title: Plasma total bilirubin levels predict amputation events in type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.
abstract: OBJECTIVE
  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
  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.
authors: Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. kimhoe_chan@yahoo.com.au
authors: K H
authors: KH
authors: Chan
authors: R L
authors: RL
authors: O'Connell
authors: D R
authors: DR
authors: Sullivan
authors: L S
authors: LS
authors: Hoffmann
authors: K
authors: K
authors: Rajamani
authors: M
authors: M
authors: Whiting
authors: M W
authors: MW
authors: Donoghoe
authors: M
authors: M
authors: Vanhala
authors: A
authors: A
authors: Hamer
authors: B
authors: B
authors: Yu
authors: R
authors: R
authors: Stocker
authors: M K C
authors: MK
authors: Ng
authors: A C
authors: AC
authors: Keech
mesh_terms: D000368:Aged; D000671:Amputation, Surgical; D000975:Antioxidants / Q000494:pharmacology; D001663:Bilirubin / Q000097:blood* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015331:Cohort Studies; D048909:Diabetes Complications / Q000175:diagnosis*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000473:pathology; D005260:Female; D011345:Fenofibrate / Q000627:therapeutic use*; D006801:Humans; D035002:Lower Extremity / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D012737:Sex Factors; D016896:Treatment Outcome
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D001663:Bilirubin; D011345:Fenofibrate