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Background In the Women’s Health Initiative (WHI) dietary modification (DM) randomised trial, the low-fat dietary intervention reduced deaths from breast cancer ( P  = 0.02). Extending these findings, secondary analysis examined dietary intervention influence on breast cancer mortality by metabolic syndrome (MS) components. Methods In total, 48,835 postmenopausal women with no prior breast cancer were randomised to a low-fat dietary intervention or comparison groups. Four MS components were determined at entry in 45,833 participants: (1) high waist circumference, (2) high blood pressure, (3) high cholesterol and (4) diabetes history. Forest plots of hazard ratios (HRs) were generated with P -values for interaction between randomisation groups and MS component score. Primary outcome was death from breast cancer by metabolic syndrome score. Results HRs and 95% confidence intervals (CI) for dietary intervention influence on death from breast cancer were with no MS components ( n  = 10,639), HR 1.09, 95% CI 0.63–1.87; with 1–2 MS components ( n  = 30,948), HR 0.80, 95% CI 0.62–1.02; with 3–4 MS components ( n  = 4,246), HR 0.31, 95% CI 0.14–0.69 (interaction P  = 0.01). Conclusions While postmenopausal women with 3–4 MS components were at higher risk of death from breast cancer, those randomised to a low-fat dietary intervention more likely had reduction in this risk. Registry ClinicalTrials.gov (NCT00000611).

Background Triglyceride-glucose (TyG) index has been determined to play a role in the onset of metabolic syndrome (MetS). Whether the TyG index and TyG with the combination of obesity indicators are associated with the clinical outcomes of the MetS population remains unknown. Method Participants were extracted from multiple cycles of the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2018 years. Three indicators were constructed including TyG index, TyG combining with waist circumference (TyG-WC), and TyG combining with waist-to-height ratio (TyG-WHtR). The MetS was defined according to the National Cholesterol Education Program (NCPE) Adult Treatment Panel III. Kaplan-Meier (KM) curves, restricted cubic splines (RCS), and the Cox proportional hazard model were used to evaluate the associations between TyG-related indices and mortality of the MetS population. The sensitive analyses were performed to check the robustness of the main findings. Results There were 10,734 participants with MetS included in this study, with 5,570 females and 5,164 males. The median age of the study population was 59 years old. The multivariate Cox regression analyses showed high levels of TyG-related indices were significantly associated with the all-cause mortality of MetS population [TyG index: adjusted hazard ratio (aHR): 1.36, 95%confidence interval (CI): 1.18–1.56, p  < 0.001; TyG-WHtR index: aHR = 1.29, 95%CI: 1.13–1.47, p  < 0.001]. Meanwhile, the TyG-WC and TyG-WHtR index were associated with cardiovascular mortality of the MetS population (TyG-WC: aHR = 1.45, 95%CI: 1.13–1.85, p  = 0.004; TyG-WHtR: aHR = 1.50 95%CI: 1.17–1.92, p  = 0.002). Three TyG-related indices showed consistent significant correlations with diabetes mortality (TyG: aHR = 4.06, 95%CI: 2.81–5.87, p  < 0.001; TyG-WC: aHR = 2.55, 95%CI: 1.82–3.58, p  < 0.001; TyG-WHtR: aHR = 2.53 95%CI: 1.81–3.54, p  < 0.001). The RCS curves showed a non-linear trend between TyG and TyG-WC indices with all-cause mortality (p for nonlinearity = 0.004 and 0.001, respectively). The sensitive analyses supported the positive correlations between TyG-related indices with mortality of the MetS population. Conclusion Our study highlights the clinical value of TyG-related indices in predicting the survival of the MetS population. TyG-related indices would be the surrogate biomarkers for the follow-up of the MetS population.

