Association of Combined Cardiometabolic and Muscle Impairment Index with Cardiovascular-Kidney-Metabolic Syndrome Progression Among Middle-Aged and Older Adults: A Prospective Two-Cohort Study

Introduction: Advanced cardiovascular-kidney-metabolic (CKM) syndrome portends poor cardiovascular outcomes. The cardiometabolic index (CMI) and muscle-loss index (MLI) independently reflect metabolic and cardiovascular risk, but their combined effect on CKM syndrome remains unexplored. We aimed to evaluate the association of CMI-MLI with advanced CKM stages cross-sectionally and with incident CVD longitudinally, among adults aged 45 years and older. Methods: We analyzed data from adults aged ≥45 years in the CHARLS (2011–2020) and NHANES (1999–2004). The CMI-MLI index was calculated as the natural logarithm of CMI × MLI, where CMI = (triglycerides/HDL-cholesterol) × (waist/height) and MLI = cystatin C/creatinine. CKM syndrome was staged from 0 to 4 per metabolic, cardiovascular, and renal status, with Stage 3 defined by a high 10-year Framingham risk (≥21.6% in men, ≥21.5% in women) or advanced CKD. Logistic regression assessed the cross-sectional association of CMI-MLI with advanced CKM stages, with a sensitivity analysis defining Stage 3 solely by advanced CKD to address potential circularity; Cox regression evaluated its relationship with incident cardiovascular disease (CVD). Results: Among 6921 CHARLS and 3185 NHANES participants (the latter serving as a cross-sectional replication cohort), higher CMI-MLI quartiles were significantly associated with advanced CKM stages in both cohorts (p for trend <0.0001). Over a median 9-year follow-up of 5768 CHARLS participants with baseline CKM stages 0–3, 1384 incident CVD events occurred. Participants in the highest CMI-MLI quartile had a significantly higher risk of incident CVD (HR 1.35, 95% CI 1.15–1.59) than those in the lowest quartile, and each SD increase in CMI-MLI was independently associated with a higher CVD risk (HR 1.11, 95% CI 1.04–1.17). Conclusions: CMI-MLI was significantly associated with advanced CKM stages and independently predicted incident CVD among individuals free of baseline disease. The cross-sectional association was attenuated when Stage 3 was defined solely by advanced CKD, suggesting partial circularity between the CMI components and the risk score, whereas the prospective association with incident CVD was unaffected. Although its discriminatory ability was modest (area under the curve 0.605) and its incremental value over CMI alone was limited, CMI-MLI may serve as a simple, parsimonious marker for identifying individuals with concurrent cardiometabolic and muscle-related risk.