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01.03.2015 | Article

The relationship of fibroblast growth factor 21 with cardiovascular outcome events in the Fenofibrate Intervention and Event Lowering in Diabetes study

verfasst von: Kwok-Leung Ong, Andrzej S. Januszewski, Rachel O’Connell, Alicia J. Jenkins, Aimin Xu, David R. Sullivan, Philip J. Barter, Wei-Ting Hung, Russell S. Scott, Marja-Riitta Taskinen, Anthony C. Keech, Kerry-Anne Rye

Erschienen in: Diabetologia | Ausgabe 3/2015

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Abstract

Aims/hypothesis

Circulating fibroblast growth factor 21 (FGF21) levels are often elevated in obesity, dyslipidaemia, insulin resistance and type 2 diabetes. This study investigated the relationship of plasma FGF21 levels with cardiovascular events in patients with type 2 diabetes.

Methods

Plasma FGF21 levels were measured by ELISA at baseline in 9,697 individuals with type 2 diabetes participating in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. We assessed the association of FGF21 levels with the incidence of different cardiovascular outcomes over 5 years. The primary outcome was total cardiovascular disease (CVD) events and the secondary outcomes were the four individual components: coronary heart disease events, total stroke, CVD mortality and coronary and carotid revascularisation. The tertiary outcome was hospitalisation for angina pectoris.

Results

Higher baseline FGF21 levels were associated with higher risks of all cardiovascular outcome events after adjusting for the study treatment allocation (all p < 0.01). The associations remained significant for total CVD events and for coronary and carotid revascularisation after further adjusting for confounding factors, with the HR (95% CI) being 1.28 (1.10, 1.50) and 1.26 (1.01, 1.56), respectively, for the highest tertile compared with the lowest tertile (overall effect p = 0.002 and 0.007, respectively). The addition of FGF21 levels to a model including established CVD risk factors predicting total CVD events led to a non-significant increase in the C-statistic but there was a significant improvement in integrated discrimination and net reclassification.

Conclusions/interpretation

Higher baseline plasma FGF21 levels were associated with higher risk of cardiovascular events in patients with type 2 diabetes.

Trial registration: ISRCTN64783481

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Kharitonenkov A, Shiyanova TL, Koester A et al (2005) FGF-21 as a novel metabolic regulator. J Clin Invest 115:1627–1635PubMedCentralPubMedCrossRef

Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E (2007) Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 5:426–437PubMedCrossRef

Inagaki T, Dutchak P, Zhao G et al (2007) Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab 5:415–425PubMedCrossRef

Woo YC, Xu A, Wang Y, Lam KS (2013) Fibroblast growth factor 21 as an emerging metabolic regulator: clinical perspectives. Clin Endocrinol (Oxf) 78:489–496CrossRef

Wente W, Efanov AM, Brenner M et al (2006) Fibroblast growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes 55:2470–2478PubMedCrossRef

Kharitonenkov A, Wroblewski VJ, Koester A et al (2007) The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 148:774–781PubMedCrossRef

Zhang X, Yeung DC, Karpisek M et al (2008) Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 57:1246–1253PubMedCrossRef

Li H, Fang Q, Gao F et al (2010) Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride. J Hepatol 53:934–940PubMedCrossRef

Lin Z, Wu Z, Yin X et al (2010) Serum levels of FGF-21 are increased in coronary heart disease patients and are independently associated with adverse lipid profile. PLoS One 5:e15534PubMedCentralPubMedCrossRef

10.

Chen C, Cheung BM, Tso AW et al (2011) High plasma level of fibroblast growth factor 21 is an independent predictor of type 2 diabetes: a 5.4-year population-based prospective study in Chinese subjects. Diabetes Care 34:2113–2115PubMedCentralPubMedCrossRef

11.

Wu AL, Kolumam G, Stawicki S et al (2011) Amelioration of type 2 diabetes by antibody-mediated activation of fibroblast growth factor receptor 1. Sci Transl Med 3:113ra126PubMedCrossRef

12.

Foltz IN, Hu S, King C et al (2012) Treating diabetes and obesity with an FGF21-mimetic antibody activating the βKlotho/FGFR1c receptor complex. Sci Transl Med 4:162ra153PubMedCrossRef

13.

Mu J, Pinkstaff J, Li Z et al (2012) FGF21 analogs of sustained action enabled by orthogonal biosynthesis demonstrate enhanced antidiabetic pharmacology in rodents. Diabetes 61:505–512PubMedCentralPubMedCrossRef

14.

Gaich G, Chien JY, Fu H et al (2013) The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab 18:333–340PubMedCrossRef

15.

Planavila A, Redondo I, Hondares E et al (2013) Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat Commun 4:2019PubMedCrossRef

16.

Liu SQ, Tefft BJ, Roberts DT et al (2012) Cardioprotective proteins upregulated in the liver in response to experimental myocardial ischemia. Am J Physiol Heart Circ Physiol 303:H1446–H1458PubMedCrossRef

17.

FIELD Study Investigators (2004) The need for a large-scale trial of fibrate therapy in diabetes: the rationale and design of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. [ISRCTN64783481]. Cardiovasc Diabetol 3:9CrossRef

18.

Keech A, Simes RJ, Barter P et al (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 366:1849–1861PubMedCrossRef

19.

Rajamani K, Colman PG, Li LP 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 373:1780–1788PubMedCentralPubMedCrossRef

20.

Keech AC, Mitchell P, Summanen PA et al (2007) Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 370:1687–1697PubMedCrossRef

21.

