose Disposal Rate (eGDR) and Systemic Inflammation Response Index (SIRI)-validated surrogates for IR and inflammatory status-to refine risk stratification and elucidate their reciprocal associations on MASLD survival. METHODS: This observational analysis included 7520 MASLD adults from the continuous National Health and Nutrition Examination Survey (NHANES) (1999-2018) and an independent external validation cohort of 1182 ultrasound-confirmed patients from NHANES III (1988-1994), with mortality linked through 2019. Multivariable Cox models and restricted cubic splines were employed to evaluate the associations between biomarkers and mortality. The combined model's predictive performance and clinical benefit were quantified via Receiver Operating Characteristic curves, Net Reclassification Improvement (NRI), Integrated Discrimination Improvement (IDI), and Decision Curve Analysis. Furthermore, exploratory bidirectional mediation analysis was conducted to assess the potential statistical interplay between the two markers. RESULTS: Over a median follow-up of 138 months, 1375 all-cause and 442 cardiovascular deaths occurred. Lower eGDR and higher SIRI were independently and linearly associated with increased mortality. A low eGDR/high SIRI phenotype was identified as the highest-risk category, exhibiting a 1.860-fold risk of all-cause mortality (95% CI 1.439-2.405) and a 2.395-fold risk of cardiovascular mortality (95% CI 1.379-4.159). The combined model demonstrated superior predictive accuracy (Area Under the Curve (AUC) 0.686-0.848) and significant reclassification improvement (NRI 0.161; IDI 0.017), and higher clinical net benefit than either indicator alone (p < 0.001). Furthermore, mediation analysis suggested that SIRI statistically accounted for 10.31% of the association between eGDR and all-cause mortality, highlighting a potential reciprocal statistical interplay. Crucially, this high-risk 'low eGDR/high SIRI' phenotype was successfully validated in the imaging-confirmed external cohort (ACM: HR = 2.354; CVM: HR = 3.153; both p < 0.001). CONCLUSIONS: Integrating eGDR and SIRI identifies a high-risk MASLD phenotype with the poorest prognosis, reflecting a synergistic metabolic-inflammatory burden. This joint assessment significantly improves predictive accuracy and offers superior net clinical benefits for long-term mortality prediction.
Changes in the estimated glucose disposal rate and cardiometabolic multimorbidity in middle-aged and older adults.
Cui C, Zhang T, Li J … +8 more , Shi F, Cao J, Zhao S, Liu H, Zhang Z, Liu Y, Liu L, Du J
Cardiovasc Diabetol · 2026 Apr · PMID 42046047 · Full text
BACKGROUND: Insulin resistance has been widely recognized as an independent risk factor for cardiovascular diseases and diabetes. The estimated glucose disposal rate (eGDR) is a well-established surrogate marker of insul...
BACKGROUND: Insulin resistance has been widely recognized as an independent risk factor for cardiovascular diseases and diabetes. The estimated glucose disposal rate (eGDR) is a well-established surrogate marker of insulin sensitivity; however, limited evidence exists regarding the dynamic changes of eGDR and their association with cardiometabolic multimorbidity. This study aimed to evaluate the associations of cumulative eGDR and eGDR change with the risk of cardiometabolic multimorbidity in middle-aged and older adults. METHODS: This prospective cohort study included 4059 participants from the China Health and Retirement Longitudinal Study (CHARLS) who were free of cardiovascular disease and diabetes at baseline. Groups of eGDR change were identified using K-means clustering method based on eGDR values at two time points. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident cardiometabolic multimorbidity. RESULTS: During a median follow-up of 9.0 years, 843 (20.8%) participants developed cardiometabolic multimorbidity. Compared with the highest quartile of cumulative eGDR, the lowest quartile was significantly associated with a 1.67-fold increased risk of cardiometabolic multimorbidity (HR: 1.67; 95% CI 1.34–2.08; P < 0.001) after adjusting for potential confounders. Four distinct eGDR change groups were identified: consistent high, consistent moderate, consistent low, and moderate-low. Compared with the consistent high group, the moderate-low group showed the highest risk of cardiometabolic multimorbidity (HR: 1.64; 95% CI 1.30–2.06; P < 0.001), followed by consistent low group (HR: 1.62; 95% CI 1.32–1.99; P < 0.001) and consistent moderate group (HR: 1.26; 95% CI 1.04–1.53; P = 0.017). CONCLUSIONS: Cumulative eGDR and eGDR change were independently associated with increased risk of cardiometabolic multimorbidity in middle-aged and older adults. These findings highlight the importance of monitoring longitudinal eGDR change for early identification of individuals at high risk of cardiometabolic multimorbidity.
