Intensity of glycemic control and risk of cardiovascular and limb events in peripheral artery disease

Abstract Background Diabetes is a strong risk factor for the development of peripheral artery disease (PAD). The relationship between intensity of glycemic control and the risk of cardiovascular and limb events in patients with new onset PAD remains unknown. Methods Using data from the Veterans Affairs (VA) Peripheral Artery Disease: Long-term Survival Study (PEARLS) — a longitudinal registry of incident PAD, we identified 45,934 patients with diabetes on or before the date of PAD diagnosis (index), with at least one hemoglobin (Hgb) A1c value in the two years before index (baseline period), and at least one Hgb A1c value within 2 years after index but before first event. Using multivariable Cox proportional hazards regression, we examined the association between longitudinal glycemic control and risk of cardiovascular (CV: myocardial infarction, stroke) and limb (chronic limb threatening ischemia, major amputation) events over a 5-year follow-up. Outcomes were assessed in monthly increments and mean Hgb A1c in the preceding 24 months was modeled as a time-varying exposure. Patient demographics, smoking status, PAD severity and comorbidities were included as fixed effects and death was modeled as a competing risk. Results Mean age was 70.4 years, 97.8% were men and 19.8% were Black. The median number of Hgb A1c values per patient were 10 (IQR: 7-14). The mean Hgb A1c during the baseline period was 7.5% (SD: 1.5%). Compared to patients with Hgb A1c ≤7% during the baseline period, those in higher categories of Hgb A1c were younger, more likely to be Hispanic, have severe PAD and were current smokers (Table 1). Differences in co-morbidities across categories were statistically significant but small in magnitude (Table 1). Prescriptions for diabetes medications were more common in patients with higher Hgb A1c at baseline. Insulin and metformin were the most prescribed drugs, while SGLT-2 and GLP-1 were prescribed in 5% (Table 1). Over a 5-year follow-up, the incidence of CV events was 18.3% and limb events was 18.1%. In adjusted analysis, there was a strong graded association between follow-up Hgb A1c categories and clinical events. Compared with Hgb A1c ≤7%, the relative hazard of CV events was 44% higher and the relative hazard of limb events was 77% higher in patients with Hgb A1c 8% (P value 0.001 for both; Table 2). The above findings were consistent in a range of sensitivity analyses using alternative approaches to modeling Hgb A1c control. Conclusion Among diabetic patients with a new diagnosis of PAD, poor glycemic control was associated with increased risk of clinical events. Clinical trials are needed to determine whether improving glycemic control in PAD patients reduces the risk of clinical events, especially limb events.Table 1.Baseline Characteristics Table 2.Endpoints and Hazard Ratios