Combined metabolic-frailty index flags risk of advanced cardiovascular-kidney-metabolic progression

A composite measure that multiplies the triglyceride-glucose index by the frailty index has emerged as a potential early-warning signal for people whose cardiovascular-kidney-metabolic syndrome is still in its earliest stages. In a prospective cohort study drawing on the China Health and Retirement Longitudinal Study, or CHARLS, researchers followed 3,473 adults who were classified at CKM stages 0 to 2 when the study began and who underwent repeat exposure and outcome assessments at a later wave. The work, published in Cardiovascular Diabetology, examined whether a single combined value, its accumulated burden over time, and its trajectory between two measurement points could identify who would advance to the syndrome’s more severe stages.

The combined triglyceride-glucose and frailty index, abbreviated TyG-FI, was calculated by multiplying the TyG index, a marker of metabolic dysregulation, by the frailty index, which captures multisystem vulnerability through accumulated health deficits. The study design was structured around three distinct exposure definitions. Baseline TyG-FI was evaluated with Cox regression, while estimated cumulative TyG-FI, which combined the two measurements and the time interval between them, and two-wave patterns identified through K-means clustering were evaluated with logistic regression. Discrimination, internal K-fold cross-validation, and sensitivity analyses were also assessed.

By the follow-up assessment, 319 participants had met the criteria for CKM stage 4 and 975 had met the criteria for CKM stages 3 to 4. In fully adjusted models, each one-standard-deviation increase in baseline TyG-FI was associated with a hazard ratio of 1.33 for stage 4, with a 95 percent confidence interval of 1.20 to 1.47, and a hazard ratio of 1.10 for stages 3 to 4, with a 95 percent confidence interval of 1.03 to 1.18.

The cumulative exposure results were more pronounced. Each standard-deviation increase in estimated cumulative TyG-FI was associated with an odds ratio of 1.83 for stage 4, with a 95 percent confidence interval of 1.62 to 2.06, and an odds ratio of 1.42 for stages 3 to 4, with a 95 percent confidence interval of 1.29 to 1.56. When participants were grouped into tertiles of cumulative exposure, those in the highest tertile had an odds ratio of 12.40 for stage 4 compared with those in the lowest tertile, with a 95 percent confidence interval of 7.43 to 20.67, and an odds ratio of 2.38 for stages 3 to 4, with a 95 percent confidence interval of 1.86 to 3.04.

The trajectory analysis added a further dimension. K-means clustering of the two-wave TyG-FI values identified three distinct patterns, and participants in Class 3 had an odds ratio of 5.93 for stage 4, with a 95 percent confidence interval of 3.88 to 9.07, and an odds ratio of 2.30 for stages 3 to 4, with a 95 percent confidence interval of 1.67 to 3.17. This indicates that not only the level of the combined index but also its pattern across two consecutive measurements carried information about progression status at follow-up.

Spline analyses revealed that the associations were nonlinear. The predictive performance of baseline TyG-FI, measured by the area under the receiver operating characteristic curve, was 0.67 for stage 4 and 0.57 for stages 3 to 4, and the study reported that this performance was similar to that of the frailty index alone. These discrimination values indicate modest ability to separate those who progressed from those who did not, rather than the high accuracy needed for standalone clinical screening.

The authors concluded that higher baseline TyG-FI was associated with subsequent CKM progression, while cumulative TyG-FI and two-wave patterns were associated with progression status at follow-up. They suggested that TyG-FI may provide an accessible composite measure for identifying individuals with early CKM syndrome who are at increased risk of advanced-stage progression.

The study’s strengths include its prospective design, the use of repeat exposure measurements rather than a single baseline snapshot, and the inclusion of internal cross-validation and sensitivity analyses. The population was drawn from CHARLS, a longitudinal study of adults in China, and the findings therefore describe associations within that cohort. As an observational study, it establishes associations rather than causal effects, and the reported discrimination values indicate that the composite index is best understood as one component among several in assessing progression risk rather than a definitive standalone predictor.

The work sits within a growing body of research on combined metabolic-frailty measures in cardiovascular-kidney-metabolic syndrome. Related open-access articles published in the same journal have examined the combined effect of the triglyceride-glucose index and frailty index on advanced stages among CKM syndrome patients, nine triglyceride-glucose-frailty composite indices and incident cardiovascular disease across CKM syndrome stages 0 to 3, and the association between the triglyceride-glucose-frailty index and all-cause and cardiovascular mortality with the poverty-income ratio as a mediating factor. Together, these studies reflect increasing interest in whether simple composite indices can help stratify risk across the CKM spectrum, with the current study extending that question to the specific transition from the earliest syndrome stages to the most advanced ones.

Subject of Research: A prospective CHARLS cohort study of associations between the combined triglyceride-glucose and frailty index and progression to advanced cardiovascular-kidney-metabolic syndrome stages.

Article Title: Associations of baseline levels, cumulative exposure, and two-wave patterns of the combined triglyceride-glucose index and frailty index with progression from cardiovascular-kidney-metabolic syndrome stages 0–2 to stages 3–4 and stage 4: a prospective cohort study from CHARLS

Article References: Xiong, H., Lei, Y., Zhou, J., & Zou, J. (2026). Associations of baseline levels, cumulative exposure, and two-wave patterns of the combined triglyceride-glucose index and frailty index with progression from cardiovascular-kidney-metabolic syndrome stages 0–2 to stages 3–4 and stage 4: a prospective cohort study from CHARLS. Cardiovascular Diabetology, 25(1), Article 316. https://doi.org/10.1186/s12933-026-03411-w

Image Credits: AI Generated

DOI: 10.1186/s12933-026-03411-w

Keywords: TyG-FI, frailty index, triglyceride-glucose index, cardiovascular-kidney-metabolic syndrome, CHARLS, cohort study, CKM stage progression, cumulative exposure, K-means clustering, Cox regression, logistic regression, risk prediction