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REVIEW ARTICLE
Year : 2013  |  Volume : 40  |  Issue : 2  |  Page : 61-63

Pioglitazone: A boon we know less about


Department of Internal Medicine, Princess Durru Shehvar Children's and General Hospital, Purana Haveli, Hyderabad, India

Date of Web Publication23-Jul-2013

Correspondence Address:
Dilip Gude
Department of Internal Medicine, Princess Durru Shehvar Children's and General Hospital, Hyderabad
India
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Source of Support: Durru Shehvar Children's and General Hospital Hyderabad, AP, India, Conflict of Interest: None


DOI: 10.4103/0974-5009.115471

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  Abstract 

Pioglitazone is a thiazolidinedione that has significant extra-glycemic benefits most promising of which is its anti-atherogenicity. Pioglitazone may be cardioprotective interfering with atherosclerosis at various points such as atherogenesis, plaque inflammation, plaque rupture and hemostatic disturbances (i.e., thrombus/embolism formation), and microangiopathy. The far reaching effects of pioglitazone and its extra-glycemic benefits warrant a better place for it in the plethora of drugs that a diabetic is treated with. A review of literature is presented.

Keywords: Atherosclerosis, cardioprotective, pioglitazone


How to cite this article:
Gude D. Pioglitazone: A boon we know less about. J Sci Soc 2013;40:61-3

How to cite this URL:
Gude D. Pioglitazone: A boon we know less about. J Sci Soc [serial online] 2013 [cited 2019 Oct 23];40:61-3. Available from: http://www.jscisociety.com/text.asp?2013/40/2/61/115471


  Introduction Top


Pioglitazone has demonstrated considerable efficacy in glycemic control of type 2 diabetics. Of late research has been focused on its extra-glycemic benefits and has been promising thus far. A variety of advantages apart from glucose lowering have been documented such as halting atherosclerosis, improving lipid profile, and blood pressure (BP), which may translate into cardioprotection. Many of such effects are independent of its glucose lowering action, especially its anti-inflammatory effects. The role of pioglitazone in such extra-glycemic aspects is discussed.


  Role in Atherosclerosis Top


Pioglitazone is known to reduce coronary plaque burden, plaque area, thin-cap fibroatheroma prevalence, and percentage of necrotic core area. It also significantly lowers neointimal volume, homeostatic model assessment-index, interleukin (IL)-6, and tumor necrosis factor (TNF)-α levels. [1] A randomized study on 543 patients compared glimepiride with pioglitazone and after 18 months, based on coronary intravascular ultrasonography those on the latter showed significantly lower rate of progression of coronary atherosclerosis (decreased percent atheroma volume) compared to the former along with improved high-density lipoprotein (HDL) and triglyceride levels. [2] Not only known to slow carotid intima-media thickness (CIMT) progression, [3] pioglitazone may also induce and maintain CIMT regression as shown in a Japanese study on about 90 patients. [4] In another study, pioglitazone rapidly improved carotid plaque echolucency within 1 month of therapy initiation in patients with acute coronary syndrome and type 2 diabetes mellitus. [5] Pioglitazone attenuates atherosclerotic plaque inflammation independent of glucose lowering effect and this is corroborated in a study via 18 F-fluorodeoxyglucose positron emission tomography. [6] Use of bare-metal stents in conjunction with pioglitazone may equate the risks of death, target lesion revascularization, myocardial infarction, and stent thrombosis compared with drug-eluting stents use. [7] Benefits of pioglitazone in atherosclerosis may in-part be mediated by increased HDL. A study showed that the increase in HDL at 24 weeks contributed to the decreased progression of CIMT at 72 weeks. [8]


