Comparison of non-traditional biomarkers, and combinations of biomarkers, for vascular risk prediction in people with type 2 diabetes: The Edinburgh Type 2 Diabetes Study

Anna H Price, Christopher J Weir, Paul Welsh, Stela McLachlan, Mark W J Strachan, Naveed Sattar, Jackie F Price, Anna H Price, Christopher J Weir, Paul Welsh, Stela McLachlan, Mark W J Strachan, Naveed Sattar, Jackie F Price

Abstract

Background and aims: We aimed at comparing the impact of multiple non-traditional biomarkers (ankle brachial pressure index (ABI), N-terminal pro-brain natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin (hs-cTnT), gamma-glutamyl transpeptidase (GGT) and four markers of systemic inflammation), both individually and in combination, on cardiovascular risk prediction, over and above traditional risk factors incorporated in the QRISK2 score, in older people with type 2 diabetes.

Methods: We conducted a prospective study of 1066 men and women aged 60-75 years with type 2 diabetes mellitus, living in Lothian, Scotland.

Results: After 8 years, 205 cardiovascular events occurred. Higher levels of hs-cTNT and NT-proBNP and lower ABI at baseline were associated with increased risk of CV events, independently of traditional risk factors (basic model). The C statistic of 0.722 (95% CI 0.681, 0.763) for the basic model increased on addition of individual biomarkers, most markedly for hs-cTnT (0.732; 0.690, 0.774)). Models including different combinations of biomarkers had even greater C statistics, with the highest for ABI, hs-cTnT and GGT combined (0.740; 0.699, 0.781).

Conclusions: Individually, hs-cTnT appeared to be the most promising biomarker in terms of improving vascular risk prediction in people with type 2 diabetes, over and above traditional risk factors incorporated in the QRISK2 score. Combining several non-traditional biomarkers added further predictive value, and this approach merits further investigation when developing cost effective risk prediction tools for use in clinical practice.

Keywords: Biomarkers; Cardiovascular disease; Epidemiology; Risk prediction; Type 2 diabetes.

Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

References

    1. The Emerging Risk Factors C Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215–2222.
    1. Hippisley-Cox J., Coupland C., Vinogradova Y., Robson J., Minhas R., Sheikh A., Brindle P. Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2. BMJ Clin. Res. ed) 2008;336:1475–1482.
    1. Hippisley-Cox J., Coupland C., Brindle P. Validation of QRISK2(2014) in patients with diabetes. 2014. QRISK.
    1. Simmons R.K., Coleman R.L., Price H.C., Holman R.R., Khaw K.T., Wareham N.J., Griffin S.J. Performance of the UK prospective diabetes study risk engine and the Framingham risk equations in estimating cardiovascular disease in the EPIC- Norfolk cohort. Diabetes care. 2009;32:708–713.
    1. van der Heijden A.A., Ortegon M.M., Niessen L.W., Nijpels G., Dekker J.M. Prediction of coronary heart disease risk in a general, pre-diabetic, and diabetic population during 10 years of follow-up: accuracy of the Framingham, SCORE, and UKPDS risk functions: the Hoorn Study. Diabetes care. 2009;32:2094–2098.
    1. van Dieren S., Beulens J.W., Kengne A.P., Peelen L.M., Rutten G.E., Woodward M., van der Schouw Y.T., Moons K.G. Prediction models for the risk of cardiovascular disease in patients with type 2 diabetes: a systematic review. Heart (British Card. Soc. 2012;98:360–369.
    1. Fowkes F.G., Murray G.D., Butcher I., Heald C.L., Lee R.J., Chambless L.E., Folsom A.R., Hirsch A.T., Dramaix M., deBacker G., Wautrecht J.C., Kornitzer M., Newman A.B., Cushman M., Sutton-Tyrrell K., Fowkes F.G., Lee A.J., Price J.F., d'Agostino R.B., Murabito J.M., Norman P.E., Jamrozik K., Curb J.D., Masaki K.H., Rodriguez B.L., Dekker J.M., Bouter L.M., Heine R.J., Nijpels G., Stehouwer C.D., Ferrucci L., McDermott M.M., Stoffers H.E., Hooi J.D., Knottnerus J.A., Ogren M., Hedblad B., Witteman J.C., Breteler M.M., Hunink M.G., Hofman A., Criqui M.H., Langer R.D., Fronek A., Hiatt W.R., Hamman R., Resnick H.E., Guralnik J., McDermott M.M. Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis. JAMA J. Am. Med. Assoc. 2008;300:197–208.
    1. Welsh P., Doolin O., Willeit P., Packard C., Macfarlane P., Cobbe S., Gudnason V., Di Angelantonio E., Ford I., Sattar N. N-terminal pro-B-type natriuretic peptide and the prediction of primary cardiovascular events: results from 15-year follow-up of WOSCOPS. Eur. heart J. 2013;34:443–450.
    1. Hillis G.S., Welsh P., Chalmers J., Perkovic V., Chow C.K., Li Q., Jun M., Neal B., Zoungas S., Poulter N., Mancia G., Williams B., Sattar N., Woodward M. The relative and combined ability of high-sensitivity cardiac troponin T and N-terminal pro-B-type natriuretic peptide to predict cardiovascular events and death in patients with type 2 diabetes. Diabetes care. 2014;37:295–303.
    1. Kengne A.P., Czernichow S., Stamatakis E., Hamer M., Batty G.D. Gamma-glutamyltransferase and risk of cardiovascular disease mortality in people with and without diabetes: pooling of three British Health Surveys. J. Hepatology. 2012;57:1083–1089.
    1. Kaptoge S., Di Angelantonio E., Pennells L., Wood A.M., White I.R., Gao P., Walker M., Thompson A., Sarwar N., Caslake M., Butterworth A.S., Amouyel P., Assmann G., Bakker S.J., Barr E.L., Barrett-Connor E., Benjamin E.J., Bjorkelund C., Brenner H., Brunner E., Clarke R., Cooper J.A., Cremer P., Cushman M., Dagenais G.R., D'Agostino R.B., Sr., Dankner R., Davey-Smith G., Deeg D., Dekker J.M., Engstrom G., Folsom A.R., Fowkes F.G., Gallacher J., Gaziano J.M., Giampaoli S., Gillum R.F., Hofman A., Howard B.V., Ingelsson E., Iso H., Jorgensen T., Kiechl S., Kitamura A., Kiyohara Y., Koenig W., Kromhout D., Kuller L.H., Lawlor D.A., Meade T.W., Nissinen A., Nordestgaard B.G., Onat A., Panagiotakos D.B., Psaty B.M., Rodriguez B., Rosengren A., Salomaa V., Kauhanen J., Salonen J.T., Shaffer J.A., Shea S., Ford I., Stehouwer C.D., Strandberg T.E., Tipping R.W., Tosetto A., Wassertheil-Smoller S., Wennberg P., Westendorp R.G., Whincup P.H., Wilhelmsen L., Woodward M., Lowe G.D., Wareham N.J., Khaw K.T., Sattar N., Packard C.J., Gudnason V., Ridker P.M., Pepys M.B., Thompson S.G., Danesh J. C-reactive protein, fibrinogen, and cardiovascular disease prediction. N. Engl. J. Med. 2012;367:1310–1320. Emerging Risk Factors C.
    1. Kumar R.G., Rubin J.E., Berger R.P., Kochanek P.M., Wagner A.K. Principal components derived from CSF inflammatory profiles predict outcome in survivors after severe traumatic brain injury. Brain, Behav. Immun. 2016;53:183–193.
