Heart Failure: a Major Cardiovascular Complication of Diabetes Mellitus

Current Diabetes Reports

Volumn 16, Issue 11, 2016, Pages

  Bahtiyar, Gül ^a,b,c   Gutterman, David ^d   Lebovitz, Harold ^a  

^a SUNY DOWNSTATE MEDICAL CENTER   (United States)

^b WOODHULL MEDICAL CENTER   (United States)

^c NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d MEDICAL COLLEGE OF WISCONSIN   (United States)

Author keywords

Cardiovascular complications; Diabetes mellitus; Heart failure

Indexed keywords

ANGIOTENSIN; ANGIOTENSIN 2 RECEPTOR ANTAGONIST; ANGIOTENSIN II; ANGIOTENSIN NEPRILYSIN INHIBITOR; ANTIDIABETIC AGENT; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; DIURETIC AGENT; ENKEPHALINASE INHIBITOR; HEMOGLOBIN A1C; IVABRADINE; MEMBRANE METALLOENDOPEPTIDASE; MINERALOCORTICOID ANTAGONIST; RENIN INHIBITOR; UNCLASSIFIED DRUG; ANGIOTENSIN RECEPTOR ANTAGONIST; GLYCOSYLATED HEMOGLOBIN; HEMOGLOBIN A1C PROTEIN, HUMAN; RENIN;

AGE; CARDIOVASCULAR MORTALITY; CARDIOVASCULAR RISK; CAUSE OF DEATH; DIABETES MELLITUS; GLYCEMIC CONTROL; HEART EJECTION FRACTION; HEART FAILURE; HUMAN; HYPERGLYCEMIA; IMPLANTABLE CARDIOVERTER DEFIBRILLATOR; MORTALITY; PATHOGENESIS; PROGNOSIS; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; ANTAGONISTS AND INHIBITORS; DIABETES COMPLICATIONS;

ANGIOTENSIN RECEPTOR ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; DIABETES COMPLICATIONS; HEART FAILURE; HEMOGLOBIN A, GLYCOSYLATED; HUMANS; HYPERGLYCEMIA; RENIN;

EID: 84991087150     PISSN: 15344827     EISSN: 15390829     Source Type: Journal    
DOI: 10.1007/s11892-016-0809-4     Document Type: Review

References (96)

