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

Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia, .
Diabetologia (Impact Factor: 6.88). 01/2013; 56(4). DOI: 10.1007/s00125-012-2818-4
Source: PubMed

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, HbA(1c), 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.

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    • "Actually, ESRD patients presenting higher bilirubin levels showed also high hemoglobin concentration and hematocrit and erythrocyte counts, suggesting that the red cell mass and hemoglobin concentration are associated with interindividual variations of bilirubin, as previously reported in a healthy population [30] [34] and in individuals with Gilbert's syndrome [35]. High bilirubin levels may be associated also with a decrease in the inflammatory status [36]. Actually, moderate and elevated unconjugated bilirubin concentrations have been associated with a reduced inflammatory status, namely, with lower levels of IL-6 [34] [35]. "
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    ABSTRACT: We evaluated the potential cardiovascular risk protection of bilirubin in hemodialysis (HD) patients. An enlarged set of studies were evaluated in 191 HD patients, including hematological study, lipid profile, iron metabolism, nutritional, inflammatory markers, and dialysis adequacy. The TA duplication screening in the UDP-glucuronosyltransferase 1 A1 (UGT1A1) promoter region was also performed. The UGT1A1 genotype frequencies in HD patients were 49.2%, 42.4%, and 8.4% for 6/6, 6/7, and 7/7 genotypes, respectively. Although no difference was found in UGT1A1 genotype distribution between the three tertiles of bilirubin, significant differences were found with increasing bilirubin levels, namely, a decrease in platelet, leukocyte, and lymphocyte counts, transferrin, oxidized low-density lipoprotein (ox-LDL), ox-LDL/low-density lipoprotein cholesterol ratio, apolipoprotein (Apo) A, Apo B, and interleukin-6 serum levels and a significant increased concentration of hemoglobin, hematocrit, erythrocyte count, iron, transferrin saturation, Apo A/Apo B ratio, adiponectin, and paraoxonase 1 serum levels. After adjustment for age these results remained significant. Our data suggest that higher bilirubin levels are associated with beneficial effects in HD patients, by improving lipid profile and reducing the inflammatory grade, which might contribute to increase in iron availability. These results suggest a potential cardiovascular risk protection of bilirubin in HD patients.
    BioMed Research International 09/2014; 2014:175286. DOI:10.1155/2014/175286 · 2.71 Impact Factor
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    • "In a validation experiment (n ¼ 80), a strong correlation between total bilirubin and unconjugated bilirubin (Spearman's r ¼ 0.92, P < 0.001), as well as between total bilirubin and conjugated bilirubin (Spearman's r ¼ 0.82, P < 0.001) was observed [24]. In the present study we used total bilirubin, in agreement with other studies [10] [13] [14] [24]. Adiponectin and lipoproteins were measured in EDTAanticoagulated plasma. "
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    ABSTRACT: Objective: Bilirubin may protect against atherosclerotic cardiovascular disease (CVD). The heme oxygenase pathway is crucial for bilirubin generation, and is stimulated by adiponectin. We tested the relationship of plasma bilirubin with adiponectin, and determined whether the association of incident CVD with bilirubin is modified by adiponectin. Methods: A community-based prospective nested case control study (PREVEND cohort) was carried out in 87 non-diabetic men who developed a first cardiovascular event (cases) and 94 controls during a median follow-up of 6.1 (2.8-10.6) years. Results: In all subjects combined, bilirubin was positively related to adiponectin (r = 0.205, P = 0.006). Age-adjusted incident CVD was inversely associated with bilirubin (hazard ratio (HR): 0.80 (95% CI 0.65-0.99), P=0.048), independently of adiponectin (HR: 0.78 (95% CI 0.63-0.97), P=0.027). Adiponectin did not modify the association of CVD with bilirubin (interaction term: P=0.65). After additional adjustment for CVD risk factors, neither the association of incident CVD with bilirubin nor with adiponectin remained significant (P>0.20 for both), and there was again no interaction between bilirubin and adiponectin on CVD risk (P=0.67). Conclusion: Bilirubin is related to adiponectin, but the association of bilirubin with CVD risk is largely unaffected by adiponectin.
    Atherosclerosis 06/2014; 235(2):380-383. DOI:10.1016/j.atherosclerosis.2014.05.938 · 3.97 Impact Factor
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    ABSTRACT: A study by Chan et al in this issue of Diabetologia (DOI: 10.1007/s00125-012-2818-4 ) reports that low plasma bilirubin levels are associated with an increased risk of amputation in patients with type 2 diabetes mellitus participating in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. These findings raise the interesting and clinically relevant hypothesis that bilirubin protects against risk of amputation in patients with type 2 diabetes. This commentary considers some of the limitations associated with research aiming to define any link between circulating bilirubin levels and vascular disease. Numerous confounding factors (several of which may be present in patients with type 2 diabetes) may explain why the literature regarding this potentially protective role of bilirubin remains controversial.
    Diabetologia 01/2013; 56(4). DOI:10.1007/s00125-013-2840-1 · 6.88 Impact Factor
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