LDL-C combined with Chinese visceral adiposity index as a risk stratification tool for cardiometabolic multimorbidity in middle-aged and older Chinese adults: a national prospective cohort study.
Shao X, Yu T, Luo L … +3 more , Zheng H, Yang F, Dong J
Cardiovasc Diabetol · 2026 Apr · PMID 42036685 · Full text
BACKGROUND: Cardiometabolic multimorbidity (CMM) poses a growing public health challenge, calling for better primary prevention strategies. While both elevated LDL-C and visceral adiposity (assessed by Chinese visceral a...
BACKGROUND: Cardiometabolic multimorbidity (CMM) poses a growing public health challenge, calling for better primary prevention strategies. While both elevated LDL-C and visceral adiposity (assessed by Chinese visceral adiposity index (CVAI)) are established risk factors, their combined utility for risk stratification is unclear. METHODS: This prospective analysis included 8813 CMM-free adults from the China Health and Retirement Longitudinal Study (CHARLS). We proposed a novel integrated metric, the Visceral Lipoprotein Risk (VLR) index, defined as CVAI × LDL-C (mg/dL). Its association with incident CMM was evaluated using Cox regression, Kaplan-Meier analysis, and restricted cubic spline (RCS). The incremental predictive value of VLR was assessed via receiver operating characteristic (ROC) analysis, with robustness examined through sensitivity analyses. Mediation analysis explored underlying pathways. RESULTS: Over a median follow-up of 9 years, 729 (8.27%) participants developed CMM. After multivariable adjustment, each standard deviation (SD) increase in VLR was associated with an 31% higher risk of CMM (HR: 1.31, 95%CI 1.24–1.39). Participants in the highest VLR quartile had a 3.12-fold increased risk (95%CI 2.39–4.08) compared to the lowest quartile. Kaplan-Meier curves (log-rank P < 0.001) and RCS models confirmed a strong, positive, and non-linear dose-response relationship. The VLR index demonstrated good discriminative ability (AUC: 0.78). Subgroup analyses revealed effect heterogeneity, which mediation analysis attributed to distinct underlying pathways: while Triglyceride-Glucose Index (TyG) and Atherogenic Index of Plasma (AIP) were key mediators in the overall population, white blood cell (WBC) count emerged as a significant but minor mediator (proportion mediated 3.17%) in individuals free of any baseline cardiometabolic disease (CMD), whereas HbA1c remained the predominant mediator in the obese subgroup. CONCLUSIONS: The VLR index, its non-linear association and mediation mechanisms underscore biological plausibility and utility for refined risk stratification, offering a practical tool for early identification and targeted primary prevention in middle-aged and older adults.
Metabolic status modifies the predictive value of the C-reactive protein-triglyceride-glucose Index-waist-to-height ratio for major adverse cardiovascular and cerebrovascular events: a prospective cohort study from the China Health and Retirement Longitudinal Study (CHARLS).
Li X, Meng Y, Zhang L … +2 more , Li T, Yan G
Cardiovasc Diabetol · 2026 Apr · PMID 42036684 · Full text
BACKGROUND: The C-reactive protein–triglyceride–glucose index combined with the waist-to-height ratio (CTI-WHtR) is a novel composite biomarker integrating inflammation, insulin resistance, and central obesity. Whether i...
