Advertisement
Canadian Journal of Cardiology

How Diabetes and Heart Failure Modulate Each Other and Condition Management

  • Varinder Kaur Randhawa
    Affiliations
    Cardiovascular Medicine, Kaufman Center for Heart Failure, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA
    Search for articles by this author
  • Savita Dhanvantari
    Affiliations
    Metabolism and Diabetes, Imaging Program, Lawson Health Research Institute and Medical Biophysics, Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
    Search for articles by this author
  • Kim A. Connelly
    Correspondence
    Corresponding author: Dr Kim A. Connelly, Division of Cardiology, Department of Medicine, St Michael’s Hospital, 30 Bond Street, 7-052, Toronto, Ontario M5B 1W8, Canada. Tel.: +1-416-864-5201, ext. 5425; fax: +1-416-864-5571.
    Affiliations
    Division of Cardiology, Department of Medicine, St Michael's Hospital, Keenan Research Centre for Biomedical Research, Toronto, Ontario, Canada
    Search for articles by this author
Published:December 01, 2020DOI:https://doi.org/10.1016/j.cjca.2020.11.014

      Abstract

      Heart failure (HF) and diabetes mellitus (DM) confer considerable burden on the health care system. Although these often occur together, DM can increase risk of HF, whereas HF can accelerate complications of DM. HF is a clinical syndrome resulting from systolic or diastolic impairment caused by ischemic, nonischemic (eg, DM), or other etiologies. HF exists along a spectrum from stage A (ie, persons at risk of DM) to stage D (ie, refractory HF from end-stage DM cardiomyopathy [DMCM]). HF is further categorized by reduced, midrange, and preserved ejection fraction (EF). In type 2 DM, the most prevalent form of DM, several pathophysiological mechanisms (eg, insulin resistance and hyperglycemia) can contribute to myocardial damage, leading to DMCM. Management of HF and DM and patient outcomes are guided by EF and drug efficacy. In this review, we focus on the interplay between HF and DM on disease pathophysiology, management, and patient outcomes. Specifically, we highlight the role of novel antihyperglycemic (eg, sodium glucose cotransporter 2 inhibitors) and HF therapies (eg, renin-angiotensin-aldosterone system inhibitors) on HF outcomes in patients with DM and HF.

      Résumé

      L'insuffisance cardiaque (IC) et le diabète représentent un fardeau considérable pour le système de soins de santé. Même si ces deux affections sont souvent observées conjointement, le diabète peut accroître le risque d'IC, tandis que l'IC peut accélérer les complications du diabète. L'IC est un syndrome clinique qui est le résultat d'une dysfonction systolique ou diastolique d'origine ischémique, non ischémique (p. ex. diabète) ou autre. Le spectre de l'IC va du stade A (c.-à-d., personnes à risque de diabète) au stade D (c.-à-d., IC réfractaire attribuable à une cardiomyopathie diabétique au stade terminal). L'IC est également classée selon la fraction d'éjection ([FE] réduite, intermédiaire, préservée). Dans le diabète de type 2, qui est la forme de diabète la plus courante, plusieurs mécanismes physiopathologiques (p. ex. insulinorésistance et hyperglycémie) peuvent contribuer aux dommages causés au myocarde, et entraîner ainsi une cardiomyopathie diabétique. La FE et l'efficacité du médicament guident la prise en charge de l'IC et du diabète, et influencent les résultats observés chez les patients. Dans cet article, nous aborderons l'influence réciproque de l'IC et du diabète sur la physiopathologie de la maladie, la prise en charge et les résultats pour les patients. Nous soulignerons plus particulièrement le rôle des nouveaux antihyperglycémiants (p. ex. inhibiteurs du cotransporteur sodium-glucose de type 2 [SGLT2]) et des traitements contre l'IC (p. ex. inhibiteurs du système rénine-angiotensine-aldostérone) dans l'IC chez les patients atteints de diabète et d'IC.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Canadian Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Heart and Stroke Foundation
        2016 Report on the Health of Canadians.
        (Available at:)
        • Diabetes Canada Clinical Practice Guidelines Expert Committee
        Diabetes Canada 2018 clinical practice guidelines for the prevention and management of diabetes in Canada.