    1. Marioni R.E., Strachan M.W., Reynolds R.M., Lowe G.D., Mitchell R.J., Fowkes F.G., Frier B.M., Lee A.J., Butcher I., Rumley A., Murray G.D., Deary I.J., Price J.F. Association between raised inflammatory markers and cognitive decline in elderly people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes. 2010;59:710–713.
    1. Price J.F., Reynolds R.M., Mitchell R.J., Williamson R.M., Fowkes F.G., Deary I.J., Lee A.J., Frier B.M., Hayes P.C., Strachan M.W. The Edinburgh type 2 diabetes study: study protocol. BMC Endocr. Disord. 2008;8:18.
    1. SIMD Scottish index of multiple deprivation [article online] 2012. Available from: Accessed 10 August 2016.
    1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-Juanatey JR, Harjola V-P, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, Filippatos G, McMurray JJV, Aboyans V, Achenbach S, Agewall S, Al-Attar N, Atherton JJ, Bauersachs J, John Camm A, Carerj S, Ceconi C, Coca A, Elliott P, Erol Ç, Ezekowitz J, Fernández-Golfín C, Fitzsimons D, Guazzi M, Guenoun M, Hasenfuss G, Hindricks G, Hoes AW, Iung B, Jaarsma T, Kirchhof P, Knuuti J, Kolh P, Konstantinides S, Lainscak M, Lancellotti P, Lip GYH, Maisano F, Mueller C, Petrie MC, Piepoli MF, Priori SG, Torbicki A, Tsutsui H, van Veldhuisen DJ, Windecker S, Yancy C, Zamorano JL, Zamorano JL, Aboyans V, Achenbach S, Agewall S, Badimon L, Barón-Esquivias G, Baumgartner H, Bax JJ, Bueno H, Carerj S, Dean V, Erol Ç, Fitzsimons D, Gaemperli O, Kirchhof P, Kolh P, Lancellotti P, Lip GYH, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Roffi M, Torbicki A, Vaz Carneiro A, Windecker S, Sisakian HS, Isayev E, Kurlianskaya A, Mullens W, Tokmakova M, Agathangelou P, Melenovsky V, Wiggers H, Hassanein M, Uuetoa T, Lommi J, Kostovska ES, Juillière Y, Aladashvili A, Luchner A, Chrysohoou C, Nyolczas N, Thorgeirsson G, Marc Weinstein J, Di Lenarda A, Aidargaliyeva N, Bajraktari G, Beishenkulov M, Kamzola G, Abdel-Massih T, Čelutkienė J, Noppe S, Cassar A, Vataman E, Abir-Khalil S, van Pol P, Mo R, Straburzyńska-Migaj E, Fonseca C, Chioncel O, Shlyakhto E, Otasevic P, Goncalvesová E, Lainscak M, Díaz Molina B, Schaufelberger M, Suter T, Yılmaz MB, Voronkov L, Davies C: 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. <div xmlns=“”><span class=“subtitle”>The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)<br/>Developed with the special contribution of the Heart Failure Association (HFA) of the ESC</span></div> 2015.
    1. NICE CG95 . 2010. Chest Pain of Recent Onset: Assessment and Diagnosis.
    1. Saunders J.T., Nambi V., de Lemos J.A., Chambless L.E., Virani S.S., Boerwinkle E., Hoogeveen R.C., Liu X., Astor B.C., Mosley T.H., Folsom A.R., Heiss G., Coresh J., Ballantyne C.M. Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study. Circulation. 2011;123:1367–1376.
    1. Welsh P., Hart C., Papacosta O., Preiss D., McConnachie A., Murray H., Ramsay S., Upton M., Watt G., Whincup P., Wannamethee G., Sattar N. Prediction of cardiovascular disease risk by cardiac biomarkers in 2 United Kingdom cohort studies: does utility depend on risk thresholds for treatment? Hypertension. 2016;67:309–315.
    1. Wannamethee S.G., Welsh P., Lowe G.D., Gudnason V., Di Angelantonio E., Lennon L., Rumley A., Whincup P.H., Sattar N. N-terminal pro-brain natriuretic Peptide is a more useful predictor of cardiovascular disease risk than C-reactive protein in older men with and without pre-existing cardiovascular disease. J. Am. Coll. Cardiol. 2011;58:56–64.
    1. Murphy T.P., Dhangana R., Pencina M.J., D'Agostino Sr R.B. Ankle–brachial index and cardiovascular risk prediction: an analysis of 11,594 individuals with 10-year follow-up. Atherosclerosis. 2012;220:160–167.
    1. Fowkes F., Murray G., Butcher I., Folsom A., Hirsch A., Couper D., DeBacker G., Kornitzer M., Newman A., Sutton-Tyrrell K., Cushman M., Lee A., Price J., D'Agostino R., Murabito J., Norman P., Masaki K., Bouter L., Heine R., Stehouwer C., McDermott M., Stoffers H., Knottnerus J., Ogren M., Hedblad B., Koenig W., Meisinger C., Cauley J., Franco O., Hunink M., Hofman A., Witteman J., Criqui M., Langer R., Hiatt W., Hamman R., Collaboration ABI Development and validation of an ankle brachial index risk model for the prediction of cardiovascular events. Eur. J. Prev. Cardiol. 2014;21:310–320.
    1. Berg A.H., Scherer P.E. Adipose tissue, inflammation, and cardiovascular disease. Circ. Res. 2005;96:939–949.
