Association of Metabolic Vulnerability Index With Incident Type 2 Diabetes in General Population and All‐Cause Mortality in Patients With Diabetes: A Cohort Study Based on <scp>UK</scp> Biobank

BACKGROUND: Metabolic dysregulation plays a pivotal role in the pathogenesis of type 2 diabetes mellitus (T2DM). While the metabolic vulnerability index (MVX) captures multidimensional metabolic characteristics, its utility as a composite score and its specific association with incident T2DM risk and diabetes-related mortality outcomes require further validation in large-scale populations. METHODS: This study harnessed data from the UK Biobank (UKB), comprising a cohort of over 500 000 native UK residents recruited between 2006 and 2010. We conducted two independent analyses: incident T2DM in the general population and all-cause mortality in the baseline diabetes cohort. After excluding individuals with baseline diabetes and those missing MVX information, the analysis of incident T2DM included 453 209 participants; while the all-cause mortality analysis among diabetes cohort included 34 735 diabetic patients after excluding those with missing MVX information. Cox proportional hazards models were employed to evaluate the associations between MVX and outcomes. Subgroup analyses were performed by gender, age and BMI, and sensitivity analyses were conducted to assess the robustness of the findings. RESULTS: Each 1-standard deviation (SD) increase in MVX was associated with a 14% increased risk of incident T2DM (HR = 1.14, 95% CI: 1.11-1.16, p < 0.001). Participants in the highest quartile (Q4) showed a 32% higher risk compared to the lowest quartile (Q1) (HR = 1.32, 95% CI: 1.24-1.39, p = 0.004). Subgroup analyses indicated that the association was more pronounced in individuals with normal BMI, females, and those aged < 60 years. Specifically, each 1-SD increase in MVX was associated with a 24% increased risk of incident T2DM in the normal BMI group (HR = 1.24, 95% CI: 1.16-1.32, p < 0.001), a 17% increased risk in females (HR = 1.17, 95% CI: 1.14-1.20, p < 0.001) and an 18% increased risk in participants aged < 60 years (HR = 1.18, 95% CI: 1.14-1.22, p < 0.001). Regarding mortality, each 1-SD increase in MVX was associated with a 10% higher risk of all-cause mortality among participants with diabetes (HR = 1.10, 95% CI: 1.07-1.13, p < 0.001) and a 16% higher risk of cardiovascular disease (CVD) mortality (HR = 1.16, 95% CI: 1.06-1.26, p < 0.001). Moreover, subgroup analysis revealed an 18% increased risk of all-cause mortality in individuals with T1DM (HR = 1.18, 95% CI: 1.07-1.30, p < 0.001) and a 7% increased risk in those with T2DM (HR = 1.07, 95% CI: 1.04-1.10, p < 0.001). Sensitivity analyses corroborated the robustness of the associations between MVX and incident T2DM, as well as all-cause mortality in patients with diabetes. CONCLUSIONS: This study highlights the independent association between MVX and T2DM outcomes as well as diabetes-related mortality. The strength of MVX lies in capturing the risk of incident T2DM in individuals with normal BMI, younger populations and females, thereby serving as a valuable supplementary tool for clinical early screening and the identification of high-risk individuals missed by traditional indicators.