Heart Failure Reviews

, Volume 23, Issue 3, pp 469–479 | Cite as

Heart failure risk and major cardiovascular events in diabetes: an overview of within-group differences in non-insulin antidiabetic treatment

  • Paola Terlizzese
  • Fabrizio Losurdo
  • Massimo Iacoviello
  • Nadia Aspromonte


Recently, great attention is paid to cardiovascular impact of non-insulin glucose-lowering drugs, particularly in terms of major cardiovascular events and risk of heart failure. In this regard, a surprising diversity among different molecules within the same pharmacological class has been noticed, yielding to an intra-class discrepancy which has no analogous in other cardiovascular fields. The aim of this paper is to review the literature, giving an insight of the heterogeneous effects among groups and within group shown by oral antidiabetic drugs, with a special concern to fragile patients, such as those with or at risk of heart failure.


Heart failure Diabetes Oral antidiabetic drugs Biguanides Sulfonylureas Thiazolidinediones Alpha-glucosidase inhibitors GLP-1 agonists SGLT-2 inhibitors 


  1. 1.
    Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Magid D, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, Moy CS, Mussolino ME, Nichol G, Paynter NP, Schreiner PJ, Sorlie PD, Stein J, Turan TN, Virani SS, Wong ND, Woo D, Turner MB, American Heart Association Statistics Committee and Stroke Statistics Subcommittee (2013) Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 127:e6–245CrossRefPubMedGoogle Scholar
  2. 2.
    De Marco R, Locatelli F, Zoppini G, Verlato G, Bonora E, Muggeo M (1999) Cause-specific mortality in type 2 diabetes. Verona Diabetes Study Diabetes Care 22:756–761CrossRefPubMedGoogle Scholar
  3. 3.
    Beckman JA, Creager MA, Libby P (2002) Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 287:2570–2581Google Scholar
  4. 4.
    Nichols GA, Gullion CM, Koro CE, Ephross SA, Brown JB (2004) The incidence of congestive heart failure in type 2 diabetes: an update. Diabetes Care 27:1879–1884CrossRefPubMedGoogle Scholar
  5. 5.
    Gilbert RE, Krum H (2015) Heart failure in diabetes: effects of anti-hyperglycaemic drug therapy. Lancet 385:2107–2117CrossRefPubMedGoogle Scholar
  6. 6.
    Bell DS (2003) Heart failure: the frequent, forgotten, and often fatal complication of diabetes. Diabetes Care 26:2433–2441CrossRefPubMedGoogle Scholar
  7. 7.
    Krum H, Gilbert RE (2003) Demographics and concomitant disorders in heart failure. Lancet 362:147–158CrossRefPubMedGoogle Scholar
  8. 8.
    Mosterd A, Cost B, Hoes AW, de Bruijne MC, Deckers JW, Hofman A, Grobbee DE (2001) The prognosis of heart failure in the general population: the Rotterdam Study. Eur Heart J 22:1318–1327CrossRefPubMedGoogle Scholar
  9. 9.
    FDA. Guidance for industry: diabetes mellitus-evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. 2008. Accessed 19 July 2015
  10. 10.
    Knatterud L. (2005) University Group Diabetes Program (UGDP). Encyclopedia of Biostatistics, Online 2005. John Wiley & Sons, Inc. New York, NY.Google Scholar
  11. 11.
    The University Group Diabetes Program (1975) A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. V. Evaluation of pheniformin therapy. Diabetes 24(Suppl 1):65–184Google Scholar
  12. 12.
    UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853CrossRefGoogle Scholar
  13. 13.
  14. 14.
    Home PD, Popcock SJ, Beck-Nielsen H et al (2009) Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 373:2125–2135CrossRefPubMedGoogle Scholar
  15. 15.
    Dormandy JA, Charbonnel B, Eckland DJ et al (2005) 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 366:1279–1289CrossRefPubMedGoogle Scholar
  16. 16.
    Hanefeld M, Catagay M, Petrowitsch T et al (2004) Acarbose reduces the risk of myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term studies. Eur Heart J 25:10–16Google Scholar