        Can J Diabetes. 2018; 42: S1-S325
        • Lipsombe L.
        • Booth G.
        • Butalia S.
        • et al.
        Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada: pharmacologic glycemic management of type 2 diabetes in adults.
        Can J Diabetes. 2018; 42: S88-S103
        • Lesyuk W.
        • Kriza C.
        • Kolominsky-Rabas P.
        Cost-of-illness studies in heart failure: a systematic review 2004-2016.
        BMC Cardiovasc Disord. 2018; 18: 74
        • Greene S.J.
        • Vaduganathan M.
        • Khan M.S.
        • et al.
        Prevalent and incident heart failure in cardiovascular outcome trials of patients with type 2 diabetes.
        J Am Coll Cardiol. 2018; 71: 1379-1390
        • Defronzo R.A.
        Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus.
        Diabetes. 2009; 58: 773-795
        • Jia G.
        • Hill M.A.
        • Sowers J.R.
        Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity.
        Circ Res. 2018; 122: 624-638
        • Evangelista I.
        • Nuti R.
        • Picchioni T.
        • Dotta F.
        • Palazzuoli A.
        Molecular dysfunction and phenotypic derangement in diabetic cardiomyopathy.
        Int J Mol Sci. 2019; 20: 3264
        • Laustsen P.G.
        • Russell S.J.
        • Cui L.
        • et al.
        Essential role of insulin and insulin-like growth factor 1 receptor signaling in cardiac development and function.
        Mol Cell Biol. 2007; 27: 1649-1664
        • Mellor K.M.
        • Bell J.R.
        • Ritchie R.H.
        • Delbridge L.M.
        Myocardial insulin resistance, metabolic stress and autophagy in diabetes.
        Clin Experiment Pharmacol Physiol. 2013; 40: 56-61
        • Frustaci A.
        • Kajstura J.
        • Chimenti C.
        • et al.
        Myocardial cell death in human diabetes.
        Circ Res. 2000; 87: 1123-1132
        • Shi Y.
        • Vanhoutte P.M.
        Macro- and microvascular endothelial dysfunction in diabetes.
        J Diabetes. 2017; 9: 434-449
        • Seferovic P.M.
        • Paulus W.J.
        Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes.
        Eur Heart J. 2015; 36: 1718-1727
        • Rubler S.
        • Dlugash J.
        • Yuceoglu Y.Z.
        • et al.
        New type of cardiomyopathy associated with diabetic glomerulosclerosis.
        Am J Cardiol. 1972; 30: 595-602
        • Streng K.W.
        • Nauta J.F.
        • Hillege H.L.
        • et al.
        Non-cardiac comorbidities in heart failure with reduced, mid-range and preserved ejection fraction.
        Int J Cardiol. 2018; 271: 132-139
        • Aroor A.R.
        • Mandavia C.H.
        • Sowers J.R.
        Insulin resistance and heart failure: molecular mechanisms.
        Heart Fail Clin. 2012; 8: 609-617
        • Nichols G.A.
        • Hillier T.A.
        • Erbey J.R.
        • Brown J.B.
        Congestive heart failure in type 2 diabetes: prevalence, incidence, and risk factors.
        Diabetes Care. 2001; 24: 1614-1619
        • Shah A.D.
        • Langenberg C.
        • Rapsomaniki E.
        • et al.
        Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1.9 million people.
        Lancet Diabetes Endocrinol. 2015; 3: 105-113
        • Zareini B.
        • Rørth R.
        • Holt A.
        • et al.
        Heart failure and the prognostic impact and incidence of new-onset of diabetes mellitus: a nationwide cohort study.
        Cardiovasc Diabetol. 2019; 18: 79
        • Kannel W.B.
        • McGee D.L.
        Diabetes and cardiovascular disease: the Framingham study.
        JAMA. 1979; 241: 2035-2038
        • Echouffo-Tcheugui J.B.
        • Xu H.
        • DeVore A.D.
        • et al.
        Temporal trends and factors associated with diabetes mellitus among patients hospitalized with heart failure: findings from Get With The Guidelines heart failure registry.
