Skip to main content

Advertisement

Log in

Treatment of Diabetes in Patients with Heart Failure

  • Myocardial Disease (A Abbate, Section Editor)
  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

This review aims to summarize and discuss heart failure outcomes for current glucose-lowering agents in patients with type 2 diabetes mellitus.

Recent Findings

Current regulations require cardiovascular outcomes trials for new glucose-lowering therapies to establish that there is no unacceptable increase in cardiovascular risk prior to approval. These cardiovascular outcomes trials include glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose cotransporter-2 inhibitors. Overall, 87,162 patients have been studied in 10 published cardiovascular outcomes trials. There was no significant increase in major adverse cardiovascular events including cardiovascular mortality, myocardial infarction, and stroke in any of these trials. Heart failure was a component of the secondary endpoint of all of these trials, but only two of these studies show a significant improvement in rates of hospitalization for heart failure.

Summary

Expanded regulatory labeling for reduction in cardiovascular mortality (empagliflozin) and reduction in major adverse cardiovascular events (liraglutide) has recently been established. Saxagliptin and to a lesser part alogliptin have been associated with an increased rate of hospitalization for heart failure. Canagliflozin and empagliflozin are the only two medications that have shown a clear benefit in rates of heart failure hospitalization in treatment of patients with type 2 diabetes mellitus.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major Importance

  1. Nichols GA, Hillier TA, Erbey JR, Brown JB. Congestive heart failure in type 2 diabetes: prevalence, incidence, and risk factors. Diabetes Care. 2001;24(9):1614–9.

    Article  CAS  PubMed  Google Scholar 

  2. Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL, Goff DC Jr. Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care. 2004;27(3):699–703.

    Article  PubMed  Google Scholar 

  3. Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, et al. Heart disease and stroke Statistics-2018 update: a report from the American Heart Association. Circulation. 2018;137(12):e67–e492. https://doi.org/10.1161/cir.0000000000000558.

    Article  PubMed  Google Scholar 

  4. Echouffo-Tcheugui JB, Xu H, DeVore AD, Schulte PJ, Butler J, Yancy CW, 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. https://doi.org/10.1016/j.ahj.2016.07.025.

    Article  PubMed  Google Scholar 

  5. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ (Clinical research ed). 2000;321(7258):405–12.

    Article  CAS  Google Scholar 

  6. Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575–85. https://doi.org/10.1056/NEJMoa1001286.

    Article  CAS  PubMed  Google Scholar 

  7. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560–72. https://doi.org/10.1056/NEJMoa0802987.

    Article  CAS  PubMed  Google Scholar 

  8. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129–39. https://doi.org/10.1056/NEJMoa0808431.

    Article  CAS  PubMed  Google Scholar 

  9. 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(1):91–91.e6. https://doi.org/10.1016/j.ahj.2005.10.008.

    Article  CAS  PubMed  Google Scholar 

  10. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334(9):574–9. https://doi.org/10.1056/nejm199602293340906.

    Article  CAS  PubMed  Google Scholar 

  11. Administration USFaD. FDA drug safety communication: FDA revises warnings regardings use of the diabetes medicine metformin in certain patients with reduced kidney function.

  12. • Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. Consensus Statement By The American Association Of Clinical Endocrinologists And American College Of Endocrinology On The Comprehensive Type 2 Diabetes Management Algorithm - 2018 Executive Summary. Endocr Pract. 2018;24(1):91–120. https://doi.org/10.4158/cs-2017-0153. This document provides a uptodate detailed approach to treatment in patients with Type 2 diabetes mellitus.

    Article  PubMed  Google Scholar 

  13. • Connelly KA, Gilbert RE, Liu P. Treatment of diabetes in people with heart failure. Can J Diabetes. 2018;42(Suppl 1):S196–200. https://doi.org/10.1016/j.jcjd.2017.10.026. This paper offers a dedicated approach to treatment of diabetes in patients with heart failure.

    Article  PubMed  Google Scholar 

  14. Facila L, Fabregat-Andres O, Bertomeu V, Navarro JP, Minana G, Garcia-Blas S, et al. Metformin and risk of long-term mortality following an admission for acute heart failure. J Cardiovasc Med (Hagerstown). 2017;18(2):69–73. https://doi.org/10.2459/jcm.0000000000000420.

    Article  CAS  Google Scholar 

  15. Andersson C, Olesen JB, Hansen PR, Weeke P, Norgaard ML, Jorgensen CH, et al. Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: a retrospective nationwide cohort study. Diabetologia. 2010;53(12):2546–53. https://doi.org/10.1007/s00125-010-1906-6.

    Article  CAS  PubMed  Google Scholar 

  16. Ashcroft FM. Mechanisms of the glycaemic effects of sulfonylureas. Horm Metab Res. 1996;28(9):456–63. https://doi.org/10.1055/s-2007-979837.

    Article  CAS  PubMed  Google Scholar 

  17. UKPDS Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet (London, England). 1998;352(9131):837–53.

  18. Zeller M, Danchin N, Simon D, Vahanian A, Lorgis L, Cottin Y, et al. Impact of type of preadmission sulfonylureas on mortality and cardiovascular outcomes in diabetic patients with acute myocardial infarction. J Clin Endocrinol Metab. 2010;95(11):4993–5002. https://doi.org/10.1210/jc.2010-0449.

