Serum total bilirubin levels predict amputation events in type 2 diabetic mellitus
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Authors: Chan,K. H.;Stocker,R.;Sullivan,D.;Rajamani,K.;Ng,M.;O’Connell,R.;Keech,A.
Objectives: Bilirubin is well known for its antioxidant and anti-inflammatory properties, and may protect against vascular disease. It has previously been demonstrated that higher serum bilirubin levels were associated with reduced peripheral arterial disease (PAD) prevalence. However, the relationship between bilirubin and lower limb amputation, a consequence of PAD, is currently unknown. We hypothesized that bilirubin protects against amputation events in type 2 diabetic patients with PAD.
Methods: The relationship between baseline serum total bilirubin level and amputation events was analyzed in 9795 type 2 diabetic patients from the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study in a pre-specified subsidiary analysis. Lower limb amputation was adjudicated blinded to treatment allocation. Relevant clinical and biochemical data were available for analyses. Bilirubin was analyzed continuously using Cox regression techniques.
Results: Serum bilirubin level was significantly inversely associated with lower limb amputation rate. When bilirubin was analyzed continuously, patients with lower bilirubin levels had an increased risk of amputation compared with patients with higher bilirubin levels (HR 1.38 per 5 Î¼mol/L decrease in bilirubin, 95% CI 1.07-1.79, p=0.013). The same association persisted after adjustment for baseline variables including age, sex, height, smoking status, alcohol intake, GGT, ALT, HbA1c, and history of hypertension, hypercholesterolemia, previous PAD, prior revascularization, amputation, ulcer, neuropathy, renal dysfunction and diabetic retinopathy (p=0.032), as well as treatment allocation (placebo vs. fenofibrate).
Conclusion: Our results identify a highly significant inverse relationship between serum bilirubin level and lower limb amputation rate. Our data is consistent with the hypothesis that bilirubin plays a protective role against amputation in the setting of type 2 diabetes.