LETTER TO THE EDITORS

Stay vigilant: a glitazone (pioglitazone) can hide a glitazar!

Dominique Hillaire-Buys & Jean-Luc Faillie &

Jean-Louis Montastruc & Pierre Petit

Received: 18 April 2012 /Accepted: 18 April 2012 /Published online: 11 May 2012# Springer-Verlag 2012

Between 1995 and 2000, many peroxisome proliferator-activated receptor (PPAR) agonists were developed forthe treatment of type 2 diabetes mellitus. WhereasPPARα agonists (fibrates) improve lipid metabolism,PPARγ agonists (thiazolidinediones) sensitize insulinaction and improve glycemic control. The search for awider pharmacodynamic effect with synergism on lipidand glucose homeostasis in patients with metabolicsyndrome or type 2 diabetes led to the concept ofdual-acting PPARα and PPARγ agonists [1, 2]. Thesedual agonists, named glitazars, were all stopped duringpreclinical or clinical development, mainly because ofcarcinogenic effects in animals, especially bladdertumors in male rats [3]. In September 2010, the U.S.Food and Drug Administration issued an alert in

connection with a potential relationship between theoccurrence of bladder cancers in patients and the pre-scription of pioglitazone at high doses and for longperiods [4].

Reviewing the PROactive study safety data, wereported that the incidence of bladder cancers wassignificantly higher in the pioglitazone-treated groupthan in the placebo group, with an estimated cruderelative risk of 2.83 (95 % CI 1.02–7.85) [5]. Thisresult is supported by a recent study from Neumannet al. [6], showing a dose-dependent increase in theincidence of bladder cancer in pioglitazone-exposeddiabetic patients. Analysis of the pharmacological datapublished so far gives evidence that pioglitazone has apharmacodynamic profile comparable to that of theglitazar compounds (Table 1); specifically, it has a dualpharmacological effect on both PPARα and PPARγ thatcan be obtained in humans at the concentrations clini-cally used.

In order to explain hyperplasia and bladder cancersin male rats during the preclinical development of pio-glitazone, the Takeda group favored the hypothesis ofurolithiasis [4, 7]. This hypothesis is supported by thepresence of crystals causing continuous irritation, par-ticularly in ventral bladder. Recently, Sato and col-leagues reported data from a 24-month mechanisticstudy showing decreased formation of urinary micro-crystals when using an acidifying diet [7]; under theseconditions, the elevated incidence of advanced prolifer-ative changes in pioglitazone-treated animals was sig-nificantly decreased. However, the incidence ofhyperplasia was not reduced, and the incidence of

D. Hillaire-BuysDepartment of Medical Pharmacology and Toxicology,CHRU Montpellier and INSERM U1058,Montpellier, France

J.-L. FaillieDepartment of Medical Pharmacology and Toxicology,CHRU Montpellier,Montpellier, France

J.-L. MontastrucDepartment of Clinical Pharmacology andPharmacoepidemiology, CHRU Toulouse and INSERM U1027,Toulouse, France

P. Petit (*)Department of Medical Pharmacology and Toxicology,CHRU Montpellier and CNRS FRE3400,Montpellier, Francee-mail: p-petit@chu-montpellier.fr

Eur J Clin Pharmacol (2012) 68:1681–1683DOI 10.1007/s00228-012-1299-1

proliferative lesions more severe than simple hyperpla-sia was still 2.5 %, in comparison with 0 % in twoindependent control groups with 78 (mechanistic study)and 60 (original 2-year carcinogenicity study) animals.From these data, it can be concluded that the pre-sence of microcrystals exacerbates a hyperplasic re-sponse but cannot be considered the sole cause of thehyperplasic changes, in contradiction to the “crystalluriahypothesis.”

A similar carcinogenic effect has been reported withnaveglitazar, without urolithiasis as an inciting event [8,9]. Urothelial cells coexpress PPARα and PPARγ, andan interaction study with rosiglitazone (PPARγ agonist)and fenofibrate (PPARα agonist), alone or in combina-tion, showed synergy in inducing Egr-1 transcriptionfactor [10], which was suggested as a candidate bio-marker for the carcinogenic effect of dual-acting PPARagonists [11]. Thus, urothelial carcinogenicity of dual-acting PPAR agonists may be caused by receptor-mediated effects. As the specific PPARγ agonist rosi-glitazone causes cancer promotion rather than initiation[12], PPARα activation may have relevance for urothe-lial cancer initiation.

Considering the glitazar-like pharmacological profileof pioglitazone and the toxicological data, the potentialrisk of urothelial carcinogenicity of this compound in-dependent of any changes in urinary parameters can besuggested. If a cytotoxic effect of some pioglitazonemetabolites within the bladder cannot be excluded,these mechanisms may be nonexclusive and could ex-acerbate each other. This discussion underlines the fact

that deep examination of the pharmacodynamic proper-ties of a new drug is absolutely necessary to properlyevaluate or anticipate the side effect profile and toimplement an appropriate risk management plan.

