Clinical and Biomarker Predictors of Expanded Heart Failure Outcomes in Patients With Type 2 Diabetes Mellitus After a Recent Acute Coronary Syndrome: Insights From the EXAMINE Trial

Abhinav Sharma, Muthiah Vaduganathan, João Pedro Ferreira, Yuyin Liu, George L Bakris, Christopher P Cannon, William B White, Faiez Zannad, Abhinav Sharma, Muthiah Vaduganathan, João Pedro Ferreira, Yuyin Liu, George L Bakris, Christopher P Cannon, William B White, Faiez Zannad

Abstract

Background Improved heart failure (HF) risk stratification after a recent acute coronary syndrome may identify those who can benefit from therapies that reduce HF risk. We aimed to identify clinical and biomarker predictors for expanded HF outcomes in patients with type 2 diabetes mellitus after recent acute coronary syndrome. Methods and Results The EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial was a multicenter, non-inferiority, double-masked, placebo-controlled study which randomized 5380 patients with type 2 diabetes mellitus after recent acute coronary syndrome to alogliptin or placebo. Baseline biomarkers were measured in 5154 patients: NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity troponin I, adiponectin, growth-differentiation-factor-15, and galectin-3. Our primary outcome was cardiovascular) death, HF hospitalization, elevated NT-proBNP during follow-up, or loop diuretics initiation. The association between clinical variables, biomarkers, and outcomes were assessed using Cox regression models. In the study population, the median age was 61.0 years, 67.7% were men, and 28.0% had baseline HF (median follow-up was 18 months). In multivariable analyses, NT-proBNP had the strongest association with the primary outcome (per log2, hazard ratio 1.24; Wald χ2 67.4; P<0.0001) followed by a prior HF history (hazard ratio 1.42; Wald χ2 20.8; P<0.0001). A model with clinical variables and biomarkers allowed for risk prediction for expanded HF outcomes (C-statistic=0.72). Discrimination results were similar for cardiovascular death or HF hospitalization. Conclusions Among patients with type 2 diabetes mellitus after recent acute coronary syndrome, the use biomarkers such as N-terminal pro-B-type natriuretic peptide and clinical variables enables risk stratification for expanded HF outcomes. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00968708.

Keywords: biomarkers; heart failure; natriuretic peptide; risk stratification.

