Skip to main content
SpringerLink
Log in

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

  • Original Research Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Background and objective: Concern has been expressed over the cardiovascular risks associated with rosiglitazone and pioglitazone. This study investigates the association between oral antihyperglycaemics (rosiglitazone, pioglitazone, sulfonylureas and metformin) with myocardial infarction, congestive heart failure, angina pectoris, stroke and transient ischaemic attack.

Methods: We used Taiwan’s 2000–5 National Health Insurance database to conduct a population-based, retrospective cohort study of 473 483 newly diagnosed patients with type 2 diabetes mellitus. We classified study patients into five basic groups based on the agents they were prescribed during the study period: (i) rosiglitazone monotherapy; (ii) pioglitazone monotherapy; (iii) sulfonylurea-based therapy; (iv) metformin-based therapy; and (v) sulfonylurea and metformin-based therapy. Cox proportional hazards models were used to evaluate the association between the use of rosiglitazone or pioglitazone and the occurrence of cardiovascular events.

Results: Patients receiving rosiglitazone monotherapy were at higher risk for any cardiovascular event (hazard ratio [HR] 1.89; 95% CI 1.57, 2.28), myocardial infarction (HR 2.09; 95% CI 1.36, 3.24), angina pectoris (HR 1.79; 95% CI 1.39, 2.30) and transient ischaemic attack (HR 2.57; 95% CI 1.33, 4.96) than those receiving metformin monotherapy. Overall, add-on rosiglitazone and pioglitazone were associated with comparable cardiovascular risk. Based on our point estimates, pioglitazone as an add-on therapy was found to have a favourable, but nonsignificant, effect on outcome.

Conclusions: Our findings extend the evidence from current literature to a real-world setting and support data from clinical trials that the disadvantages or harm caused by thiazolidinediones, especially rosiglitazone, may outweigh their benefits in patients with type 2 diabetes.

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
Fig. 2
Fig. 3
Fig. 4
Table I
Table II
Table III

Similar content being viewed by others

References

  1. Diamant M, Heine RJ. Thiazolidinediones in type 2 diabetes mellitus: current clinical evidence. Drugs 2003; 63: 1373–405

    Article  PubMed  CAS  Google Scholar 

  2. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356: 2457–71

    Article  PubMed  CAS  Google Scholar 

  3. Home PD, Pocock SJ, Beck-Nielsen H, et al., on behalf of the RECORD Study Group. Rosiglitazone evaluated for cardiovascular outcomes-an interim analysis. N Engl J Med 2007; 357: 28–38

    Article  PubMed  CAS  Google Scholar 

  4. US Food and Drug Administration. Rosiglitazone maleate (marketed as Avandia, Avandamet, and Avandaryl) information, 2007 [online]. Available from URL: http://www.fda.gov/cder/drug/infopage/rosiglitazone/default.htm. [Accessed 2008 Apr 2]

  5. US Food and Drug Administration. Pioglitazone HCl (marketed as Actos, Actoplus Met, and Duetact) information, 2007 [online]. Available from URL: http://www.fda.gov/cder/drug/infopage/pioglitazone/default.htm. [Accessed 2008 Apr 2]

  6. Roper NA, Bilous RW, Kelly WF, et al. Excess mortality in a population with diabetes and the impact of material deprivation: longitudinal, population-based study. BMJ 2001; 322: 1389–93

    Article  PubMed  CAS  Google Scholar 

  7. US Food and Drug Administration. Summary for Actos and Avandia, 2002 [online]. Available from URL: http://www.fda.gov/medwatch/safety/2002/summary-actos-avandia.pdf [Accessed 2008 Apr 2]

  8. Takeda Pharmaceuticals. Actos prescribing information, 2002 [online]. Available from URL: http://www.actos.com/pi.pdf [Accessed 2008 Apr 2]

  9. GlaxoSmithKline Pharmaceuticals. Avandia prescribing information, 2002 [online]. Available from URL: http://us.gsk.com/products/assets/us_avandia.pdf [Accessed 2008 Apr 2]

  10. Nesto RW, Bell D, Bonow RO, et al., on behalf of the American Heart Association, American Diabetes Association. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and the American Diabetes Association. Circulation 2003; 108: 2941–8

    Article  PubMed  Google Scholar 

  11. 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 2007; 370: 1129–36

    Article  PubMed  CAS  Google Scholar 

  12. 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 

  13. 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 

  14. Maru S, Koch GG, Stender M, et al. Antidiabetic drugs and heart failure risk in patients with type 2 diabetes in the U.K. primary care setting. Diabetes Car 2005; 28: 20–6