Disclosure statement The authors declare that there is no conflict ofinterest associated with this manuscript.

References

1. Duran-Sandoval D, Thomas AN, Bailleul B, Fruchart JC, Staels B(2003) Pharmacologie des agonistes PPARα et PPARγ et desactivateurs mixtes en déveleppement clinique. Med Sci 19:819–825

2. Rubenstrunk A, Hanf R, Hum DW, Fruchart JC, Staels B (2007)Safety issues and prospects for future generations of PPAR mod-ulators. Biochem Biophys Acta 1771:1065–1081

3. El-Hage J (2004) Preclinical and clinical safety assessments for PPARagonists. http://www.fda.gov/cder/present/DIA2004/Elhage.ppt.Accessed 1 March 2005

4. Food and Drug Administration (2010) FDA drug safety commu-nication: ongoing safety review of actos (pioglitazone) and poten-tial increased risk of bladder cancer after two years exposure.http://www.fda.gov/Drugs/DrugSafety/ucm226214.htm..Accessed 1 October 2010

5. Hillaire-Buys D, Faillie JL, Montastruc JL (2011) Pioglitazone andbladder cancer. Lancet 378:1543–1544

6. Neumann A, Weill A, Ricordeau P, Fagot JP, Alla F, Allemand H(2012) Pioglitazone and risk of bladder cancer among diabeticpatients in France: a population-based cohort study. Diabetologia.doi:10.1007/s00125-012-2538-9

7. Sato K, Awasaki Y, Kandori H, Tanakamaru ZY, Nagai H,Baron D, Yamamoto M (2011) Suppressive effects of acid-

Table 1 Pharmacological properties of different human PPAR agonists

PPARα partialagonism

PPARγ full agonism Affinity PPARαEC50 (μM)

Affinity PPARγEC50 (μM)

Selectivity γ/αa Ratio Cmax/EC50α Ratio Cmax/EC50γ

Pioglitazone 60 % 140 % 4.3 2 2.15 0.91b 1.97b

6.7c 0.6c 11c 0.59b,c 6.55b,c

Farglitazar 65 % 100 % 0.13 0.0014 92.9 NA NA

Muraglitazar 70 % 110 % 0.1 0.002 50 NA NA

Tesaglitazar 50 % 90 % 0.4 0.1 3.6 NA NA

Ragaglitazar 50 % 110 % 3.2 0.6 5.3 NA NA

Full agonists are compounds that are able to elicit a maximum response following receptor occupation and activation. Partial agonists arecompounds that can activate receptors but are unable to elicit the maximum response of the receptor system

Values are from Rubenstrunk et al. [2], except when otherwise specified; NA not availablea Selectivity γ/α is evaluated as PPARα EC50/PPARγ EC50b Ratio Cmax/EC50 is calculated using data from Kasichayanula et al. [13]: pioglitazone 45 mg Cmax is 3.927 μMcAccording to Duran-Sandoval et al. [1]

1682 Eur J Clin Pharmacol (2012) 68:1681–1683

forming diet against the tumorigenic potential of pioglitazonehydrochloride in the urinary bladder of male rats. ToxicolAppl Pharmacol 251:234–244

8. Long GG, Reynolds VL, Lopez-Martinez A, Ryan TE, White SL,Eldridge SR (2008) Urothelial carcinogenesis in the urinary blad-der of rats treated with naveglitazar, a gamma-dominant PPARalpha/gamma agonist: lack of evidence for urolithiasis as an incit-ing event. Toxicol Pathol 36:218–231

9. Long GG, Reynolds VL, Dochterman LW, Ryan TE (2009) Neo-plastic and non-neoplastic changes in F-344 rats treated withNaveglitazar, a gamma-dominant PPAR alpha/gamma agonist.Toxicol Pathol 37:741–753

10. Egerod FL, Brünner N, Svendsen JE, Oleksiewicz MB (2010)PPARα and PPARγ are co-expressed, functional and show

positive interactions in the rat urinary bladder urothelium. J ApplToxicol 30:151–162

11. Oleksiewicz MB, Southgate J, Iversen L, Egerod FL (2008) Raturinary bladder carcinogenesis by dual-acting PPARα + γ ago-nists. PPAR Res 2008:103167

12. Lubet RA, Fischer SM, Steele VE, Juliana MM, Desmond R,Grubbs CJ (2008) Rosiglitazone, a PPAR gamma agonist: potentpromoter of hydroxybutyl(butyl)nitrosamine-induced urinary blad-der cancers. Int J Cancer 123:2254–2259

13. Kasichayanula S, Liu X, Shyu WC, Zhang W, Pfister M, GriffenSC, Li T, LaCreta FP, Boulton DW (2011) Lack of pharmacoki-netic interaction between dapagliflozin, a novel sodium-glucosetransporter 2 inhibitor, and metformin, pioglitazone, glimepiride orsitagliptin in healthy subjects. Diabetes Obes Metab 13:47–54

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