        Am Heart J. 2016; 182: 9-20
        • Bertoni A.G.
        • Hundley W.G.
        • Massing M.W.
        • et al.
        Heart failure prevalence, incidence, and mortality in the elderly with diabetes.
        Diabetes Care. 2004; 27: 699-703
        • Meindl C.
        • Hochadel M.
        • Frankenstein L.
        • et al.
        The role of diabetes in cardiomyopathies of different etiologies: characteristics and 1-year follow-up results of the EVITA-HF registry.
        PLoS One. 2020; 15e0234260
        • Segar M.W.
        • Vaduganathan M.
        • Patel K.V.
        • et al.
        Machine learning to predict the risk of incident heart failure hospitalization among patients with diabetes: the WATCH-DM Risk Score.
        Diabetes Care. 2019; 42: 2298-2306
        • Dutka D.P.
        • Pitt M.
        • Pagano D.
        • et al.
        Myocardial glucose transport and utilization in patients with type 2 diabetes mellitus, left ventricular dysfunction, and coronary artery disease.
        J Am Coll Cardiol. 2006; 48: 2225-2231
        • van Melle J.P.
        • Bot M.
        • de Jonge P.
        • et al.
        Diabetes, glycemic control, and new-onset heart failure in patients with stable coronary artery disease: data from the heart and soul study.
        Diabetes Care. 2010; 33: 084-089
        • Barzilay J.I.
        • Davis B.R.
        • Pressel S.L.
        • et al.
        Long-term effects of incident diabetes mellitus on cardiovascular outcomes in people treated for hypertension: the ALLHAT diabetes extension study.
        Circ Cardiovasc Qual Outcomes. 2012; 5: 53-62
        • Wright Jr., J.T.
        • Probstfield J.L.
        • Cushman W.C.
        • et al.
        ALLHAT findings revisited in the context of subsequent analyses, other trials, and meta-analyses.
        Arch Intern Med. 2009; 169: 832-842
        • Chen Y.T.
        • Vaccarino V.
        • Williams C.S.
        • et al.
        Risk factors for heart failure in the elderly: a prospective community-based study.
        Am J Med. 1999; 106: 605-612
        • Rørth R.
        • Jhund P.S.
        • Mogensen U.M.
        • et al.
        Risk of incident heart failure in patients with diabetes and asymptomatic left ventricular systolic dysfunction.
        Diabetes Care. 2018; 41: 1285-1291
        • Ofstad A.P.
        • Atar D.
        • Gullestad L.
        • Langslet G.
        • Johansen O.E.
        The heart failure burden of type 2 diabetes mellitus: a review of pathophysiology and interventions.
        Heart Fail Rev. 2018; 23: 303-323
        • Stratton I.M.
        • Adler A.I.
        • Neil H.A.
        • et al.
        Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.
        BMJ. 2000; 321: 405-412
        • Held C.
        • Gerstein H.C.
        • Yusuf S.
        • et al.
        Glucose levels predict hospitalization for congestive heart failure in patients at high cardiovascular risk.
        Circulation. 2007; 115: 1371-1375
        • Gerstein H.C.
        • Swedberg K.
        • Carlsson J.
        • et al.
        • CHARM Program Investigators
        The hemoglobin A1c level as a progressive risk factor for cardiovascular death, hospitalization for heart failure, or death in patients with chronic heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program.
        Arch Intern Med. 2008; 168: 1699-1704
        • Bertoni A.G.
        • Kirk J.K.
        • Goff Jr., D.C.
        • Wagenknecht L.E.
        Excess mortality related to diabetes mellitus in elderly Medicare beneficiaries.
        Ann Epidemiol. 2004; 14: 362-367
        • Boonman-de Winter L.J.
        • Rutten F.H.
        • Cramer M.J.
        • et al.
        High prevalence of previously unknown heart failure and left ventricular dysfunction in patients with type 2 diabetes.
        Diabetologia. 2012; 55: 2154-2162
        • Faden G.
        • Faganello G.
        • De Feo S.
        • et al.
