Pioglitazone - the forgotten drug with multidirectional action
DOI:
https://doi.org/10.12775/JEHS.2023.24.01.001Keywords
pioglitazone, type 2 diabetes, insulin resistance, NAFLD, cardiovascular risk, nephroprotectionAbstract
Introduction: Pioglitazone (PG) which belongs to thiazolidinedione class is a drug used in the treatment of type 2 diabetes. PG increases the insulin sensitivity of peripheral tissues. Type 2 diabetes mellitus (T2DM) is one of the most common and fastest developing diseases. The antihyperglycemic effect of pioglitazone (PG) is not its only one. This drug has a number of other metabolically beneficial effects. Many outcome trials indicate a positive impact of PG on the functioning of other systems.
Aim of the study: The aim of this study is to summarize the current knowledge on the effectiveness and safety of pioglitazone based on the available scientific literature.
Materials and methods: Literature review based on PubMed, Google Scholar database using the following phrases: pioglitazone, type 2 diabetes, pioglitazone in non-alcoholic fatty liver disease (NAFLD) therapy, pioglitazone and cardiovascular risk, pioglitazone nephroprotective effect, pioglitazone safety profile.
State of knowledge: Pioglitazone is an oral antidiabetic drug used in the therapy of T2DM. PG belongs to the ‘insulin- sensitizers’. It is included in the treatment in the case of intolerance, contraindications to metformin or as part of combination therapy.
Conclusions: Recently, interest in pioglitazone has waned due to the perception of significant side effects. The analysis of the papers showed a positive effect of PG on the cardiovascular system, central nervous system, NAFLD and nephroprotection. The acceptable safety profile of pioglitazone with the appropriate selection of patients as well as its multidirectional action and effectiveness mean that clinicians should reconsider the use of this drug guided by the balance of profits and losses.
References
Cole JB, Florez JC. Genetics of diabetes mellitus and diabetes complications. Nat Rev Nephrol. 2020 Jul;16(7):377-390. doi: 10.1038/s41581-020-0278-5. Epub 2020 May 12. PMID: 32398868; PMCID: PMC9639302.
Artasensi A, Pedretti A, Vistoli G, Fumagalli L. Type 2 Diabetes Mellitus: A Review of Multi-Target Drugs. Molecules. 2020 Apr 23;25(8):1987. doi: 10.3390/molecules25081987. PMID: 32340373; PMCID: PMC7221535.
Nabrdalik, K., Cichocka, E., Żywiec, J., Chodkowski, A., & Gumprecht, J. (2014). Pioglitazone for the treatment of type 2 diabetes. Clinical Diabetology, 3(4), 176-180.
Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, Ostolaza H, Martín C. Pathophysiology of Type 2 Diabetes Mellitus. Int J Mol Sci. 2020 Aug 30;21(17):6275. doi: 10.3390/ijms21176275. PMID: 32872570; PMCID: PMC7503727.
Tan SY, Mei Wong JL, Sim YJ, Wong SS, Mohamed Elhassan SA, Tan SH, Ling Lim GP, Rong Tay NW, Annan NC, Bhattamisra SK, Candasamy M. Type 1 and 2 diabetes mellitus: A review on current treatment approach and gene therapy as potential intervention. Diabetes Metab Syndr. 2019 Jan-Feb;13(1):364-372. doi: 10.1016/j.dsx.2018.10.008. Epub 2018 Oct 10. PMID: 30641727.
Pfützner A, Weber MM, Forst T. Pioglitazone: update on an oral antidiabetic drug with antiatherosclerotic effects. Expert Opin Pharmacother. 2007 Aug;8(12):1985-98. doi: 10.1517/14656566.8.12.1985. PMID: 17696799.
Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature. 2000 May 25;405(6785):421-4. doi: 10.1038/35013000. PMID: 10839530.
Suzuki S., Arnold L.L., Pennington K.L. i wsp. Effects of pio- glitazone, a peroxisome proliferator-activated receptor gamma agonist, on the urine and urothelium of the rat. Toxicol. Sci. 2010; 113: 349–357.
Drzewoski J., Mikołajczyk M.: Agoniści receptorów aktywowanych proliferatorem peroksysomów γ. W: Grzeszczak W. (red.): Farmakoterapia w cukrzycy. Wyd. 2. Via Medica, Gdańsk 2010: 105-122.