    1. Bettencourt N., Oliveira S., Toschke A.M., Rocha J., Leite D., Carvalho M., Xara S., Schuster A., Chiribiri A., Leite-Moreira A., Nagel E., Alves H., Gama V. Predictors of circulating endothelial progenitor cell levels in patients without known coronary artery disease referred for multidetector computed tomography coronary angiography. Rev. Port. Cardiol. 2011;30:753–760.
    1. Olsen M.H., Hansen T.W., Christensen M.K., Gustafsson F., Rasmussen S., Wachtell K., Ibsen H., Torp-Pedersen C., Hildebrandt P.R. N-terminal pro-brain natriuretic peptide, but not high sensitivity C-reactive protein, improves cardiovascular risk prediction in the general population. Eur. heart J. 2007;28:1374–1381.
    1. Kengne A.P., Czernichow S., Stamatakis E., Hamer M., Batty G.D. Fibrinogen and future cardiovascular disease in people with diabetes: aetiological associations and risk prediction using individual participant data from nine community-based prospective cohort studies. Diabetes & Vasc. Dis. Res. 2013;10:143–151.
    1. van der Leeuw J., Beulens J.W., van Dieren S., Schalkwijk C.G., Glatz J.F., Hofker M.H., Verschuren W.M., Boer J.M., van der Graaf Y., Visseren F.L., Peelen L.M., van der Schouw Y.T. Novel biomarkers to improve the prediction of cardiovascular event risk in type 2 diabetes mellitus. J. Am. Heart Assoc. 2016:5.
    1. Alman A.C., Kinney G.L., Tracy R.P., Maahs D.M., Hokanson J.E., Rewers M.J., Snell-Bergeon J.K. Prospective association between inflammatory markers and progression of coronary artery calcification in adults with and without type 1 diabetes. Diabetes care. 2013;36:1967–1973.
    1. Hsu F.-C., Kritchevsky S.B., Liu Y., Kanaya A., Newman A.B., Perry S.E., Visser M., Pahor M., Harris T.B., Nicklas B.J. Study ftHA: association between inflammatory components and physical function in the Health, aging, and body composition study: a principal component analysis approach. The journals of gerontology series a: Biol. Sci. Med. Sci. 2009;64A:581–589.
    1. Bedenis R., Price A.H., Robertson C.M., Morling J.R., Frier B.M., Strachan M.W., Price J.F. Association between severe hypoglycemia, adverse macrovascular events, and inflammation in the Edinburgh type 2 diabetes study. Diabetes care. 2014;37(12):3301–3308.
    1. Lee D.H., Silventoinen K., Hu G., Jacobs D.R., Jr., Jousilahti P., Sundvall J., Tuomilehto J. Serum gamma-glutamyltransferase predicts non-fatal myocardial infarction and fatal coronary heart disease among 28,838 middle-aged men and women. Eur. heart J. 2006;27:2170–2176.
    1. Jousilahti P., Rastenyte D., Tuomilehto J. Serum gamma-glutamyl transferase, self-reported alcohol drinking, and the risk of stroke. Stroke. 2000;31:1851–1855.
    1. Morling J.R., Fallowfield J.A., Williamson R.M., Robertson C.M., Glancy S., Guha I.N., Strachan M.W., Price J.F. γ-Glutamyltransferase, but not markers of hepatic fibrosis, is associated with cardiovascular disease in older people with type 2 diabetes mellitus: the Edinburgh Type 2 Diabetes Study. Diabetologia. 2015;58(7):1484–1493.
    1. Kengne A.P., Batty G.D., Hamer M., Stamatakis E., Czernichow S. Association of C-reactive protein with cardiovascular disease mortality according to diabetes status: pooled analyses of 25,979 participants from four U.K. prospective cohort studies. Diabetes care. 2012;35:396–403.
    1. Ndrepepa G., Braun S., Cassese S., Fusaro M., Laugwitz K.L., Schunkert H., Kastrati A. Relation of gamma-glutamyl transferase to cardiovascular events in patients with acute coronary syndromes. Am. J. Cardiol. 2016;117:1427–1432.
    1. Kunutsor S.K., Bakker S.J., Kootstra-Ros J.E., Gansevoort R.T., Dullaart R.P. Circulating gamma glutamyltransferase and prediction of cardiovascular disease. Atherosclerosis. 2015;238:356–364.
    1. Retnakaran R., Cull C.A., Thorne K.I., Adler A.I., Holman R.R. Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes. 2006;55:1832–1839.
    1. Koro C.E., Lee B.H., Bowlin S.J. Antidiabetic medication use and prevalence of chronic kidney disease among patients with type 2 diabetes mellitus in the United States. Clin. Ther. 2009;31:2608–2617.
    1. Hippisley-Cox J., Coupland C., Brindle P. Derivation and validation of QStroke score for predicting risk of ischaemic stroke in primary care and comparison with other risk scores: a prospective open cohort study. BMJ Clin. Res. ed) 2013;346:f2573.
    1. Cook N.R. Statistical evaluation of prognostic versus diagnostic models: beyond the ROC curve. Clin. Chem. 2008;54:17–23.
    1. Winocour P.H., Fisher M. Prediction of cardiovascular risk in people with diabetes. Diabet. Med. 2003;20:515–527.

Source: PubMed

3
Subskrybuj