Plasma total bilirubin levels predict amputation events in type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

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Authors: Chan,K. H.;O’Connell,R. L.;Sullivan,D. R.;Hoffmann,L. S.;Rajamani,K.;Whiting,M.;Donoghoe,M. W.;Vanhala,M.;Hamer,A.;Yu,B.;Stocker,R.;Ng,M. K.;Keech,A. C.;FIELD Study Investigators

Publication: Diabetologia

Year: 2013

Volume: 56

Issue: 4

Start Page: 724

ABSTRACT:

AIMS/HYPOTHESIS: Bilirubin has antioxidant and anti-inflammatory activities. Previous studies demonstrated that higher bilirubin levels were associated with reduced prevalence of peripheral arterial disease (PAD). However, the relationship between bilirubin and lower-limb amputation, a consequence of PAD, is currently unknown. We hypothesised that, in patients with type 2 diabetes, bilirubin concentrations may inversely associate with lower-limb amputation.

METHODS: The relationship between baseline plasma total bilirubin levels and amputation events was analysed in 9,795 type 2 diabetic patients from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. The analysis plan was pre-specified. Lower-limb amputation was adjudicated blinded to treatment allocation. Relevant clinical and biochemical data were available for analyses. Amputation was a pre-specified tertiary endpoint.

RESULTS: Bilirubin concentrations were significantly inversely associated with lower-limb amputation, with a greater than threefold risk gradient across levels. Individuals with lower bilirubin concentrations had a higher risk for first amputation (HR 1.38 per 5 mumol/l decrease in bilirubin concentration, 95% CI 1.07, 1.79, p = 0.013). The same association persisted after adjustment for baseline variables, including age, height, smoking status, gamma-glutamyltransferase level, HbA1c, trial treatment allocation (placebo vs fenofibrate), as well as previous PAD, non-PAD cardiovascular disease, amputation or diabetic skin ulcer, neuropathy, nephropathy and diabetic retinopathy (HR 1.38 per 5 mumol/l decrease in bilirubin concentration, 95% CI 1.05, 1.81, p = 0.019).

CONCLUSIONS/INTERPRETATION: Our results identify a significant inverse relationship between bilirubin levels and total lower-limb amputation, driven by major amputation. Our data raise the hypothesis that bilirubin may protect against amputation in type 2 diabetes.

  • Author/s: Chan,K. H.;O'Connell,R. L.;Sullivan,D. R.;Hoffmann,L. S.;Rajamani,K.;Whiting,M.;Donoghoe,M. W.;Vanhala,M.;Hamer,A.;Yu,B.;Stocker,R.;Ng,M. K.;Keech,A. C.;FIELD Study Investigators
  • Publication: Diabetologia
  • Year: 2013
  • Volume: 56
  • Issue: 4
  • Start Page: 724
  • Article Keywords: Aged;Amputation;Antioxidants/pharmacology;Bilirubin/blood/metabolism;Biomarkers/metabolism;Cohort Studies;Diabetes Complications/diagnosis;Diabetes Mellitus, Type 2/blood/pathology;Female;Fenofibrate/therapeutic use;Humans;Lower Extremity/pathology;Male;Middle Aged;Predictive Value of Tests;Randomized Controlled Trials as Topic;Risk Factors;Sex Factors;Treatment Outcome