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Thiazolidinediones and Risk of Heart Failure in Patients with or at High Risk of Type 2 Diabetes Mellitus

A Meta-Analysis and Meta-Regression Analysis of Placebo-Controlled Randomized Clinical Trials

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Abstract

Background

Recent meta-analyses of randomized clinical trials (RCTs) demonstrated a higher risk of heart failure (HF) with the use of thiazolidinediones (TZDs). However, this effect may have been diluted by including active controls. Also, it is uncertain whether the risk of HF is similar with rosiglitazone and pioglitazone.

Objectives

This study quantified the risks of HF with the use of TZDs in patients with or at high risk of developing type 2 diabetes mellitus (DM), and evaluated differential effects by type of TZD. Secondarily, we evaluated risks of peripheral edema.

Methods

We performed a systematic review and meta-analysis of placebo-controlled RCTs evaluating the effect of rosiglitazone or pioglitazone on investigator-reported HF and edema. Articles published before 31 December 2009 were searched in MEDLINE, The Web of Science, and Scopus, and the data were extracted by three investigators. RCTs with ≥100 patients and ≥3 months of follow-up were included. We quantified the effect of TZDs as odds ratios (ORs) by using the Mantel-Haenzel and alternative models. We further evaluated the risk of serious/severe HF, and the effect of several trial characteristics on HF risk by subgroup analysis and meta-regression analysis.

Results

29 trials (n = 20254) were evaluated. TZDs were significantly associated with HF (TZD 360/6807 [5.3%] vs placebo 234/6328 [3.7%], OR 1.59; 95% CI 1.34, 1.89; p<0.00001). The risk of HF was higher with rosiglitazone than with pioglitazone (2.73 [95% CI 1.46, 5.10] vs 1.51 [1.26, 1.81]; p = 0.06). TZDs were associated with a similar risk of serious/severe HF (OR 1.47; 95% CI 1.16, 1.87; p = 0.002). Use of TZDs was also associated with edema (OR 2.04; 95% CI 1.85, 2.26; p<0.00001). HF and edema risks were consistent using Peto and random effects models. Risks of HF were significantly high for the subgroups of trials including patients with or at high risk for type 2 DM, and for the subgroup of trials with ≥12 months of follow-up. Meta-regression analysis showed that trials with lower overall baseline risk had higher HF risks.

Conclusion

In placebo-controlled trials of adult patients with or at high risk for type 2 DM, TZD therapy is significantly and consistently associated with a higher risk of HF. The risk of serious/severe HF is also increased with the use of TZDs. HF risks are similar to those of meta-analyses combining active- and placebo-controlled trials. The benefit/risk profile of TZDs should be considered when treating diabetic patients with or without prior HF.

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Acknowledgments

No external funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents. The authors have no relevant conflicts of interest.

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Authors and Affiliations

  1. Health Outcomes and Clinical Epidemiology Section, Department of Quantitative Health Sciences/JJN3-01, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    Adrian V. Hernandez MD, PhD (Assistant Professor of Medicine)

  2. Department of Hospital Medicine, Institute of Medicine, Cleveland Clinic, Cleveland, Ohio, USA

    Ali Usmani & Anitha Rajamanickam

  3. General Medicine Unit, Rochester General Hospital, Rochester, New York, USA

    A. Moheet

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  1. Adrian V. Hernandez MD, PhD
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Correspondence to Adrian V. Hernandez MD, PhD.

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Hernandez, A.V., Usmani, A., Rajamanickam, A. et al. Thiazolidinediones and Risk of Heart Failure in Patients with or at High Risk of Type 2 Diabetes Mellitus. Am J Cardiovasc Drugs 11, 115–128 (2011). https://doi.org/10.2165/11587580-000000000-00000

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