  Mechanism Top


Pioglitazone is known to ameliorate accelerated atherosclerosis, probably through peroxisome proliferator-activated receptor (PPARγ)-independent and -dependent mechanisms to modulate the regulatory/effector T cells imbalance. The inhibition of atherosclerosis may be via increased plasma adiponectin level and the increased expression of AdipoR1 mRNA in vessels. [9] Pioglitazone ameliorates the hypercholesterolemia-induced rise in plaque matrix metalloproteinase (MMP) and macrophage response (as demonstrated by serial optical molecular imaging). [10] Apart from MMP-9, it also causes significant reduction in high-sensitivity C-reactive protein levels and monocyte chemoattractant protein (MCP-1) levels. In a study, compared with control, pioglitazone significantly decreased toll-like receptor (TLR)-2 and TLR4 expression, along with reduction in TLR ligand-induced nuclear factor-κB activity, IL-1β, IL-6, MCP-1, and TNF-α. [11] Pioglitazone treatment up-regulates telomerase activity, telomere-stabilizing proteins, and reduces senescence markers in vascular cells along with the reduction of lipopolysaccharide-induced endothelial apoptosis. [12] It increases 15-epi-lipoxin A4 (a lipid mediator with strong anti-inflammatory and inflammation-resolving effects) and cyclic oxygenase (COX-2)-derived prostacyclin production. [13],[14] It also reduces circulating levels of thiobarbituric acid-reacting substances and S100A8/A9 complex levels (markers of reactive oxidative stress) in the absence of significant changes in body mass index. [15],[16] Hepatic expression of suppressor of cytokine signaling (SOCS-3) and markers of neutrophil infiltration are significantly lowered. [17] The effect of pioglitazone against insulin resistance was studied in polycystic ovary syndrome and its use reflected a reduction in soluble CD36 which correlates with measures of insulin sensitivity independent of central fat mass. [18]


  Role in Endothelial Dysfunction Top


Pioglitazone significantly improves endothelial and adipose tissue dysfunction. It is known to reduce intracellular superoxide radical generation. Pioglitazone augments flow-mediated dilation (FMD), increases high molecular weight adiponectin, and decreases TNF-α (all linked to an increased glucose disposal). [19] In a study, pioglitazone for 6 months in young women with Polycystic ovary syndrome improved FMD similar to that of metformin. [20] It increases the forearm blood flow response to acetylcholine, increases nitric oxide bioavailability, and decreases urinary excretion of 8-hydroxy-2′-deoxyguanosine (a critical biomarker of oxidative stress). [21] It is also known to lower endothelin-1 levels and attenuate angiotensin II induced increased systolic BP and atherosclerosis via the interaction with smooth muscle cell-specific PPARγ. Pioglitazone also increases neoangiogenesis and prevents apoptosis, thereby increasing the number and function of endothelial progenitor cells.


  Role in Blood Pressure Top


Pioglitazone is believed to have marked beneficial effects on BP and hepatic function and may be more effective than metformin to reduce risk factors in diabetic patients with metabolic syndrome at preventing atherosclerosis. The BP lowering effects are known to be direct and independent of improved endothelial function and insulin sensitivity. [22],[23] In experimental models, pioglitazone blunted the contractile response of vascular smooth muscle secondary to norepinephrine by 42% mediated primarily by blockade of calcium uptake by vascular smooth muscle. [24] Combining with metformin also decreases the BP apart from reducing inflammatory markers such as highly sensitive C-reactive protein. [25] The BP lowering effect also echoed in another study on insulin-resistant congenital adrenal hyperplasia patients. [26] Another study showed that pioglitazone was effective in reducing BP values in diabetic patients without nocturnal BP dipping (lowering). [27]


  Role in Lipid Profile Top


Pioglitazone is known to significantly improve lipid profile. Long-term pioglitazone therapy durably improves triglycerides and HDL cholesterol levels, irrespective of baseline anti-hyperglycemic therapy or statin use. [28] Especially when compared with rosiglitazone, pioglitazone significantly improves triglycerides, HDL cholesterol, low-density lipoprotein (LDL) particle concentration, and LDL particle size. [29] Pioglitazone increases PPARγ-liver receptor X and ATP cassette binding transporter (ABC) A1/G1 expressions, which in turn enhance cholesterol efflux from macrophages. [30]


  Adverse Effects Top


Significant adverse effects are usually limited to weight gain, peripheral edema, precipitation of heart failure, and an increase in bone fractures. Headache, myalgias, and a minimally increased incidence of sinusitis and pharyngitis are also reported. The overall adverse effect profile is usually favorable and the drug is well tolerated. [31]


  Conclusion Top


The indomitable emerging effects of pioglitazone on atherogenesis have garnered the drug a special place apart from better glycemic control in the management of diabetic and glucose intolerant patients who are at high risk for coronary artery disease. Clinicians' awareness of the same is the need of the hour.


  Acknowledgments Top


I thank our colleagues and staff of the department of Internal medicine for their perpetual support.