BACKGROUND: The C-reactive protein–triglyceride–glucose index combined with the waist-to-height ratio (CTI-WHtR) is a novel composite biomarker integrating inflammation, insulin resistance, and central obesity. Whether its predictive value for major adverse cardiovascular and cerebrovascular events (MACCE) varies across metabolic states remains unknown. METHODS: We included 6993 participants free of cardiovascular disease at baseline from the China Health and Retirement Longitudinal Study (CHARLS, 2011–2020), classified into normal glucose tolerance (NGT, n = 2916), prediabetes (n = 3106), and type 2 diabetes (T2D, n = 971). Stratified Cox regression, interaction testing, head-to-head comparison of eight metabolic indices, restricted cubic spline (RCS) analyses, and multiple sensitivity analyses including multiple imputation (MICE) were performed. RESULTS: Over a mean follow-up of 8.0 ± 2.0 years, 1467 MACCE events occurred. After full adjustment including BMI, each standard deviation increase in CTI-WHtR was significantly associated with MACCE in the NGT group (HR 1.26, 95% CI 1.11–1.43, P = 0.0003), but not in prediabetes (HR 1.04, P = 0.43) or T2D (HR 1.06, P = 0.49). Multiple imputation (N = 14,606) yielded a consistent but attenuated NGT estimate (pooled HR 1.13, 95% CI 1.04–1.24, P = 0.0068). Pairwise interaction testing provided suggestive evidence of effect modification (prediabetes vs. NGT P = 0.027). RCS analyses revealed a consistently linear dose–response in the NGT group (all P-non-linearity > 0.25) but a non-linear inverted-U shape in T2D (P-non-linearity = 0.017). In head-to-head comparisons, CTI-based indices achieved higher C-indices in the NGT group while TyG-based indices performed better in T2D, suggesting a potential “group-switching” pattern warranting confirmation in larger studies. CONCLUSIONS: The predictive value of CTI-WHtR for MACCE is modified by metabolic status (operationalized as glycemic status) in both magnitude and functional form. CTI-WHtR demonstrates a statistically significant, linear association with MACCE in normoglycemic individuals (complete-case HR 1.26; multiple imputation HR 1.13), while the dose–response transforms to an inverted-U shape in T2D. These exploratory findings suggest that metabolic status may merit consideration when interpreting metabolic index–cardiovascular risk associations, pending validation in larger, multi-ethnic cohorts (overall interaction likelihood ratio test [LRT] P = 0.057).
Emerging multidimensional biomarker system for cardiovascular-kidney-metabolic syndrome: from multi-omics integration to clinical artificial intelligence.
Li FH, Li YY, Zhang Y … +6 more , Yang L, Pan SK, Liu DW, Liu ZS, Gao ZX, Wu P
Cardiovasc Diabetol · 2026 Apr · PMID 42036643 · Full text
Cardiovascular-kidney-metabolic (CKM) syndrome is an emerging clinical entity that highlights the complex, bidirectional interplay among cardiovascular disease, chronic kidney disease, and metabolic disorders, representi...
Cardiovascular-kidney-metabolic (CKM) syndrome is an emerging clinical entity that highlights the complex, bidirectional interplay among cardiovascular disease, chronic kidney disease, and metabolic disorders, representing a substantial and growing global health burden. This conceptualization marks a paradigm shift from viewing these conditions in isolation to understanding them as an interconnected disease continuum. Traditional biomarkers face significant limitations in the early detection, risk stratification, and precise management of CKM, necessitating a transition towards an integrated framework that captures its multisystem nature. This review systematically outlines an emerging multidimensional biomarker system encompassing key pathological axes such as metabolism, immuno-inflammation, oxidative stress, and biological aging, offering refined risk assessment beyond conventional metrics. The development of this system is propelled by revolutionary platforms, including accessible sampling techniques (e.g., dried blood spots), advanced in vitro models (e.g., multi-organ-on-a-chip), and multi-omics technologies. These platforms not only facilitate a deeper dissection of the heterogeneous origins and inter-organ crosstalk in CKM but also accelerate the discovery and validation of novel biomarkers. Concurrently, artificial intelligence serves as a pivotal tool for clinical translation, effectively integrating high-dimensional data to transform complex molecular profiles into actionable clinical insights. By enabling the construction of dynamic risk prediction and decision-support systems, this review charts a pathway toward proactive, individualized, and precise prevention and management of CKM syndrome.
