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Published in: Cardiovascular Diabetology 1/2017

Open Access 01-12-2017 | Review

Pioglitazone and the secondary prevention of cardiovascular disease. A meta-analysis of randomized-controlled trials

Authors: Marit de Jong, H. Bart van der Worp, Yolanda van der Graaf, Frank L. J. Visseren, Jan Westerink

Published in: Cardiovascular Diabetology | Issue 1/2017

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Abstract

Background and aims

Pioglitazone targets multiple pathogenic pathways involved in the development of cardiovascular diseases (CVD). The aim of this systematic review and meta-analysis is to assess the effects of pioglitazone treatment on the secondary prevention of CVD.

Methods

Randomized-controlled trials of pioglitazone in patients with CVD were identified through PubMed, Embase, Cochrane and CINAHL, in a search up to May 2016. Studies were included if pioglitazone was compared with any control (usual care, placebo or active comparator) and if patients were previously diagnosed with CVD. The outcomes of interest included major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, all-cause mortality and heart failure (HF). All outcomes were compared by pooled risk ratios (RR) with a 95% confidence interval (CI). Pooled estimates were calculated using a random-effects model.

Results

Ten studies reported the effects of pioglitazone on any of the outcomes of interest. Pioglitazone reduced recurrent MACE (RR 0.74, 95% 0.60–0.92; I2 = 35), MI (RR 0.77, 95% CI 0.64–0.93; I2 = 0%), or stroke (RR 0.81, 95% CI 0.68–0.96; I2 = 0%). Pioglitazone did not reduce all-cause mortality (RR 0.94, 95% CI 0.81–1.08; I2 = 0%), whereas pioglitazone treatment was associated with an increased risk of HF (RR 1.33, 95% CI 1.14–1.54).

