Thiazolidinedione drugs in the treatment of type 2 diabetes mellitus: past, present and future

Abstract

Thiazolidinedione (TZD) drugs used in the treatment of type 2 diabetes mellitus (T2DM) have proven effective in improving insulin sensitivity, hyperglycemia, and lipid metabolism. Though well tolerated by some patients, their mechanism of action as ligands of peroxisome proliferator-activated receptors (PPARs) results in the activation of several pathways in addition to those responsible for glycemic control and lipid homeostasis. These pathways, which include those related to inflammation, bone formation, and cell proliferation, may lead to adverse health outcomes. As treatment with TZDs has been associated with adverse hepatic, cardiovascular, osteological, and carcinogenic events in some studies, the role of TZDs in the treatment of T2DM continues to be debated. At the same time, new therapeutic roles for TZDs are being investigated, with new forms and isoforms currently in the pre-clinical phase for use in the prevention and treatment of some cancers, inflammatory diseases, and other conditions. The aims of this review are to provide an overview of the mechanism(s) of action of TZDs, a review of their safety for use in the treatment of T2DM, and a perspective on their current and future therapeutic roles.

Keywords:

• Thiazolidinedione
• diabetes
• mechanism
• drug safety
• adverse effects
• hepatotoxicity
• myocardial infarction
• heart failure
• bone fracture
• cancer

Acknowledgements

The authors are grateful to two referees for constructive comments that served to improve the original version of this review.

Declaration of interest

The authors declare that they have no actual or potential competing financial interest. Funding to conduct this work was provided through an Ontario Graduate Scholarship (M. Davidson). D. Krewski is the Natural Sciences and Engineering Research Council of Canada Chair in Risk Science at the University of Ottawa. He also serves as Chief Risk Scientist and CEO for Risk Sciences International (RSI), a Canadian company established in 2006 in partnership with the University of Ottawa to provide consulting services in risk science to both public and private sector clients. To date, RSI has not conducted work on antihyperglycemics, the subject of the present paper. D. Mattison was supported by RSI. L. Azoulay is the recipient of a Chercheur-Boursier career award from the Fonds de recherché du Québec – Santé and is a McGill William Dawson Scholar.

The review strategy, the conduct of the review, and the interpretation and synthesis of the findings were exclusively the work of the authors. All authors had full access to all the literature assessed for the study and had final responsibility for the decision to submit for publication. M. Davidson devised the conceptual framework of the study and wrote the first draft of the manuscript. All investigators contributed to the interpretation of the data and to the writing of the article. None of the authors have appeared in legal or regulatory proceedings related to the contents of this review. However, recognizing that some of the contents of this paper may be the topic of future legal and/or regulatory proceedings, the authors acknowledge that they may be asked to participate in such proceedings.

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