nach oben

Erschienen in:

01.04.2013 | Article

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

verfasst von: 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, on behalf of the FIELD study investigators

Erschienen in: Diabetologia | Ausgabe 4/2013

Einloggen, um Zugang zu erhalten

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.

Nur mit Berechtigung zugänglich

Gordois A, Scuffham P, Shearer A (2003) The health care cost of diabetic peripheral neuropathy in the US. Diabetes Care 26:1790–1795PubMedCrossRef

Tongers J, Roncalli J, Losordo D (2008) Therapeutic angiogenesis for critical limb ischemia: microvascular therapies coming of age. Circulation 118:9–16PubMedCrossRef

Rajamani K, Colman P, Li L et al (2009) Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet 373:1780–1788PubMedCrossRef

Ohnaka K, Kono S (2010) Bilirubin, cardiovascular diseases and cancer: epidemiological perspectives. Expert Rev Endocrinol Metab 5:891–904CrossRef

Breimer L, Mikhailidis D (2011) Is bilirubin a marker of vascular disease and/or cancer and is it a potential therapeutic target? Curr Pharm Des 17:3644–3655PubMedCrossRef

Lin J, Vitek L, Schwertner H (2010) Serum bilirubin and genes controlling bilirubin concentrations as biomarkers for cardiovascular disease. Clin Chem 56:1535–1543PubMedCrossRef

Stocker R, Perrella M (2006) Heme oxygenase-1: a novel drug target for atherosclerotic diseases? Circulation 114:2178–2189PubMedCrossRef

Chan K, Ng M, Stocker R (2011) Haem oxygenase-1 and cardiovascular disease: mechanisms and therapeutic potential. Clin Sci (Lond) 120:493–504CrossRef

Kawamura K, Ishikawa K, Wada Y et al (2005) Bilirubin from heme oxygenase-1 attenuates vascular endothelial activation and dysfunction. Arterioscler Thromb Vasc Biol 25:155–160PubMed

10.

Stocker R, Yamamoto Y, McDonagh A, Glazer A, Ames B (1987) Bilirubin is an antioxidant of possible physiological importance. Science 235:1043–1046PubMedCrossRef

11.

Stocker R, Glazer A, Ames B (1987) Antioxidant activity of albumin-bound bilirubin. Proc Natl Acad Sci USA 84:5918–5922PubMedCrossRef

12.

Inoguchi T, Sasaki S, Kobayashi K, Takayanagi R, Yamada T (2007) Relationship between Gilbert Syndrome and prevalence of vascular complications in patients with diabetes. JAMA 12:1398–1400

13.

Tapan S, Dogru T, Tasci I, Ercin C, Ozgurtas T, Erbil M (2009) Soluble CD40 ligand and soluble P-selectin levels in Gilbert’s syndrome: a link to protection against atherosclerosis? Clin Biochem 42:791–795PubMedCrossRef

14.

Vıtek L, Jirsa M, Brodanova M et al (2002) Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis 160:449–456PubMedCrossRef

15.

Abraham N, Kappas A (2008) Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev 60:79–127PubMedCrossRef

16.

Stocker R, Keaney JF (2004) Role of oxidative modifications in atherosclerosis. Physiol Rev 84:1381–1478PubMedCrossRef

17.

Breimer L, Spyropolous K, Winder A, Mikhailidis D, Hamilton G (1994) Is bilirubin protective against coronary artery disease? Clin Chem 40:1987–1988PubMed

18.

Rantner B, Kollerits B, Anderwald-Stadler M et al (2008) Association between the UGT1A1 TA-repeat polymorphism and bilirubin concentration in patients with intermittent claudication: results from the CAVASIC study. Clin Chem 54:851–857PubMedCrossRef

19.

Perlstein T, Pande R, Beckman J, Creager M (2008) Serum total bilirubin level and prevalent lower-extremity peripheral arterial disease: National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. Arterioscler Thromb Vasc Biol 28:166–172PubMedCrossRef

20.

Wang H, Han P, Zhang W et al (2012) Serum bilirubin level is negatively correlated with disease progression of peripheral arterial disease: an observational cohort study. Angiology 63:248–253PubMedCrossRef

21.

Johannesson A, Larsson G, Ramstrand N, Turkiewicz A, Wiréhn A, Atroshi I (2009) Incidence of lower-limb amputation in the diabetic and nondiabetic general population: a 10-year population-based cohort study of initial unilateral and contralateral amputations and reamputations. Diabetes Care 32:275–280PubMedCrossRef

22.

