C urrent guidelines for the manage- ment of type 2 diabetes mellitus (T2DM) recommend metformin pharma- cotherapy first line, along with lifestyle and dietary changes. 1,2 Among the second- line pharmacotherapy add-on options, for patients whose T2DM remains uncon- trolled, are peroxisome proliferator-acti- vated receptor-γ (PPAR-γ) agonists. PPAR-γ agonists, also known as thiazol- idinediones (TZDs), improve insulin sen- sitivity and may have pancreatic β-cell protective effects, systemic antiinflamma- tory properties, and possible beneficial ef- fects on lipid levels (Figure 1). 3 There have been many problems with this class of agents. The first one ap- proved, troglitazone, was removed from the market because of increased risk of hepatotoxicity compared with other agents within the class. More recently, rosiglitazone has shown an increased risk for bone fractures and cardiovascu- lar events, including heart failure and myocardial infarction (MI). 4-13 While still available on the US market only as part of the AVANDIA-Rosiglitazone Medicines Access Program, the use of rosiglitazone has significantly declined. 14 It has been re- moved from the European and New Zealand markets. Cur- rently, pioglitazone is the most used TZD, as its association with cardiovascular events has not been demonstrated to the same extent as that of rosiglitazone. 4-13 However, recent evi- dence of a possible increased risk of bone fractures and blad- der cancer associated with long-term use of pioglitazone has raised additional concerns. 15-20 A fourth agent, rivoglitazone, has been developed by Daiichi Sankyo and is undergoing Phase 3 trials in the US and Japan. 21 We review the current literature regarding rivoglitazone to determine its potential place in therapy for the treatment of T2DM. Rivoglitazone: A New Thiazolidinedione for the Treatment of Type 2 Diabetes Mellitus Robin L Koffarnus, Kurt A Wargo, Haley M Phillippe New Drug Developments The Annals of Pharmacotherapy ■ 2013 June, Volume 47 ■ 877 theannals.com OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of the thiazolidinedione rivoglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, to determine its potential role in the treatment of type 2 diabetes mellitus. DATA SOURCES: A MEDLINE search (1966-February 2013) was conducted for English-language studies in humans, using the terms rivoglitazone and CS011. Abstracts presented at the American Diabetes Association and European Association for the Study of Diabetes annual meetings from 2007 to 2012 were also evaluated for relevant data. STUDY SELECTION AND DATA EXTRACTION: Articles pertinent to the pharmacology, pharmacokinetics, efficacy, and safety of rivoglitazone were reviewed. DATA SYNTHESIS: Rivoglitazone has been shown, through small clinical studies, to decrease hemoglobin A 1c (A1C) by 0.11-1.1% when compared with placebo and may provide greater A1C reduction than pioglitazone. Rivoglitazone reduces hyperglycemia, hyperinsulinemia, and hypertriglyceridemia by acting as an agonist of PPAR-γ. Rivoglitazone is the most potent PPAR-γ agonist; the initial recommended dose is 1 mg daily, with adjustment as needed to a maximum dose of 2 mg daily. Additionally, rivoglitazone has a longer half-life than other PPAR-γ agonists. Similar to those of the other PPAR-γ agonists, rivoglitazone’s adverse effects include peripheral edema and weight gain. CONCLUSIONS: Rivoglitazone is the fourth agent in the thiazolidinedione class of antidiabetes drugs. Although rivoglitazone appears to be more potent in its ability to lower A1C levels compared with other thiazolidinediones, further studies of longer duration are needed to fully assess the risks associated with this drug. Until these can be completed, we cannot recommend rivoglitazone over currently approved drugs in this class. Ann Pharmacother 2013;47:877-85. Published Online, 30 Apr 2013, theannals.com, doi: 10.1345/aph.1R754 Author information provided at end of text. © 1967-2013 Harvey Whitney Books Co. All rights reserved. No part of this document may be reproduced or transmitted in any form or by any means without prior written permission of Harvey Whitney Books Co. For reprints of any article appearing in The Annals, please contact 415sales@hwbooks.com by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from