        The increasing detection of asymptomatic left ventricular dysfunction in patients with type 2 diabetes mellitus without overt cardiac disease: data from the SHORTWAVE study.
        Diabetes Res Clin Pract. 2013; 101: 309-316
        • Cavender M.A.
        • Steg P.G.
        • Smith Jr., S.C.
        • 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: 923-931
        • MacDonald M.R.
        • Petrie M.C.
        • Varyani F.
        • et al.
        CHARM Investigators. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme.
        Eur Heart J. 2008; 29: 1377-1385
        • McHugh K.
        • DeVore A.D.
        • Wu J.
        • et al.
        Heart failure with preserved rjection fraction and diabetes: JACC State-of-the-Art Review.
        J Am Coll Cardiol. 2019; 73: 602-611
        • Meagher P.
        • Adam M.
        • Civitarese R.
        • et al.
        Heart failure with preserved ejection fraction in diabetes: mechanisms and management.
        Can J Cardiol. 2018; 34: 632-643
        • Sandesara P.B.
        • O'Neal W.T.
        • Kelli H.M.
        • et al.
        The prognostic significance of diabetes and microvascular complications in patients with heart failure with preserved ejection fraction.
        Diabetes Care. 2018; 41: 150-155
        • Ezekowitz J.A.
        • O'Meara E.
        • McDonald M.A.
        • et al.
        2017 Comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure.
        Can J Cardiol. 2017; 33: 1342-1433
        • O'Meara E.
        • McDonald M.
        • Chan M.
        • et al.
        CCS/CHFS heart failure guidelines: clinical trial update on functional mitral regurgitation, SGLT2 inhibitors, ARNI in HFpEF, and tafamidis in amyloidosis.
        Can J Cardiol. 2020; 36: 159-169
        • Erdmann E.
        • Charbonnel B.
        • Wilcox R.G.
        • et al.
        Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08).
        Diabetes Care. 2007; 30: 2773-2778
        • Komajda M.
        • McMurray J.J.V.
        • Beck-Nielsen H.
        • et al.
        Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial.
        Eur Heart J. 2010; 31: 824-831
        • Fievet C.
        • Fruchart J.C.
        • Staels B.
        PPARalpha and PPARgamma dual agonists for the treatment of type 2 diabetes and the metabolic syndrome.
        Curr Opin Pharmacol. 2006; 6: 606-614
        • Castagno D.
        • Baird-Gunning J.
        • Jhund P.S.
        • et al.
        Intensive glycemic control has no impact on the risk of heart failure in type 2 diabetic patients: evidence from a 37,229 patient meta-analysis.
        Am Heart J. 2011; 162: 938-948.e2
        • Sasso F.C.
        • Carbonara O.
        • Cozzolino D.
        • et al.
        Effects of insulin-glucose infusion on left ventricular function at rest and during dynamic exercise in healthy subjects and noninsulin dependent diabetic patients: a radionuclide ventriculographic study.
        J Am Coll Cardiol. 2000; 36: 219-226
        • Gerstein H.C.
        • Bosch J.
        • Dagenais G.R.
        • et al.
        • ORIGIN Trial Investigators
        Basal insulin and cardiovascular and other outcomes in dysglycemia.
        N Engl J Med. 2012; 367: 319-328
        • Schauer P.R.
        • Bhatt D.L.
        • Kirwan J.P.
        • et al.
        Bariatric surgery versus intensive medical therapy for diabetes: 5-year outcomes.
        N Engl J Med. 2017; 376: 641-651
        • Zheng S.L.
        • Roddick A.J.
        • Aghar-Jaffar R.
        • et al.
        Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes: a systematic review and meta-analysis.
        JAMA. 2018; 319: 1580-1591
        • Banks A.Z.
        • Mentz R.J.
        • Stebbins A.
        • et al.
        Response to exercise training and outcomes in patients with heart failure and diabetes mellitus: insights from the HF-ACTION trial.
        J Card Fail. 2016; 22: 485-491
        • Sagar V.A.
        • Davies E.J.
        • Briscoe S.
        • et al.
        Exercise-based rehabilitation for heart failure: systematic review and meta-analysis.