The FIELD Study Investigators (2005) Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366:1849–1861CrossRef

23.

Barrett-Connor E, Orchard T (1985) Diabetes and heart disease. In: National Diabetes Data Group. Diabetes in America: diabetes data compiled 1984. US Department of Health and Human Services, Washington, pp XVI, 1–41

24.

Nakayama K (1995) Differences between enzymatic and diazo methods for measuring direct bilirubin. Eur J Clin Chem Clin Biochem 33:513–517PubMed

25.

Selvin E, Erlinger T (2004) Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999–2000. Circulation 110:738–743PubMedCrossRef

26.

Pasta D (2009) Learning when to be discrete: continuous vs. categorical predictors. SAS Glob Forum Pap 248:1–10

27.

Djousse L, Levy D, Cupples L, Evans J, D’Agostino R, Ellison R (2001) Total serum bilirubin and risk of cardiovascular disease in the Framingham offspring study. Am J Cardiol 87:1196–1200PubMedCrossRef

28.

Ekblom K, Marklund S, Jansson J et al (2010) Plasma bilirubin and UGT1A1*28 are not protective factors against first-time myocardial infarction in a prospective, nested case-referent setting. Circ Cardiovasc Genet 3:340–347PubMedCrossRef

29.

Schwertner H, Jackson W, Tolan G (1994) Association of low serum concentration of bilirubin with increased risk of coronary artery disease. Clin Chem 40:18–23PubMed

30.

Breimer L, Wannamethee G, Ebrahim S, Shaper A (1995) Serum bilirubin and risk of ischemic heart disease in middle-aged British men. Clin Chem 41:1504–1508PubMed

31.

Hopkins P, Wu L, Hunt S, James B, Vincent M, Wiliams R (1996) Higher serum bilirubin is associated with decreased risk for early familial coronary artery disease. Arterioscler Thromb Vasc Biol 16:250–255PubMedCrossRef

32.

Madhavan M, Wattigney W, Srinivasan S, Berenson G (1997) Serum bilirubin distribution and its relation to cardiovascular risk in children and young adults. Atherosclerosis 131:107–113PubMedCrossRef

33.

Temme E, Zhang J, Schouten E, Kesteloot H (2001) Serum bilirubin and 10-year mortality risk in a Belgian population. Cancer Causes Control 12:887–894PubMedCrossRef

34.

Bosma P, van der Meer IM, Bakker C, Hofman A, Paul-Abrahamse M, Witteman J (2003) UGT1A1*28 allele and coronary heart disease: the Rotterdam Study. Clin Chem 49:1180–1181PubMedCrossRef

35.

Novotny L, Vıtek L (2003) Inverse relationship between serum bilirubin and atherosclerosis in men. A meta-analysis of published studies. Exp Biol Med 228:568–571

36.

Lin J, O’Donnell C, Schwaiger J et al (2006) Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease. Circulation 114:1476–1481PubMedCrossRef

37.

Troughton J, Woodside J, Young I et al (2007) Bilirubin and coronary heart disease risk in the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Eur J Cardiovasc Prev Rehabil 14:79–84PubMedCrossRef

38.

Chen Y, Chau L, Chen J, Lin S (2008) Serum bilirubin and ferritin levels link heme oxygenase-1 gene promoter polymorphism and susceptibility to coronary artery disease in diabetic patients. Diabetes Care 31:1615–1620PubMedCrossRef

39.

Kimm H, Yun J, Jo J, Jee S (2009) Low serum bilirubin level as an independent predictor of stroke incidence: a prospective study in Korean men and women. Stroke 40:3422–3427PubMedCrossRef

40.

Erdogan D, Gullu H, Yildirim E et al (2006) Low serum bilirubin levels are independently and inversely related to impaired flow-mediated vasodilation and increased carotid intima-media thickness in both men and women. Atherosclerosis 184:431–437PubMedCrossRef

41.

Vítek L, Novotny L, Sperl M, Holaj R, Spacil J (2006) The inverse association of elevated serum bilirubin levels with subclinical carotid atherosclerosis. Cerebrovasc Dis 21:408–414PubMedCrossRef

42.

Maruhashi T, Soga J, Fujimura N et al (2012) Hyperbilirubinemia, augmentation of endothelial function, and decrease in oxidative stress in Gilbert syndrome. Circulation 126:598–603PubMedCrossRef

43.