Moderate-intensity statin plus ezetimibe as an alternative to high-intensity statin therapy.
Albawa'neh AS, Ali BR
Cardiovasc Diabetol · 2026 Apr · PMID 42035099 · Full text
Abstract loading — click title to view on PubMed.
Cardiovascular outcome trials (CVOTs) in cardiorenal metabolic medicine: a decade of transformative progress (2016-2026).
Wen S, Wang C, Xu Z … +14 more , Chen L, He Y, Ren Y, Yuan Y, Li Y, Dong M, Gong M, Wang C, Li X, Xu D, Yuan X, Jin J, Li J, Zhou L
Cardiovasc Diabetol · 2026 Apr · PMID 42035095 · Full text
The decade from 2016 to 2026 has witnessed an extraordinary transformation in cardiometabolic medicine, propelled by the maturation of cardiovascular outcome trials (CVOTs). What began as regulatory requirements to estab...
The decade from 2016 to 2026 has witnessed an extraordinary transformation in cardiometabolic medicine, propelled by the maturation of cardiovascular outcome trials (CVOTs). What began as regulatory requirements to establish cardiovascular safety for novel glucose-lowering agents has evolved into a robust body of evidence demonstrating profound cardiorenal protective effects-often extending beyond diabetes itself. Landmark trials such as EMPA-REG OUTCOME, LEADER, SELECT, SURPASS-CVOT, and VESALIUS-CV have not only redefined therapeutic priorities but have also catalyzed a conceptual shift from glucocentric management to an integrated cardiorenal metabolic (CRM) framework. This narrative review traces the epidemiological imperatives driving this evolution, chronicles the historical trajectory of CVOTs, synthesizes key findings across major pharmacological classes, and reflects on emerging therapies and risk markers that are shaping the precision-medicine paradigm of 2026.
Comprehensive evaluation of the triglyceride glucose index (TyG) and body roundness index (BRI) on cardiovascular disease risk prediction: a 9-year prospective cohort study in Chinese middle-aged and older adults.
Gu M, Hu H, Gu D
Cardiovasc Diabetol · 2026 Apr · PMID 42032735 · Full text
BACKGROUND: Cardiovascular disease (CVD) remains a leading cause of mortality in China. The triglyceride-glucose (TyG) index and body roundness index (BRI)-have separately shown associations with CVD risk, but their inte...
