Evidence from two large prospective cohorts: variations in remnant cholesterol inflammation index and the risk of cardiometabolic multimorbidity in middle-aged and elderly populations.
Jul 2026· Diabetes Research and Clinical Practice· Vol 239, pp.
113448
· 0 citations· 31 references
Medicine
TL;DR
By integrating lipid and inflammatory pathways, the RCII was significantly associated with incident CMM and may enhance early risk stratification and may enhance early risk stratification.
Abstract
Objective
While residual cholesterol (RC) and high-sensitivity C-reactive protein (hs-CRP) are independent risk factors for cardiometabolic multimorbidity (CMM), their combined predictive value remains unclear. We investigated the predictive utility of the remnant cholesterol inflammation index (RCII) for CMM incidence.
Methods
The RCII was derived from 5,870 participants in the China Health and Retirement Longitudinal Study (CHARLS) and 2,295 in the English Longitudinal Study of Ageing (ELSA), calculated as RC (mg/dL) × hs-CRP (mg/L) / 10. Longitudinal analyses in a subcohort (n = 5,966) further assessed the associations between cumulative RCII, changes in RCII and CMM incidence.
Results
Each ln-unit increase in baseline RCII was associated with a 14% (CHARLS: HR 1.14, 95% CI 1.09-1.19) and 21% (ELSA: HR 1.21, 95% CI 1.10-1.34) higher CMM risk. Similarly, cumulative RCII increments raised CMM risk by 20% (CHARLS: HR 1.20, 95% CI 1.11-1.29) and 30% (ELSA: HR 1.30, 95% CI 1.11-1.51). Transition patterns analysis showed that stable high RCII levels conferred the highest CMM risk compared to stable low RCII levels. RCII demonstrated moderate independent predictive capability for CMM and outperformed RC or hs-CRP alone.
Conclusion
By integrating lipid and inflammatory pathways, the RCII was significantly associated with incident CMM and may enhance early risk stratification.
Cardiometabolic multimorbidity (CMM) is an escalating public health challenge. The uric acid (UA)-to-high-density lipoprotein cholesterol (HDL-C) ratio (UHR) is a composite biomarker reflecting metabolic disturbance, but prospective evidence regarding the association between UHR and CMM remains limited. This prospective cohort study included 7435 adults aged ≥ 45 years from China Health and Retirement Longitudinal Study followed from 2011 to 2018. Cox proportional hazards models and restricted cubic spline analyses were used to examine the associations of UHR and cumulative UHR (CumUHR) with CMM. Receiver operating characteristic curves, net reclassification improvement, and integrated discrimination improvement were used to compare the incremental predictive performance of UHR and CumUHR with that of UA and HDL-C alone. Subgroup and sensitivity analyses were conducted to test the robustness of the findings. Among the 7435 participants, 1748 developed CMM. Kaplan–Meier analysis showed that the cumulative event rate of CMM increased progressively across UHR quartiles (log-rank + < .001). In the fully adjusted model, the highest UHR quartile (Q4) was associated with a significantly increased risk of CMM compared with the lowest quartile (Q1) (hazard ratio = 1.48, 95% confidence interval 1.27–1.77). When cumulative exposure was considered, elevated CumUHR remained an independent predictor of CMM (hazard ratio = 1.26, 95% confidence interval 1.15–1.39). Restricted cubic spline analyses further demonstrated significant nonlinear associations of both UHR and CumUHR with CMM risk, with inflection points observed around 8.5 for UHR and 35.7 for CumUHR. Furthermore, UHR and CumUHR showed better predictive performance for CMM than their individual components, with higher areas under the curve and significant improvements in net reclassification improvement and integrated discrimination improvement, whereas UA and HDL-C alone did not significantly improve these predictive indices. Higher UHR and CumUHR levels were independently associated with an increased risk of CMM in middle-aged and older adults. As composite indicators integrating UA and HDL-C, UHR and CumUHR may provide complementary information for cardiometabolic risk assessment and may help identify individuals at elevated risk of CMM when considered alongside established clinical risk factors.
