Cumulative metabolic burden linked to higher cardiometabolic risk in non-diabetic adults

In a prospective cohort study published in Cardiovascular Diabetology, researchers tracked 3,788 non-diabetic adults with cardiovascular-kidney-metabolic (CKM) syndrome stages 0–3, drawn from the China Health and Retirement Longitudinal Study (CHARLS). All participants were free of diabetes at both the 2011 baseline and a 2015 landmark assessment. Over a median follow-up of 5.0 years, 154 participants — 4.1 percent of the cohort — developed cardiometabolic multimorbidity (CMM).

The study’s central innovation was its head-to-head comparison of six cumulative metabolic indices, each calculated from repeated measurements taken in 2012 and 2015. Cumulative exposure scores integrate metabolic status over time, offering a time-integrated view of long-term metabolic burden as a complement to single baseline measurements. The indices compared included cumulative CHG, cumulative NHHR, cumulative TyG and cumulative eGDR, among others. The authors note that the comparative prognostic value of such indices for predicting incident CMM in people with CKM syndrome had remained unclear before this work.

After full statistical adjustment, higher cumulative CHG, NHHR and TyG were each independently associated with an increased risk of incident CMM. Comparing the highest with the lowest quartile, the hazard ratios were 3.21 (95% CI, 1.92–5.37) for cumulative CHG, 3.52 (95% CI, 2.05–6.05) for cumulative NHHR, and 3.18 (95% CI, 1.83–5.53) for cumulative TyG, all with P < 0.001. In contrast, higher cumulative eGDR was associated with a lower CMM risk, with a hazard ratio of 0.30 (95% CI, 0.15–0.58; P for trend < 0.001). Restricted cubic spline analyses found no evidence of nonlinearity for most indices, with the exception of cumulative TyG, where the P value for nonlinearity was 0.048.

The researchers also assessed whether any index improved prediction beyond a reference model, using 5-year area under the receiver operating characteristic curve (AUC) derived from Cox model-predicted risks, along with net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Cumulative CHG showed the largest numerical incremental discrimination, with a change in AUC of 0.040 (DeLong P = 0.037), a category-free NRI of 0.213, and an IDI of 0.017. However, the authors emphasize that no index demonstrated statistically significant superiority after multiple-comparison correction, and cumulative eGDR was inversely oriented in these analyses.

Beyond the metabolic indices themselves, the study examined joint associations with renal function. Participants with both high cumulative CHG and lower estimated glomerular filtration rate (eGFR) had the highest observed risk of incident CMM. The authors are careful to frame this as a descriptive joint association rather than a validated risk-stratification tool, and no statistically significant multiplicative interaction was observed between cumulative CHG and eGFR (P = 0.341). The associations remained consistent across subgroup analyses and multiple sensitivity analyses designed to test robustness.

The authors conclude that among non-diabetic adults with CKM stages 0–3, higher cumulative metabolic burden — particularly as captured by cumulative CHG — was independently associated with an increased risk of incident CMM, while cumulative eGDR exhibited an inverse association. They describe these as exploratory findings that support the potential value of longitudinal metabolic assessment in the early stages of CKM syndrome, but stress that external validation is required before any clinical implementation. The study was published as open access research on 27 October 2026, and the version shared at that date is subject to further edits ahead of the final Version of Record.

Subject of Research: Cumulative metabolic indices and their association with incident cardiometabolic multimorbidity in non-diabetic adults with CKM syndrome

Article Title: Head-to-head comparison of six cumulative metabolic indices and joint association with renal function for incident cardiometabolic multimorbidity in non-diabetic adults with CKM syndrome stages 0–3: a prospective cohort study

Article References: Li, M., Duan, H., Lou, T., Wang, N., Luo, C., Liu, M., Ma, X., Gong, S., & Shi, D. (2026). Head-to-head comparison of six cumulative metabolic indices and joint association with renal function for incident cardiometabolic multimorbidity in non-diabetic adults with CKM syndrome stages 0–3: a prospective cohort study. Cardiovascular Diabetology. https://doi.org/10.1186/s12933-026-03422-7

Image Credits: AI Generated

DOI: 10.1186/s12933-026-03422-7

Keywords: cardiometabolic multimorbidity, CKM syndrome, cumulative metabolic indices, cumulative CHG, TyG index, eGDR, eGFR, renal function, CHARLS, prospective cohort study, risk prediction, metabolic burden