Öllinger R, Bilban M, Erat A et al (2005) Bilirubin: a natural inhibitor of vascular smooth muscle cell proliferation. Circulation 112:1030–1039PubMedCrossRef

44.

Tenhunen R, Marver H, Schmid R (1968) The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci USA 61:748–755PubMedCrossRef

45.

Endler G, Exner M, Schillinger M et al (2004) A microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with increased bilirubin and HDL levels but not with coronary artery disease. Thromb Haemost 91:155–161PubMed

46.

Lublinghoff N, Winkler K, Winkelmann B et al (2009) Genetic variants of the promoter of the heme oxygenase-1 gene and their influence on cardiovascular disease (the Ludwigshafen Risk and Cardiovascular Health study). BMC Med Genet 10:36PubMedCrossRef

47.

Gajdos V, Petit F, Perret C et al (2006) Further evidence that the UGT1A1*28 allele is not associated with coronary heart disease: the ECTIM Study. Clin Chem 52:2313–2314PubMedCrossRef

48.

Oda E (2010) Bilirubin is negatively associated with A1C independently of fasting plasma glucose, age, obesity, inflammation, hemoglobin, and iron in apparently healthy Japanese men and women. Diabetes Care 22:e131CrossRef

49.

Ohnaka K, Kono S, Inoguchi T et al (2010) Inverse associations of serum bilirubin with high sensitivity C-reactive protein, glycated hemoglobin, and prevalence of type 2 diabetes in middle-aged and elderly Japanese men and women. Diabetes Res Clin Pract 88:103–110PubMedCrossRef

50.

Ames B, Cathcart R, Schwiers E, Hochstein P (1981) Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A 78:6858–6862PubMedCrossRef

Titel: Plasma total bilirubin levels predict amputation events in type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study
verfasst von: 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
on behalf of the FIELD study investigators
Publikationsdatum: 01.04.2013
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 4/2013
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-012-2818-4

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Alphablocker schützt vor Miktionsproblemen nach der Biopsie

16.05.2024 alpha-1-Rezeptorantagonisten Nachrichten

Nach einer Prostatabiopsie treten häufig Probleme beim Wasserlassen auf. Ob sich das durch den periinterventionellen Einsatz von Alphablockern verhindern lässt, haben australische Mediziner im Zuge einer Metaanalyse untersucht.

Eingreifen von Umstehenden rettet vor Erstickungstod!

15.05.2024 Fremdkörperaspiration Nachrichten

Wer sich an einem Essensrest verschluckt und um Luft ringt, benötigt vor allem rasche Hilfe. Dass Umstehende nur in jedem zweiten Erstickungsnotfall bereit waren, diese zu leisten, ist das ernüchternde Ergebnis einer Beobachtungsstudie aus Japan. Doch es gibt auch eine gute Nachricht.

Neue S3-Leitlinie zur unkomplizierten Zystitis: Auf Antibiotika verzichten?

15.05.2024 Harnwegsinfektionen Nachrichten

Welche Antibiotika darf man bei unkomplizierter Zystitis verwenden und wovon sollte man die Finger lassen? Welche pflanzlichen Präparate können helfen? Was taugt der zugelassene Impfstoff? Antworten vom Koordinator der frisch überarbeiteten S3-Leitlinie, Prof. Florian Wagenlehner.

Schadet Ärger den Gefäßen?

14.05.2024 Arteriosklerose Nachrichten

In einer Studie aus New York wirkte sich Ärger kurzfristig deutlich negativ auf die Endothelfunktion gesunder Probanden aus. Möglicherweise hat dies Einfluss auf die kardiovaskuläre Gesundheit.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2013

Erratum to: Sedentary time in adults and the association with diabetes, cardiovascular disease and death: systematic review and meta-analysis

Growth arrest specific protein (GAS) 6: a role in the regulation of proliferation and functional capacity of the perinatal rat beta cell

Non-muscle myosin IIA is involved in focal adhesion and actin remodelling controlling glucose-stimulated insulin secretion

miRNA-30a-5p-mediated silencing of Beta2/NeuroD expression is an important initial event of glucotoxicity-induced beta cell dysfunction in rodent models

Overexpression of the antioxidant enzyme catalase does not interfere with the glucose responsiveness of insulin-secreting INS-1E cells and rat islets