Top

Published in:

01-03-2017 | Original Article

Serum bilirubin concentrations and incident coronary heart disease risk among patients with type 2 diabetes: the Dongfeng–Tongji cohort

Authors: Jing Wang, Xiaofen Wu, Yaru Li, Xu Han, Hua Hu, Fei Wang, Caizheng Yu, Xiulou Li, Kun Yang, Jing Yuan, Ping Yao, Xiaoping Miao, Sheng Wei, Youjie Wang, Weihong Chen, Yuan Liang, Huan Guo, Handong Yang, Tangchun Wu, Xiaomin Zhang, Meian He

Published in: Acta Diabetologica | Issue 3/2017

Abstract

Aims

Elevated serum bilirubin levels are associated with decreased coronary heart disease (CHD) risk in cross-sectional studies among diabetic patients, but prospective evidence is limited. We investigated the relationship of serum bilirubin levels with incident CHD risk among type 2 diabetes patients.

Methods

In a prospective study of 2918 type 2 diabetes embedded in the Dongfeng–Tongji cohort, serum total bilirubin (TBil), direct bilirubin (DBil), and indirect bilirubin (IBil) were measured at baseline. Cox proportional hazards models were used to examine the association between serum bilirubin levels and CHD risk.

Results

A total of 440 CHD cases were identified during 12,017 person-years of follow-up. Compared with extreme quartiles, the adjusted hazard ratio and 95% confidence interval of incident CHD were 0.74 (0.56–0.99) with P trend = 0.08 in IBil, while in TBil and DBil, the bilirubin–CHD associations were not significant. Moreover, serum TBil and IBil levels were interacted with drinking status on the risk of incident CHD (P interaction = 0.021 and 0.037, respectively), and the associations were evident in ever drinkers. In drinkers, when serum TBil or IBil concentrations increased 1 μmol/L, the CHD risk both decreased 6% (95% CIs 0.89–0.99 and 0.87–1.00, respectively).

Conclusions

Serum IBil levels were marginally related to decreased incident CHD risk among type 2 diabetes. Drinking could potentially enhance the associations of serum TBil and DBil levels with incident CHD risk.

Available only for authorised users

van Dieren S, Beulens JW, van der Schouw YT, Grobbee DE, Neal B (2010) The global burden of diabetes and its complications: an emerging pandemic. Eur J Cardiovasc Prev Rehabil 17(Suppl 1):S3–S8. doi:10.1097/01.hjr.0000368191.86614.5a CrossRefPubMed

Shah AD, Langenberg C, Rapsomaniki E et al (2015) Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1.9 million people. Lancet Diabetes Endocrinol 3(2):105–113. doi:10.1016/S2213-8587(14)70219-0 CrossRefPubMedPubMedCentral

Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107(9):1058–1070. doi:10.1161/CIRCRESAHA.110.223545 CrossRefPubMedPubMedCentral

Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352(16):1685–1695. doi:10.1056/NEJMra043430 CrossRefPubMed

Back M, Hansson GK (2015) Anti-inflammatory therapies for atherosclerosis. Nat Rev Cardiol 12(4):199–211. doi:10.1038/nrcardio.2015.5 CrossRefPubMed

Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39(1):44–84. doi:10.1016/j.biocel.2006.07.001 CrossRefPubMed

Stocker R, Glazer AN, Ames BN (1987) Antioxidant activity of albumin-bound bilirubin. Proc Natl Acad Sci USA 84(16):5918–5922CrossRefPubMedPubMedCentral

Wu TW, Fung KP, Wu J, Yang CC, Weisel RD (1996) Antioxidation of human low density lipoprotein by unconjugated and conjugated bilirubins. Biochem Pharmacol 51(6):859–862CrossRefPubMed

Dong H, Huang H, Yun X et al (2014) Bilirubin increases insulin sensitivity in leptin-receptor deficient and diet-induced obese mice through suppression of ER stress and chronic inflammation. Endocrinology 155(3):818–828. doi:10.1210/en.2013-1667 CrossRefPubMedPubMedCentral

10.

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(1):155–160. doi:10.1161/01.ATV.0000148405.18071.6a CrossRefPubMed

11.

Breimer LH, Wannamethee G, Ebrahim S, Shaper AG (1995) Serum bilirubin and risk of ischemic heart disease in middle-aged British men. Clin Chem 41(10):1504–1508PubMed

12.