BACKGROUND: Cardiovascular disease (CVD) remains a leading cause of mortality in China. The triglyceride-glucose (TyG) index and body roundness index (BRI)-have separately shown associations with CVD risk, but their interaction, as well as their combined effects and interplay with inflammatory markers remain unclear. METHODS: We conducted a prospective cohort study using data from the China Health and Retirement Longitudinal Study (CHARLS) from 2011 to 2020. A total of 7,853 participants without pre-existing CVD were included. We examined mediation, cross-lagged path, interaction and joint association analysis to explore the interrelationships between TyG and BRI on CVD. Cox proportional hazards models and restricted cubic spline analysis, receiver operating characteristic (ROC), and weighted quantile sum (WQS) were performed to further investigate the associations between TyG, BRI, and CVD. RESULTS: During a median follow-up of 9.0 years, 1,922 participants (24.48%) developed CVD. In fully adjusted models, baseline BRI mediated 40.14% of the association between baseline TyG and CVD risk, with an indirect effect HR of 1.053 (95% CI: 1.035-1.073). Follow-up BRI mediated 51.46% of the association between baseline TyG and CVD risk, with an indirect effect HR of 1.046 (95% CI: 1.028-1.068). Per standard deviation increase in baseline BRI led to an average increase of 0.12 standard deviation in follow-up TyG levels. A significant antagonistic interaction was observed, aligned with the finding that the combination of low TyG and high BRI presents the highest CVD risk. Additionally, WQS analysis highlights waist circumference (WC) as the most substantial contributor (weight = 0.523). Joint elevation of composite indexes (TyG-BRI and TyG + BRI) with hs-CRP further stratified CVD risk, with participants having elevated levels of all markers showing the highest risk. Composite indexes, particularly TyG + BRI, showed the highest CVD risk (HR: 1.773, 95% CI: 1.499-2.097), along with the limited discriminatory ability on CVD (AUC < 0.65). CONCLUSION: In conclusion, our study highlights the critical role of BRI as a mediator in the relationship between TyG and CVD risk. The findings indicate that both baseline and follow-up BRI significantly contribute to the pathway linking TyG to CVD, suggesting that individuals with higher BRI are at an increased risk. The antagonistic interaction underscores the complexity of metabolic risk factors in CVD development and emphasizes the need for a multifaceted approach in risk assessment and management. Future research should focus on elucidating the biological mechanisms underlying this interaction and exploring potential interventions that target body composition and metabolic health to mitigate CVD risk in high-risk populations.
Novel OGTT metrics do not provide incremental predictive value beyond conventional glycemic criteria for remission of prediabetes in individuals with impaired fasting glucose: results from the PREVIEW trial.
Zhu R, Guo J, Stratton G … +12 more , Macdonald IA, Handjieva-Darlenska T, Handjiev S, Navas-Carretero S, Poppitt SD, Silvestre MP, Fogelholm M, Adam T, Raben A, Martinez JA, Xie M, Brand-Miller J
Cardiovasc Diabetol · 2026 Apr · PMID 42021301 · Full text
BACKGROUND: While conventional metrics of glycemia (fasting and 2-h glucose and HbA1c) define prediabetes and are associated with its progression, they do not capture the full heterogeneity of individual glucose metaboli...
BACKGROUND: While conventional metrics of glycemia (fasting and 2-h glucose and HbA1c) define prediabetes and are associated with its progression, they do not capture the full heterogeneity of individual glucose metabolism. We aimed to examine whether novel OGTT-derived metrics provide incremental predictive value beyond conventional metrics for prediabetes remission during long-term lifestyle intervention. METHODS: This post-hoc analysis used longitudinal data from PREVIEW, a 3-year, multinational, randomized trial, which assessed lifestyle interventions for diabetes prevention in adults with overweight/obesity and predominantly impaired fasting glucose (IFG). Participants underwent 8-week weight loss followed by 148-week lifestyle-based weight maintenance. Conventional metrics of glycemia included fasting and 2-h glucose and HbA1c. Novel OGTT metrics included 1-h glucose, time to glucose peak, maximum glucose excursion, peak glucose, area under the curve during OGTT, and curve shape. Outcomes were prediabetes remission at 1, 2, and 3 years. Restricted cubic spline analysis and modified Poisson regression models examined the associations of baseline conventional glycaemic and novel OGTT metrics with remission. Incremental predictive value of individual OGTT metrics was assessed using Likelihood ratio tests and optimism-adjusted area under the receiver operating characteristic curve (AUROC) and net reclassification improvement (NRI) via bootstrapping. RESULTS: 1187 participants (262 remitters and 925 non-remitters at 1 year) were included. There was a non-linear association between baseline fasting glucose and prediabetes remission at 1 year (P = 0.008), while inverse linear associations were observed at 2 and 3 years, independent of 2-h glucose and HbA1c. Higher baseline HbA1c, but not 2-h glucose, was associated with lower likelihood of remission at 1, 2, and 3 years, regardless of fasting and 2-h glucose. After adjustment for conventional metrics, there were no significant associations of baseline novel OGTT metrics with prediabetes remission. Incremental value analysis showed that adding individual novel OGTT metrics did not yield significant improvements in model fit or discrimination (P > 0.05 for Likelihood ratio tests and tests for ΔAUROC and NRI). CONCLUSION: In long-term lifestyle intervention among individuals who predominantly had IFG, individual novel OGTT metrics do not provide incremental predictive value for prediabetes remission beyond conventional metrics of glycemia. Trial registration Clinical trial reg. NCT01777893, clinicaltrials.gov.