  17. 17.
    Nakamura K, Oe H, Kihara H, Shimada K, Fukuda S, Watanabe K, Takagi T, Yunoki K, Miyoshi T, Hirata K, Yoshikawa J, Ito H (2014) DPP-4 inhibitor and alpha glucosidase inhibitor equally improve endothelial function in patients with type 2 diabetes. EDGE Study Cardiovasc Diabetol 13:110CrossRefPubMedGoogle Scholar
  18. 18.
    Kitano D, Chiku M, Li Y, Okumura Y, Fukamachi D, Takayama T, Hiro T, Saito S, Hirayama A (2013) Miglitol improves postprandial endothelial dysfunction in patients with acute coronary syndrome and new-onset postprandial hyperglycemia. Cardiovasc Diabetol 12:92CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Scirica BM, Bhatt DL, Braunwald E, SAVOR-TIMI 53 Steering Committee and Investigators et al (2013) Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 369:1317–1326CrossRefPubMedGoogle Scholar
  20. 20.
    Green JB, Bethel MA, Armstrong PW et al (2015) Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 373:232–224Google Scholar
  21. 21.
    Zannad F, Cannon CP, Cushman WC et al (2015) Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet 385:2067–2076Google Scholar
  22. 22.
    White WB, Cannon CP, Cushman WC et al (2013) EXAMINE investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabets. N Engl J Med 369:1327–1335CrossRefPubMedGoogle Scholar
  23. 23.
    McMurray J (2013) The Vildagliptin in Ventricular Dysfunction Diabetes (VIVIDD) trial. Heart Failure Congress 2013:25–28Google Scholar
  24. 24.
    McInnes G, Evans M, Del Prato S (2015) Cardiovascular and heart failure profile of Vildagliptin: a meta-analysis of 17000 patients. Diabetes Obes Metab 17:1085–1092CrossRefPubMedGoogle Scholar
  25. 25.
    Marso SP, Daniels GH, Brown-Frandsen K, LEADER Steering committee on behalf of the LEADER trial investigators et al (2016) Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 375:311–322Google Scholar
  26. 26.
    Pfeffer MA, Claggett B, Diaz R et al (2015) Lixisenatide in in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 373:2247–2257CrossRefPubMedGoogle Scholar
  27. 27.
    Fitchett D, Zinman B, Wanner C et al (2016) 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 37:1526–1534Google Scholar
  28. 28.
    Neal B, Perkovic V, Mahaffey KW, on behalf of the CANVAS Program Collaborative Group et al (2017) Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377:644–657CrossRefPubMedGoogle Scholar
  29. 29.
    Endocrinologic and Metabolic Drugs Advisory Committee Meeting. Dapaglifozin BMS-512148. Dec 12, 2013. MeetingMaterials/Drugs/EndocrinologicAndMetabolicDrugsAdvisoryCommittee/UCM379659.pdf (accessed March 22, 2015)
  30. 30.
    Hsiao FY, Huang WF, Wen YW, Chen PF, Kuo KN, Tsai YW (2009) Thiazolidinediones and cardiovascular events in patients with type 2 diabetes mellitus: a retrospective cohort study of over 473,000 patients using the National Health Insurance Database in Taiwan. Drug Saf 32:675–690CrossRefPubMedGoogle Scholar
  31. 31.
    Tsoulaki I, Molokhia M, Curcin V, Little MP, Millet CJ, Ng A, Hughes RI, Khunti K, Wilkins MR, Majeed A, Elliot P (2009) Risk of cardiovascular disease and all-cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ 339:b4731CrossRefGoogle Scholar
  32. 32.
    Klepzig H, Kober G, Matter C et al (1999) Sulfonylureas and ischaemic preconditioning; a double-blind, placebo-controlled evaluation of glimepiride and glibenclamide. Eur Heart J 20:439–446CrossRefPubMedGoogle Scholar
  33. 33.
    Pantalone KM, Kattan MW, Yu C et al (2009) The risk of developing coronary artery disease or congestive heart failure, and overall mortality, in type 2 diabetic patients receiving rosiglitazone, pioglitazone, metformin or sulfonylureas: a retrospective analysis. Acta Diabetol 46:145–154CrossRefPubMedGoogle Scholar
  34. 34.