Background The prevalence of obesity-associated insulin resistance (IR) is increasing along with the increase in obesity rates. In this study, we compared the predictive utility of four alternative indexes of IR [triglyceride glucose index (TyG index), metabolic score for insulin resistance (METS-IR), the triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio and homeostatic model assessment of insulin resistance (HOMA-IR)] for all-cause mortality and cardiovascular mortality in the general population based on key variables screened by the Boruta algorithm. The aim was to find the best replacement index of IR. Methods In this study, 14,653 participants were screened from the National Health and Nutrition Examination Survey (2001–2018). And TyG index, METS-IR, TG/HDL-C and HOMA-IR were calculated separately for each participant according to the given formula. The predictive values of IR replacement indexes for all-cause mortality and cardiovascular mortality in the general population were assessed. Results Over a median follow-up period of 116 months, a total of 2085 (10.23%) all-cause deaths and 549 (2.61%) cardiovascular disease (CVD) related deaths were recorded. Multivariate Cox regression and restricted cubic splines analysis showed that among the four indexes, only METS-IR was significantly associated with both all-cause and CVD mortality, and both showed non-linear associations with an approximate “U-shape”. Specifically, baseline METS-IR lower than the inflection point (41.33) was negatively associated with mortality [hazard ratio (HR) 0.972, 95% CI 0.950–0.997 for all-cause mortality]. In contrast, baseline METS-IR higher than the inflection point (41.33) was positively associated with mortality (HR 1.019, 95% CI 1.011–1.026 for all-cause mortality and HR 1.028, 95% CI 1.014–1.043 for CVD mortality). We further stratified the METS-IR and showed that significant associations between METS-IR levels and all-cause and cardiovascular mortality were predominantly present in the nonelderly population aged < 65 years. Conclusions In conjunction with the results of the Boruta algorithm, METS-IR demonstrated a more significant association with all-cause and cardiovascular mortality in the U.S. population compared to the other three alternative IR indexes (TyG index, TG/HDL-C and HOMA-IR), particularly evident in individuals under 65 years old.

Background Cardiovascular-Kidney-Metabolic (CKM) syndrome typically commences with the interaction of insulin resistance (IR), excessive or dysfunctional obesity, and the consequent systemic inflammatory response and oxidative stress. The relationship between the triglyceride-glucose (TyG) index and TyG-related indices that may simply assess IR and obesity, as well as the mortality risk in the CKM syndrome population, remains ambiguous. Methods This study included 6,383 participants from the National Health and Nutrition Examination Survey (NHANES) 2009–2018. The TyG index, TyG-waist-to-height ratio (TyG-WHtR), TyG-waist circumference (TyG-WC), and TyG-body mass index (TyG-BMI) were developed. Cox proportional hazards models, smooth curve fitting, and two-stage Cox proportional hazards models were employed to examine the association of TyG and TyG-related indices with all-cause and cardiovascular mortality in the CKM syndrome population. Subgroup analyses and interaction tests were conducted to evaluate the risk within various demographics. Results In survey-weighted multifactorial regression analyses, a significant positive association existed between TyG, TyG-related indices, and both all-cause mortality and cardiovascular mortality, except for the TyG index, which did not demonstrate a significant link with all-cause mortality. Of these indices, the TyG-WC index exhibited the strongest correlation with all-cause mortality, with a hazard ratio (HR) of 1.50 and a 95% confidence interval (CI) of 1.18–1.92, followed by the TyG-WHtR index (HR: 1.45, 95%CI 1.13–1.85). The TyG-WHtR index demonstrated the strongest correlation with cardiovascular mortality (HR: 1.85, 95% CI 1.19–2.86), followed by the TyG-WC index(HR: 1.83, 95%CI 1.21–2.78). An L-shaped association was identified between TyG-WHtR, TyG-BMI, and all-cause mortality in CKM syndrome during the examination of nonlinear relationships (both P for log-likelihood ratio < 0.05). The TyG-WHtR, TyG-WC, and TyG-BMI indices exhibited a more pronounced correlation with all-cause mortality in those with CKM syndrome stages 1 and 3 (P value < 0.05, P for interaction < 0.05). Conclusion Our study emphasizes the association between TyG and TyG-related indices and mortality in individuals with CKM syndrome stages 0–3. Individuals with CKM syndrome stages 1 and 3 should be more vigilant to abnormal alterations in TyG-related indices.

