Background The associations of the triglyceride-glucose (TyG) index and its derived indices with the progression of cardiovascular-kidney-metabolic (CKM) syndrome remain poorly elucidated. Methods We conducted a systematic review and dose-response meta-analysis of 80 observational studies encompassing populations within CKM stages 0–3, evaluating TyG, TyG-BMI, TyG-WC, TyG-WHtR, and CTI for all-cause mortality, cardiovascular disease (CVD) mortality, and CVD incidence (including stroke, coronary heart disease, heart failure and major adverse cardiovascular events). A one-stage mixed-effects approach was used, supplemented by subgroup, meta-regression, leave-one-out, and trim-and-fill analyses. Results In both continuous (per 1-SD increment) and categorical (highest vs. lowest) analyses, TyG-derived indices generally demonstrated stronger risk associations with target outcomes than TyG alone. Notably, CTI, TyG-WC, and TyG-WHtR exhibited higher risk associations. In the highest-category analysis, TyG-WC yielded the most pronounced risk for CVD mortality (RR = 1.52, 95% CI: 1.35–1.70, 95% PI: 1.26–1.82). CTI was associated with a 57% increase in incident CVD (RR = 1.57, 95% CI: 1.33–1.85, 95% PI: 1.00–2.46). Conversely, TyG-BMI showed non-significant associations with mortality-related outcomes (P > 0.05), though it predicted a 51% risk increase for incident CVD (RR = 1.51, 95% CI: 1.36–1.67, 95% PI: 1.05–2.16). Subgroup analysis indicated that these positive associations were pronounced in CKM stages 1–3 but entirely non-significant in stage 0 and the obesity subgroup had a significant impact on the risk of mortality. Dose-response analyses revealed a significant non-linear U-shaped association of the TyG index with all-cause mortality (Pnon-linearity < 0.0001; nadir = 8.90). For CVD mortality, the overall association was significant (Poverall = 0.005; nadir = 8.91), whereas a monotonic increasing trend was observed for CVD incidence (Poverall = 0.0014). In sensitivity analyses excluding participants with cancer or consumptive diseases at baseline, as well as those in CKM stage 0, the U-shaped patterns remained stable (mortality nadir shifted to 9.1). Conclusions TyG-derived indices, particularly TyG-WC, TyG-WHtR, and CTI, show stronger risk associations than the TyG index for cardiovascular risk assessment in CKM populations, whereas the clinical utility of TyG-BMI is relatively limited. Moderate elevations in TyG were associated with lower mortality risk within a certain range, though the non-linear association was confirmed only for all-cause mortality. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251111362, identifier CRD420251111362.
J. An, Xue He, Qian-Ying Hao et al.· Frontiers in Endocrinology· 0 citations
Background It remains unclear whether cardiovascular-kidney-metabolic (CKM) syndrome and genetic susceptibility are associated with cancer incidence. This study aims to evaluate the associations between CKM health status, genetic susceptibility, and cancer incidence, and to develop a machine learning-based prediction model for cancer risk in patients with advanced CKM syndrome. Methods This study included 399,034 UK Biobank participants (389,289 with genetic data). CKM health was categorized into stages 0–4. Genetic susceptibility was assessed via a polygenic risk score (PRS). Associations were evaluated using Cox proportional hazard models. For participants with advanced CKM, candidate predictors were screened via the Boruta algorithm, LASSO regression, and multivariable logistic regression. Eight machine learning models were constructed and validated, and their predictive discrimination, calibration performance, and clinical practical value were further assessed. Additionally, Shapley Additive Explanations (SHAP) were adopted to interpret the internal mechanism of the optimal model. The dose–response relationship was assessed using restricted cubic splines (RCS), and mediation analysis was further performed to explore the underlying mechanism of the observed associations. Results During a median follow-up of 13.7 years, 48,247 incident cancer cases were identified. Compared to CKM stage 0, multivariable-adjusted hazard ratios (HRs) were 1.01 (95% CI: 0.91-1.12) for stage 1, 1.21 (1.10–1.33) for stage 2, and 2.17 (1.95–2.42) for advanced CKM (stage 3–4). Participants with high PRS and advanced CKM faced the highest cancer risk (HR 3.24, 95% CI 2.68–3.93). A total of 14 predictors were retained after screening. The GBM model achieved the best predictive performance (test AUC = 0.801). A web-based calculator was developed to realize individualized cancer risk prediction. RCS analyses indicated that diastolic blood pressure (Pnonlinearity<0.05), neutrophil count(Pnonlinearity<0.05), alkaline phosphatase (Pnonlinearity=0.001), and TyG-BMI (Pnonlinearity<0.05) were significantly and nonlinearly associated with cancer risk. Total bilirubin the strongest positive mediating effect, explaining 44.45% of the total association (P < 0.001). Conclusions Advanced CKM syndrome independently increases incident cancer risk, and this elevated risk is significantly amplified by high genetic susceptibility. The validated GBM model provides an interpretable tool for individualized risk estimation, which serves as a valuable complementary tool for clinical risk stratification and cancer patients with, cancer.
Xue He, J. An, Chun-Jia Yan et al.· Frontiers in Endocrinology· 0 citations
Background Cardiovascular-kidney-metabolic (CKM) syndrome spans stages 0–4, with stage 4 denoting clinical cardiovascular disease (CVD). While individuals in stages 0–3 face elevated incident CVD risk, how different durations of physical activity (PA) associate with this risk remains unclear. Methods This prospective UK Biobank cohort included 88,281 participants aged 37–73 in CKM syndrome stages 0–3, excluding those with baseline CVD. Overall and stage-specific analyzes were performed to evaluate the associations between PA and incident CVD risk. PA was categorized into light PA (LPA) and moderate-to-vigorous PA (MVPA), then divided into quartiles by weekly duration. Multivariable Cox models were used to estimate hazard ratios. An isochronous substitution model using component analysis was used to assess the associated risk differences of replacing LPA with MVPA. Results During a median follow-up of 7.29 years, 7,514 new CVD cases occurred among 88,281 individuals with CKM syndrome stages 0-3. LPA was associated with a lower CVD risk most markedly in stage 2 individuals, with the highest quartile showing a 18% lower risk versus the lowest (HR = 0.82; 95% CI 0.75-0.90). MVPA was associated with a lower CVD risk in stages 1 and 2, with the highest quartile associated with a 42% (HR = 0.58; 95% CI 0.50-0.66) and 33% (HR = 0.67; 95% CI 0.61-0.73) lower risk, respectively. Overall, LPA and MVPA exhibited nonlinear L-shaped relationships across stages 0–3, with overall inflection points at 2,357 (95% CI: 2335-2379) min/week for LPA and 213 (95% CI: 207-219) min/week for MVPA. Specifically, MVPA in stage 3 population exhibited a U-shaped CVD risk curve, increasing beyond 460 (95%CI: 449-472) min/week. In the general population at stages 0-3, when LPA exceeded 2,551 min/week, third-quartile MVPA was associated with a similarly lower risk as the fourth quartile. Substituting MVPA for LPA was associated with further lower risk in stages 1 and 2, while these inverse associations plateaued or declined after reaching 350 min/week in stage 0 and 300 min/week in stage 3, respectively. Conclusion Associations between physical activity and incident CVD differ across CKM stages 0–3. These stage-specific differences for LPA and MVPA warrant further validation to inform future guidelines.
J. An, Xue He, Jing-Yi Ding et al.· Frontiers in Endocrinology· 0 citations
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