 
  References Top

1.You SH, Kim BS, Hong SJ, Ahn CM, Lim DS. The effects of pioglitazone in reducing atherosclerosis progression and neointima volume in type 2 diabetic patients: Prospective randomized study with volumetric intravascular ultrasonography analysis. Korean Circ J 2010;40:625-31.  Back to cited text no. 1
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2.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.  Back to cited text no. 2
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3.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.  Back to cited text no. 3
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4.Yamasaki Y, Katakami N, Furukado S, Kitagawa K, Nagatsuka K, Kashiwagi A, et al. Long-term effects of pioglitazone on carotid atherosclerosis in Japanese patients with type 2 diabetes without a recent history of macrovascular morbidity. J Atheroscler Thromb 2010;17:1132-40.  Back to cited text no. 4
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5.Hirano M, Nakamura T, Kitta Y, Yano T, Kobayashi T, Sano K, et al. Rapid improvement of carotid plaque echogenicity within 1 month of pioglitazone treatment in patients with acute coronary syndrome. Atherosclerosis 2009;203:483-8.  Back to cited text no. 5
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6.Mizoguchi M, Tahara N, Tahara A, Nitta Y, Kodama N, Oba T, et al. Pioglitazone attenuates atherosclerotic plaque inflammation in patients with impaired glucose tolerance or diabetes a prospective, randomized, comparator-controlled study using serial FDG PET/CT imaging study of carotid artery and ascending aorta. JACC Cardiovasc Imaging 2011;4:1110-8.  Back to cited text no. 6
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7.Nishio K, Hosaka M, Shigemitsu M, Kobayashi Y. Three-year clinical outcome in type 2 diabetic patients with drug-eluting stents versus bare-metal stents with pioglitazone. Cardiovasc Revasc Med 2011;12:197-202.  Back to cited text no. 7
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8.Davidson M, Meyer PM, Haffner S, Feinstein S, D'Agostino R Sr, Kondos GT, et al. Increased high-density lipoprotein cholesterol predicts the pioglitazone-mediated reduction of carotid intima-media thickness progression in patients with type 2 diabetes mellitus. Circulation 2008;117:2123-30.  Back to cited text no. 8
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9.Da-Wa CR, Zhao F, Qi YF, Chen LZ, Huo Y. Role of adiponectin and its receptors in anti-atherosclerotic effects of pioglitazone on ApoE knocked out mice. Beijing Da Xue Xue Bao 2009;41:174-8.  Back to cited text no. 9
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10.Chang K, Francis SA, Aikawa E, Figueiredo JL, Kohler RH, McCarthy JR, et al. Pioglitazone suppresses inflammation in vivo in murine carotid atherosclerosis: Novel detection by dual-target fluorescence molecular imaging. Arterioscler Thromb Vasc Biol 2010;30:1933-9.  Back to cited text no. 10
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11.Dasu MR, Park S, Devaraj S, Jialal I. Pioglitazone inhibits Toll-like receptor expression and activity in human monocytes and db/db mice. Endocrinology 2009;150:3457-64.  Back to cited text no. 11
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12.Werner C, Gensch C, Pöss J, Haendeler J, Böhm M, Laufs U. Pioglitazone activates aortic telomerase and prevents stress-induced endothelial apoptosis. Atherosclerosis 2011;216:23-34.  Back to cited text no. 12
    
13.Gutierrez AD, Sathyanarayana P, Konduru S, Ye Y, Birnbaum Y, Bajaj M. The effect of pioglitazone treatment on 15-epi-lipoxin A4 levels in patients with type 2 diabetes. Atherosclerosis 2012;223:204-8.  Back to cited text no. 13
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14.Hernanz R, Martín Á, Pérez-Girón JV, Palacios R, Briones AM, Miguel M, et al. Pioglitazone treatment increases COX-2-derived prostacyclin production and reduces oxidative stress in hypertensive rats: Role in vascular function. Br J Pharmacol 2012;166:1303-19.  Back to cited text no. 14
    
15.Nakatsuji H, Kishida K, Funahashi T, Shimomura I, Senri Study II Group. Three-month treatment with pioglitazone reduces circulating levels of thiobarbituric acid-reacting substances, a marker of reactive oxidative stress, without change in body mass index, in Japanese patients with type 2 diabetes. Atherosclerosis 2010;212:243-5.  Back to cited text no. 15
    
16.Nakatsuji H, Kishida K, Funahashi T, Shimomura I, Senri Study II Group. Three-month treatment with pioglitazone reduces circulating levels of S100A8/A9 (MRP8/14) complex, a biomarker of inflammation, without changes in body mass index, in type 2 diabetics with abdominal obesity. Diabetes Res Clin Pract 2012;95:e58-60.  Back to cited text no. 16
    