The American Heart Association recently issued guidelines introducing the concept of cardiovascular-kidney-metabolic (CKM) syndrome to emphasize the importance of multidisciplinary approaches to prevention, risk stratification, and treatment for these diseases. This study assessed the prevalence of CKM syndrome stages and the mortality risk associated with its components in a large Asian cohort. We analyzed a retrospective cohort of 515,602 participants aged ≥20 years from a health screening program conducted between 1996 and 2017 in Taiwan. We assessed the associations of all-cause mortality, cardiovascular disease (CVD) mortality, and cause-specific mortality with CKM stages and its components-hypertension, diabetes mellitus, chronic kidney disease (CKD), metabolic syndrome, and hyperlipidemia. All participants were followed for a median of 16.5 years (interquartile range: 11.5, 21.2 years). Multivariate Cox proportional hazards models, adjusted for age, sex, educational level, smoking status, alcohol drinking status, and physical activity groups, were used to calculate hazard ratios (HRs). We used Chiang's life table method to estimate years of life lost due to each CKM component. Among all participants, 257,535 (49.9%) were female. The majority of participants (n = 368,578 participants, (71.5%)) met criteria for CKM syndrome, with prevalence rates of 19.5%, 46.3%, 1.9%, and 3.8% for stages 1, 2, 3, and 4, respectively. CKM syndrome was associated with higher risks of all-cause mortality (HR: 1.33; 95% confidence interval, CI: 1.28, 1.39), CVD mortality (HR: 2.81; 95% CI: 2.45, 3.22), and incident end-stage kidney disease (ESKD) (HR: 10.15; 95% CI: 7.54, 13.67). Each additional CKM component was associated with a 22% increase in the risk of all-cause mortality (HR: 1.22; 95% CI: 1.21, 1.23), a 37% increase in the risk of CVD mortality (HR: 1.37; 95% CI: 1.35, 1.40) compared with those without any CKM components. In addition, each additional component reduced average life expectancy by 3 years. The population-attributable fractions of CKM syndrome were 18.7% (95% CI: 15.8, 21.7) for all-cause mortality and 55.0% (95% CI: 49.0, 60.4) for CVD mortality. We estimated that failing to include CKD in CKM syndrome could result in the missed attribution of 11% of CVD deaths. The primary limitation is that our analysis relied on baseline measurements only, without accounting for longitudinal changes. In the large cohort study, the prevalence of CKM syndrome and its components were associated with risks of all-cause mortality, CVD mortality, and ESKD. These findings highlight the clinical need for integrated care within CKM health.

Abstract Objective This study examined the relationship between cystatin C (CysC) levels and all-cause, cardiovascular disease (CVD), and cancer mortality in US metabolic syndrome (MetS) patients. Methods The 1999-2002 National Health and Nutrition Examination Survey (NHANES) prospective cohort research included 1980 MetS participants. To assess CysC levels and all-cause, CVD, and cancer mortality, fitted curves, Kaplan-Meier survival curves, Cox regression analysis, and receiver operating characteristic curves were performed. Results During a mean follow-up of 15.3 ± 5.4 years, a total of 819 deaths occurred. The fitted and Kaplan-Meier survival curves revealed that greater CysC levels were linked to higher all-cause, CVD, and cancer mortality rates (P < .05). After adjusting for variables, CysC level was associated with all-cause, CVD, and cancer mortality at 1.63 (1.42-1.88), 1.53 (1.19-1.95), and 1.53 (1 ∼ 2.32), respectively (P < .05). Tertile models showed consistent results: high CysC Tertile participants showed higher risk of all-cause mortality (HR 1.87; 1.43-2.45), CVD mortality (HR 1.97, 1.15 ∼ 3.38), and cancer mortality (HR 1.72, 1.01 ∼ 2.91) compared to those in the lowest tertile (P < .05). Subgroup studies by sex and other characteristics confirmed the findings. CysC demonstrated the higher predictive efficacy across mortality outcomes, followed by eGFR, outperforming urea nitrogen, creatinine, uric acid, and C-reactive protein. CysC alone exhibited substantial predictive value for all-cause (AUC 0.773; P < .05) and CVD mortality (AUC 0.726; P < .05). Combining CysC with age enhanced predictive value for all-cause mortality to 0.861 and CVD mortality to 0.771 (P < .05). Conclusion MetS patients with elevated CysC levels have a higher risk of all-cause, CVD, and cancer death. CysC may predict MetS all-cause and CVD mortality.