        Open Heart. 2015; 2e000163
        • Piché M.E.
        • Poirier P.
        • Marette A.
        • et al.
        Benefits of 1-year lifestyle modification program on exercise capacity and diastolic function among coronary artery disease men with and without type 2 diabetes.
        Metab Syndr Relat Disord. 2019; 17: 149-159
        • Kenny H.C.
        • Abel E.D.
        Heart failure in type 2 diabetes mellitus.
        Circ Res. 2019; 124: 121-141
        • Bergmark B.A.
        • Bhatt D.L.
        • McGuire D.K.
        • et al.
        Metformin use and clinical outcomes among patients with diabetes mellitus with or without heart failure or kidney dysfunction: observations from the SAVOR-TIMI 53 trial.
        Circulation. 2019; 140: 1004-1014
        • Roussel R.
        • Travert F.
        • Pasquet B.
        • et al.
        Metformin use and mortality among patients with diabetes and atherothrombosis.
        Arch Intern Med. 2010; 170: 1892-1899
        • Eurich D.T.
        • Weir D.L.
        • Majumdar S.R.
        • et al.
        Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients.
        Circ Heart Fail. 2013; 6: 395-402
        • Scheen A.J.
        GLP-1 receptor agonists and heart failure in diabetes.
        Diabetes Metab. 2017; 43 (2S13-9)
        • Htike Z.Z.
        • Yates T.
        • Brady E.M.
        • et al.
        Rationale and design of the randomised controlled trial to assess the impact of liraglutide on cardiac function and structure in young adults with type 2 diabetes (the LYDIA study).
        Cardiovasc Diabetol. 2016; 15: 102
        • Margulies K.B.
        • Hernandez A.F.
        • Redfield M.M.
        • et al.
        NHLBI Heart Failure Clinical Research Network. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial.
        JAMA. 2016; 316: 500-508
        • Scheen A.J.
        Cardiovascular effects of new oral glucose-lowering agents: DPP-4 and SGLT-2 inhibitors.
        Circ Res. 2018; 122: 1439-1459
        • McGuire D.K.
        • Alexander J.H.
        • Johansen O.E.
        • et al.
        Linagliptin effects on heart failure and related outcomes in individuals with type 2 diabetes mellitus at high cardiovascular and renal risk in CARMELINA.
        Circulation. 2019; 139: 351-361
        • McMurray J.J.V.
        • Ponikowski P.
        • Bolli G.B.
        • et al.
        VIVIDD Trial Committees and Investigators. Effects of vildagliptin on ventricular function in patients with type 2 diabetes mellitus and heart failure: a randomized placebo-controlled trial.
        JACC Heart Fail. 2018; 6: 8-17
        • Mikhail N.
        Effects of incretin-based therapy in patients with heart failure and myocardial infarction.
        Endocrine. 2014; 47: 21-28
        • Rosenstock J.
        • Allison D.
        • Birkenfeld A.L.
        • et al.
        Effect of Additional oral semaglutide vs sitagliptin on glycated hemoglobin in adults with type 2 diabetes uncontrolled with metformin alone or with sulfonylurea: the PIONEER 3 randomized clinical trial.
        JAMA. 2019; 321: 1466-1480
        • Scirica B.M.
        • Braunwald E.
        • Raz I.
        • et al.
        SAVOR-TIMI 53 Steering Committee and Investigators. Heart Failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial.
        Circulation. 2014; 130: 1579-1588
        • Webb D.R.
        • Htike Z.Z.
        • Swarbrick D.J.
        • et al.
        A randomized, open-label, active comparator trial assessing the effects of 26 weeks of liraglutide or sitagliptin on cardiovascular function in young obese adults with type 2 diabetes.
        Diabetes Obes Metab. 2020; 22: 1187-1196
        • Zannad F.
        • Cannon C.P.
        • Cushman W.C.
        • et al.
        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
        • Koyani C.N.
        • Trummer C.
        • Shrestha N.
        • et al.
        Saxagliptin but not sitagliptin inhibits CaMKII and PKC via DPP9 inhibition in cardiomyocytes.
        Front Physiol. 2018; 9: 1622
        • Verma S.