    Tzoulaki I, Molokhia M, Curcin V et al (2009) Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ 339:b4731CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Rosenstock J, Kikolaus M, Kahn SE et al (2013) Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: rationale for the active-comparator CAROLINA trial. Diab Vasc Dis Res 10:289–301CrossRefPubMedGoogle Scholar
  36. 36.
    Loke YK, Kwok CS, Singh S (2011) Comparative cardiovascular effects of thiazolidinediones: a systematic review and meta-analysis of observational studies. BMJ 342:d1309CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Chen X, Yang L, Zhai SD (2012) Risk of cardiovascular disease and all-cause mortality among diabetic patients prescribed rosiglitazone or pioglitazone: a meta-analysis of retrospective cohort studies. Chin Med J 125:4301–4306PubMedGoogle Scholar
  38. 38.
    Roussel R, Travert F, Pasquet B et al (2010) Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med 170:1892–1899CrossRefPubMedGoogle Scholar
  39. 39.
    Inzucchi SE, Masoudi FA, McGuire DK (2007) Metformin in heart failure. Diabetes Care 30:e129CrossRefPubMedGoogle Scholar
  40. 40.
    Eurich DT, Weir DL, Majumdar SR, Tsuyuki RT, Johnson JA, Tjosvold L, Vanderloo SE, McAlister FA (2013) 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 6:395–402Google Scholar
  41. 41.
    Boussageon R, Supper I, Bejan-Angoulvant T, Kellou N, Cucherat M, Boissel J-P, Kass B, Moreau A, Gueyffier F, Cornu C (2012) Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS Med 9:e1001204CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    American Diabetic Association (2017) Pharmacologic approaches to glycemic treatment. Diabetes Care 40(Suppl 1):S64–S74CrossRefGoogle Scholar
  43. 43.
    National Institute for Health and Care Excellence (NICE) (2017) Type 2 diabetes in adults: management [NG28]. NICE, LondonGoogle Scholar
  44. 44.
    Ponikowski P, Voors AA, Anker SD, Bueno H et al (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 37:2129–2200Google Scholar
  45. 45.
    Shah DD, Fonarow GC, Horwich TB (2010) Metformin therapy and outcomes in patients with advanced systolic heart failure and diabetes. J Card Fail 16:200–206CrossRefPubMedGoogle Scholar
  46. 46.
    Inzucchi SE (2002) Oral Antihyperglycemic therapy for type 2 diabetes: scientific review. J Am Med Assoc 287:360–372CrossRefGoogle Scholar
  47. 47.
    Masoudi FA, Inzucchi SE (2007) Diabetes mellitus and heart failure: epidemiology, mechanisms, and pharmacotherapy. Am J Cardiol 99:113b–132bCrossRefPubMedGoogle Scholar
  48. 48.
    Knatterud GL, Klimt CR, Levin ME, Jacobson ME, Goldner MG (1978) Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. VII. Mortality and selected nonfatal events with insulin treatment. J Am Med Assoc 240:37–42CrossRefGoogle Scholar
  49. 49.
    Morgan CL, Poole CD, Evans M, Barnett AH, Jenkins-Jones S, Currie CJ (2012) What next after metformin? A retrospective evaluation of the outcome of the second-lne, glucose-lowering therapies in people with type 2 diabetes. Journal Clin Endcrinol Metab 97:4605–4612CrossRefGoogle Scholar
  50. 50.
    Johansen OE, Birkeland KI (2007) Defining the role of repaglinide in the management of type 2 diabetes mellitus: a review. Am J Cardiovasc Drugs 7:319–335Google Scholar
  51. 51.
    Fisman EZ, Motro M, Tenenbaum A (2008) Non-insulin antidiabetic therapy in cardiac patients: current problems and future prospects. Adv Cardiol 45:154–170CrossRefPubMedGoogle Scholar
  52. 52.
    Rizzo MR, Barbieri M, Grella R, Passariello N, Paolisso G (2005 Jun) Repaglinide has more beneficial effect on cardiovascular risk factors than glimepiride: data from meal-test study. Diabetes Metab 31(3 Pt 1):255–260CrossRefPubMedGoogle Scholar
  53. 53.