Background Composite cardiometabolic and inflammatory indices can be calculated from routine anthropometric and laboratory measures, but their value for cardiovascular disease (CVD) risk assessment in Chinese populations remain unclear. Methods We analyzed 7,170 participants free of CVD at baseline from the China Health and Retirement Longitudinal Study (CHARLS) and the Shanghai Diabetes Study (SHDS). Mean follow-up was approximately 41 months in both cohorts. The evaluated indices included body mass index (BMI), Chinese visceral adiposity index (CVAI), lipid accumulation product (LAP), triglyceride-glucose index (TyG), atherogenic index of plasma (AIP), high-sensitivity C-reactive protein (hs-CRP), hs-CRP to high-density lipoprotein cholesterol ratio (hs-CRP/HDL-C), and hs-CRP-glucose index (CTI). Cox proportional hazards models were used to examine associations with incident CVD, with cohort interactions tested to assess cross-cohort consistency. Dose-response and nonlinearity were evaluated using quartile-based analyses and restricted cubic splines. Predictive performance and the added value of each index beyond a common clinical base model were evaluated in terms of clinical utility. Results During follow-up, 343 CVD events occurred in CHARLS and 148 occurred in SHDS. CVAI was the only index consistently associated with incident CVD across both cohorts and adjustment models. In the fully adjusted model, the HR per SD increase in CVAI was 1.221 (95% CI: 1.070–1.392, P = 0.003) in CHARLS, and 1.330 (95% CI: 1.067–1.656, P = 0.011) in SHDS. Other indices showed cohort-specific patterns: CTI, hs-CRP, and hs-CRP/HDL-C remained associated with CVD in CHARLS, whereas LAP remained associated across models in SHDS. Quartile-based and spline analyses generally supported approximately linear dose-response patterns. When added to the clinical base model, individual indices produced only modest changes in discrimination, and decision curve net benefit. Conclusions In two Chinese cohorts, CVAI showed the most reproducible association with short- to mid-term CVD risk, whereas other indices provided more cohort-specific signals. These indices may help describe cardiometabolic risk burden, but their incremental predictive value beyond conventional clinical factors was limited. Further studies with longer follow-up, verified outcomes, and more diverse populations are needed.
Tumalisi Julaiti, Qinghua Chen, Jun-Xi Lu et al.· Frontiers in Cardiovascular...· 0 citations
BACKGROUND
Frailty represents a critical geriatric syndrome characterized by increased vulnerability to stressors, underpinned by chronic inflammation and metabolic dysregulation. This study aimed to investigate the prospective association between baseline Remnant Cholesterol Inflammatory Index (RCII) and both baseline frailty and long-term progression trajectories in two large, ethnically diverse aging cohorts.
METHODS
This study utilized data from the China Health and Retirement Longitudinal Study (CHARLS; n = 8916) and the English Longitudinal Study of Aging (ELSA; n = 5732). RCII was calculated from baseline remnant cholesterol (RC) and high-sensitivity C-reactive protein (hs-CRP). Frailty was assessed using a 32-item frailty index (FI). Linear mixed-effect models were used to examine associations between RCII tertiles and FI trajectories.
RESULTS
In cross-sectional analyses, the highest RCII tertile was associated with a significantly increased baseline FI in both CHARLS and ELSA after full adjustment. In longitudinal analyses, results for RC alone indicated that while high levels were associated with consistently elevated frailty, they were not consistently associated with an accelerated rate of progression, characterized by parallel trajectories. A significant interaction between the highest RCII tertile and time was observed in CHARLS (β = 0.197, 95% CI: 0.060 to 0.335, P = 0.020) and ELSA (β = 0.055, 95% CI: 0.042 to 0.069, P < 0.001).
CONCLUSION
Higher baseline RCII is consistently associated with both greater baseline frailty and is also associated with steeper frailty trajectories in older adults. These findings suggest that RCII may serve as a valuable biomarker to identify older adults at high risk for functional decline.
Mengling Deng, Dejun Wu, Xiao-Qiang Mao et al.· Experimental Gerontology· 0 citations
The remnant cholesterol inflammation index (RCII) combines remnant cholesterol (RC) and high-sensitivity C-reactive protein (hs-CRP), two markers that may reflect residual lipid-related and inflammatory vascular burden. We examined whether baseline RCII was associated with incident stroke among hypertensive middle-aged and older adults and whether this association was nonlinear.
We analyzed 3,823 stroke-free hypertensive participants aged 45 years or older from the China Health and Retirement Longitudinal Study (CHARLS). Participants were excluded if they lacked follow-up information, were younger than 45 years, had missing or biologically implausible RCII components, had hs-CRP > 10 mg/L, or had missing covariates. RCII was analyzed per 1-standard deviation (SD) increase and by quartiles. Cox proportional hazards models, restricted cubic splines, an exploratory two-piecewise Cox model, subgroup analyses, and sensitivity analyses were performed.
During a median follow-up of 9.08 years (interquartile range, 9.08–9.17), 526 incident strokes occurred (13.8%). In the fully adjusted model, the original-scale linear estimate was positive but not statistically significant (HR per 1-SD increase, 1.06; 95% CI, 0.99–1.14;
P
= 0.110). Compared with Q1, adjusted HRs were 1.38 (95% CI, 1.06–1.81) for Q2, 1.66 (95% CI, 1.28–2.15) for Q3, and 1.60 (95% CI, 1.23–2.08) for Q4 (
P
for trend <0.001). Spline and threshold analyses suggested a nonlinear association, with a data-driven inflection point near RCII 3.80 and apparent flattening at higher values. Subgroup findings were broadly consistent, although current drinking status showed an exploratory interaction. Sensitivity analyses supported the robustness of the quartile-based associations.