1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail. 2016. doi:10.1002/ejhf.592.
2. Braunwald E. Heart Failure. JCHF. 2013;1(1):1–20. doi:10.1016/j.jchf.2012.10.002.
3. Braunwald E. The war against heart failure: the Lancet lecture. Lancet. 2015;385:812–24.
4. IDF Diabetes Atlas 7th Edition. International Diabetes Federation. 2015
5. Cavender MA, Steg G, Smith Jr SC, Eagle K, Ohman EM, Goto S, et al. 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;132:923–31. This study reveals that diabetes mellitus substantially increases the risk of death, ischemic events, and heart failure.
6. Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin converting enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362:772–6.
7. McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin-Neprilysin inhibition versus Enalapril in heart failure. N Engl J Med. 2014;371:993–1004.
8. Kannel WB, Hjortland M, Castelli WP. The role of diabetes in congestive heart failure:the Framingham study. Am J Cardiol. 1974;34:29–34.
9. Nichols GA, Gullion CM, Koro CF, Ephross SA, Brown JB. The incidence of congestive heart failure in type 2 diabetes. Diabetes Care. 2005;27:1879–84.
10. Del Cas A, Khan SS, Butler J, Mentz RJ, Bonow RO, Avogaro A, et al. Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure. L Am Coll Cardiol HF. 2015;3:136–45.
11. MacDonald MR, Petrie MC, Varyani F, Ostyergren J, Michelson EL, Young JB, et al. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure. Eur Heart J. 2008;29:1377–85.
12. Kristensen SL, Preiss D, Jhund PS, Squire I, Cardoso JS, Merkely B, et al. Risk-related to pre-diabetes mellitus and diabetes mellitus in heart failure with reduced ejection fraction. Insights from prospective comparison of ARNI with ACEI to determine global mortality and morbidity in heart failure trial. Circ Heart Fail. 2016;9(1):e002560. doi:10.1161/CIRCHEARTFAILURE.115.002560.
13. ACC Foundation and AHA task force (Chair Sharon Ann Hunt). 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for diagnosis and management of heart failure in adults. J Am Coll Cardiol. 2009;15:e8–e88.
14. New York Heart Association, Inc., Diseases of the Heart and Blood Vessels. Nomenclature and Criteria for Diagnosis, 6th ed. Boston, Little Brown, 1964, p 114
15. Greenberg BH, Abraham WT, Albert NM, Chiswell K, Clare R, Stough WG, et al. Influence of diabetes on characteristics and outcomes in patients hospitalized with heart failure: A report from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF). Am Heart J. 2007;154:277. e1-e8.
16. Wong YW, Thomas L, Sun J-L, McMurray JJV, Krum H, Hernandez AF, et al. Predictors of incident heart failure hospitalizations among patients with impaired glucose tolerance. Circ Heart Fail. 2013;6:203–10.
17. Iribarren C, Karter AJ, Go AS, Ferrara A, Liu JY, Sidney S, et al. Glycemic control and heart failure among adults with diabetes. Circulation. 2001;103:2668–73.
18. Lind M, Olsson M, Rosengren A. Svensson A_M, Bounias I, Gudbjornsdottir S: The relationship between glycaemic control and heart failure in 83,021 patients with type 2 diabetes. Diabetologia. 2012;55:2946–53.
19. Glogner S, Rosengren A, Olsson M, Gudbjornsdottir S, Svensson A-M, Lind M. The association between BMI and hospitalization for heart failure in 83,021 persons with type 2 diabetes: a population-based study from the Swedish National Diabetes Registry. Diabet Med. 2014;31:586–94. This study describes the strong association between obesity and hospitalization for heart failure in people with Type 2 diabetes. Authors also comments on preventing weight gain and promoting weight loss that may be crucial in reducing the incidence of future hospitalizations for heart failure in this population.
20. Waring ME, Saczynski JS, McManus D, Zacharias M, Lessard D, Gore JM, et al. Weight and mortality following heart failure hospitalization among diabetic patients. Am J Med. 2011;124:834–40.
21. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by Echocardiography. J Am Soc Echocardiogr. 2015;28:1–39.
22. Abbate A, Arena R, Abouzaki N, Van Tassell BW, Canada J, Shah K, et al. Heart failure with preserved ejection fraction: refocusing on diastole. Int J Cardiol. 2015;179:430–40.
23. Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by heart failure and echocardiography associations of the European society of cardiology. Eur Heart j. 2007;28:2539–50.
24. Velagaleti RS, Gona P, Pencina MJ, Aragam J, Wang TJ, Levy D, et al. Left ventricular hypertrophy patterns and incidence of heart failure with preserved versus reduced ejection fractions. Am J Cardiol. 2014;113:117–22.
25. Borbely A, Papp Z, Edes I, Paulus WJ. Molecular determinants of heart failure with normal left ventricular ejection fractions. Pharmacological Reports. 2009;61:139–45.
26. Kemp CD, Conte JV. The pathophysiology of heart failure. Cardiovascular Pathology. 2012;21:365–71.
27. Mentz RJ, O’Connor CM. Pathophysiology and clinical evaluation of acute heart failure. Nat Rev Cardiol. 2016;13:28–35.
28. Haydock PM, Cowie MR. Heart failure: classification and pathophysiology. Medicine. 2010;38:467–72.
29. Volpe M, Carnovali M, Mastromarino V. The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment. Clinical Science. 2016;130:57–77.
30. Von Lueder TG, Krum H. New medical therapies for heart failure. Nat Rev Cardiol. 2015;12:730–40.
