Abstract
BACKGROUND: Stress hyperglycemia ratio (SHR) has emerged as an innovative biomarker for stress-induced hyperglycemia and various disease prognosis, yet its relationship with mortality in patients with type 2 diabetes and obesity (termed as diabesity) remains unclear. Accelerated biological aging increases susceptibility to chronic diseases and death. This study sought to examine the association between SHR and mortality in type 2 diabetes and obesity, and also investigate the potential mediating effects of accelerated biological aging in this relationship. METHODS: We analyzed 4253 individuals with type 2 diabetes and obesity from National Health and Nutritional Examination Survey, with mortality outcomes ascertained through linkage to the National Death Index (NDI). Two accelerated biological aging (PhenoAgeAccel and KDMAgeAccel) were calculated using chronological age and blood biomarkers. The clinical endpoints encompassed all-cause mortality, cardiovascular disease (CVD) mortality, and cancer mortality. We visualized survival differences through Kaplan-Meier methodology. We employed multivariable Cox regression, restricted cubic spline (RCS) analysis, and general linear regression models to evaluate the relationships. Mediation analysis was performed to quantify the accelerated biological aging' contribution to the SHR-mortality link. Subgroup and sensitivity assessments were applied to verify the robustness of findings. RESULTS: Over a median follow-up period of 110.00 months (interquartile range, 40.00-152.00 months), we recorded 1139 all-cause deaths (26.78%), including 318 CVD deaths (7.48%), and 215 cancer death (5.06%). Kaplan-Meier curves showed higher SHR levels were associated with reduced survival (P < 0.001). After full adjustment for covariates, participants in the highest SHR tertile exhibited significantly elevated hazard ratios (HRs) compared to the reference tertile, with adjusted HRs of 1.32 for all-cause mortality, 1.38 for CVD mortality, and 1.61 for cancer mortality (all P < 0.001). RCS analysis revealed U-shaped relationships for all-cause and CVD mortality, while cancer mortality showed a linear positive correlation with SHR. Both two aging metrics exhibited linear relationships with the mortalities, with SHR positively correlated with KDMAgeAccel and PhenoAgeAccel (β = 5.00 and 1.15, respectively, both P < 0.01). Mediation analysis indicated KDMAgeAccel mediated 10.31%, 12.81%, and 3.65% of SHR's effects on all-cause, CVD, and cancer mortality, respectively (all P < 0.05), while PhenoAgeAccel showed the suppression effect of SHR on all-cause and CVD mortality, as well as exacerbated SHR's effect on cancer mortality. These findings remained consistent across all subgroup and sensitivity analyses. CONCLUSION: Both SHR and accelerated biological aging independently predict higher all-cause, CVD, and cancer mortality in patients with type 2 diabetes and obesity. Furthermore, KDMAgeAccel could significantly mediates these associations, while PhenoAgeAccel could potentially suppress the direct effect of SHR on all-cause and CVD mortality, and exacerbate SHR's direct effect on cancer mortality. Interventions targeting both stress hyperglycemia and aging-related pathways may reduce mortality risks in patients with type 2 diabetes and obesity.