17.Collino M, Aragno M, Castiglia S, Miglio G, Tomasinelli C, Boccuzzi G, et al. Pioglitazone improves lipid and insulin levels in overweight rats on a high cholesterol and fructose diet by decreasing hepatic inflammation. Br J Pharmacol 2010;160:1892-902.  Back to cited text no. 17
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18.Glintborg D, Højlund K, Andersen M, Henriksen JE, Beck-Nielsen H, Handberg A. Soluble CD36 and risk markers of insulin resistance and atherosclerosis are elevated in polycystic ovary syndrome and significantly reduced during pioglitazone treatment. Diabetes Care 2008;31:328-34.  Back to cited text no. 18
    
19.Rizza S, Cardellini M, Porzio O, Pecchioli C, Savo A, Cardolini I, et al. Pioglitazone improves endothelial and adipose tissue dysfunction in pre-diabetic CAD subjects. Atherosclerosis 2011;215:180-3.  Back to cited text no. 19
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20.Naka KK, Kalantaridou SN, Kravariti M, Bechlioulis A, Kazakos N, Calis KA, et al. Effect of the insulin sensitizers metformin and pioglitazone on endothelial function in young women with polycystic ovary syndrome: A prospective randomized study. Fertil Steril 2011;95:203-9.  Back to cited text no. 20
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21.Hidaka T, Nakagawa K, Goto C, Soga J, Fujii Y, Hata T, et al. Pioglitazone improves endothelium-dependent vasodilation in hypertensive patients with impaired glucose tolerance in part through a decrease in oxidative stress. Atherosclerosis 2010;210:521-4.  Back to cited text no. 21
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22.Kato T, Sawai Y, Kanayama H, Taguchi H, Terabayashi T, Taki F, et al. Comparative study of low-dose pioglitazone or metformin treatment in Japanese diabetic patients with metabolic syndrome. Exp Clin Endocrinol Diabetes 2009;117:593-9.  Back to cited text no. 22
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23.Schneider F, Vossler S, Franke S, Bär F, Konrad T. Impact of insulin sensitivity treatment with pioglitazone on endothelial function in non-diabetic patients with arterial hypertension. Int J Clin Pharmacol Ther 2009;47:311-20.  Back to cited text no. 23
    
24.Buchanan TA, Meehan WP, Jeng YY, Yang D, Chan TM, Nadler JL, et al. Blood pressure lowering by pioglitazone. Evidence for a direct vascular effect. J Clin Invest 1995;96:354-60.  Back to cited text no. 24
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25.Derosa G, Fogari E, Cicero AF, D'Angelo A, Ciccarelli L, Piccinni MN, et al. Blood pressure control and inflammatory markers in type 2 diabetic patients treated with pioglitazone or rosiglitazone and metformin. Hypertens Res 2007;30:387-94.  Back to cited text no. 25
    
26.Kroese JM, Mooij CF, van der Graaf M, Hermus AR, Tack CJ. Pioglitazone improves insulin resistance and decreases blood pressure in adult patients with congenital adrenal hyperplasia. Eur J Endocrinol 2009;161:887-94.  Back to cited text no. 26
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27.Negro R, Dazzi D, Hassan H, Pezzarossa A. Pioglitazone reduces blood pressure in non-dipping diabetic patients. Minerva Endocrinol 2004;29:11-7.  Back to cited text no. 27
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28.Spanheimer R, Betteridge DJ, Tan MH, Ferrannini E, Charbonnel B, PROactive Investigators. Long-term lipid effects of pioglitazone by baseline anti-hyperglycemia medication therapy and statin use from the PROactive experience (PROactive 14). Am J Cardiol 2009;104:234-9.  Back to cited text no. 28
    
29.Goldberg RB, Kendall DM, Deeg MA, Buse JB, Zagar AJ, Pinaire JA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005;28:1547-54.  Back to cited text no. 29
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30.Ozasa H, Ayaori M, Iizuka M, Terao Y, Uto-Kondo H, Yakushiji E, et al. Pioglitazone enhances cholesterol efflux from macrophages by increasing ABCA1/ABCG1 expressions via PPARã/LXRα pathway: Findings from in vitro and ex vivo studies. Atherosclerosis 2011;219:141-50.  Back to cited text no. 30
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  In this article
Abstract
Introduction
Role in Atherosc...
Mechanism
Role in Endothel...
Role in Blood Pr...
Role in Lipid Pr...
Adverse Effects
Conclusion
Acknowledgments
References

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