Glucose-lowering drugs and heart failure: implications of recent cardiovascular outcome trials in type 2 diabetes


      Heart failure (HF) is common in Type-2 diabetes mellitus (T2DM), and viceversa, leading to a mutual impact on prognosis. Knowledge about this complex interplay has dramatically changed recently, due to development of new glucose-lowering drugs, and to specific FDA and EMA Guidance mandating to perform cardiovascular outcome trials (CVOTs), aimed at establishing cardiovascular safety, for new anti-diabetic treatments before they enter the market.
      Such CVOTs have demonstrated that the effects of the new antidiabetic drugs on the mutual interactions between T2DM and HF may develop across different phases:
      • -
        BEFORE HF ONSET (PRIMARY PREVENTION): evidence of benefit in preventing HF in T2DM (direct data)
      • -
        WHEN HF IS ALREADY PRESENT (SECONDARY PREVENTION): evidence of benefits in T2DM patients with HF (subgroup analysis data).
      Results of such trials can be summarized as: (a) all different classes of novel glucose-lowering drugs have good cardiovascular safety profile; (b) with respect to HF, DPP4 inhibitors might tend to increase risk; (c) sodium-glucose co-transporter 2 inhibitors (SGTLi), significantly reduce it; (d) glucagon-like peptide 1 receptor agonists (GLP1) tend to be neutral.
      These CVOTs data have led to guideline recommendations indicating appropriate therapy to T2DM patients with HF not at glycemic control target with metformin therapy.


      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 to Diabetes Research and Clinical Practice
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Dei Cas A.
        • Khan S.S.
        • Butler J.
        • Mentz R.J.
        • Bonow R.O.
        • Avogaro A.
        • et al.
        Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure.
        JACC Heart Fail. 2015; 3: 136-145
        • Guglin M.
        • Lynch K.
        • Krischer J.
        Heart failure as a risk factor for diabetes mellitus.
        Cardiology. 2014; 129: 84-92
        • Guglin M.
        • Villafranca A.
        • Morrison A.
        Cardiogenic diabetes.
        Heart Fail Rev. 2014; 19: 595-602
        • Echouffo-Tcheugui J.B.
        • Xu H.
        • DeVore A.D.
        • Schulte P.J.
        • Butler J.
        • Yancy C.W.
        • 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
        • Seferović P.M.
        • Petrie M.C.
        • Filippatos G.S.
        • Anker S.D.
        • Rosano G.
        • Bauersachs J.
        • 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 May; 20: 853-872
        • 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
        • Nissen S.E.
        • Wolski K.
        Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.
        N Engl J Med. 2007 Jun 14; 356: 2457-2471
      1. US Department of Health and Human Services, Guidance for Industry. Diabetes Mellitus – evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes (December 2008). <>.

      2. European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus (May 2012). <>.

        • McMurray J.J.
        • Gerstein H.C.
        • Holman R.R.
        • Pfeffer M.A.
        Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored.
        Lancet Diabet. Endocrinol. 2014; 2 (Oct): 843-851
        • Brochu Bradley
        • Chan Michael
        Treatment of diabetes and heart failure: a paradigm shift for cardiologists?.
        Curr Opin Cardiol. 2019; 34: 207-212
        • McGuire D.K.
        • Marx N.
        • Johansen O.E.
        • Inzucchi S.E.
        • Rosenstock J.
        • George J.T.
        FDA guidance on antihyperglyacemic therapies for type 2 diabetes: One decade later.
        Diabetes Obes Metab. 2019 May; 21: 1073-1078
        • Cefalu W.T.
        • Kaul S.
        • Gerstein H.C.
        • Holman R.R.
        • Zinman B.
        • Skyler J.S.
        • et al.
        Cardiovascular outcomes trials in type 2 diabetes: where do we go from here? reflections from a diabetes care editors' expert forum.
        Diabet. Care. 2018 Jan; 41: 14-31
        • Wiviott S.D.
        • Raz I.
        • Bonaca M.P.
        • Mosenzon O.
        • Kato E.T.
        • Cahn A.
        • et al.
        Investigators D-T. dapaglifozin and cardiovascular outcomes in Type 2 diabetes.
        N Engl J Med. 2019; 380: 347-357
        • Foretz M.
        • Guigas B.
        • Bertrand L.
        • Pollak M.
        • Viollet B.
        Metformin: from mechanisms of action to therapies.
        Cell Metab. 2014; 20: 953-966
        • Eurich D.T.
        • Weir D.L.
        • Majumdar S.R.
        • Tsuyuki R.T.
        • Johnson J.A.
        • Tjosvold L.
        • 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
        • Eurich D.T.
        • McAlister F.A.
        • Blackburn D.F.
        • Majumdar S.R.
        • Tsuyuki R.T.
        • Varney J.
        • et al.
        Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review.
        BMJ. 2007; 335: 497
        • 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: 53-58
        • Hippisley-Cox J.
        • Coupland C.
        Diabetes treatments and risk of heart failure, cardiovascular disease, and all cause mortality: cohort study in primary care.
        BMJ. 2016; 354i3477
        • Perfetti R.
        • D’Amico E.
        Rational drug design and PPAR agonists.
        Curr Diab Rep. 2005; 5: 340-345
        • Scirica B.M.
        • Bhatt D.L.
        • Braunwald E.
        • et al.
        SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
        N Engl J Med. 2013; 369: 1317-1326
        • White W.B.
        • Cannon C.P.
        • Heller S.R.
        • et al.
        EXAMINE Investigators Alogliptin after acute coronary syndrome in patients with type 2 diabetes.
        N Engl J Med. 2013; 369: 1327-1335
        • Green J.B.
        • Bethel M.A.
        • Armstrong P.W.
        • et al.
        TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2015; 373: 232-242
        • Pfeffer M.A.
        • Claggett B.
        • Diaz R.
        • et al.
        ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
        N Engl J Med. 2015; 373: 2247-2257
        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • et al.
        EMPAREG OUTCOME Investigators Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2128
        • Marso S.P.
        • Daniels G.H.
        • Brown-Frandsen K.
        LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2016; 375: 311-322
        • Marso S.P.
        • Bain S.C.
        • Consoli A.
        • et al.
        SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
        N Engl J Med. 2016; 375: 1834-1844
        • Holman Rury R.
        • Bethel M. Angelyn
        • Mentz Robert J.
        • Thompson Vivian P.
        • Lokhnygina Yuliya
        • Buse John B.
        • Chan Juliana C.
        • Choi Jasmine
        • Gustavson Stephanie M.
        • Iqbal Nayyar
        • Maggioni Aldo P.
        • Marso Steven P.
        • Öhman Peter
        • Pagidipati Neha J.
        • Poulter Neil
        • Ramachandran Ambady
        • Zinman Bernard
        • Hernandez Adrian F.
        Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2017; 377: 1228-1239
        • Neal B.
        • Perkovic V.
        • Mahaffey K.W.
        CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes.
        N Engl J Med. 2017; 377: 644-657
      3. Hernandez AF, Green JB, Janmohamed S, D'Agostino RB Sr, Granger CB, Jones NP, et al; Harmony Outcomes committees and investigators. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018 Oct 27;392(10157):1519-1529.