References

    1. Sharma A, Zhao X, Hammill BG, Hernandez AF, Fonarow GC, Felker GM, Yancy CW, Heidenreich PA, Ezekowitz JA, DeVore AD. Trends in noncardiovascular comorbidities among patients hospitalized for heart failure. Circ Heart Fail. 2018;11:e004646.
    1. Cavender MA, Steg PG, Smith SC, Eagle K, Ohman EM, Goto S, Kuder J, Im K, Wilson PW, Bhatt DL. Impact of diabetes mellitus on hospitalization for heart failure, cardiovascular events, and death: outcomes at 4 years from the reduction of atherothrombosis for continued health (REACH) registry. Circulation. 2015;132:923–931.
    1. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American college of cardiology foundation/American Heart Association task force on practice guidelines. Circulation. 2013;128:1810–1852.
    1. Sharma A, Green A, Dunning A, Lokhnygina Y, Al‐Khatib SM, Lopes RD, Buse JB, Lachin JM, Van de Werf F, Armstrong PW, Kaufman KD, Standl E, Chan JCN, Distiller LA, Scott R, Peterson ED, Holman RR. Causes of death in a contemporary cohort of patients with type 2 diabetes and atherosclerotic cardiovascular disease: insights from the TECOS trial. Diabetes Care. 2017;40:1763–1770.
    1. White WB, Kupfer S, Zannad F, Mehta CR, Wilson CA, Lei L, Bakris GL, Nissen SE, Cushman WC, Heller SR, Bergenstal RM, Fleck PR, Cannon CP. Cardiovascular mortality in patients with type 2 diabetes and recent acute coronary syndromes from the EXAMINE trial. Diabetes Care. 2016;39:1267–1273.
    1. Rawshani A, Rawshani A, Franzén S, Franzen S, Sattar N, Eliasson B, Svensson AM, Zethelius B, Miftaraj M, McGuire DK, Rosengren A, Gudbjornsdottir S. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2018;379:633–644.
    1. Home PD, Pocock SJ, Beck‐Nielsen H, Curtis PS, Gomis R, Hanefeld M, Jones NP, Komajda M, McMurray JJ. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open‐label trial. Lancet. 2009;373:2125–2135.
    1. Dormandy JA, Charbonnel B, Eckland DJA, Erdmann E, Massi‐Benedetti M, Loules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl EM, Wilcox RG Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial in macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279–1289.
    1. Sharma A, Cooper LB, Fiuzat M, Mentz RJ, Ferreira JP, Butler J, Fitchett D, Moses AC, O'Connor C, Zannad F. Antihyperglycemic therapies to treat patients with heart failure and diabetes mellitus. JACC Heart Fail. 2018;6:813–822.
    1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128.
    1. Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA‐REG OUTCOME® trial. Eur Heart J. 2016;37:1526–1534.
    1. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–657.
    1. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause‐Nilsson IAM, Fredriksson M, Johansson PA, Langkilde AM, Sabatine MS. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:1881–1882.
    1. Chow SL, Maisel AS, Anand I, Bozkurt B, de Boer RA, Felker GM, Fonarow GC, Greenberg B, Januzzi JL Jr, Kiernan MS, Liu PP, Wang TJ, Yancy CW, Zile MR. Role of biomarkers for the prevention, assessment, and management of heart failure: a scientific statement from the American Heart Association. Circulation. 2017;135:e1054–e1091.
    1. White WB, Bakris GL, Bergenstal RM, Cannon CP, Cushman WC, Fleck P, Heller S, Mehta C, Nissen SE, Perez A, Wilson C, Zannad F. EXamination of CArdiovascular OutcoMes with AlogliptIN versus Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE): a cardiovascular safety study of the dipeptidyl peptidase 4 inhibitor alogliptin in patients with type 2 diabetes with acute coronary syndrome. Am Heart J. 2011;162:620–626.e1.
    1. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Cushman WC, Zannad F. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–1335.
    1. Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Lam H, White WB. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double‐blind trial. Lancet. 2015;385:2067–2076.
    1. Sharma A, Cannon CP, White WB, Liu Y, Bakris GL, Cushman WC, Zannad F. Early and chronic dipeptidyl‐peptidase‐IV inhibition and cardiovascular events in patients with type 2 diabetes mellitus after an acute coronary syndrome: a landmark analysis of the EXAMINE trial. J Am Heart Assoc. 2018;7:e007649 DOI:10.1161/JAHA.117.007649.
    1. Hwang YC, Morrow DA, Cannon CP, Liu Y, Bergenstal R, Heller S, Mehta C, Cushman W, Bakris GL, Zannad F, White WB. High‐sensitivity C‐reactive protein, low‐density lipoprotein cholesterol and cardiovascular outcomes in patients with type 2 diabetes in the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial. Diabetes Obes Metab. 2018;20:654–659.
    1. Jarolim P, White WB, Cannon CP, Gao Q, Morrow DA. Serial measurement of natriuretic peptides and cardiovascular outcomes in patients with type 2 diabetes in the EXAMINE trial. Diabetes Care. 2018;41:1510–1515.
    1. Cavender MA, White WB, Jarolim P, Bakris GL, Cushman WC, Kupfer S, Gao Q, Mehta CR, Zannad F, Cannon CP, Morrow DA. Serial measurement of high‐sensitivity troponin i and cardiovascular outcomes in patients with type 2 diabetes mellitus in the examine trial (examination of cardiovascular outcomes with alogliptin versus standard of care). Circulation. 2017;135:1911–1921.
