Combined Insulin Resistance and Muscle Marker Score Flags Lower Cardiovascular Risk

A combination of two blood-based markers — estimated glucose disposal rate (eGDR), a surrogate for insulin resistance, and the normalized creatinine-to-cystatin C ratio (NCCR), a body-weight-adjusted index related to skeletal muscle mass — identified distinct levels of cardiovascular disease risk in a large cohort of middle-aged and older Chinese adults, according to a study published in Cardiovascular Diabetology.

Researchers analyzed 4,935 participants aged 45 and older from the China Health and Retirement Longitudinal Study who were free of cardiovascular disease at baseline in 2011. Participants had eGDR and NCCR values within the 1st to 99th percentile ranges and complete data on the fully adjusted model’s covariates. Incident cardiovascular disease was defined as the first self-reported heart disease or stroke through 2020, with the event time assigned to the survey year of the first positive report.

During a median follow-up of nine years, 1,235 incident cardiovascular events occurred. Using participants with both low eGDR and low NCCR as the reference group, those with high values of both markers had a fully adjusted hazard ratio of 0.629 (95% confidence interval 0.538–0.734), corresponding to roughly a 37% lower hazard of incident cardiovascular disease.

The association followed a graded pattern. Cardiovascular risk decreased progressively across participants with zero, one, and two high markers, with a trend that was statistically significant (P for trend < 0.001). According to the researchers, this suggests the two markers may be useful together for joint epidemiological risk characterization, even though a formal statistical interaction between them was absent.

The team also tested whether the markers improved prediction beyond an established clinical model. At nine years, the area under the receiver operating curve was 0.618 for the base model, 0.638 when eGDR was added, 0.623 when NCCR was added, and 0.638 when both were added. Adding NCCR to a model that already contained eGDR did not produce a discernible improvement in discrimination, indicating that the incremental predictive value of NCCR beyond eGDR alone was limited.

The methods included Cox regression, restricted cubic splines, joint-exposure analyses, prediction evaluation, subgroup analyses, and sensitivity analyses, with multiple imputation additionally conducted as a sensitivity analysis. These approaches allowed the investigators to examine the shape of the associations, the combined exposure categories, and the robustness of the findings to assumptions about missing data.

eGDR reflects insulin-resistance burden and has previously been associated with cardiovascular disease as a practical surrogate measure. NCCR is a creatinine-cystatin C and body-weight-based biomarker originally proposed as a biochemical correlate of body-weight-adjusted skeletal muscle mass; creatinine-to-cystatin C-based indices have been investigated as indirect blood-based correlates of muscle mass and function. The rationale for combining them was to link metabolic burden with a muscle-related marker in a single risk phenotype.

The authors note an important caveat about the muscle marker: NCCR showed substantial mathematical coupling with body weight in this cohort, which complicates its interpretation as a pure measure of muscle mass. They also emphasize that clinical use of the combined phenotype requires external validation before it could be considered beyond epidemiological risk characterization.

Several limitations frame the findings. The outcome relied on self-reported heart disease and stroke rather than adjudicated clinical diagnoses, and the analysis was restricted to participants with complete covariate data, a complete-case design of 4,935 adults. The study population consisted of middle-aged and elderly Chinese adults, so generalizability to other populations remains to be established.

Within those constraints, the study’s central result stands: adults with high eGDR and high NCCR experienced a substantially lower adjusted hazard of incident cardiovascular disease over nine years than those with low values of both markers, and risk declined stepwise as the number of high markers increased. The findings support using eGDR and NCCR jointly to characterize cardiovascular risk in epidemiological settings, while the modest gain in predictive discrimination suggests the combination adds most value as a risk phenotype rather than as a replacement for existing prediction models.

Subject of Research: Joint association of insulin resistance and muscle-related biomarkers with incident cardiovascular disease

Article Title: Joint association of estimated glucose disposal rate and normalized creatinine-to-cystatin C ratio with incident cardiovascular disease

Article References: Zhong, S., He, L., Xiao, L., Xie, X., Hu, X., Wang, X., Hu, Z., Zhang, Y., Zhang, X., & Huang, X. (2026). Joint association of estimated glucose disposal rate and normalized creatinine-to-cystatin C ratio with incident cardiovascular disease. Cardiovascular Diabetology. https://doi.org/10.1186/s12933-026-03402-x

Image Credits: AI Generated

DOI: 10.1186/s12933-026-03402-x

Keywords: estimated glucose disposal rate, normalized creatinine-to-cystatin C ratio, insulin resistance, cardiovascular disease, skeletal muscle mass, cohort study, risk prediction, China Health and Retirement Longitudinal Study, biomarkers, epidemiology, Joint, association