Conclusions

Pioglitazone lowers the risk of recurrent MACE, stroke, or MI in patients with clinical manifest vascular disease. Pioglitazone does not lower the risk for all-cause mortality, and increases the risk for the development of HF.
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Literature
6.
go back to reference Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome an american heart association/national heart, lung, and blood institute scientific statement. Circulation. 2005;112:2735–52. doi:10.1161/CIRCULATIONAHA.105.169404.CrossRefPubMed Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome an american heart association/national heart, lung, and blood institute scientific statement. Circulation. 2005;112:2735–52. doi:10.​1161/​CIRCULATIONAHA.​105.​169404.CrossRefPubMed
7.
go back to reference Wassink AMJ, Van Der Graaf Y, Olijhoek JK, Visseren FL. Metabolic syndrome and the risk of new vascular events and all-cause mortality in patients with coronary artery disease, cerebrovascular disease, peripheral arterial disease or abdominal aortic aneurysm. Eur Heart J. 2008;29:213–23. doi:10.1093/eurheartj/ehm582.CrossRefPubMed Wassink AMJ, Van Der Graaf Y, Olijhoek JK, Visseren FL. Metabolic syndrome and the risk of new vascular events and all-cause mortality in patients with coronary artery disease, cerebrovascular disease, peripheral arterial disease or abdominal aortic aneurysm. Eur Heart J. 2008;29:213–23. doi:10.​1093/​eurheartj/​ehm582.CrossRefPubMed
8.
go back to reference Tanaka R, Yamashiro K, Okuma Y, Shimura H, Nakamura S, Ueno Y, et al. Effects of pioglitazone for secondary stroke prevention in patients with impaired glucose tolerance and newly diagnosed diabetes: the J-SPIRIT study. J Atheroscler Thromb. 2015;22:1305–16. doi:10.5551/jat.30007.CrossRefPubMed Tanaka R, Yamashiro K, Okuma Y, Shimura H, Nakamura S, Ueno Y, et al. Effects of pioglitazone for secondary stroke prevention in patients with impaired glucose tolerance and newly diagnosed diabetes: the J-SPIRIT study. J Atheroscler Thromb. 2015;22:1305–16. doi:10.​5551/​jat.​30007.CrossRefPubMed
9.
go back to reference Nissen SE, Nicholls SJ, Wolski K, Nesto R, Kupfer S, Perez A, et al. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008;299:1561–73. doi:10.1001/jama.299.13.1561.CrossRefPubMed Nissen SE, Nicholls SJ, Wolski K, Nesto R, Kupfer S, Perez A, et al. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008;299:1561–73. doi:10.​1001/​jama.​299.​13.​1561.CrossRefPubMed
10.
go back to reference Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, et al. 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;366:1279–89. doi:10.1016/S0140-6736(05)67528-9.CrossRefPubMed Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, et al. 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;366:1279–89. doi:10.​1016/​S0140-6736(05)67528-9.CrossRefPubMed
12.
go back to reference Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998;391:79–82. doi:10.1038/34178.CrossRefPubMed Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998;391:79–82. doi:10.​1038/​34178.CrossRefPubMed
17.
go back to reference Xu W, Bi Y, Sun Z, Li J, Guo L, Yang T, et al. Comparison of the effects on glycaemic control and β-cell function in newly diagnosed type 2 diabetes patients of treatment with exenatide, insulin or pioglitazone: a multicentre randomized parallel-group trial (the CONFIDENCE study). J Intern Med. 2015;277:137–50. doi:10.1111/joim.12293.CrossRefPubMed Xu W, Bi Y, Sun Z, Li J, Guo L, Yang T, et al. Comparison of the effects on glycaemic control and β-cell function in newly diagnosed type 2 diabetes patients of treatment with exenatide, insulin or pioglitazone: a multicentre randomized parallel-group trial (the CONFIDENCE study). J Intern Med. 2015;277:137–50. doi:10.​1111/​joim.​12293.CrossRefPubMed
18.
go back to reference Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab. 2002;87:2784–91. doi:10.1210/jcem.87.6.8567.CrossRefPubMed Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab. 2002;87:2784–91. doi:10.​1210/​jcem.​87.​6.​8567.CrossRefPubMed
19.
go back to reference Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, et al. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes. 2001;50:2094–9.CrossRefPubMed Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, et al. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes. 2001;50:2094–9.CrossRefPubMed
20.
21.
go back to reference Saremi A, Schwenke DC, Buchanan TA, Hodis HN, Mack WJ, Banerji M, et al. Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors. Arterioscler Thromb Vasc Biol. 2013;33:393–9. doi:10.1161/ATVBAHA.112.300346.CrossRefPubMed Saremi A, Schwenke DC, Buchanan TA, Hodis HN, Mack WJ, Banerji M, et al. Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors. Arterioscler Thromb Vasc Biol. 2013;33:393–9. doi:10.​1161/​ATVBAHA.​112.​300346.CrossRefPubMed
22.