    Article  CAS  PubMed  Google Scholar 

  19. Roumie CL, Min JY, D'Agostino McGowan L, Presley C, Grijalva CG, Hackstadt AJ et al. Comparative safety of sulfonylurea and metformin monotherapy on the risk of heart failure: a cohort study. Journal of the American Heart Association. 2017;6(4):e005379. https://doi.org/10.1161/jaha.116.005379.

  20. 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(1):168–74. https://doi.org/10.1016/j.ahj.2004.07.005.

    Article  CAS  PubMed  Google Scholar 

  21. 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(4):319–28. https://doi.org/10.1056/NEJMoa1203858.

    Article  CAS  PubMed  Google Scholar 

  22. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med. 2004;351(11):1106–18. https://doi.org/10.1056/NEJMra041001.

    Article  PubMed  Google Scholar 

  23. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, et al. 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 (London, England). 2005;366(9493):1279–89. https://doi.org/10.1016/s0140-6736(05)67528-9.

    Article  CAS  Google Scholar 

  24. Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet (London, England). 2006;368(9541):1096–105. https://doi.org/10.1016/s0140-6736(06)69420-8.

    Article  CAS  Google Scholar 

  25. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355(23):2427–43. https://doi.org/10.1056/NEJMoa066224.

    Article  CAS  PubMed  Google Scholar 

  26. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–71. https://doi.org/10.1056/NEJMoa072761.

    Article  CAS  PubMed  Google Scholar 

  27. Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet (London, England). 2009;373(9681):2125–35. https://doi.org/10.1016/s0140-6736(09)60953-3.

    Article  CAS  Google Scholar 

  28. Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet (London, England). 2007;370(9593):1129–36. https://doi.org/10.1016/s0140-6736(07)61514-1.

    Article  CAS  Google Scholar 

  29. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298(10):1180–8. https://doi.org/10.1001/jama.298.10.1180.

    Article  CAS  PubMed  Google Scholar 

  30. • U.S. Food and Drug Administration. Diabetes Mellitus: Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. Guidance for Industry. 2008. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. This guidance details the changes to the regulatory approval process for new glucose-lowering agents.

  31. Davidson MH. Cardiovascular effects of glucagonlike peptide-1 agonists. Am J Cardiol. 2011;108(3 Suppl):33b–41b. https://doi.org/10.1016/j.amjcard.2011.03.046.

    Article  CAS  PubMed  Google Scholar 

  32. •• Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Kober LV, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247–57. https://doi.org/10.1056/NEJMoa1509225. This study outlines the cardiovascular outcomes for Lixisenatide, the first of these trials for GLP-1 receptor agonists.

    Article  CAS  PubMed  Google Scholar 

  33. •• Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311–22. https://doi.org/10.1056/NEJMoa1603827. This study outlines the cardiovascular outcomes for Liraglutide, based on these results it received FDA approval for the indication to reduce major adverse cardiovascular events in adults with type 2 DM and established cardiovascular disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. •• Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44. https://doi.org/10.1056/NEJMoa1607141. This study outlines the cardiovascular outcomes for Semaglutide.

    Article  CAS  PubMed  Google Scholar 

  35. •• Mentz RJ, Bethel MA, Gustavson S, Thompson VP, Pagidipati NJ, Buse JB, et al. Baseline characteristics of patients enrolled in the Exenatide study of cardiovascular event lowering (EXSCEL). Am Heart J. 2017;187:1–9. https://doi.org/10.1016/j.ahj.2017.02.005. This study outlines the cardiovascular outcomes for Exenatide.

    Article  CAS  PubMed  Google Scholar 

  36. Margulies KB, Hernandez AF, Redfield MM, Givertz MM, Oliveira GH, Cole R, et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. JAMA. 2016;316(5):500–8. https://doi.org/10.1001/jama.2016.10260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, et al. Effects of once-weekly Exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228–39. https://doi.org/10.1056/NEJMoa1612917.

    Article  CAS  PubMed  Google Scholar 

  38. Fisher M, Petrie MC, Ambery PD, Donaldson J, Ye J, McMurray JJ. Cardiovascular safety of albiglutide in the Harmony programme: a meta-analysis. Lancet Diabetes Endocrinol. 2015;3(9):697–703. https://doi.org/10.1016/s2213-8587(15)00233-8.

    Article  CAS  PubMed  Google Scholar 

  39. •• Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26. https://doi.org/10.1056/NEJMoa1307684. This study outlines the cardiovascular outcomes for Saxagliptin and the unexpected findings of increased rate of hospitalization for heart failure.

    Article  CAS  PubMed  Google Scholar 

  40. Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P, et al. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2014;130(18):1579–88. https://doi.org/10.1161/circulationaha.114.010389.

    Article  CAS  PubMed  Google Scholar 

  41. •• 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(14):1327–35. https://doi.org/10.1056/NEJMoa1305889. Cardiovascular outcomes trial for Alogliptin that demonstrates a trend towards an increased rate of hospitalization for heart failure.