GULP1 protects against diabetic cardiomyopathy through IKIP/NF-κB-dependent improvement of mitochondrial function.
Jiang MY, Zhang XH, Zhang HL … +15 more , Hou Y, Qi MY, Zuo YX, Sun C, Dai XC, Zhang NN, Chen TQ, Zhang Y, Man WR, Li CY, Lin J, Ge W, Yang LY, Qin X, Sun DD
Cardiovasc Diabetol · 2026 Apr · PMID 42015218 · Full text
BACKGROUND: Mitochondrial structural abnormalities and impaired energy metabolism are recognized hallmarks of diabetic cardiomyopathy (DCM). GULP1 (PTB-domain engulfment adapter protein 1, also known as CED-6) is a cytop...
BACKGROUND: Mitochondrial structural abnormalities and impaired energy metabolism are recognized hallmarks of diabetic cardiomyopathy (DCM). GULP1 (PTB-domain engulfment adapter protein 1, also known as CED-6) is a cytoplasmic adaptor protein containing a phosphotyrosine-binding domain. GULP1 has been implicated in metabolic disorders, particularly in type 2 diabetes. However, its potential involvement in cardiovascular homeostasis remains unclear. This study aimed to investigate whether GULP1 attenuates DCM by preserving mitochondrial architecture and bioenergetic function, and to explore the underlying molecular mechanisms. METHODS: Cardiac-specific Gulp1 knockout (Gulp1KO) and overexpressing (Gulp1KI) mice, along with their wild-type littermates (Gulp1f/f, Gulp1WT), were fed a high-fat diet for 6 months to induce DCM. Cardiac function was assessed by echocardiography and hemodynamic measurements. Cardiac mitochondrial structure and function were evaluated using electron microscopy, enzyme activity assays, ATP production and fatty acid oxidation. Primary ventricular myocytes derived from neonatal and adult mice were employed to delineate the molecular and signaling mechanisms underlying GULP1-mediated protection against palmitic acid (PA)-induced mitochondrial morphological alterations and dysfunction. RESULTS: GULP1 expression was markedly reduced in myocardial tissues from DCM patients and mouse models. Cardiac-specific GULP1 overexpression significantly attenuated cardiac dysfunction, alleviated mitochondrial structural disruption and respiratory impairment in diabetes, while reducing oxidative stress and cardiomyocyte apoptosis. Mechanistically, GULP1 directly interacted with IKIP (inhibitor of nuclear factor κB kinase-interacting protein) to alleviate IKIP-mediated inhibition of IKKβ-dependent NF-κB activation. This interaction enhanced NF-κB signaling, upregulated OPA1 (optic atrophy 1) expression and restored mitochondrial morphology, while improving fatty acid metabolism in DCM hearts. Consistently, GULP1 prevented PA-induced mitochondrial dysfunction, oxidative stress, and cardiomyocyte apoptosis in vitro through the IKIP/NF-κB/OPA1 signaling axis. CONCLUSIONS: The IKIP/NF-κB/OPA1 signaling axis constitutes an essential mechanism through which GULP1 preserves mitochondrial morphofunction, thereby translating into cardioprotection against diabetic cardiomyopathy. These results identify GULP1 as a compelling therapeutic target for DCM.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe