Skip to main content
SpringerLink
Log in

Thiazolidinediones in Patients with Diabetes Mellitus and Heart Failure

Implications of Emerging Data

  • Current Opinion
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Individuals with diabetes mellitus have an increased risk of developing heart failure, usually as a consequence of coronary artery disease, although a specific diabetic cardiomyopathy, secondary to a microangiopathy, may also exist. The thiazolidinediones, a relatively new class of insulin-sensitizing agents used in the management of type 2 diabetes mellitus, have a number of complex metabolic actions on surrogate markers of atherogenesis, supported by the results of the recently published PROACTIVE (PROspective pioglitAzone Clinical Trial In macroVascular Events) trial. Unfortunately, the use of thiazolidinediones in individuals with diabetes mellitus and heart failure is limited because of a propensity to cause fluid retention. The underlying mechanisms of fluid retention have yet to be fully elucidated, but appear to be a dose-related class effect, exacerbated by combination therapy with insulin, and in some cases may be localized to peripheral edema. In parallel, echocardiographic studies show no significant effect of thiazolidinediones on cardiac structure or function.

The design of epidemiologic studies describing an increased risk of developing heart failure in individuals with type 2 diabetes mellitus prescribed thiazolidinediones has been questioned, and a study of ‘new users’ of antihyperglycemic treatments found no increased risk of hospitalization for heart failure with thiazolidinedione therapy. There is also increasing evidence for the potential benefits of insulin sensitization in patients with diabetes mellitus and known heart failure, and a large observational study of over 16 000 patients with a principal discharge diagnosis of heart failure found a reduced mortality (hazard ratio [HR] 0.87; 95% CI 0.80, 0.94) in those prescribed thiazolidinediones. This benefit was offset by an increased risk of readmission with heart failure (HR 1.06; 95% CI 1.00, 1.09).

Despite an increase in fluid-related events, recent studies suggest that individuals with type 2 diabetes mellitus and heart failure (New York Heart Association grade I/II) can be treated with thiazolidinediones with appropriate monitoring and adjustment of heart failure therapies. These findings would suggest the need for large-scale, prospective trials to investigate the safety and potential benefits of thiazolidinedione use in patients with diabetes mellitus and heart failure.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I

Similar content being viewed by others

References

  1. Ingelsson E, Sundstrom J, Arnlov J, et al. Insulin resistance and risk of congestive heart failure. JAMA 2005; 294(3): 334–41

    Article  PubMed  CAS  Google Scholar 

  2. Davis RC, Hobbs FDR, Lip GYH. ABC of heart failure: history and epidemiology. BMJ 2000; 320: 39–42

    Article  PubMed  CAS  Google Scholar 

  3. Kahn SE. The relative contribution of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia 2003; 46: 3–19

    Article  PubMed  CAS  Google Scholar 

  4. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 1974; 34: 29–34

    Article  PubMed  CAS  Google Scholar 

  5. Fisher BM, Frier BM. Evidence for a specific heart disease of diabetes in humans. Diabet Med 1990; 7: 478–89

    Article  PubMed  CAS  Google Scholar 

  6. Nichols GA, Hillier TA, Erbey JR, et al. Congestive heart failure in type 2 diabetes: prevalence, incidence, and risk factors. Diabetes Care 2001; 24: 1614–9

    Article  PubMed  CAS  Google Scholar 

  7. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med 2004; 351: 1106–18

    Article  PubMed  Google Scholar 

  8. Warram JH, Martin BC, Krolewski AS, et al. Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 1990; 113: 909–15

    PubMed  CAS  Google Scholar 

  9. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 2004; 27: 256–63

    Article  PubMed  CAS  Google Scholar 

  10. Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham study. JAMA 1979; 241: 2035–8

    Article  PubMed  CAS  Google Scholar 

  11. Kennedy FP. Do thiazolidinediones cause congestive heart failure? Mayo Clin Proc 2003; 78: 1076–7

    Article  PubMed  CAS  Google Scholar 

  12. Poirier P, Bogaty P, Garneau C, et al. Diastolic dysfunction in normotensive men with well-controlled type 2 diabetes: importance of maneuvers in echocardiographic screening for preclinical diabetic cardiomyopathy. Diabetes Care 2001; 24: 5–10

    Article  PubMed  CAS  Google Scholar 

  13. Iribarren C, Karter AJ, Go AS, et al. Glycemic control and heart failure among adult patients with diabetes. Circulation 2001; 103: 2668–73

    Article  PubMed  CAS  Google Scholar 

  14. 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

    Article  Google Scholar 

  15. Stevens MJ, Dayanikli F, Raffel DM, et al. Scintigraphic assessment of regionalized defects in myocardial sympathetic innervation and blood flow regulation in diabetic patients with autonomic neuropathy. J Am Coll Cardiol 1998; 31: 1575–84

