Associations of Multimarkers of Metabolic Malnutrition and Inflammation with All-Cause Mortality by Multimorbidity Status

<b>Background/Objectives</b>: The metabolic vulnerability index (MVX)-a composite biomarker reflecting metabolic malnutrition and inflammation-is associated with increased mortality risk, but its association across different levels of chronic disease burden has not been explored. We aimed to examine the associations of MVX and its subcomponents (Inflammation Vulnerability Index, IVX and Metabolic Malnutrition Index, MMX) with all-cause mortality according to multimorbidity status. <b>Methods</b>: In the PREVEND study, which included 6054 participants (mean age 54 years; 49.5% male), MVX was calculated using six plasma biomarkers measured simultaneously via nuclear magnetic resonance spectroscopy. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated. <b>Results</b>: During a median follow-up of 14.0 years, 911 deaths were recorded. In analyses adjusted for several established risk factors, the HRs (95% CIs) of mortality per 1 standard deviation increment in MVX were 1.32 (1.13-1.54; <i>p</i> < 0.001), 1.23 (1.08-1.40; <i>p</i> = 0.002), and 1.29 (1.16-1.43; <i>p</i> < 0.001) for individuals with no disease, one disease, and multimorbidity, respectively. The corresponding HRs (95% CIs) were 1.22 (1.05-1.42; <i>p</i> = 0.010), 1.17 (1.03-1.34; <i>p</i> = 0.015), and 1.25 (1.13-1.38; <i>p</i> < 0.001) for IVX and 1.29 (1.11-1.48; <i>p</i> = 0.001), 1.16 (1.02-1.31; <i>p</i> = 0.032), and 1.14 (1.03-1.25; <i>p</i> = 0.004) for MMX. The ratio of HRs showed no statistical evidence that sex modified the associations of MVX, IVX, and MMX with mortality in each multimorbidity category. However, the associations appeared stronger in males with chronic disease and in females without chronic conditions, suggesting possible sex-related trends. <b>Conclusions:</b> MVX, IVX, and MMX are independent risk indicators of all-cause mortality regardless of the burden of chronic disease, with MVX showing the strongest associations across different multimorbidity statuses. MMX should be interpreted as a proxy for metabolic malnutrition rather than a direct nutritional assessment tool.