Association of Appendicular Skeletal Muscle Mass Index and Insulin Resistance With Mortality in Multi‐Nationwide Cohorts

BACKGROUND: Although sarcopenia and insulin resistance are closely related, there is limited evidence regarding how they interact to influence mortality across different population groups. The purpose of this study was to examine the relationship between skeletal muscle mass and insulin resistance and its impact on mortality and cardiovascular disease risk using large-scale national data from Korea and the United States. METHODS: We analysed data from the National Health and Nutrition Examination Survey (NHANES) 1999-2006 and 2011-2018 and the Korea National Health and Nutrition Examination Survey (KNHANES) 2008-2011, with mortality follow-up through to 2019. Cox regression models were used to assess the effects of muscle mass (appendicular skeletal mass index, ASMI) and insulin resistance on all-cause and major adverse cardiovascular and cerebrovascular events (MACCE)-related mortality. Mediation analysis was performed to examine direct and indirect effects. RESULTS: The study included 8036 participants from NHANES and 14 449 from KNHANES. The sarcopenia group demonstrated a lower homeostasis model assessment for insulin resistance and better metabolic indices than the normal group despite having a higher mortality rate. Insulin resistance positively correlated with muscle mass (r = 0.203, p < 0.001 in the NHANES; r = 0.143, p < 0.001 in the KNHANES), and both insulin resistance and sarcopenia were identified as independent risk factors for all-cause and MACCE-related mortality. When the participants were categorized into four groups based on the presence or absence of insulin resistance and sarcopenia, those with both conditions exhibited the highest risk of all-cause mortality (hazard ratio [HR]: 2.30, 95% confidence interval [CI]: 1.72-3.08 in the NHANES; HR: 2.60, 95% CI: 2.14-3.16 in the KNHANES) and MACCE-related mortality among the groups (HR: 3.18, 95% CI: 1.99-5.08 in the NHANES; HR: 2.47, 95% CI: 1.66-3.69 in the KNHANES). Mediation analysis revealed that low muscle mass was associated with decreased insulin resistance but directly increased both all-cause mortality and MACCE-related mortality (NHANES: total natural direct effects [TNDE], HR: 2.08, 95% CI: 1.57-2.76; KNHANES: TNDE, HR: 1.69, 95% CI: 1.28-2.23). CONCLUSIONS: This study found that low ASMI was inversely associated with insulin resistance and positively associated with mortality risk in both cohorts. These findings, consistent across two large national studies, highlight the complex relationships between muscle mass, insulin sensitivity and mortality. Further studies are needed to assess the underlying mechanisms and clinical implications of these associations. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT05616013.