    Article  PubMed  CAS  Google Scholar 

  16. Lopaschuk GD. Metabolic abnormalities in the diabetic heart. HeartFail Rev 2002; 7: 149–59

    CAS  Google Scholar 

  17. Ganguly PK, Pierce GN, Dhalla KS, et al. Defective sarcoplasmic reticular calcium transport in diabetic cardiomyopathy. Am J Physiol 1983; 244: E528–35

    PubMed  CAS  Google Scholar 

  18. Zhou Y-T, Grayburn P, Karim A, et al. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci U S A 2000; 97: 1784–9

    Article  PubMed  CAS  Google Scholar 

  19. Kendall DM. Thiazolidinediones: the case for early use. Diabetes Care 2006; 29: 154–7

    Article  PubMed  CAS  Google Scholar 

  20. Murphy EJ, Davern TJ, Shakil AO, et al. Troglitazone-induced fulminant hepatic failure: Acute Liver Failure Study Group. Dig Dis Sci 2000; 45: 549–53

    Article  PubMed  CAS  Google Scholar 

  21. Lebovitz HE. Differentiating members of the thiazolidinedione class: a focus on safety. Diabetes Metab Res Rev 2002; 18 Suppl. 2: 23–9

    Article  Google Scholar 

  22. Chiquette E, Ramirez G, DeFronzo R. A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factors. Arch Intern Med 2004; 164: 2097–104

    Article  PubMed  CAS  Google Scholar 

  23. Bennett SM, Agrawal A, Elasha H, et al. Rosiglitazone improves insulin sensitivity, glucose tolerance and ambulatory blood pressure in subjects with impaired glucose tolerance. Diabet Med 2004; 21: 415–22

    Article  PubMed  CAS  Google Scholar 

  24. Fullert S, Schneider F, Haak E, et al. Effects of pioglitazone in nondiabetic patients with arterial hypertension: a double blind placebo controlled study. J Clin Endocrinol Metab 2002; 87: 5503–6

    Article  PubMed  CAS  Google Scholar 

  25. Watanabe Y, Sunayama S, Shimada K, et al. Troglitazone improves endothelial dysfunction in patients with insulin resistance. J Atheroscler Thromb 2000; 7: 159–63

    PubMed  CAS  Google Scholar 

  26. Nesto R. C-reactive protein, its role in inflammation, type 2 diabetes and cardiovascular disease, and the effects of insulin-sensitizing treatment with thiazolidinediones. Diabet Med 2004; 21: 810–7

    Article  PubMed  CAS  Google Scholar 

  27. Koshiyama H, Shimono D, Kuwamura N, et al. Rapid communication: inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 2001; 86: 3452–6

    Article  PubMed  CAS  Google Scholar 

  28. Choi D, Kim S-K, Choi S-H, et al. Preventative effects of rosiglitazone on restenosis after coronary stent implantation in patients with type 2 diabetes. Diabetes Care 2004; 27: 2654–60

    Article  PubMed  CAS  Google Scholar 

  29. The 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

    Article  Google Scholar 

  30. Wang CH, Weisel RD, Liu PP, et al. Glitazones and heart failure. Circulation 2003; 107: 1350–4

    Article  PubMed  Google Scholar 

  31. Schiffrin EL. Peroxisome proliferator-activated receptors and cardiovascular remodelling. Am J Physiol Heart Circ Physiol 2005; 288: H1037–43

    Article  PubMed  CAS  Google Scholar 

  32. Bryant D, Becker L, Richardson J, et al. Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. Circulation 1998; 97: 1375–81

    Article  PubMed  CAS  Google Scholar 

  33. Neve BP, Fruchart JC, Staels B. Role of the peroxisome proliferator-activated receptors (PPAR) in atherosclerosis. Biochem Pharmacol 2000; 60: 1245–50

    Article  PubMed  CAS  Google Scholar 

  34. Cheng TO. Endothelin receptor blockade in congestive heart failure. Circulation 2001; 104: e96

    Article  PubMed  CAS  Google Scholar 

  35. Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 1998; 47: 507–14

    Article  PubMed  CAS  Google Scholar 

  36. Young MM, Squassante L, Werner J, et al. Troglitazone has no effect on red cell mass or other erythropoietic parameters. Eur J Clin Pharmacol 1999; 55: 101–4

    Article  PubMed  CAS  Google Scholar 

  37. Kendall DM, Buse JB, Goldberg RB, et al. A comparison of edema and weight gain effects of piogliazone and rosiglitazone in patients with type 2 diabetes and dyslipidaemia [abstract]. J Am Coll Cardiol 2005; 45(3 Suppl. A): 186A