go back to reference Martens FM, Visseren FL, De Koning EJ, Rabelink TJ. Short-term pioglitazone treatment improves vascular function irrespective of metabolic changes in patients with type 2 diabetes. J Cardiovasc Pharmacol. 2005;46:773–77821.CrossRefPubMed Martens FM, Visseren FL, De Koning EJ, Rabelink TJ. Short-term pioglitazone treatment improves vascular function irrespective of metabolic changes in patients with type 2 diabetes. J Cardiovasc Pharmacol. 2005;46:773–77821.CrossRefPubMed
29.
go back to reference Hong SJ, Choi SC, Cho JY, Joo HJ, Park JH, Yu CW, et al. Pioglitazone increases circulating microRNA-24 with decrease in coronary neointimal hyperplasia in type 2 diabetic patients- optical coherence tomography analysis. Circ J. 2015;79:880–8. doi:10.1253/circj.CJ-14-0964.CrossRefPubMed Hong SJ, Choi SC, Cho JY, Joo HJ, Park JH, Yu CW, et al. Pioglitazone increases circulating microRNA-24 with decrease in coronary neointimal hyperplasia in type 2 diabetic patients- optical coherence tomography analysis. Circ J. 2015;79:880–8. doi:10.​1253/​circj.​CJ-14-0964.CrossRefPubMed
31.
go back to reference Suryadevara S, Ueno M, Tello-Montoliu A, Ferreiro JL, Desai B, Rollini F, et al. Effects of pioglitazone on platelet P2Y12-mediated signalling in clopidogrel-treated patients with type 2 diabetes mellitus. Thromb Haemost. 2012;108:930–6. doi:10.1160/TH12-06-0397.CrossRefPubMed Suryadevara S, Ueno M, Tello-Montoliu A, Ferreiro JL, Desai B, Rollini F, et al. Effects of pioglitazone on platelet P2Y12-mediated signalling in clopidogrel-treated patients with type 2 diabetes mellitus. Thromb Haemost. 2012;108:930–6. doi:10.​1160/​TH12-06-0397.CrossRefPubMed
32.
go back to reference Takagi T, Okura H, Kobayashi Y, Kataoka T, Taguchi H, Toda I, et al. A prospective, multicenter, randomized trial to assess efficacy of pioglitazone on in-stent neointimal suppression in type 2 diabetes: POPPS (prevention of in-stent neointimal proliferation by pioglitazone study). JACC Cardiovasc Interv. 2009;2:524–31. doi:10.1016/j.jcin.2009.04.007.CrossRefPubMed Takagi T, Okura H, Kobayashi Y, Kataoka T, Taguchi H, Toda I, et al. A prospective, multicenter, randomized trial to assess efficacy of pioglitazone on in-stent neointimal suppression in type 2 diabetes: POPPS (prevention of in-stent neointimal proliferation by pioglitazone study). JACC Cardiovasc Interv. 2009;2:524–31. doi:10.​1016/​j.​jcin.​2009.​04.​007.CrossRefPubMed
33.
go back to reference Kaneda H, Shiono T, Miyashita Y, Takahashi S, Taketani Y, Domae H, et al. Efficacy and safety of pioglitazone in patients with ST elevation myocardial infarction treated with primary stent implantation. Heart. 2009;95:1079–84. doi:10.1136/hrt.2008.162842.CrossRefPubMed Kaneda H, Shiono T, Miyashita Y, Takahashi S, Taketani Y, Domae H, et al. Efficacy and safety of pioglitazone in patients with ST elevation myocardial infarction treated with primary stent implantation. Heart. 2009;95:1079–84. doi:10.​1136/​hrt.​2008.​162842.CrossRefPubMed
35.
go back to reference Wilcox R, Bousser MG, Betteridge DJ, Schernthaner G, Pirags V, Kupfer S, et al. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke. 2007;38:865–73. doi:10.1161/01.STR.0000257974.06317.49.CrossRefPubMed Wilcox R, Bousser MG, Betteridge DJ, Schernthaner G, Pirags V, Kupfer S, et al. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke. 2007;38:865–73. doi:10.​1161/​01.​STR.​0000257974.​06317.​49.CrossRefPubMed
36.
go back to reference Wilcox R, Kupfer S, Erdmann E. Effects of pioglitazone on major adverse cardiovascular events in high-risk patients with type 2 diabetes: results from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive 10). Am Heart J. 2008;155:712–7. doi:10.1016/j.ahj.2007.11.029.CrossRefPubMed Wilcox R, Kupfer S, Erdmann E. Effects of pioglitazone on major adverse cardiovascular events in high-risk patients with type 2 diabetes: results from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive 10). Am Heart J. 2008;155:712–7. doi:10.​1016/​j.​ahj.​2007.​11.​029.CrossRefPubMed
38.
go back to reference Liao H, Saver JL, Wu Y, Chen T, Lee M, Ovbiagele B. Pioglitazone and cardiovascular outcomes in patients with insulin resistance, pre-diabetes and type 2 diabetes: a systematic review and meta-analysis. BMJ. 2017;7:1–13. doi:10.1136/bmjopen-2016-013927. Liao H, Saver JL, Wu Y, Chen T, Lee M, Ovbiagele B. Pioglitazone and cardiovascular outcomes in patients with insulin resistance, pre-diabetes and type 2 diabetes: a systematic review and meta-analysis. BMJ. 2017;7:1–13. doi:10.​1136/​bmjopen-2016-013927.
40.
go back to reference Varas-Lorenzo C, Margulis AV, Pladevall M, Riera-Guardia N, Calingaert B, Hazell L, et al. The risk of heart failure associated with the use of noninsulin blood glucose-lowering drugs: systematic review and meta-analysis of published observational studies. BMC Cardiovasc Disord. 2014;14:129. doi:10.1186/1471-2261-14-129.CrossRefPubMedPubMedCentral Varas-Lorenzo C, Margulis AV, Pladevall M, Riera-Guardia N, Calingaert B, Hazell L, et al. The risk of heart failure associated with the use of noninsulin blood glucose-lowering drugs: systematic review and meta-analysis of published observational studies. BMC Cardiovasc Disord. 2014;14:129. doi:10.​1186/​1471-2261-14-129.CrossRefPubMedPubMedCentral
