Do thiazolidinediones still have a role in treatment of type 2 diabetes mellitus?

Abstract

Thiazolidinediones have been introduced in the treatment of type 2 diabetes mellitus (T2DM) since the late 1990s. Although troglitazone was withdrawn from the market a few years later due to liver toxicity, both rosiglitazone and pioglitazone gained widespread use for T2DM treatment. In 2010, however, due to increased risk of cardiovascular events associated with its use, the European Medicines Agency recommended suspension of rosiglitazone use and the Food and Drug Administration severely restricted its use. Thus pioglitazone is the only thiazolidinedione still significantly employed for treating T2DM and it is the only molecule of this class still listed in the American Diabetes Association-European Association for the Study of Diabetes 2012 Position Statement. However, as for the other thiazolidinediones, use of pioglitazone is itself limited by several side effects, some of them potentially dangerous. This, together with the development of novel therapeutic strategies approved in the last couple of years, has made it questionable whether or not thiazolidinediones (namely pioglitazone) should still be used in the treatment of T2DM. This article will attempt to formulate an answer to this question by critically reviewing the available data on the numerous advantages and the potentially worrying shortcomings of pioglitazone treatment in T2DM. Keywords: PPAR-gamma agonist, thiazolidinediones, type 2 diabetes Date submitted 7 September 2012; date of first decision 23 November 2012; date of final acceptance 15 March 2013 IntroductionThiazolidinediones are selective ligands of the nuclear transcription factor peroxisome-proliferator-activated receptor γ (PPARγ ). These are a subfamily of the 48-member nuclear-receptor superfamily which, once activated by ligand binding, bind to DNA in complex with the retinoid X receptor (RXR), thus modulating the transcription of a number of specific genes [1]. Since the late 1990s, thiazolidinediones have been introduced in the treatment of type 2 diabetes mellitus (T2DM), mostly as second-line agents, in combination with metformin. Three thiazolidinedione molecules have been used in clinical practice over the last 15 years: troglitazone, rosiglitazone and pioglitazone. Troglitazone, the first thiazolidinedione approved for clinical use in 1997, was withdrawn from the market 3 years later, after reports of a few individual cases of liver injury and failure associated with use of the drug [2]. On the other hand both rosiglitazone and pioglitazone gained widespread employment for T2DM treatment in the early years of the last decade. Then, mostly prompted by the results of a meta-analysis showing association of its use with increased cardiovascular events [3], rosiglitazone underwent very close scrutiny by both Food and Drug Administration (FDA) andCorrespondence to: Prof. Agostino Consoli, MD, Department of Medicine and Aging Sciences, Edificio CeSi, Room 271, University of Chieti, via dei Vestini, 1, 66100 Chieti, Italy. E-mail: consoli@unich.it European Medicines Agency (EMA) [4]...

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