Sokołowska M, Kowalski ML, Pawliczak R. Receptory aktywowane przez proliferatory peroksysomów-gamma (PPAR-gamma) oraz ich rola w immunoregulacji i kontroli reakcji zapalnej [Peroxisome proliferator-activated receptors-gamma (PPAR-gamma) and their role in immunoregulation and inflammation control]. Postepy Hig Med Dosw (Online). 2005;59:472-84. Polish. PMID: 16258412.
Al-Majed A, Bakheit AH, Abdel Aziz HA, Alharbi H, Al-Jenoobi FI. Pioglitazone. Profiles Drug Subst Excip Relat Methodol. 2016;41:379-438. doi: 10.1016/bs.podrm.2015.11.002. Epub 2016 Feb 2. PMID: 26940171.
de Pablos-Velasco P. Pioglitazone: beyond glucose control. Expert Rev Cardiovasc Ther. 2010 Aug;8(8):1057-67. doi: 10.1586/erc.10.98. PMID: 20670183.
Aronoff S, Rosenblatt S, Braithwaite S, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care. 2000 Nov;23(11):1605-11. doi: 10.2337/diacare.23.11.1605. PMID: 11092281.
Herz M, Johns D, Reviriego J, Grossman LD, Godin C, Duran S, Hawkins F, Lochnan H, Escobar-Jiménez F, Hardin PA, Konkoy CS, Tan MH. A randomized, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic medication-naive patients with type 2 diabetes mellitus. Clin Ther. 2003 Apr;25(4):1074-95. doi: 10.1016/s0149-2918(03)80068-1. PMID: 12809958.
Tan MH, Baksi A, Krahulec B, Kubalski P, Stankiewicz A, Urquhart R, Edwards G, Johns D; GLAL Study Group. Comparison of pioglitazone and gliclazide in sustaining glycemic control over 2 years in patients with type 2 diabetes. Diabetes Care. 2005 Mar;28(3):544-50. doi: 10.2337/diacare.28.3.544. PMID: 15735185.
Kaku K. Efficacy and safety of therapy with metformin plus pioglitazone in the treatment of patients with type 2 diabetes: a double-blind, placebo-controlled, clinical trial. Curr Med Res Opin. 2009 May;25(5):1111-9. doi: 10.1185/03007990902820816. PMID: 19309251.
Schöndorf T, Karagiannis E, Posseldt RE, Forst T, Pfützner A. Competact, a fixed combination of pioglitazone and metformin, improves metabolic markers in type 2 diabetes patients with insufficient glycemic control by metformin alone--results from a post-marketing surveillance trial under daily routine conditions. Diabetes Technol Ther. 2009 Jun;11(6):379-83. doi: 10.1089/dia.2008.0108. PMID: 19459767.
Chalmers J, Hunter JE, Robertson SJ, Baird J, Martin M, Franks CI, Whately-Smith CR, Mariz S, Campbell IW. Effects of early use of pioglitazone in combination with metformin in patients with newly diagnosed type 2 diabetes. Curr Med Res Opin. 2007 Aug;23(8):1775-81. doi: 10.1185/030079907x210606. PMID: 17712875.
DeFronzo R.A., Tripathy D., Schwenke D.C. i wsp. Pioglitazone for diabetes prevention in impaired glucose tolerance. N. Engl. J. Med. 2011; 364: 1104–1115.
Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Kawakubo M, Buchanan TA. Effect of pioglitazone on pancreatic beta-cell function and diabetes risk in Hispanic women with prior gestational diabetes. Diabetes. 2006 Feb;55(2):517-22. doi:10.2337/diabetes.55.02.06.db05-1066. PMID: 16443789; PMCID: PMC1389697.
Nesti L, Tricò D, Mengozzi A, Natali A. Rethinking pioglitazone as a cardioprotective agent: a new perspective on an overlooked drug. Cardiovasc Diabetol. 2021 May 18;20(1):109. doi: 10.1186/s12933-021-01294-7. PMID: 34006325; PMCID: PMC8130304.
Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefèbvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Korányi L, Laakso M, Mokán M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J; PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005 Oct 8;366(9493):1279-89. doi: 10.1016/S0140-6736(05)67528-9. PMID: 16214598.
Harashima K, Hayashi J, Miwa T, Tsunoda T. Long-term pioglitazone therapy improves arterial stiffness in patients with type 2 diabetes mellitus. Metabolism. 2009 Jun;58(6):739-45. doi: 10.1016/j.metabol.2008.09.015. PMID: 19446110.
Tsuchiya K, Akaza I, Yoshimoto T, Hirata Y. Pioglitazone improves endothelial function with increased adiponectin and high-density lipoprotein cholesterol levels in type 2 diabetes. Endocr J. 2009;56(5):691-8. doi: 10.1507/endocrj.k08e-308. Epub 2009 Jun 9. PMID: 19506330.
