Associations of Multimarkers of Metabolic Malnutrition and Inflammation With All‐Cause Mortality and Their Interplay With Thyroid Function

ABSTRACT Introduction The metabolic vulnerability index (MVX)—a composite biomarker reflecting metabolic malnutrition and inflammation—has been linked to increased mortality risk in populations with cardiovascular disease. Thyroid function, a key regulator of metabolism and inflammation, may confound or modify this relationship, but evidence in the general population is limited. Objectives To evaluate the interplay between MVX and its subcomponents (inflammation vulnerability index, IVX and metabolic malnutrition index, MMX), thyroid function, and mortality risk in the general population. Methods In the PREVEND prospective study, which included 5446 participants (mean age 54 years; 49.9% male), both MVX (estimated using six metabolites measured simultaneously through nuclear magnetic resonance spectroscopy) and thyroid function (FT3, FT4, TSH) were evaluated at baseline. Hazard ratios (HRs) with 95% confidence intervals (CIs) for all‐cause mortality were estimated. Results During a median follow‐up of 14.1 years, 806 deaths were recorded. Spline analyses showed graded dose–response relationships of MVX, IVX and MMX with mortality risk. In separate analyses adjusted for several established risk factors, the HRs (95% CIs) of mortality were 1.28 (1.18–1.38), 1.23 (1.14–1.32) and 1.16 (1.07–1.25) per 1 standard deviation increment in MVX, IVX and MMX, respectively. The HRs remained consistent on further adjustment for FT3, FT4 and TSH. Sex as well as levels of FT3, FT4 and TSH did not significantly modify the associations. Conclusions The MVX and its subcomponents (IVX and MMX) are independently associated with all‐cause mortality, consistent with graded dose–response relationships. Thyroid function does not confound or modify these associations.