    Google Scholar 

  38. Raskin P, Rendell M, Riddle MC, et al. A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes. Diabetes Care 2001; 24: 1226–32

    Article  PubMed  CAS  Google Scholar 

  39. Parke-Davis Pharmaceuticals. Rezulin (troglitazone) package insert. Morris Plains (NY): Parke-Davis Pharmaceuticals, 1997

    Google Scholar 

  40. Takeda Pharmaceuticals. Actos (pioglitazone) package insert. Lincolnshire (IL): Takeda Pharmaceuticals, 2000

    Google Scholar 

  41. GlaxoSmithKline Pharmaceuticals. Avandia (rosiglitazone) package insert. Philadelphia (PA): GlaxoSmithKline Pharmaceuticals, 2001

    Google Scholar 

  42. Tang WHW, Francis GS, Hoogwerf BJ, et al. Fluid retention after initiation of thiazolidinedione therapy in diabetic patients with established chronic heart failure. J Am Coll Cardiol 2003; 41: 1394–8

    Article  PubMed  CAS  Google Scholar 

  43. Malone RM, DeWalt DA, Pignone MP, et al. Is the tolerability of long-term thiazolidinedione therapy overstated? J Am Coll Cardiol 2003; 42: 1334–5

    Article  PubMed  Google Scholar 

  44. Singh N. Rosiglitazone and heart failure: long-term vigilance. J Cardiovasc Pharmacol Ther 2004; 9: 21–5

    Article  PubMed  Google Scholar 

  45. Srivastava PM, Calafiore P, MacIsaac RJ, et al. Thiazolidinediones and congestive heart failure: exacerbation or new onset of left ventricular dysfunction? Diabet Med 2004; 21(8): 945–50

    Article  PubMed  CAS  Google Scholar 

  46. Karter AJ, Ahmed AT, Liu J, et al. Pioglitazone initiation and subsequent hospitalization for congestive heart failure. Diabet Med 2005; 22: 986–93

    Article  PubMed  CAS  Google Scholar 

  47. Niemeyer NV, Janney LM. TZD-induced edema. Pharmacotherapy 2002; 22: 924–9

    Article  PubMed  Google Scholar 

  48. Zhang HL, Sowers JR, Ram JL, et al. Effects of pioglitazone in calcium channels in vascular smooth muscle. Hypertension 1994; 24: 170–5

    Article  PubMed  CAS  Google Scholar 

  49. Emoto M, Anno T, Sato Y, et al. Troglitazone treatment increases plasma vascular endothelial growth factor in diabetic patients and its mRNA in 3T3-L1 adipocytes. Diabetes 2001; 50: 1166–70

    Article  PubMed  CAS  Google Scholar 

  50. Arima S, Kohagura K, Takeuchi K, et al. Biphasic vasodilator action of troglitazone on the renal microcirculation. J Am Soc Nephrol 2002; 13: 342–9

    PubMed  CAS  Google Scholar 

  51. Guan Y, Hao C, Cha DR, et al. Thiazolidinediones expand body fluid volume through PPARgamma stimulation of ENaC-mediated renal salt absorption. Nat Med 2005; 11: 861–6

    Article  PubMed  CAS  Google Scholar 

  52. Zhang H, Zhang A, Kohan DE, et al. Collecting duct-specific deletion of peroxisome proliferator-activated receptor gamma blocks thiazolidinedione-induced fluid retention. Proc Natl Acad Sci U S A 2005; 102: 9406–11

    Article  PubMed  CAS  Google Scholar 

  53. DeFronzo RA. The effect of insulin on renal sodium metabolism: a review with clinical implications. Diabetologia 1981; 21: 779–84

    Google Scholar 

  54. Shimoyama M, Ogino K, Tanaka Y, et al. Hemodynamic basis for the acute cardiac effects of troglitazone in isolated perfused rat hearts. Diabetes 1999; 48: 609–15

    Article  PubMed  CAS  Google Scholar 

  55. Shiomi T, Tsutsui H, Hayashidani S, et al. Pioglitazone, a peroxisome proliferatoractivated receptor-gamma agonist, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation 2002; 106: 3126–32

    Article  PubMed  Google Scholar 

  56. Ghazzi MN, Perez JE, Antonucci TK, et al., for the Troglitazone Study Group. Cardiac and glycemic benefits of troglitazone treatment in NIDDM. Diabetes 1997; 46: 433–9

    Article  PubMed  CAS  Google Scholar 

  57. St John Sutton M, Rendell M, Dandona P, et al. A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with type 2 diabetes. Diabetes Care 2002; 25: 2058–64

    Article  PubMed  Google Scholar 

  58. Dargie H, Hildebrandt PR, Riegger G, et al. Rosiglitazone does not adversely affect cardiac structure and function as determined by echocardiography in patients with diabetes and classI/II heart failure [abstract]. J Am Coll Cardiol 2005; 45(3 Suppl. A): 186A