Background Cardiovascular-Kidney-Metabolic (CKM) syndrome, as a new clinical concept, emphasizes the multifaceted interaction between metabolic disorders, chronic kidney disease (CKD), and cardiovascular disease (CVD). Some evidence suggests atherogenic index of plasma (AIP) is strongly linked to cardiovascular mortality. However, data on its association with mortality across CKM syndrome remain scarce. Our study aimed to investigate the association between AIP and all-cause and cardiovascular mortality among individuals with CKM syndrome. Methods This study included 15,703 participants with CKM syndrome from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. The AIP index is calculated as log10(triglycerides/high-density lipoprotein cholesterol [TG/HDL-C]). Mortality outcomes were determined by linking NHANES participants with the National Death Index (NDI), with follow-up data available through December 31, 2019. Kaplan–Meier (K–M) survival curves, Cox regression analysis, restricted cubic spline (RCS) and subgroups analysis were used to explore the relationship between AIP levels and mortality in individuals with CKM syndrome. Results Over a median follow-up of 7.67 years, a total of 1570 deaths were documented, including 344 cardiovascular deaths. Kaplan-Meier survival analysis demonstrated that the lowest all-cause and CVD mortality rates were observed in the lowest AIP tertile. Compared with individuals in the lowest AIP tertile, Cox analysis indicated that those in highest tertile were associated with a higher risk of all-cause and CVD mortality (HR = 1.19, 95% CI 1.08–1.31, P  < 0.001; HR = 1.38, 95% CI 1.22–1.57, P  < 0.001) after adjusting for covariates, respectively. As a continuous variable, AIP levels had an approximate positive linear dose-response relationship with all-cause and CVD mortality. Subgroup analysis revealed no significant interactions with the examined variables, except for gender. Conclusions This study demonstrated that elevated AIP levels in individuals with CKM syndrome are strongly linked to higher mortality risks, notably all-cause mortality in advanced stages and CVD mortality across both non-advanced and advanced stages. These findings further highlight the importance of AIP as a valuable risk biomarker, providing a simple and effective tool for identifying mortality risk in individuals with CKM syndrome. Graphical abstract

Background The American Heart Association (AHA) proposed the concept of cardiovascular–kidney–metabolic (CKM) syndrome, underscoring the interconnectedness of cardiovascular, renal, and metabolic diseases. The stress hyperglycemia ratio (SHR) represents an innovative indicator that quantifies blood glucose fluctuations in patients experiencing acute or subacute stress, correlating with detrimental clinical effects. Nevertheless, the prognostic significance of SHR within individuals diagnosed with CKM syndrome in stages 0 to 3, particularly with respect to all-cause or cardiovascular disease (CVD) mortality risks, has not been fully understood yet. Methods The current study analyzed data from 9647 participants with CKM syndrome, covering stages 0 to 3, based on the NHANES (National Health and Nutrition Examination Survey) collected from 2007 to 2018. In this study, the primary exposure variable was the SHR, computed as fasting plasma glucose divided by (1.59 * HbA1c − 2.59). The main endpoints of study were all-cause mortality as well as CVD mortality, with death registration data sourced through December 31, 2019. The CHARLS database (China Health and Retirement Longitudinal Study) was utilized as validation to enhance the reliability of the findings. Results This study included 9647 NHANES participants, who were followed for a median duration of 6.80 years. During this period, 630 all-cause mortality cases and 135 CVD-related deaths in total were recorded. After full adjustment for covariates, our results displayed a robust positive association of SHR with all-cause mortality (Hazard ratio [HR] = 1.09, 95% Confidence interval [CI] 1.04–1.13). However, the SHR exhibited no significant relationship with CVD mortality (HR = 1.00, 95% CI 0.91–1.11). The mediation analysis results suggested that the relationship between SHR and all-cause mortality risk is partially mediated by RDW, albumin, and RAR. Specifically, the mediating effects were − 17.0% (95% CI − 46.7%, − 8.7%), − 10.1% (95% CI − 23.9%, − 4.7%), and − 23.3% (95% CI − 49.0%, − 13.0%), respectively. Additionally, analyses of the CHARLS database indicated a significant positive correlation between SHR and all-cause mortality among individuals diagnosed with CKM across stages 0–3 during the follow-up period from 2011 to 2020. Conclusions An increased SHR value is positively associated with an elevated likelihood of all-cause mortality within individuals diagnosed with CKM syndrome across stages 0–3, yet it shows no significant association with CVD mortality. SHR is an important tool for predicting long-term adverse outcomes in this population. Graphical abstract Research insights summary Cardiovascular–kidney–metabolic (CKM) syndrome emphasizes the interconnectedness of cardiovascular, kidney, and metabolic diseases. The stress hyperglycemia ratio (SHR) is a novel marker reflecting stress-induced glucose fluctuations, but its prognostic value in individuals with CKM syndrome (stages 0–3) remains uncertain. This study explores the association between SHR and all-cause and cardiovascular disease (CVD) mortality in this population. Our findings indicate that SHR is significantly associated with an increased risk of all-cause mortality (HR = 1.09, 95% CI 1.04–1.13), but not with CVD mortality (HR = 1.00, 95% CI: 0.91–1.11). Mediation analysis results suggested that the relationship between SHR and all-cause mortality risk is partially mediated by RDW, albumin, and RAR. Specifically, the mediating effects were − 17.0% (95% CI − 46.7%, − 8.7%), − 10.1% (95% CI − 23.9%, − 4.7%), and − 23.3% (95% CI − 49.0%, − 13.0%), respectively. Validation using the CHARLS database supports these findings. These results suggest that SHR could serve as a prognostic biomarker for long-term mortality risk in CKM patients, offering potential clinical utility in risk stratification and management.