    Lund SS, Tarnow L, Stehouwer CD et al (2008) Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes. Eur J Endocrinol 158:631–641Google Scholar
  54. 54.
    Cioffi G, Faggiano P, Lucci D et al (2013) Left ventricular dysfunction and outcome at two-year follow-up in patients with type 2 diabetes: the DYDA study. Diabetes Res Clin Pract 101:236–242Google Scholar
  55. 55.
    NAVIGATOR, Study Group, Holman RR, Haffner SM, McMurray JJ et al (2010) Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med 362:1463–1476Google Scholar
  56. 56.
    Scheen AJ (2010) NAVIGATOR: a trial of prevention of cardiovascular complications and type 2 diabetes with valsartan and/or nateglinide. Rev Med Liege 65:217–223Google Scholar
  57. 57.
    Nissen SE, Wolski K (2008) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 359:1092–1095CrossRefGoogle Scholar
  58. 58.
    Defronzo RA, Mehta RJ, Schnure JJ (2013) Pleiotropic effects of thiazolidinediones: implications for the treatment of patients with type 2 diabetes mellitus. Hosp Pract (1995) 41:132–147Google Scholar
  59. 59.
    Roussel R, Hadjadj S, Pasquet B et al (2013) Thiazolidinedione use is not associated with worse cardiovascular outcomes: a study in 28,332 high risk patients with diabetes in routine clinical practice: brief title: thiazolidinedione use and mortality. Int J Cardiol 167:1380–1384Google Scholar
  60. 60.
    Winkelmayer WC, Setoguchi S, Levin R, Solomon DH (2008) Comparison of cardiovascular outcomes in elderly patients with diabetes who initiated rosiglitazone vs pioglitazone therapy. Arch Intern Med 168:2368–2375CrossRefPubMedGoogle Scholar
  61. 61.
    Lago RM, Singh PP, Nesto RW (2007) Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet 370:1129–1136CrossRefPubMedGoogle Scholar
  62. 62.
    Nesto RW, Bell D, Bonow RO, American Heart Association, American Diabetes Association et al (2003) Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Circulation 108:2941–2948Google Scholar
  63. 63.
    Standl E, Schnell O (2012) Alpha-glucosidase inhibitors 2012-cardiovascular considerations and trial evaluation. Diab Vasc Dis Res 9:163–169Google Scholar
  64. 64.
  65. 65.
    Toh S, Hampp C, Reichman ME et al (2016) Risk for hospitalized heart failure among new users of saxagliptin, sitagliptin and other antihyperglycemic drugs: a retrospective cohort study. Ann Int Med 164:705–714CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Margulies KB, Hernandez AF, Redfield MM et al (2016) Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction a randomized clinical trial. JAMA 316:500–508Google Scholar
  67. 67.
    Jorsal A, Kistorp C, Holmager P et al (2017) Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)—a multicentre, double-blind, randomised, placebo-controlled trial. Eur J Heart Fail 19:69–77CrossRefPubMedGoogle Scholar
  68. 68.
    Nigro SC, Riche DM, Pheng M et al (2013) Canaglifozin, a novel SGLT2 inhibitor for treatment of type 2 diabetes. Ann Pharmacother 47:1301–1311CrossRefPubMedGoogle Scholar
  69. 69.
    Zinman B, Wanner C, Lachin JM et al (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373:2117–2128CrossRefPubMedGoogle Scholar
  70. 70.
    Grempler R, Thomas L, Eckhardt M et al (2012) Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterization and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab 14:83–90Google Scholar
  71. 71.
    Sano M (2017) Hemodynamic effects of sodium-glucose cotransporter 2 inhibitors. J Clin Med Res 9:457–460Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of CardiologyUniversity of BariBariItaly
  2. 2.Diabetic Foot Care CenterHumanitas GavazzeniBergamoItaly
  3. 3.Cardiology Unit, Cardiothoracic DepartmentPoliclinic University HospitalBariItaly
  4. 4.Department of Cardiovascular and Thoracic SciencesCatholic University of the Sacred Heart, Agostino Gemelli FoundationRomeItaly

Personalised recommendations