Troughton JA, Woodside JV, Young IS et al (2007) Bilirubin and coronary heart disease risk in the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Eur J Cardiovasc Prev Rehabil 14(1):79–84. doi:10.1097/01.hjr.0000230097.81202.9f CrossRefPubMed

13.

Lin JP, O’Donnell CJ, Schwaiger JP et al (2006) Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study. Circulation 114(14):1476–1481. doi:10.1161/circulationaha.106.633206 CrossRefPubMed

14.

Song YS, Koo BK, Cho NH, Moon MK (2014) Effect of low serum total bilirubin levels (≤0.32 mg/dl) on risk of coronary artery disease in patients with metabolic syndrome. Am J Cardiol 114(11):1695–1700. doi:10.1016/j.amjcard.2014.08.043 CrossRefPubMed

15.

Bosma PJ, van der Meer IM, Bakker CT, Hofman A, Paul-Abrahamse M, Witteman JC (2003) UGT1A1*28 allele and coronary heart disease: the Rotterdam study. Clin Chem 49(7):1180–1181. doi:10.1373/49.7.1180 CrossRefPubMed

16.

Stender S, Frikke-Schmidt R, Nordestgaard BG, Grande P, Tybjaerg-Hansen A (2013) Genetically elevated bilirubin and risk of ischaemic heart disease: three Mendelian randomization studies and a meta-analysis. J Intern Med 273(1):59–68. doi:10.1111/j.1365-2796.2012.02576.x CrossRefPubMed

17.

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 298(12):1398–1400. doi:10.1001/jama.298.12.1398-b CrossRefPubMed

18.

Fukui M, Tanaka M, Shiraishi E et al (2008) Relationship between serum bilirubin and albuminuria in patients with type 2 diabetes. Kidney Int 74(9):1197–1201. doi:10.1038/ki.2008.398 CrossRefPubMed

19.

Hwang HJ, Kim SH (2010) Inverse relationship between fasting direct bilirubin and metabolic syndrome in Korean adults. Clin Chim Acta 411(19–20):1496–1501. doi:10.1016/j.cca.2010.06.003 CrossRefPubMed

20.

Pineda S, Bang OY, Saver JL et al (2008) Association of serum bilirubin with ischemic stroke outcomes. J Stroke Cerebrovasc Dis 17(3):147–152. doi:10.1016/j.jstrokecerebrovasdis.2008.01.009 CrossRefPubMedPubMedCentral

21.

Wang F, Zhu J, Yao P et al (2013) Cohort profile: the Dongfeng–Tongji cohort study of retired workers. Int J Epidemiol 42(3):731–740. doi:10.1093/ije/dys053 CrossRefPubMed

22.

Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15(7):539–553. doi:10.1002/(SICI)1096-9136(199807)15:7<539:AID-DIA668>3.0.CO;2-S CrossRefPubMed

23.

Yang L, Yang H, He M et al (2016) Longer sleep duration and midday napping are associated with a higher risk of CHD incidence in middle-aged and older Chinese: the Dongfeng–Tongji Cohort Study. Sleep 39(3):645–652. doi:10.5665/sleep.5544 CrossRefPubMedPubMedCentral

24.

World Health Organization (1979) Report of the joint international society and federation of cardiology/world health organization task force on standardization of clinical nomenclature: nomenclature and criteria for diagnosis of ischemic heart disease. Circulation 59:607–609CrossRef

25.

Schwertner HA, Jackson WG, Tolan G (1994) Association of low serum concentration of bilirubin with increased risk of coronary artery disease. Clin Chem 40(1):18–23PubMed

26.

Oda E, Kawai R (2012) A possible cross-sectional association of serum total bilirubin with coronary heart disease and stroke in a Japanese health screening population. Heart Vessels 27(1):29–36. doi:10.1007/s00380-011-0123-7 CrossRefPubMed

27.

Kang SJ, Kim D, Park HE et al (2013) Elevated serum bilirubin levels are inversely associated with coronary artery atherosclerosis. Atherosclerosis 230(2):242–248. doi:10.1016/j.atherosclerosis.2013.06.021 CrossRefPubMed

28.

Yeh SY, Doupis J, Rahangdale S, Horr S, Malhotra A, Veves A (2009) Total serum bilirubin does not affect vascular reactivity in patients with diabetes. Vasc Med 14(2):129–136. doi:10.1177/1358863x08098273 CrossRefPubMedPubMedCentral

29.

Fevery J (2008) Bilirubin in clinical practice: a review. Liver Int 28(5):592–605. doi:10.1111/j.1478-3231.2008.01716.x CrossRefPubMed

30.

Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN (1987) Bilirubin is an antioxidant of possible physiological importance. Science 235(4792):1043–1046CrossRefPubMed

31.

Neuzil J, Stocker R (1994) Free and albumin-bound bilirubin are efficient co-antioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation. J Biol Chem 269(24):16712–16719PubMed

32.

Dennery PA, McDonagh AF, Spitz DR, Rodgers PA, Stevenson DK (1995) Hyperbilirubinemia results in reduced oxidative injury in neonatal Gunn rats exposed to hyperoxia. Free Radic Biol Med 19(4):395–404CrossRefPubMed

33.

Mazzone GL, Rigato I, Ostrow JD, Tiribelli C (2009) Bilirubin effect on endothelial adhesion molecules expression is mediated by the NF-kappaB signaling pathway. Biosci Trends 3(4):151–157PubMed

34.

Liu J, Wang L, Tian XY et al (2015) Unconjugated bilirubin mediates heme oxygenase-1-induced vascular benefits in diabetic mice. Diabetes 64(5):1564–1575. doi:10.2337/db14-1391 CrossRefPubMed

35.

Blomster JI, Zoungas S, Chalmers J et al (2014) The relationship between alcohol consumption and vascular complications and mortality in individuals with type 2 diabetes mellitus. Diabetes Care. doi:10.2337/dc13-2727 CrossRefPubMed

36.

Gepner Y, Golan R, Harman-Boehm I et al (2015) Effects of initiating moderate alcohol intake on cardiometabolic risk in adults with type 2 diabetes: a 2-year randomized controlled trial. Ann Intern Med 163(8):569–579. doi:10.7326/M14-1650 CrossRefPubMed

37.

Association AD (2015) Cardiovascular disease and risk management. Sec. 8. In standards of medical care in diabetes—2015. Diabetes Care 38(Suppl):S49–S57. doi:10.2337/dc15-S011 CrossRef

38.

O’Malley SS, Gueorguieva R, Wu R, Jatlow PI (2015) Acute alcohol consumption elevates serum bilirubin: an endogenous antioxidant. Drug Alcohol Depend 149:87–92. doi:10.1016/j.drugalcdep.2015.01.023 CrossRefPubMedPubMedCentral

39.

Dullaart RP, de Vries R, Lefrandt JD (2014) Increased large VLDL and small LDL particles are related to lower bilirubin in type 2 diabetes mellitus. Clin Biochem. doi:10.1016/j.clinbiochem.2014.08.008 CrossRefPubMed

40.

Chung JO, Cho DH, Chung DJ, Chung MY (2015) The duration of diabetes is inversely associated with the physiological serum bilirubin levels in patients with type 2 diabetes. Intern Med 54(2):141–146. doi:10.2169/internalmedicine.54.2858 CrossRefPubMed

Title: Serum bilirubin concentrations and incident coronary heart disease risk among patients with type 2 diabetes: the Dongfeng–Tongji cohort
Authors: Jing Wang
Xiaofen Wu
Yaru Li
Xu Han
Hua Hu
Fei Wang
Caizheng Yu
Xiulou Li
Kun Yang
Jing Yuan
Ping Yao
Xiaoping Miao
Sheng Wei
Youjie Wang
Weihong Chen
Yuan Liang
Huan Guo
Handong Yang
Tangchun Wu
Xiaomin Zhang
Meian He
Publication date: 01-03-2017
Publisher: Springer Milan
Published in: Acta Diabetologica / Issue 3/2017
Print ISSN: 0940-5429
Electronic ISSN: 1432-5233
DOI: https://doi.org/10.1007/s00592-016-0946-x

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Serum bilirubin concentrations and incident coronary heart disease risk among patients with type 2 diabetes: the Dongfeng–Tongji cohort

Abstract

Aims

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Aims

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2017

Is all hypoglycaemia treated as equal? An observational study of how the type of diabetes and treatment prescribed prior to admission influences quality of treatment of inpatient hypoglycaemia

MicroRNA expression profiles of human iPSCs differentiation into insulin-producing cells

Resting heart rate and risk of metabolic syndrome in adults: a dose–response meta-analysis of observational studies

Maternal fasting glycemia and adverse pregnancy outcomes in a Mediterranean population

Use of the predictive low glucose management (PLGM) algorithm in Italian adolescents with type 1 diabetes: CareLink™ data download in a real-world setting

Investigation of miRNA-binding site variants and risk of gestational diabetes mellitus in Chinese pregnant women

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page