Bidirectional Mediation and Synergistic Mortality Risks in Diabetes and Cardiovascular Disease: Evidence From NHANES...

Diabetes mellitus (DM) and cardiovascular disease (CVD) are interconnected conditions that significantly contribute to global mortality, yet their bidirectional relationship and combined mortality impact remain underexplored.

Utilizing data from the NHANES 2005-2018 cohort (N = 24,934), we categorized participants aged ≥ 35 years into four groups: nondiabetic/non-pre-existing CVD, diabetic/non-pre-existing CVD, nondiabetic/pre-existing CVD, and diabetic/pre-existing CVD. Propensity score matching (PSM) and causal mediation analysis were employed to assess independent and synergistic mortality risks.

Over a mean follow-up of 7.37 years, diabetic/pre-existing CVD participants exhibited the highest mortality rates (61.37 all-cause and 23.88 cardiovascular deaths per 1000 person-years). Diabetes alone increased all-cause mortality by 34% (HR = 1.34, 95% CI = 1.22-1.47) and cardiovascular mortality by 32% (HR = 1.32, 1.10-1.58), while pre-existing CVD alone increased risks by 72% (HR = 1.72, 1.56-1.89) and 142% (HR = 2.42, 2.05-2.87), respectively. Comorbid diabetes/pre-existing CVD synergistically elevated all-cause mortality by 142% (HR = 2.42, 2.19-2.68) and cardiovascular mortality by 237% (HR = 3.37, 2.83-4.02). Although no statistically significant multiplicative interaction was observed, additive interaction metrics between diabetes and pre-existing CVD on mortality risks revealed a stronger synergistic effect on cardiovascular mortality (RERI = 0.64-1.17, AP = 12.01%-23.82%) than on all-cause mortality (RERI = 0.39-0.75, AP = 9.26%-18.73%). Mediation analysis demonstrated bidirectional effects: Diabetes mediated 6.82% of all-cause and 4.17% of cardiovascular mortality in pre-existing CVD patients, while pre-existing CVD mediated 5.47% and 7.87% in diabetic individuals.

Diabetes and pre-existing CVD independently and synergistically increase mortality risks, with additive interactions particularly pronounced for cardiovascular mortality. The bidirectional mediation effects highlight the need for integrated management strategies to mitigate the compounded mortality burden.