    1. Bergmark BA, Cannon CP, White WB, Jarolim P, Liu Y, Bonaca MP, Zannad F, Morrow DA. Baseline adiponectin concentration and clinical outcomes among patients with diabetes and recent acute coronary syndrome in the EXAMINE trial. Diabetes Obes Metab. 2017;19:962–969.
    1. Jarolim P. High sensitivity cardiac troponin assays in the clinical laboratories. Clin Chem Lab Med. 2015;53:635–652.
    1. Kempf T, Horn‐Wichmann R, Brabant G, Peter T, Allhoff T, Klein G, Drexler H, Johnston N, Wallentin L, Wollert KC. Circulating concentrations of growth‐differentiation factor 15 in apparently healthy elderly individuals and patients with chronic heart failure as assessed by a new immunoradiometric sandwich assay. Clin Chem. 2007;53:284–291.
    1. Thygesen K, Mair J, Mueller C, Huber K, Weber M, Plebani M, Hasin Y, Biasucci LM, Giannitsis E, Lindahl B, Koenig W, Tubaro M, Collinson P, Katus H, Galvani M, Venge P, Alpert JS, Hamm C, Jaffe AS. Recommendations for the use of natriuretic peptides in acute cardiac care: a position statement from the Study Group on Biomarkers in Cardiology of the ESC Working Group on Acute Cardiac Care. Eur Heart J. 2012;33:2001–2006.
    1. Greene SJ, Mentz RJ, Fiuzat M, Butler J, Solomon SD, Ambrosy AP, Mehta C, Teerlink JR, Zannad F, O'Connor CM. Reassessing the role of surrogate end points in drug development for heart failure. Circulation. 2018;138:1039–1053.
    1. Shen L, Jhund PS, Mogensen UM, Køber L, Claggett B, Rogers JK, McMurray JJV. Re‐examination of the best trial using composite outcomes, including emergency department visits. JACC Heart Fail. 2017;5:591–599.
    1. Gori M, Gupta DK, Claggett B, Selvin E, Folsom AR, Matsushita K, Bello NA, Cheng S, Shah A, Skali H, Vardeny O, Ni H, Ballantyne CM, Astor BC, Klein BE, Aguilar D, Solomon SD. Natriuretic peptide and high‐sensitivity troponin for cardiovascular risk prediction in diabetes: the Atherosclerosis Risk in Communities (ARIC) study. Diabetes Care. 2016;39:677–685.
    1. Sharma A, Stevens SR, Lucas J, Fiuzat M, Adams KF, Whellan DJ, Donahue MP, Kitzman DW, Pina IL, Zannad F, Kraus WE, O'Connor CM, Felker GM. Utility of growth differentiation factor‐15, a marker of oxidative stress and inflammation, in chronic heart failure: insights from the HF‐ACTION study. JACC Heart Fail. 2017;5:724–734.
    1. Kempf T, Eden M, Strelau J, Naguib M, Willenbockel C, Tongers J, Heineke J, Kotlarz D, Xu J, Molkentin JD, Niessen HW, Drexler H, Wollert KC. The transforming growth factor‐β superfamily member growth‐differentiation factor‐15 protects the heart from ischemia/reperfusion injury. Circ Res. 2006;98:351–360.
    1. Kociol RD, Pang PS, Gheorghiade M, Fonarow GC, O'Connor CM, Felker GM. Troponin elevation in heart failure: prevalence, mechanisms, and clinical implications. J Am Coll Cardiol. 2010;56:1071–1078.
    1. Januzzi JL, Filippatos G, Nieminen M, Gheorghiade M. Troponin elevation in patients with heart failure: on behalf of the third Universal Definition of Myocardial Infarction Global Task Force: Heart Failure Section. Eur Heart J. 2012;33:2265–2271.
    1. Sharma UC, Pokharel S, van Brakel TJ, van Berlo JH, Cleutjens JP, Schroen B, André S, Crijns HJ, Gabius HJ, Maessen J, Pinto YM. Galectin‐3 marks activated macrophages in failure‐prone hypertrophied hearts and contributes to cardiac dysfunction. Circulation. 2004;110:3121–3128.
    1. Lok DJ, Lok SI, Bruggink‐André de la Porte PW, Badings E, Lipsic E, van Wijngaarden J, de Boer RA, van Veldhuisen DJ, van der Meer P. Galectin‐3 is an independent marker for ventricular remodeling and mortality in patients with chronic heart failure. Clin Res Cardiol. 2013;102:103–110.
    1. Collaboration Natriuretic Peptides Studies . Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual‐participant‐data meta‐analysis. Lancet Diabetes Endocrinol. 2016;4:840–849.
    1. Jong CB, Li HY, Pan SL, Hsieh MY, Su FY, Chen KC, Yin WH, Chan SH, Wu YW, Wang KY, Chang KC, Hwang JJ, Wu CC. Relationship between body mass index, antidiabetic agents, and midterm mortality in patients with both type 2 diabetes mellitus and acute coronary syndrome. J Am Heart Assoc. 2019;8:e011215 DOI: 10.1161/JAHA.118.011215.
    1. Swoboda PP, McDiarmid AK, Erhayiem B, Ripley DP, Dobson LE, Garg P, Musa TA, Witte KK, Kearney MT, Barth JH, Ajjan R, Greenwood JP, Plein S. Diabetes mellitus, microalbuminuria, and subclinical cardiac disease: identification and monitoring of individuals at risk of heart failure. J Am Heart Assoc. 2017;6:005539 DOI: 10.1161/JAHA.117.005539.
    1. Cooper L, Lippmann S, Greiner M, Sharma A, Kelly J, Fonarow G, Yancy C, Heidenreich P, Hernandez A. Use of mineralocorticoid receptor antagonists in patients with heart failure and comorbid diabetes mellitus or chronic kidney disease. J Am Heart Assoc. 2017;6:e006540 DOI: 10.1161/JAHA.117.006540.
    1. Rørth R, Jhund PS, Mogensen UM, Kristensen SL, Petrie MC, Køber L, McMurray JJV. Risk of incident heart failure in patients with diabetes and asymptomatic left ventricular systolic dysfunction. Diabetes Care. 2018;41:1285–1291.
    1. Greene SJ, Vaduganathan M, Khan MS, Bakris GL, Weir MR, Seltzer JH, Sattar N, McGuire DK, Januzzi JL, Stockbridge N, Butler J. Prevalent and incident heart failure in cardiovascular outcome trials of patients with type 2 diabetes. J Am Coll Cardiol. 2018;71:1379–1390.

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