31. The Task Force on diabetes, pre-diabetes and cardiovascular diseases of the European Society of Cardiology. ESC Guidelines on diabetes. pre-diabetes and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2013;34:3035–87.
32. 2013 ACCF/AHA Guideline for the management of heart failure. J Am Coll Cardiol. 2013;62(16):e147–e239.
33. Sharma K, Kass DA. Unmet needs in cardiovascular science and medicine. Circ Res. 2014;115:79–96.
34. Hoenig MR, Bianchi C, Rosenzweig A, Sellke EW. The cardiac microvasculature in hypertension, cardiac hypertrophy and diastolic heart failure. Curr Vasc Pharmacol. 2008;6:292–300.
35. Kawata T, Daimon M, Miyazaki S, Ichikawa R, Maruyama M, Chiang S-J, et al. Coronary microvascular function is independently associated with left ventricular filling pressure in patients with type 2 diabetes mellitus. Cardiovasc Diabetol. 2015;14:98–106.
36. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355:251–9.
37. Aquilar D, Deswal A, Ramasubbu K, Mann DL, Bozkurt B. Comparison of patients with heart failure and preserved ejection fraction among those with versus without diabetes mellitus. Am J Cardiol. 2010;105:373–7.
38. Cubbon RM, Adams B, Rajwani A, Mercer BN, Patel PA, Gheradi G, et al. Diabetes mellitus is associated with adverse prognosis in chronic heart failure of ischaemic and non-ischaemic aetiology. Diab Vasc Dis Res. 2013;10:330–6.
39. Bando YK, Murohara T. Diabetes-related heart failure-Does diabetic cardiomyopathy exist? Circulation Journal. 2014;78:576–83. This article reviews the link between diabetes and heart failure and illustrates the current concepts of diabetic cardiomyopathy with new molecular mechanisms.
40. Amaral N, O’okonko DO. Metabolic abnormalities of the heart in type 2 diabetes. Diabetes & Vascular Disease Research. 2015;12:239–48.
41. Skali H, Shah A, Gupta DK, Cheng S, Claggett B, Liu J, et al. Cardiac structure and function across the glycemic spectrum in elderly men and women free of prevalent heart disease. The Atherosclerosis Risk in Community Study. Circ Heart Fail. 2015;8:448–54.
42. Bugger H, Able ED. Molecular mechanisms of diabetic cardiomyopathy. Diabetologia. 2014;57:660–71.
43. Miki T, Yuda S, Kouzu H, Miura T. Diabetic cardiomyopathy: pathophysiology and clinical features. Heart Fail Rev. 2013;18:149–66.
44. Wang ZV, Li DL, Hill JA. Heart failure and loss of metabolic control. J Cardiovasc Pharmacol. 2014;63:302–13.
45. Bertoni AG, Tsai A, Kasper EK, Brancati FL. Diabetes and idiopathic cardiomyopathy. Diabetes Care. 2003;26:2791–5.
46. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–86.
47. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007;93:1137–46.
48. Ahmed A, Aronow WS, Fleg JL. Higher New York Heart Association classes and increased mortality and hospitalizations in heart failure patients with preserved left ventricular function. Am Heart J. 2006;151:444–50.
49. Gotsman I, Shauer A, Lotan C, Keren A. Impaired fasting glucose: a predictor of reduced survival in patients with heart failure. Eur J Heart Fail. 2014;16:1190–8.
50. Flores-Le Roux J, Comin J, Pedro-Botet J, Benaiges D, Puig-de Dou J, Chillaron JJ, et al. Seven-year mortality in heart failure patients with undiagnosed diabetes: an observational study. Cardiovascular Diabetology. 2011;10:39–46.
51. Helfand BKI, Maselli NJ, Lessard DM, Yarzebski J, Gore JM, McManus DD, et al. Elevated serum glucose levels and survival after acute heart failure: A population-based perspective. Diabetes & Vascular Disease Research. 2015;12:119–25. This study summarizes the characteristics, treatment and survival in patients without diabetes mellitus, previously diagnosed diabetes mellitus and patients with hyperglycemia who present with acute decompensated heart failure with a conclusion of higher mortality rate among patients with elevated blood glucose levels at hospital admission.
52. Mesotten d, Van den Berghe G. Glycemic targets and approaches to management of the patient with critical illness. Curr Diab Rep. 2012;12:101–7.
53. Pocock SJ, Ariti CA, McMurray JJV, Maggioni A, Keber L, Squire IB, et al. Predicting survival in heart failure: a risk score based on 39,372 patients from 30 studies. Eur Heart J. 2013;34:1404–13.
54. Levy WC, Mozaffarian D, Linker DT, Sutradhar SC, Anker SD, Cropp AB, et al. The Seattle Heart Failure Model. Prediction of survival in heart failure. Circulation. 2006;113:1424–33.
55. Garg R, Yusuf S. Overview of randomized trials of angiotensin converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE inhibitor trials. JAMA. 1995;273:1450–6.
56. CONSENSUS trial study group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429–35.
57. SOLVD investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293–302.
58. SOLVD investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685–91.
59. Konstam MA, Neaton JD, Dickstein K, Drexler H, Komaida M, Martinez FA, et al. HEAAL investigators: Effects of high dose versus low dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomized, double-blind trial. Lancet. 2009;374:1840–8.
60. Cohn JN, Tognoni G, Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667–75.
61. Maggioni AP, Anand I, Gottlieb SO, Latini R, Tognoni G, Cohn JN. Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors. J Am Coll Cardiol. 2002;40:1414–21.
62. McMurray JJV, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin converting enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362:767–71.