43.
go back to reference Nitta Y, Tahara N, Tahara A, Honda A, Kodama N, Mizoguchi M, et al. Pioglitazone decreases coronary artery inflammation in impaired glucose tolerance and diabetes mellitus: evaluation by FDG-PET/CT imaging. JACC Cardiovasc Imaging. 2013;6:1172–82. doi:10.1016/j.jcmg.2013.09.004.CrossRefPubMed Nitta Y, Tahara N, Tahara A, Honda A, Kodama N, Mizoguchi M, et al. Pioglitazone decreases coronary artery inflammation in impaired glucose tolerance and diabetes mellitus: evaluation by FDG-PET/CT imaging. JACC Cardiovasc Imaging. 2013;6:1172–82. doi:10.​1016/​j.​jcmg.​2013.​09.​004.CrossRefPubMed
44.
45.
go back to reference Christoph M, Herold J, Berg-Holldack A, Rauwolf T, Ziemssen T, Schmeisser A, et al. Effects of the PPARγ agonist pioglitazone on coronary atherosclerotic plaque composition and plaque progression in non-diabetic patients: a double-center, randomized controlled VH-IVUS pilot-trial. Heart Vessels. 2015;30:286–95. doi:10.1007/s00380-014-0480-0.CrossRefPubMed Christoph M, Herold J, Berg-Holldack A, Rauwolf T, Ziemssen T, Schmeisser A, et al. Effects of the PPARγ agonist pioglitazone on coronary atherosclerotic plaque composition and plaque progression in non-diabetic patients: a double-center, randomized controlled VH-IVUS pilot-trial. Heart Vessels. 2015;30:286–95. doi:10.​1007/​s00380-014-0480-0.CrossRefPubMed
46.
go back to reference Marx N, Wöhrle J, Nusser T, Walcher D, Rinker A, Hombach V, et al. Pioglitazone reduces neointima volume after coronary stent implantation: a randomized, placebo-controlled. Double-Blind Trial in Nondiabetic Patients. Circulation. 2005;112:2792–8. doi:10.1161/CIRCULATIONAHA.105.535484.PubMed Marx N, Wöhrle J, Nusser T, Walcher D, Rinker A, Hombach V, et al. Pioglitazone reduces neointima volume after coronary stent implantation: a randomized, placebo-controlled. Double-Blind Trial in Nondiabetic Patients. Circulation. 2005;112:2792–8. doi:10.​1161/​CIRCULATIONAHA.​105.​535484.PubMed
47.
go back to reference Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care. 2004;27:256–63. doi:10.2337/diacare.27.1.256.CrossRefPubMed Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care. 2004;27:256–63. doi:10.​2337/​diacare.​27.​1.​256.CrossRefPubMed
48.
49.
go back to reference Ordu S, Ozhan H, Alemdar R, Aydin M, Basar C, Caglar O, et al. Pioglitazone improves ventricular diastolic function in patients with diabetes mellitus: a tissue Doppler study. Acta Cardiol. 2010;65:401–6. doi:10.2143/AC.65.4.2053898.PubMed Ordu S, Ozhan H, Alemdar R, Aydin M, Basar C, Caglar O, et al. Pioglitazone improves ventricular diastolic function in patients with diabetes mellitus: a tissue Doppler study. Acta Cardiol. 2010;65:401–6. doi:10.​2143/​AC.​65.​4.​2053898.PubMed
51.
52.
go back to reference Clarke GD, Solis-Herrera C, Molina-Wilkins M, Martinez S, Merovci A, Cersosimo E, et al. Pioglitazone improves left ventricular diastolic function in subjects with diabetes. Diabetes care. 2017:dc170078. doi:10.2337/dc17-0078. Clarke GD, Solis-Herrera C, Molina-Wilkins M, Martinez S, Merovci A, Cersosimo E, et al. Pioglitazone improves left ventricular diastolic function in subjects with diabetes. Diabetes care. 2017:dc170078. doi:10.​2337/​dc17-0078.
54.
go back to reference Lu CJ, Sun Y, Muo CH, Chen RC, Chen PC, Hsu CY, et al. Risk of stroke with thiazolidinediones: a 10-year nationwide population-based cohort study. Cerebrovasc Dis. 2013;36:145–51. doi:10.1159/000353679.CrossRefPubMed Lu CJ, Sun Y, Muo CH, Chen RC, Chen PC, Hsu CY, et al. Risk of stroke with thiazolidinediones: a 10-year nationwide population-based cohort study. Cerebrovasc Dis. 2013;36:145–51. doi:10.​1159/​000353679.CrossRefPubMed
55.
56.
go back to reference Erdmann E, Charbonnel B, Wilcox RG, Skene AM, Massi-Benedetti M, Yates J, et al. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08). Diabetes Care. 2007;30:2773–8. doi:10.2337/dc07-0717.CrossRefPubMed Erdmann E, Charbonnel B, Wilcox RG, Skene AM, Massi-Benedetti M, Yates J, et al. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08). Diabetes Care. 2007;30:2773–8. doi:10.​2337/​dc07-0717.CrossRefPubMed
57.
go back to reference Tuccori M, Filion KB, Yin H, Yu OH, Platt RW, Azoulay L. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ. 2016;352:i1541.CrossRefPubMedPubMedCentral Tuccori M, Filion KB, Yin H, Yu OH, Platt RW, Azoulay L. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ. 2016;352:i1541.CrossRefPubMedPubMedCentral
59.
60.
Metadata
Title
Pioglitazone and the secondary prevention of cardiovascular disease. A meta-analysis of randomized-controlled trials
Authors
Marit de Jong
H. Bart van der Worp
Yolanda van der Graaf
Frank L. J. Visseren
Jan Westerink
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2017
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-017-0617-4

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