      4. Furtado RHM, Bonaca MP, Raz I, Zelniker TA, Mosenzon O, Cahn A, et al. Dapagliflozin and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Prior Myocardial Infarction: A Sub-analysis From DECLARE TIMI-58 Trial. Circulation. 2019 Mar 18. 10.1161/CIRCULATIONAHA.119.039996. [Epub ahead of print]

      5. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al; CREDENCE Trial Investigators. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019 Apr 14. 10.1056/NEJMoa1811744. [Epub ahead of print]

        • Rosenstock J.
        • Perkovic V.
        • Johansen O.E.
        • et al.
        Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial.
        JAMA. 2019; 32: 69-79
        • Gerstein H.C.
        • Colhoun H.M.
        • Dagenais G.R.
        • Diaz R.
        • Lakshmanan M.
        • Pais P.
        • et al.
        REWIND Invenstigation. Dulaglutide and cardiovascular outcome in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
        Lancet. 2019; 13 (Jul 394 (10193)): 121-130
        • Patorno E.
        • Pawar A.
        • Franklin J.M.
        • Najafzadeh M.
        • Deruaz-Luyet A.
        • Brodovicz K.G.
        • et al.
        Empaglifozin and the risk of heart failure hospitalization in routine clinical care.
        Circulation. 2019 Jun 18; 139: 2822-2830
        • Cavender M.A.
        • Norhammar A.
        • Birkeland K.I.
        • Jørgensen M.E.
        • Wilding J.P.
        • Khunti K.
        • et al.
        CVD-REAL investigators and study group. SGLT-2 inhibitors and cardiovascular risk: an analysis of CVD-REAL.
        J Am Coll Cardiol. 2018; 71 (Jun 5): 2497-2506
        • Kosiborod M.
        • Lam C.S.P.
        • Kohsaka S.
        • Kim D.J.
        • Karasik A.
        • Shaw J.
        • et al.
        CVD-REAL Investigators and study group. cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering Drugs: The CVD-REAL 2 study.
        J Am Coll Cardiol. 2018; (Epub 2018 Mar 11. Jun 12): 712628-712639
        • Lytvyn Y.
        • Bjornstad P.
        • Udell J.A.
        • Lovshin J.A.
        • Cherney D.Z.I.
        Sodium glucose cotrasporter-2 inhibition in heart failure. Potential mechanism, clinical applications and summary of clinical trials.
        Circulation. 2017; 136: 1643-1658
        • Ta Zelniker
        • Braunwald E.
        Cardiac and Renal Effects of Sodium-Glucose cotransporter 2 inhibitors in diabetes: JACC State of the Art Review.
        J Am Coll Cardiol. 2018; 72: 1845-1855
        • Heerspink H.J.
        • Perkins B.A.
        • Fitchett D.H.
        • Husain M.
        • Cherney D.Z.
        Sodium Glucose Cotransporter 2 Inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanism, and clinical applications.
        Circulation. 2016; 134: 752-772
        • Filippatos T.D.
        • Liontos A.
        • Papakitsou I.
        • Elisaf M.S.
        SGTL2 inhibitors and cardioprotection: a matter of debate and multiple hypotheses.
        Postgrad Med. 2019 Mar; 131: 82-88
        • Sato T.
        • Aizawa Y.
        • Yuasa S.
        • Kishi S.
        • Fuse K.
        • Fujita S.
        • et al.
        The effect of dapaglifozin treatment on epicardial adipose tissue volume.
        Cardiovasc Diabetol. 2018; 17: 6
        • Davies M.J.
        • D’Alessio D.A.
        • Fradkin J.
        • Kernan W.N.
        • Mathieu C.
        • Mingrone G.
        • et al.
        A consensus report by the American Diabetes Association (ADA) and the European Association for the Study od Diabetes (EASD).
        Diabetologia. 2018; 2018: 2461-2498