63. McMurray JJV, Krum H, Abraham WT, Dickstein K, Kober AV, Desai AS, et al. Aliskiren, enalapril, or aliskiren and enalapril in heart failure. N Engl J Med. 2016;374:1521–32.
64. The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomized trial. Lancet 1999, 353:9-13.
65. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Lancet 1999, 353:2001-2007.
66. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Effects of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651–8.
67. Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, Krum H, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomizrd cumulative survival (COPERNICUS) study. Circulation. 2002;106:2194–9.
68. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–17.
69. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure andmild symptoms. (EMPHASIS-HF Study). N Engl J Med. 2011;364:11–21.
70. Zois NE, Bartels ED, Hunter I, Kousholt BS, Olsen LH, Goetze JP. Natriuretic peptides in cardiometabolic regulation and disease. Nat Rev Cardiol. 2014;11:403–12.
71. Singh JSS, Lang CC. Angiotensin receptor-neprilysin inhibitors: clinical potential in heart failure and beyond. Vascular Health and Risk Management. 2015;11:283–95.
72. Swedberg K, Komaida M, Bohm M, Borer JS, Ford I, Dubost-Brama A, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized placebo controlled trial. Lancet. 2010;376:875–85.
73. Bohm M, Robertsom M, Ford I, Borer JS, Komajda M, Kindermann I, et al. Influence of cardiovascular and noncardiovascular co-morbidities on outcomes and treatment effect of heart rate reduction with Ivabradine in stable heart failure (fom the SHIFT trial). Am J Cardiol. 2015;116:1890–7.
74. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336:525–33.
75. Ahmed A, Rich MW, Fleg JL, Zile MR, Young JB, Kitzman DW, et al. Effects of digoxin on morbidity and mortality in diastolic heart failure. Circulation. 2006;114:397–403.
76. Yusuf S, Pfeffer MA, Sedberg K, Granger CB, Held P, McMurray JJV, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM Preserved Trial. Lancet. 2003;362:777–81.
77. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456–67.
78. Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomized controlled trial. Lancet. 2012;380:1387–95.
79. Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP, Duckworth WC, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52:2288–98.
80. Sud M, Wang X, Austin PC, Lipscombe LL, Newton GE, Tu JV, et al. Presentation blood glucose and death, hospitalization and future diabetes risk in patients with acute heart failure syndromes. Eur Heart J. 2015;36:924–31.
81. Maggioni AP, Greene SJ, Fonarow GC, Bohm M, Zannad F, Solomon SD, et al. Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial. Eur Heart J. 2013;34:3117–27.
82. Sarma S, Mentz RJ, Kwasny MJ, Fought AJ, Huffman M, Subacius H, et al. Association between diabetes mellitus and post-discharge outcomes in patients hospitalized with heart failure: findings from the EVEREST trial. Eur j Heart Fail. 2013;15:194–202.
83. Aguilar D, Bozkurt B, Ramasubbu K, Deswal A. Relationship of hemoglobin A1C and mortality in heart failure. J Am Coll Cardiol. 2009;54:422–8.
84. Tomova GS, Nimbal V, Horwich TB. Relation between hemoglobin A1C and outcomes in heart failure patients with and without diabetes mellitus. Am J Cardiol. 2012;109:1767–73.
85. Eshaghian S, Horwich TB, Fonarow GC. An unexpected inverse relationship between HbA1c levels and mortality in patients with diabetes and advanced systolic heart failure. Am Heart J. 2006;151:e1–6.
86. Aguilar D, Chan W, Bozkurt B, Ramasubbu K, Deswal A. Metformin use and mortality in ambulatory patients with diabetes and heart failure. Circ Heart Fail. 2011;4:53–8.
87. Tahrani AA, Varughese GI, Scarpello JH, Hanna FW. Metformin, heart failure, and lactic acidosis: is metfromin absolutely contraindicated? BMJ. 2007;335(7618):508–12.
88. Smooke S, Horwich TB, Fonarow GC. Insulin-treated diabetes is associated with a marked increase in mortality in patients with advanced heart failure. Am Heart J. 2005;149:168–74.
89. Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, Maggioni AP, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319–28.
90. Dormandy JA, Charbonnel B, Eckland DJA, Erdmann E, Massi-Benedetti M, Moules IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive (PROspective pioglitazone Clinical Trial in macrovascular Events): a randomized controlled tria. Lancet. 2005;366:1279–89.
91. Home PD. Pocock Sj, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, Jones MP, Komajda M: Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicenter, randomized, open-label trial. Lancet. 2009;373:2125–35.
92. Scirca BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mozensen O, McGuire DK, Pay KK, Leiter LA, Raz I: Saxaliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. New Engl J Med. 2013;369:1317–26.
93. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–35.
94. Green JB, Bethel A, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of Sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232–42.
95. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–22.
96. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28. This study reveals that SGLT-2 inhibitor, empagliflozin, has a unique benefit in decreasing both HF hospitalization and death in participants with T2DM at high risk for CV events.