    Article  CAS  PubMed  Google Scholar 

  42. Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, 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 (London, England). 2015;385(9982):2067–76. https://doi.org/10.1016/s0140-6736(14)62225-x.

    Article  CAS  Google Scholar 

  43. •• Green JB, Bethel MA, 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(3):232–42. https://doi.org/10.1056/NEJMoa1501352. This study detailes the cardiovascular outcomes for Sitagliptin and importantly demonstrated that there was no increased risk of hospitalization for heart failure.

    Article  CAS  PubMed  Google Scholar 

  44. Scirica BM, Mosenzon O, Bhatt DL, Udell JA, Steg PG, McGuire DK, et al. Cardiovascular outcomes according to urinary albumin and kidney disease in patients with type 2 diabetes at high cardiovascular risk: observations from the SAVOR-TIMI 53 trial. JAMA Cardiol. 2018;3(2):155–63. https://doi.org/10.1001/jamacardio.2017.4228.

    Article  PubMed  Google Scholar 

  45. White WB, Kupfer S, Zannad F, Mehta CR, Wilson CA, Lei L, et al. Cardiovascular mortality in patients with type 2 diabetes and recent acute coronary syndromes from the Examine trial. Diabetes Care. 2016;39(7):1267–73. https://doi.org/10.2337/dc16-0303.

    Article  CAS  PubMed  Google Scholar 

  46. Eurich DT, Weir DL, Simpson SH, Senthilselvan A, McAlister FA. Risk of new-onset heart failure in patients using sitagliptin: a population-based cohort study. Diabet Med. 2016;33(5):621–30. https://doi.org/10.1111/dme.12867.

    Article  CAS  PubMed  Google Scholar 

  47. Rosenstock J, Perkovic V, Alexander JH, Cooper ME, Marx N, Pencina MJ, et al. Rationale, design, and baseline characteristics of the cardiovascular safety and renal microvascular outcome study with linagliptin (CARMELINA((R))): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk. Cardiovasc Diabetol. 2018;17(1):39. https://doi.org/10.1186/s12933-018-0682-3.

    Article  PubMed  PubMed Central  Google Scholar 

  48. •• 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(22):2117–28. https://doi.org/10.1056/NEJMoa1504720. Cardiovascular outcomes trial for Empagliflozin, based on these results it received recognition from the FDA with an indcation to reduce the risk of cardiovascular death in patients with type 2 diabetes mellitus and cardiovascular disease.

    Article  CAS  PubMed  Google Scholar 

  49. Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME (R) trial. Eur Heart J. 2016;37(19):1526–34. https://doi.org/10.1093/eurheartj/ehv728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. •• Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–57. https://doi.org/10.1056/NEJMoa1611925. This study detailes the results from the integrated CANVAS program outlining the cardiovascular outcomes for canagliflozin which demonstrated a decrease in hospitalization for heart failure.

    Article  CAS  PubMed  Google Scholar 

  51. Fitchett D, Butler J, van de Borne P, Zinman B, Lachin JM, Wanner C, et al. Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME (R) trial. Eur Heart J. 2018;39(5):363–70. https://doi.org/10.1093/eurheartj/ehx511.

    Article  PubMed  Google Scholar 

  52. Mahaffey KW, Neal B, Perkovic V, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS program (Canagliflozin cardiovascular assessment study). Circulation. 2018;137(4):323–34. https://doi.org/10.1161/circulationaha.117.032038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Radholm K, Figtree G, Perkovic V, Solomon SD, Mahaffey KW, de Zeeuw D et al. Canagliflozin and heart failure in type 2 diabetes mellitus: results from the CANVAS program (Canagliflozin cardiovascular assessment study). Circulation 2018;137:00–00. https://doi.org/10.1161/circulationaha.118.034222.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors). Circulation. 2017;136(3):249–59. https://doi.org/10.1161/circulationaha.117.029190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Javed Butler.

Ethics declarations

Conflict of Interest

Christa D. Bowes reports no disclosures.

Lillian F. Lien has served as a consultant for Novo Nordisk, Merck, Eli Lilly, Sanofi, and Tandem, and receives royalties from Springer Inc.

Javed Butler has received research support from the National Institutes of Health, Patient Centered Outcomes Research Institute, and the European Union; and serves as a consultant for Adrenomed, Amgen, Array, Astra Zeneca, Bayer, Berlin Cures, Boehringer Ingelheim, Bristol Myers Squib, CVRx, G3 Pharmaceutical, Innolife, Janssen, Lantheus, Luitpold, Medtronic, Merck, Novartis, Relypsa, Roche, Sanofi, StealthPeptide, SC Pharma, Vifor, and ZS Pharma.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Myocardial Disease

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bowes, C.D., Lien, L.F. & Butler, J. Treatment of Diabetes in Patients with Heart Failure. Curr Cardiol Rep 20, 97 (2018). https://doi.org/10.1007/s11886-018-1032-5

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11886-018-1032-5

Keywords

Navigation