    Article  CAS  Google Scholar 

  15. 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; 111: 583–90

    Article  PubMed  CAS  Google Scholar 

  16. Singh S, Loke YK, Fuberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007; 298: 1189–95

    Article  PubMed  CAS  Google Scholar 

  17. Psaty BM, Furberg CD. The record of rosiglitazone and the risk of myocardial infarction. N Engl J Med 2007; 357: 67–9

    Article  PubMed  CAS  Google Scholar 

  18. Lincoff AM, Wolski K, Nicholls SJ, et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 2007; 298: 1180–8

    Article  PubMed  CAS  Google Scholar 

  19. Hernandez AV, Walker E, Ioannidis JP, et al. Challenges in meta-analysis of randomized clinical trials for rare harmful cardiovascular events: the case of rosiglitazone. Am Heart J 2008; 156: 23–30

    Article  PubMed  CAS  Google Scholar 

  20. Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med 2007; 16 147: 578–81

    PubMed  Google Scholar 

  21. Lipscombe LL, Gomes T, Lévesque LE, et al. Thiazolidinediones and cardiovascular outcomes in older patients with diabetes. JAMA 2007; 298: 2634–43

    Article  PubMed  CAS  Google Scholar 

  22. Winkelmayer WC, Setoguchi S, Levin R, et al. Comparison of cardiovascular outcomes in elderly patients with diabetes who initiated rosiglitazone vs pioglitazone therapy. Arch Intern Med 2008; 168: 2368–75

    Article  PubMed  Google Scholar 

  23. WHO Collaborating Centre for Drug Statistics Methodology. The ATC and DDD system 2008 [online]. Available from URL: http://www.whocc.no/atcddd/ [Accessed 2008 Sep 2]

  24. Gerrits CM, Bhattacharya M, Manthena S, et al. A comparison of pioglitazone and rosiglitazone for hospitalization for acute myocardial infarction in type 2 diabetes. Pharmacoepidemiol Drug Saf 2007; 16: 1065–71

    Article  PubMed  Google Scholar 

  25. Johannes CB, Koro CE, Quinn SG, et al. The risk of coronary heart disease in type 2 diabetic patients exposed to thiazolidinediones compared to metformin and sulfonylurea therapy. Pharmacoepidemiol Drug Saf 2007; 16: 504–12

    Article  PubMed  CAS  Google Scholar 

  26. McAfee AT, Koro C, Landon J, et al. Coronary heart disease outcomes in patients receiving antidiabetic agents. Pharmacoepidemiol Drug Saf 2007; 16: 711–25

    Article  PubMed  Google Scholar 

  27. Selvin E, Bolen S, Yeh HC, et al. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med 2008; 168: 2070–80

    Article  PubMed  Google Scholar 

  28. Erdmann E, Dormandy JA, Charbonnel B, et al. The effect of pioglitazone on recurrent myocardial infarction in 2, 445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05). iStudy. PROactive Investigators. J Am Coll Cardiol 2007; 49: 1772–80

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank Taiwan’s National Science Council (NSC) Grant for providing a research grant (NSC-96-N-6805). We also thank the Bureau of National Health Insurance (BNHI) and National Health Research Institutes (NHRI) for making available their databases for this study. The content of this article, however, in no way represents any official position of the BNHI or NHRI. The authors accept all responsibility for the results and their interpretation. We would like to thank Dr C. Daniel Mullins for providing consultation and assistance with the revised manuscript. We would also like to thank Mr James Steed for his assistance in editing this manuscript. This study is a component of a research grant by Taiwan’s National Science Council for which Dr W.F. Huang served as the principal investigator. The authors have no conflicts of interest to declare.

Author information

Authors and Affiliations

  1. Institute of Health and Welfare Policy/Center for Health and Welfare Policy Research, National Yang-Ming University, Taipei, Taiwan

    Fei-Yuan Hsiao & Weng-Foung Huang

  2. Pharmaceutical Health Services Research Department, University of Maryland School of Pharmacy, Baltimore, Maryland, USA

    Fei-Yuan Hsiao

  3. Center for Health Policy Research and Development, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County, 350, Taiwan

    Yu-Wen Wen, Pei-Fen Chen, Ken N. Kuo &  Yi-Wen Tsai

  4. Institute of Health and Welfare Policy, National Yang-Ming University, Taipei, Taiwan

    Yi-Wen Tsai

Authors
  1. Fei-Yuan Hsiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weng-Foung Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu-Wen Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pei-Fen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ken N. Kuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yi-Wen Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yi-Wen Tsai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hsiao, FY., Huang, WF., Wen, YW. et al. Thiazolidinediones and Cardiovascular Events in Patients with Type 2 Diabetes Mellitus. Drug-Safety 32, 675–690 (2009). https://doi.org/10.2165/00002018-200932080-00006

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-200932080-00006

Keywords

Search

Navigation