Among hypertensive CHARLS participants, higher RCII categories were associated with incident stroke. The association was better characterized by categorical and nonlinear analyses than by a single original-scale linear estimate. RCII should be interpreted as an association marker, not as a validated predictive or clinical decision tool.
Siyi Jiang, Ying Cui, Lijun Song et al.· Frontiers in Cardiovascular...· 0 citations
Cardiometabolic multimorbidity (CMM) is increasingly common and carries substantial clinical and public-health burden. The cholesterol-high-density lipoprotein-glucose (CHG) index has been linked to adverse cardiometabolic outcomes, but prospective evidence comparing baseline and cumulative exposure and testing external reproducibility under design-appropriate survey methods remains limited.
We analyzed a baseline CHG cohort (
n
= 7,077) and a cumulative-CHG subcohort (
n
= 4,881) from the China Health and Retirement Longitudinal Study (CHARLS), and conducted a supportive external replication analysis in the National Health and Nutrition Examination Survey (NHANES; 1999–2018;
n
= 23,797). Cox models were used in CHARLS and fasting-subsample survey-weighted logistic models in NHANES. CHG and cumulative CHG were modeled per 1-standard deviation (SD) increment and by tertiles. Restricted cubic spline and threshold analyses characterized dose–response patterns. Sensitivity analyses included a stricter disease-free cumulative CHARLS cohort and additional hypertension adjustment in NHANES.
Higher baseline CHG in CHARLS was associated with greater incident CMM risk (adjusted hazard ratio [HR] per 1-SD increase, 1.55; 95% CI, 1.39–1.73); participants in the highest tertile had higher risk than those in the lowest tertile (adjusted HR, 2.93; 95% CI, 2.15–4.00). Associations were stronger for cumulative CHG (adjusted HR per 1-SD increase, 1.75; 95% CI, 1.61–1.89; adjusted HR for T3 vs. T1, 5.46; 95% CI, 3.91–7.63). In weighted NHANES analyses, CHG remained positively associated with prevalent CMM (adjusted odds ratio per 1-SD increase, 1.91; 95% CI, 1.75–2.08; adjusted OR for T3 vs. T1, 3.58; 95% CI, 2.73–4.69). Baseline CHG in CHARLS showed a significant overall association without clear nonlinearity, whereas cumulative CHG in CHARLS and CHG in NHANES showed significant nonlinear patterns. Sensitivity analyses were directionally consistent with the main findings.
Higher baseline and cumulative CHG were associated with greater incident CMM risk in the longitudinal CHARLS analyses, with larger effect estimates observed for cumulative CHG. A positive association was also observed between CHG and prevalent CMM in the cross-sectional NHANES analysis. These findings suggest that CHG, particularly its cumulative exposure, may serve as a potential marker of CMM risk and burden. However, further prospective validation is needed before CHG can be used for clinical risk prediction or to define decision thresholds.
Huilin Li, Yuxin Zhang, Fuxin Zha et al.· Lipids in Health and Disease· 0 citations
Cardiometabolic multimorbidity (CMM), defined as the coexistence of two or more cardiometabolic diseases, poses a growing global health burden. However, few studies have jointly evaluated the risk of CMM using indicators of both insulin resistance and frailty. Using data from the China Health and Retirement Longitudinal Study (CHARLS), we constructed a composite index integrating the metabolic score for insulin resistance (METS-IR) and the frailty index (FI) and investigated its association with incident CMM among 2,968 middle-aged and older Chinese adults. During the follow-up period, 230 participants (7.75%) developed CMM. In fully adjusted Cox regression models, each 1-SD increase in baseline and cumulative METSIR-FI was associated with a 35% (HR = 1.35, 95%CI: 1.22-1.49) and 45% (HR = 1.45, 95%CI: 1.31-1.61) higher risk of CMM, respectively. Participants in the highest tertile of baseline METSIR-FI had a significantly higher risk of CMM (HR = 2.78, 95%CI: 1.79-4.30), with even stronger associations observed for cumulative METSIR-FI (HR = 4.29, 95%CI: 2.63-6.98) and the highest-risk cluster (HR = 3.69, 95%CI: 2.46-5.55). Restricted cubic spline analyses revealed significant nonlinear dose-response relationships with threshold effects. Incorporating METSIR-FI into conventional risk models improved the C-statistic from 71.32% to 77.47%, with significant net reclassification improvement and integrated discrimination improvement. These findings suggest that a joint metabolic-frailty burden indicator provides incremental prognostic value beyond conventional risk factors and may serve as a practical composite indicator for CMM risk stratification among middle-aged and older adults.
Yang Peng, Bimin Zhu, Bi You et al.· Scientific Reports· 0 citations
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