        • McMurray J.J.V.
        The serendipitous story of SGLT2 inhibitors in heart failure.
        Circulation. 2019; 139: 2537-2541
        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2128
        • Zelniker T.A.
        • Wiviott S.D.
        • Raz I.
        • et al.
        SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.
        Lancet. 2019; 393: 31-39
        • Figtree G.A.
        • Rådholm K.
        • Barrett T.D.
        • et al.
        Effects of canagliflozin on heart failure outcomes associated with preserved and reduced ejection fraction in type 2 diabetes mellitus.
        Circulation. 2019; 139: 2591-2593
        • Kato E.T.
        • Silverman M.G.
        • Mosenzon Ofri
        • et al.
        Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus.
        Circulation. 2019; 139: 2528-2536
        • Neal B.
        • Perkovic V.
        • Matthews D.R.
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
        N Engl J Med. 2017; 377: 644-657
        • Pratley R.E.
        • Dagogo-Jack S.
        • Cannon C.P.
        • et al.
        The VERTIS CV trial: cardiovascular outcomes following ertugliflozin treatment in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.
        American Diabetes Association (ADA) Virtual 88th Scientific Sessions. 2020;
        • Singh A.K.
        • Singh R.
        Heart failure hospitalization with SGLT-2 inhibitors: a systematic review and meta-analysis of randomized controlled and observational studies.
        Exp Rev Clin Pharmacol. 2019; 12: 299-308
        • Zou C.Y.
        • Liu X.K.
        • Sang Y.Q.
        • Wang B.
        • Liang J.
        Effects of SGLT2 inhibitors on cardiovascular outcomes and mortality in type 2 diabetes: a meta-analysis.
        Medicine (Baltimore). 2019; 98e18245
        • Verma S.
        • Mazer C.D.
        • Yan A.T.
        • et al.
        Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes mellitus and coronary artery disease: the EMPA-HEART CardioLink-6 randomized clinical trial.
        Circulation. 2019; 140: 1693-1702
        • Singh J.S.S.
        • Mordi I.R.
        • Vickneson K.
        • et al.
        Dapagliflozin versus placebo on left ventricular remodeling in patients with diabetes and heart failure: the REFORM trial.
        Diabetes Care. 2020; 43: 1356-1359
        • Abraham W.T.
        • Lindenfeld J.
        • Ponikowski P.
        • et al.
        Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes.
        Eur Heart J. 2021; 42: 700-710
        • Verma S.
        • McGuire D.K.
        • Kosiborod M.N.
        Two tales: one story. EMPEROR-Reduced and DAPA-HF.
        Circulation. 2020; 142: 2201-2204
        • McMurray J.J.V.
        • Solomon S.D.
        • Inzucchi S.E.
        • et al.
        Dapagliflozin in patients with heart failure and reduced ejection fraction.
        N Engl J Med. 2019; 381: 1995-2008
        • Zannad F.
        • Ferreira J.P.
        • Pocock S.J.
        • et al.
        SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials.
        Lancet. 2020; 396: 819-829
        • Heerspink H.J.L.
        • Stefánsson B.V.
        • Correa-Rotter R.
        • et al.
        for the DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease.
        N Engl J Med. 2020; 383: 1436-1446
        • Packer M.
        • Anker S.D.
        • Butler J.
        • et al.
        Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial.
        Circulation. 2021; 143: 326-336
        • Maack C.
        • Lehrke M.
        • Backs J.
        • et al.
        Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association-European Society of Cardiology.
        Eur Heart J. 2018; 39: 4243-4254
        • Docherty K.F.
        • Jhund P.S.
        • Inzucchi S.E.
        • et al.
        on behalf of the DAPA-HF Investigators and Committees, Effects of dapagliflozin in DAPA-HF according to background heart failure therapy. Effects of dapagliflozin in DAPA-HF according to background heart failure therapy.
        Eur Heart J. 2020; 41: 2379-2392
        • Seferović P.M.
        • Petrie M.C.
        • Filippatos G.S.
        • et al.
        Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology.
        Eur J Heart Fail. 2018; 20: 853-872
        • Korol S.