Burgess DC, Hunt D, Li L et al (2010) Incidence and predictors of silent myocardial infarction in type 2 diabetes and the effect of fenofibrate: an analysis from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Eur Heart J 31:92–99PubMedCrossRef

22.

Ong KL, Rye KA, O’Connell R et al (2012) Long-term fenofibrate therapy increases fibroblast growth factor 21 and retinol-binding protein 4 in subjects with type 2 diabetes. J Clin Endocrinol Metab 97:4701–4708PubMedCrossRef

23.

Scott R, Best J, Forder P et al (2005) Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study: baseline characteristics and short-term effects of fenofibrate [ISRCTN64783481]. Cardiovasc Diabetol 4:13PubMedCrossRef

24.

Taskinen MR, Sullivan DR, Ehnholm C et al (2009) Relationships of HDL cholesterol, ApoA-I, and ApoA-II with homocysteine and creatinine in patients with type 2 diabetes treated with fenofibrate. Arterioscler Thromb Vasc Biol 29:950–955PubMedCrossRef

25.

Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461–470PubMedCrossRef

26.

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

27.

Newson RB (2011) Comparing the predictive powers of survival models using Harrell’s C or Somers’ D. Stata J 10:339–358

28.

Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr, Vasan RS (2008) Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 27:157–172PubMedCrossRef

29.

Pencina MJ, D’Agostino RB Sr, Steyerberg EW (2011) Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers. Stat Med 30:11–21PubMedCentralPubMedCrossRef

30.

May S, Hosmer DW (1998) A simplified method of calculating an overall goodness-of-fit test for the Cox proportional hazards model. Lifetime Data Anal 4:109–120PubMedCrossRef

31.

Shen Y, Ma X, Zhou J et al (2013) Additive relationship between serum fibroblast growth factor 21 level and coronary artery disease. Cardiovasc Diabetol 12:124PubMedCentralPubMedCrossRef

32.

Chow WS, Xu A, Woo YC et al (2013) Serum fibroblast growth factor-21 levels are associated with carotid atherosclerosis independent of established cardiovascular risk factors. Arterioscler Thromb Vasc Biol 33:2454–2459PubMedCrossRef

33.

Lenart-Lipińska M, Matyjaszek-Matuszek B, Gernand W, Nowakowski A, Solski J (2013) Serum fibroblast growth factor 21 is predictive of combined cardiovascular morbidity and mortality in patients with type 2 diabetes at a relatively short-term follow-up. Diabetes Res Clin Pract 101:194–200PubMedCrossRef

34.

Lee Y, Lim S, Hong ES, Kim JH et al (2014) Serum FGF21 concentration is associated with hypertriglyceridaemia, hyperinsulinaemia and pericardial fat accumulation, independently of obesity, but not with current coronary artery status. Clin Endocrinol (Oxf) 80:57–64CrossRef

35.

de Backer G, Graham I, Cooney MT (2012) Do novel biomarkers add to existing scores of total cardiovascular risk? Eur J Prev Cardiol 19(2 Suppl):14–17PubMedCrossRef

36.

Ahluwalia N, Blacher J, Szabo de Edelenyi F et al (2013) Prognostic value of multiple emerging biomarkers in cardiovascular risk prediction in patients with stable cardiovascular disease. Atherosclerosis 228:478–484PubMedCrossRef

37.

Kosola S, Lampela H, Gylling H et al (2012) Cholesterol metabolism altered and FGF21 levels high after pediatric liver transplantation despite normal serum lipids. Am J Transplant 12:2815–2824PubMedCrossRef

38.

Habegger KM, Stemmer K, Cheng C et al (2013) Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes 62:1453–1463PubMedCentralPubMedCrossRef

39.

Lin XL, He XL, Zeng JF et al (2014) FGF21 increases cholesterol efflux by upregulating ABCA1 through the ERK1/2-PPARγ-LXRα pathway in THP1 macrophage-derived foam cells. DNA Cell Biol 33:514–521PubMedCrossRef

40.

Stepan H, Kley K, Hindricks J et al (2013) Serum levels of the adipokine fibroblast growth factor-21 are increased in preeclampsia. Cytokine 62:322–326PubMedCrossRef

41.

Lin Z, Zhou Z, Liu Y et al (2011) Circulating FGF21 levels are progressively increased from the early to end stages of chronic kidney diseases and are associated with renal function in Chinese. PLoS One 6:e18398PubMedCentralPubMedCrossRef

42.

Hindricks J, Ebert T, Bachmann A et al (2014) Serum levels of fibroblast growth factor-21 are increased in chronic and acute renal dysfunction. Clin Endocrinol (Oxf) 80:918–924CrossRef

43.

Kralisch S, Tönjes A, Krause K et al (2013) Fibroblast growth factor-21 serum concentrations are associated with metabolic and hepatic markers in humans. J Endocrinol 216:135–143PubMedCrossRef

Titel: The relationship of fibroblast growth factor 21 with cardiovascular outcome events in the Fenofibrate Intervention and Event Lowering in Diabetes study
verfasst von: Kwok-Leung Ong
Andrzej S. Januszewski
Rachel O’Connell
Alicia J. Jenkins
Aimin Xu
David R. Sullivan
Philip J. Barter
Wei-Ting Hung
Russell S. Scott
Marja-Riitta Taskinen
Anthony C. Keech
Kerry-Anne Rye
Publikationsdatum: 01.03.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 3/2015
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-014-3458-7

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