Age-Dependent Impact of Diabetes on Limb Events and Mortality in Patients with Peripheral Artery Disease

Abstract Background Peripheral artery disease (PAD) is associated with substantial risks of limb events and mortality. Although diabetes is a recognized risk factor for adverse outcomes in PAD, its prognostic impact across different ages at PAD onset remains unclear. Methods In this retrospective population-based cohort study, adults with PAD were identified from Clalit Health Services, Israel (2000-2026). Patients were stratified by diabetes status and age at PAD diagnosis (35-50 vs. > 50 years). The primary outcome was major adverse limb events (MALE), defined as lower-extremity revascularization or major amputation. All-cause mortality was a secondary outcome. Multivariable Cox regression, interaction analyses, and propensity score overlap weighting were performed. Results Among 4,538 patients aged 35-50 years at PAD diagnosis, 1,902 (42%) had diabetes. During a median follow-up of 12.0 years, diabetes was independently associated with higher risks of MALE (aHR 1.44, 95% CI 1.03-2.01, p = 0.032) and mortality (aHR 1.41, 95% CI 1.18-1.70, p < 0.001). Diabetes was associated with increased MALE risk in both age groups, with no significant interaction by age (p-interaction=0.498). In contrast, the association between diabetes and mortality was significantly stronger in patients aged 35-50 years than in those aged >50 years (aHR 2.00, 95% CI 1.72-2.33 vs. 1.30, 95% CI 1.27-1.33, p-interaction<0.001). Excess mortality associated with diabetes emerged during longer-term follow-up. Conclusions Diabetes was associated with increased risks of MALE and mortality in PAD, with a stronger association with mortality among patients diagnosed before age 50. These findings identify diabetes as a marker of particularly high risk in premature PAD.