        • White M.
        • O'Meara E.
        • et al.
        A comparison of the effects of selective and non-selective mineralocorticoid antagonism on glucose homeostasis of heart failure patients with glucose intolerance or type II diabetes: a randomized controlled double-blind trial.
        Am Heart J. 2018; 204: 190-195
        • Yamaji M.
        • Tsutamoto T.
        • Kawahara C.
        • et al.
        Effect of eplerenone versus spironolactone on cortisol and hemoglobin A(1)(c) levels in patients with chronic heart failure.
        Am Heart J. 2010; 160: 915-921
        • Preiss D.
        • Zetterstrand S.
        • McMurray J.J.
        • et al.
        Predictors of development of diabetes in patients with chronic heart failure in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program.
        Diabetes Care. 2009; 32: 915-920
        • Ogino K.
        • Kinugasa Y.
        • Kato M.
        • et al.
        Spironolactone, not furosemide, improved insulin resistance in patients with chronic heart failure.
        Int J Cardiol. 2014; 171: 398-403
        • Ukena C.
        • Dobre D.
        • Mahfoud F.
        • et al.
        Hypo- and hyperglycemia predict outcome in patients with left ventricular dysfunction after acute myocardial infarction: data from EPHESUS.
        J Card Fail. 2012; 18: 439-445
        • Preiss D.
        • van Veldhuisen D.J.
        • Sattar N.
        • et al.
        Eplerenone and new-onset diabetes in patients with mild heart failure: results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF).
        Eur J Heart Fail. 2012; 14: 909-915
        • Jordan J.
        • Stinkens R.
        • Jax T.
        • et al.
        Improved insulin sensitivity with angiotensin receptor neprilysin inhibition in individuals with obesity and hypertension.
        Clin Pharmacol Ther. 2017; 101: 254-263
        • Malek V.
        • Gaikwad A.B.
        Neprilysin inhibitors: a new hope to halt the diabetic cardiovascular and renal complications?.
        Biomed Pharmacother. 2017; 90: 752-759
        • Esser N.
        • Zraika S.
        Neprilysin inhibition: a new therapeutic option for type 2 diabetes?.
        Diabetologia. 2019; 62: 1113-1122
        • Nougué H.
        • Pezel T.
        • Picard F.
        • et al.
        Effects of sacubitril/valsartan on neprilysin targets and the metabolism of natriuretic peptides in chronic heart failure: a mechanistic clinical study.
        Eur J Heart Fail. 2019; 21: 598-605
        • Packer M.
        • Claggett B.
        • Lefkowitz M.P.
        • et al.
        Effect of neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin-angiotensin system: a secondary analysis of the PARADIGM-HF trial.
        Lancet Diabetes Endocrinol. 2018; 6: 547-554
        • Kristensen S.L.
        • Preiss D.
        • Jhund P.S.
        • 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 impact on clobal mortality and morbidity in heart failure trial.
        Circ Heart Fail. 2016; 9
        • Seferovic J.P.
        • Claggett B.
        • Seidelmann S.B.
        • et al.
        Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial.
        Lancet Diabetes Endocrinol. 2017; 5: 333-340
        • McMurray J.J.V.
        • Packer M.
        • Desai A.S.
        • et al.
        Angiotensin-neprilysin inhibition versus enalapril in heart failure.
        N Engl J Med. 2014; 371: 993-1004
        • Huynh T.
        • Harty B.J.
        • Claggett B.
        • et al.
        Comparison of outcomes in patients with diabetes mellitus treated with versus without insulin+heart failure with preserved left ventricular ejection fraction (from the TOPCAT study).
        Am J Cardiol. 2019; 123: 611-617
        • Swedberg K.
        • Komajda M.
        • Böhm M.
        • et al.
        on behalf of the SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.
        Lancet. 2010; 376: 875-885
        • Ferreira J.P.
        • Rossello X.
        • Pitt B.
        • Rossignol P.
        • Zannad F.
        Eplerenone in patients with myocardial infarction and "mid-range" ejection fraction: an analysis from the EPHESUS trial.
        Clin Cardiol. 2019; 42: 1106-1112