Objective The American Heart Association (AHA) developed the notion of cardiovascular–kidney–metabolic (CKM) syndrome, which emphasizes the interconnection of heart, kidney, and metabolic illnesses. The C-reactive protein-triglyceride-glucose (CTI) represents a potential indicator to assess the resistance to insulin and an inflammatory response. However, the connection among CTI, cardiovascular disease (CVD) incidence, and overall mortality rates remains uncertain, particularly among individuals at CKM stages 0–3. Methods The China Health and Retirement Longitudinal Study (CHARLS) enrolled 17,705 middle-aged and elderly people. The primary outcome was the occurrence of CVD and overall mortality rates. The CTI was obtained by 0.412 * Ln (CRP [mg/L]) + Ln (TG [mg/dL] × FPG [mg/dL])/2. The correlation among CTI and CVD incidence and overall mortality was assessed via Cox proportional hazard models, Kaplan–Meier curves and restricted cubic spline (RCS) analysis. To improve the study results, a stratified analysis evaluated the influence of varying socio-demographic characteristics. Results This study involved 5723 participants for CVD and 5847 participants for all-cause mortality in the CKM syndrome stages 0–3. RCS analysis revealed a notable non-linear association between CTI and CVD occurrence, as well as a linear association between CTI and all-cause death. After comprehensive multivariate adjustment, the data showed a striking 111% increase in overall mortality risk for every 1-unit rise in continuous CTI measurements. Conclusions Findings show that higher CTI level significantly associated with CVD and death risk, highlighting its potential as a biomarker for individuals with CKM stages 0–3. Graphical abstract

Background Cardiovascular-kidney-metabolic (CKM) syndrome and systemic inflammation significantly contribute to mortality. However, the joint associations of CKM stages and systemic inflammation with all-cause and cardiovascular disease (CVD) mortality remain unclear. This study aimed to evaluate the independent and joint associations of CKM stages and systemic inflammation with all-cause and CVD mortality in a representative cohort of United States adults. Methods We analyzed data from 29,459 adults aged ≥ 20 years from the National Health and Nutrition Examination Survey (1999–2018). CKM stages were classified based on metabolic risk factors, CVD, and chronic kidney disease. Systemic inflammation was assessed using multiple indicators, and time-dependent ROC analysis identified the systemic inflammatory response index (SIRI) as the most effective inflammatory marker. The associations of CKM stages and SIRI with mortality were evaluated. Results Over a median follow-up of 109 months, 5,583 all-cause deaths and 1,843 CVD-specific deaths occurred. Both advanced CKM stages and elevated SIRI were associated with higher risks of all-cause and CVD mortality. Individuals with advanced CKM stages (Stages 3–4) and elevated SIRI (> 0.81) had the highest risks of all-cause (HR: 1.84, 95% CI: 1.65–2.05) and CVD mortality (HR: 2.50, 95% CI: 2.00–3.12). These associations were particularly pronounced in adults aged < 60 years ( P  for interaction < 0.001). Conclusions Advanced CKM stages and elevated SIRI are associated with increased risks of all-cause and CVD mortality, particularly in younger adults. These findings highlight the significance of targeted interventions to address systemic inflammation and CKM progression, potentially improving long-term outcomes in high-risk populations.