Plasma total bilirubin levels predict amputation events in type 2 diabetes mellitus

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

K. H. Chan*, R. L. O'Connell, D. R. Sullivan, L. S. Hoffmann, K. Rajamani, M. Whiting, M. W. Donoghoe, M. Vanhala, A. Hamer, B. Yu, R. Stocker, M. K C Ng, A. C. Keech

*Corresponding author for this work

Research output: Contribution to journalArticle

48 Citations (Scopus)

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 μmol/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, γ-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 μmol/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.

Original languageEnglish
Pages (from-to)724-736
Number of pages13
JournalDiabetologia
Volume56
Issue number4
DOIs
Publication statusPublished - Apr 2013
Externally publishedYes

Keywords

  • Amputation
  • Bilirubin
  • Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study
  • Peripheral arterial disease
  • Type 2 diabetes mellitus

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