Choo EH, Han EJ, Kim CJ, Kim SH, O JH, Chang K, Seung KB. Effect of pioglitazone in combination with moderate dose statin on atherosclerotic inflammation: randomized controlled clinical trial using serial FDG-PET/CT. Korean Circ J. 2018;48(7):591–601.
Konrad T, Lübben G, Franzen C. Pioglitazone lowers blood pressure in hypertensive patients with type 2 diabetes mellitus : an open, multicentre, observational study. Clin Drug Investig. 2005;25(5):337-40. doi: 10.2165/00044011-200525050-00006. PMID: 17532671.
Yamanouchi, M., Furuichi, K., Hoshino, J., Ubara, Y., & Wada, T. (2020). Nonproteinuric diabetic kidney disease. Clinical and experimental nephrology, 24, 573-581.
Zhou Y, Huang Y, Ji X, Wang X, Shen L, Wang Y. Pioglitazone for the primary and secondary prevention of cardiovascular and renal outcomes in patients with or at high risk of type 2 diabetes mellitus: a meta-analysis. The Journal of Clinical Endocrinology & Metabolism. 2020;105:1670–1681.
Momeni, A., Mahmoudnia, L., & Kheiri, S. (2019). Effect of pioglitazone on decreasing of proteinuria in type 2 diabetic patients with nephropathy. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 13(1), 132-136.
Chang, Y. H., Hwu, D. W., Chang, D. M., An, L. W., Hsieh, C. H., & Lee, Y. J. (2017). Renal function preservation with pioglitazone or with basal insulin as an add-on therapy for patients with type 2 diabetes mellitus. Acta diabetologica, 54, 561-568.
Papaetis GS. Pioglitazone in diabetic kidney disease: forgotten but not gone. Arch Med Sci Atheroscler Dis. 2022 Aug 8;7:e78-e93. doi: 10.5114/amsad/151046. PMID: 36158067; PMCID: PMC9487837.
Saini AK, Saini R, Singh S. Autosomal dominant polycystic kidney disease and pioglitazone for its therapy: a comprehensive review with an emphasis on the molecular pathogenesis and pharmacological aspects. Mol Med. 2020 Dec 11;26(1):128. doi: 10.1186/s10020-020-00246-3. PMID: 33308138; PMCID: PMC7731470.
Niu SW, He JS, You-Hsien Lin H. Pioglitazone and nephrolithiasis. Kidney Int. 2019 Aug;96(2):518-519. doi: 10.1016/j.kint.2019.04.015. PMID: 31331471.
Ng SY, Lee AYW. Traumatic Brain Injuries: Pathophysiology and Potential Therapeutic Targets. Front Cell Neurosci. 2019 Nov 27;13:528. doi: 10.3389/fncel.2019.00528. PMID: 31827423; PMCID: PMC6890857.
Yonutas HM, Hubbard WB, Pandya JD, Vekaria HJ, Geldenhuys WJ, Sullivan PG. Bioenergetic restoration and neuroprotection after therapeutic targeting of mitoNEET: New mechanism of pioglitazone following traumatic brain injury. Exp Neurol. 2020 May;327:113243. doi: 10.1016/j.expneurol.2020.113243. Epub 2020 Feb 10. PMID: 32057797; PMCID: PMC7089834.
Zamanian MY, Taheri N, Opulencia MJC, Bokov DO, Abdullaev SY, Gholamrezapour M, Heidari M, Bazmandegan G. Neuroprotective and Anti-inflammatory Effects of Pioglitazone on Traumatic Brain Injury. Mediators Inflamm. 2022 Jun 17;2022:9860855. doi: 10.1155/2022/9860855. PMID: 35757108; PMCID: PMC9232315.
de Vries M, Westerink J, Kaasjager KHAH, de Valk HW. Prevalence of Nonalcoholic Fatty Liver Disease (NAFLD) in Patients With Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis. J Clin Endocrinol Metab. 2020 Dec 1;105(12):3842–53. doi: 10.1210/clinem/dgaa575. PMID: 32827432; PMCID: PMC7526735.
Lee YH, Cho Y, Lee BW, Park CY, Lee DH, Cha BS, Rhee EJ. Nonalcoholic Fatty Liver Disease in Diabetes. Part I: Epidemiology and Diagnosis. Diabetes Metab J. 2019 Feb;43(1):31-45. doi: 10.4093/dmj.2019.0011. Erratum in: Diabetes Metab J. 2019 Oct;43(5):731. PMID: 30793550; PMCID: PMC6387876.