    Google Scholar 

  59. Dormandy JA, Charbonnel B, Eckland DJA, 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 2005; 366: 1279–89

    Article  PubMed  CAS  Google Scholar 

  60. Jones CJ, Fisher M. PROactive: early criticism not justified? Pract Diabetes Int 2005; 22: 323–4

    Article  Google Scholar 

  61. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiac outcomes and regulation of glycemia in diabetes (RECORD): study design and protocol. Diabetologia 2005; 48: 1726–35

    Article  PubMed  CAS  Google Scholar 

  62. Masoudi FA, Wang Y, Inzucchi SE, et al. Metformin and thiazolidinedione use in medicare patients with heart failure. JAMA 2003; 290: 81–5

    Article  PubMed  CAS  Google Scholar 

  63. Jones GC, Macklin JP, Alexander WD. Contraindications to the use of metformin. BMJ 2003; 326: 4–5

    Article  PubMed  CAS  Google Scholar 

  64. Masoudi FA, Inzucchi SE, Wang Y, et al. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation 2005; 11: 583–90

    Article  Google Scholar 

  65. Inzucchi SE, Masoudi FA, Wang Y, et al. Insulin-sensitizing antihyperglycemic drugs and mortality after acute myocardial infarction: insights from the national heart care project. Diabetes Care 2005; 28: 1680–9

    Article  PubMed  CAS  Google Scholar 

  66. Elasy TA, Griffin M. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Response to Nesto [letter]. Diabetes Care 2004; 27: 2096

    Article  PubMed  Google Scholar 

  67. Hartung DM, Touchette DR, Bultemeier NC, et al. Risk of hospitalization for heart failure associated with thiazolidinedione therapy: a medicaid claims-based case-control study. Pharmacotherapy 2005; 25: 1329–36

    Article  PubMed  CAS  Google Scholar 

  68. Delea TE, Edelsberg JS, Hagiwara M, et al. Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes: a retrospective cohort study. Diabetes Care 2003; 26: 2983–9

    Article  PubMed  CAS  Google Scholar 

  69. Karter AJ, Ahmed AT, Liu J, et al. Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes: a retrospective cohort study. Response to Delea et al. [comment]. Diabetes Care 2004; 27: 850–1

    Article  PubMed  Google Scholar 

  70. Higgs ER, Krentz AJ. ABCD position statement on glitazones. Pract Diabetes Int 2004; 21: 293–5

    Article  Google Scholar 

  71. El Muayed M, Lavis VR, Safi HJ, et al. Use of glitazones in cardiac patients: case for B-type natriuretic peptide monitoring? Am J Cardiol 2004; 93: 600–2

    Article  PubMed  Google Scholar 

  72. Dargie H, Hildebrandt PR, Riegger G, et al. Baseline B-type natriuretic peptide identifies patients with type 2 diabetes and class I/II heart failure at risk of fluid retention when treated with rosiglitazone [abstract]. J Am Coll Cardiol 2005; 45(3 Suppl. A): 139A

    Google Scholar 

  73. Rajagopalan R, Rosenson RS, Fernandes AW, et al. Association between congestive heart failure and hospitalization in patients with type 2 diabetes mellitus receiving treatment with insulin or pioglitazone: a retrospective data analysis. Clin Ther 2004; 26: 1400–10

    Article  PubMed  CAS  Google Scholar 

  74. Goldner MG, Knatterud GL, Prout TE. Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes: III. Clinical implications of UGDP results. JAMA 1971; 218: 1400–10

    Article  PubMed  CAS  Google Scholar 

  75. Gross G, Auchampach JA. Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circ Res 1992; 70: 223

    Article  PubMed  CAS  Google Scholar 

  76. UK Prospective Diabetes Study (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). Lancet 1998; 352: 837–53

    Article  Google Scholar 

Download references

Acknowledgments

No sources of funding were used to assist in the preparation of this review. Dr Fisher has served on advisory boards for Glaxo Smith Kline and Takeda, and has received speaker’s fees from Glaxo Smith Kline and Takeda.

Author information

Authors and Affiliations

  1. Diabetes Centre, Wards 4 and 5, Glasgow Royal Infirmary, 84 Castle Street, Glasgow, G4 0SF, UK

    David P. Macfarlane & Miles Fisher

Authors
  1. David P. Macfarlane
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miles Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David P. Macfarlane.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Macfarlane, D.P., Fisher, M. Thiazolidinediones in Patients with Diabetes Mellitus and Heart Failure. Am J Cardiovasc Drugs 6, 297–304 (2006). https://doi.org/10.2165/00129784-200606050-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00129784-200606050-00002

Keywords

Search

Navigation