medRxiv [Preprint]. 2026 Jun 22:2026.06.18.26356017. doi: 10.64898/2026.06.18.26356017.
ABSTRACT
BACKGROUND: Although diabetes is a potent risk factor for the development of peripheral artery disease (PAD), the effect of cumulative metabolic exposure to hyperglycemia on risk of cardiovascular or limb events in patients with PAD remains unclear.
METHODS: The Peripheral Artery Disease: Long-term Survival (PEARLS) is a longitudinal registry of Veterans with newly diagnosed PAD identified using a natural language processing approach. Included patients had ankle brachial index ≤0.9 or toe brachial index ≤0.7, and no history of lower extremity revascularization or major amputation. Among patients with diabetes in this cohort, we assessed cumulative exposure to hyperglycema based on a 24-month rolling average of hemoglobin (Hgb) A1c values, categorized as ≤7%, >7% to ≤8%, and >8%. Multivariable Cox regression models evaluated the association between categories of HgbA1c, modeled as a time-varying exposure, and risk of cardiovascular (CV: myocardial infarction or stroke) and limb (chronic limb threatening ischemia [CLTI] or major amputation) events.
RESULTS: Among 45,109 patients with new diagnosis of PAD and pre-existing diabetes, the mean HgbA1c at baseline was 7.5%, with nearly one-third (30.4%) having HgbA1c >8%. The mean age was 70.4 years, 19.8% were Black and 4% were Hispanic. Patients with baseline HgbA1c >8% were younger and compared to those with HgbA1c ≤7%, more likely to have coronary disease, kidney disease, and obesity. Over a median follow up of 4.2 years, 8,306 (18.4%) patients experienced a CV event, and 8,199 (18.2%) experienced a limb event. The adjusted association between HgbA1c and hazard of CV events was 12% higher in patients exposed to HgbA1c >7% to ≤8% (HR 1.12; 95%CI: 1.05-1.18) and 38% higher in those exposed to HgbA1c >8% (HR 1.38; 95%CI: 1.30-1.46), compared to HgbA1c <7%. The association with limb events was even stronger, with 20% and 60% higher hazard in those exposed to >7% to ≤8% (HR 1.20; 95%CI: 1.13-1.28) and HgbA1c >8% (HR 1.60; 95%CI: 1.51-1.70), respectively when compared to HgbA1c ≤7%. These findings were consistent in subgroups based on age and severity of PAD.
CONCLUSIONS: Among diabetic patients with PAD, cumulatiave metabolic exposure to hyperglycemia is associated with a markedly increased risk of clinical events, especially limb events.
CLINICAL PERSPECTIVE: What is new? (maximum 100 words, formatted as 2-3 bullets): Among > 45,000 patients with diabetes and new-onset PAD in a large, multi-center registry, we found a graded positive association between cumulative metabolic exposure to hyperglycemia and risk of cardiovascular (CV) and limb events.Poor glycemic control was more strongly associated with limb events than CV events, and this association was consistent in older patients and those with severe PAD.What are the clinical implications? (maximum 100 words, formatted as 2-3 bullets).: Patients with PAD have been underrepresented in previous trials evaluating the effect of intensive control of diabetes on CV outcomes.Given the remarkably high burden of CV and limb events in those with PAD and diabetes, our findings support the need for a randomized controlled trial to evaluate the role of glycemic control in mitigating vascular disease risk in this population.
PMID:42396336 | PMC:PMC13321114 | DOI:10.64898/2026.06.18.26356017