Younossi ZM, Golabi P, de Avila L, Paik JM, Srishord M, Fukui N, Qiu Y, Burns L, Afendy A, Nader F. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol. 2019 Oct;71(4):793-801. doi: 10.1016/j.jhep.2019.06.021. Epub 2019 Jul 4. PMID: 31279902.
Sberna AL, Bouillet B, Rouland A, Brindisi MC, Nguyen A, Mouillot T, Duvillard L, Denimal D, Loffroy R, Vergès B, Hillon P, Petit JM. European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity (EASO) clinical practice recommendations for the management of non-alcoholic fatty liver disease: evaluation of their application in people with Type 2 diabetes. Diabet Med. 2018 Mar;35(3):368-375. doi: 10.1111/dme.13565. Epub 2018 Jan 10. PMID: 29247558.
Lian J, Fu J. Pioglitazone for NAFLD Patients With Prediabetes or Type 2 Diabetes Mellitus: A Meta-Analysis. Front Endocrinol (Lausanne). 2021 Apr 28;12:615409. doi: 10.3389/fendo.2021.615409. Erratum in: Front Endocrinol (Lausanne). 2022 Feb 16;13:840299. PMID: 33995271; PMCID: PMC8115121.
Zhao Y, Zhao W, Wang H, Zhao Y, Bu H, Takahashi H. Pioglitazone on nonalcoholic steatohepatitis: A systematic review and meta-analysis of 15 RCTs. Medicine (Baltimore). 2022 Nov 18;101(46):e31508. doi: 10.1097/MD.0000000000031508. PMID: 36401449; PMCID: PMC9678615.
Lian J, Fu J. Efficacy of Various Hypoglycemic Agents in the Treatment of Patients With Nonalcoholic Liver Disease With or Without Diabetes: A Network Meta-Analysis. Front Endocrinol (Lausanne). 2021 Mar 24;12:649018. doi: 10.3389/fendo.2021.649018. PMID: 33841337; PMCID: PMC8024567.
Russell-Jones D, Cuddihy RM, Hanefeld M, Kumar A, González JG, Chan M, Wolka AM, Boardman MK; DURATION-4 Study Group. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes Care. 2012 Feb;35(2):252-8. doi: 10.2337/dc11-1107. Epub 2011 Dec 30. PMID: 22210563; PMCID: PMC3263915.
Del Prato S, Chilton R. Practical strategies for improving outcomes in T2DM: The potential role of pioglitazone and DPP4 inhibitors. Diabetes Obes Metab. 2018 Apr;20(4):786-799. doi: 10.1111/dom.13169. Epub 2017 Dec 21. PMID: 29171700; PMCID: PMC5887932.
Viscoli CM, Inzucchi SE, Young LH, Insogna KL, Conwit R, Furie KL, Gorman M, Kelly MA, Lovejoy AM, Kernan WN; IRIS Trial Investigators. Pioglitazone and Risk for Bone Fracture: Safety Data From a Randomized Clinical Trial. J Clin Endocrinol Metab. 2017 Mar 1;102(3):914-922. doi: 10.1210/jc.2016-3237. PMID: 27935736; PMCID: PMC5460686.
McGuire DK, Inzucchi SE. New drugs for the treatment of diabetes mellitus: part I: Thiazolidinediones and their evolving cardiovascular implications. Circulation. 2008 Jan 22;117(3):440-9. doi: 10.1161/CIRCULATIONAHA.107.704080. PMID: 18212301.
Erdmann, E., Charbonnel, B., Wilcox, R. G., Skene, A. M., Massi-Benedetti, M., Yates, J., ... & PROactive Investigators. (2007). Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08). Diabetes care, 30(11), 2773-2778
Tripathy D, Solis-Herrera C, Ryder REJ. Cardioprotective Effects of Pioglitazone in Type 2 Diabetes. Diabetes Spectr. 2021 Aug;34(3):243-247. doi: 10.2337/ds20-0078. Epub 2021 Aug 18. PMID: 34511850; PMCID: PMC8387608.
Lewis JD, Habel LA, Quesenberry CP, Strom BL, Peng T, Hedderson MM, Ehrlich SF, Mamtani R, Bilker W, Vaughn DJ, Nessel L, Van Den Eeden SK, Ferrara A. Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes. JAMA. 2015 Jul 21;314(3):265-77. doi: 10.1001/jama.2015.7996. PMID: 26197187.
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