The peroxisome proliferator-activated receptor-gamma agonist pioglitazone represses inflammation in a peroxisome proliferator-activated receptor-alpha-dependent manner in vitro and in vivo in mice. Analysis of the relationship between the Pro12Ala variant in the PPAR-gamma2 gene and the response rate to therapy with pioglitazone in patients with type 2 diabetes. Improvement of cardiovascular risk markers by pioglitazone is independent from glycemic control: results from the pioneer study. Effects of Pioglitazone for Secondary Stroke Prevention in Patients with Impaired Glucose Tolerance and Newly Diagnosed Diabetes: The J-SPIRIT Study. Rapid communication: inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes.
OBJECTIVES Our aim was to investigate if the peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone modulates inflammation through PPARalpha mechanisms . BACKGROUND The thiazolidinediones ( TZDs ) pioglitazone and rosiglitazone are insulin-sensitizing PPARgamma agonists used to treat type 2 diabetes ( T2DM ) . Despite evidence for TZDs limiting inflammation and atherosclerosis , questions exist regarding differential responses to TZDs . In a double-blinded , placebo-controlled 16-week trial among recently diagnosed T2DM subjects ( n = 34 ) , pioglitazone-treated subjects manifested lower triglycerides and lacked the increase in soluble vascular cell adhesion molecules (sVCAM)-1 evident in the placebo group . Previously we reported PPARalpha but not PPARgamma agonists could repress VCAM-1 expression . Since both triglyceride-lowering and VCAM-1 repression characterize PPARalpha activation , we studied pioglitazone 's effects via PPARalpha . METHODS Pioglitazone effects on known PPARalpha responses -- lig and binding domain activation and PPARalpha target gene expression -- were tested in vitro and in vivo , including in wild-type and PPARalpha-deficient cells and mice , and compared with the effects of other PPARgamma ( rosiglitazone ) and PPARalpha ( WY14643 ) agonists . RESULTS Pioglitazone repressed endothelial TNFalpha-induced VCAM-1 messenger ribonucleic acid expression and promoter activity , and induced hepatic IkappaBalpha in a manner dependent on both pioglitazone exposure and PPARalpha expression . Pioglitazone also activated the PPARalpha lig and binding domain and induced PPARalpha target gene expression , with in vitro effects that were most pronounced in endothelial cells . In vivo , pioglitazone administration modulated sVCAM-1 levels and IkappaBalpha expression in wild-type but not PPARalpha-deficient mice . CONCLUSIONS Pioglitazone regulates inflammatory target genes in hepatic ( IkappaBalpha ) and endothelial ( VCAM-1 ) setting s in a PPARalpha-dependent manner . These data offer novel mechanisms that may underlie distinct TZD responses OBJECTIVE To investigate the influence of peroxisome proliferator-activated receptor-gamma ( PPAR-gamma ) gene variants on the response rate to therapy with the thiazolidinedione ( TZD ) pioglitazone , because in vitro studies have suggested that genetic variants of the PPAR-gamma gene may influence the drug efficacy of TZD . RESEARCH DESIGN AND METHODS A total of 131 patients were treated in an open-label , r and omized , multicenter study with pioglitazone ( 45 mg o.d . ) during a course of > or=26 weeks . Response to the pioglitazone therapy was defined by either a > 20 % decrease in fasting plasma glucose or a > 15 % decrease in HbA(1c ) values after 26 weeks of pioglitazone treatment . We evaluated the association between the PPAR-gamma genotype and the response rate to pioglitazone treatment . RESULTS The Pro12Ala and the Pro12Pro variants in the PPAR-gamma gene are not associated with the response rate to pioglitazone treatment in patients with type 2 diabetes . However , we identified initial fasting plasma glucose level > 11.0 mmol/l , HbA(1c ) value > 9.0 % , BMI > 32 kg/m(2 ) , and fasting C-peptide concentrations at baseline > 2.5 pmol/l as predominant confounding factors for the responder frequency to pioglitazone treatment . CONCLUSIONS The Pro12Ala variant in the PPAR-gamma gene does not affect the therapy efficacy of pioglitazone , suggesting that the drug-treatment response is independent from pharmacogenetic effects between PPAR-gamma and its lig and pioglitazone . Whether the Ala12Ala genotype plays a role in the response rate to TZD therapy remains to be determined OBJECTIVES This study was performed to assess whether the anti-inflammatory and antiatherogenic effects of pioglitazone suggested by animal experiments are reproducible in man and independent from improvements in metabolic control . BACKGROUND Type 2 diabetes is associated with increased cardiovascular risk . METHODS A total of 192 patients were enrolled into a six-month , prospect i ve , open-label , controlled clinical study . They were r and omized to receive either pioglitazone ( 45 mg ) or glimepiride ( 1 to 6 mg , with the intent to optimize therapy ) . Biochemical and clinical markers to assess therapeutic effects included HbA1c , fasting glucose , insulin , adiponectin , lipids , high-sensitivity C-reactive protein ( hsCRP ) , intracellular adhesion molecule , vascular cell adhesion molecule , vascular endothelial growth factor , fibrinogen , von Willebr and factor , matrix metalloproteinase (MMP)-9 , monocyte chemoattractant protein (MCP)-1 , soluble CD40 lig and , and carotid intima-media thickness ( IMT ) . RESULTS The study was completed by 173 patients ( 66 female , 107 male ; age [ + /- SD ] : 63 + /- 8 years ; disease duration : 7.2 + /- 7.2 years ; HbA1c : 7.5 + /- 0.9 % ; pioglitazone arm : 89 patients ) . A comparable reduction in HbA1c was seen in both groups ( p < 0.001 ) . In the pioglitazone group , reductions were observed for glucose ( p < 0.001 vs. glimepiride group at end point ) , insulin ( p < 0.001 ) , low-density lipoprotein/high-density lipoprotein ratio ( p < 0.001 ) , hsCRP ( p < 0.05 ) , MMP-9 ( p < 0.05 ) , MCP-1 ( p < 0.05 ) , and carotid IMT ( p < 0.001 ) , and an increase was seen in high-density lipoprotein ( p < 0.001 ) and adiponectin ( p < 0.001 ) . Spearman ranks analysis revealed only one correlation between the reduction in cardiovascular risk parameters and the improvement in the metabolic parameters ( MMP-9 and fasting blood glucose , p < 0.05 ) CONCLUSIONS This prospect i ve study gives evidence of an anti-inflammatory and antiatherogenic effect of pioglitazone versus glimepiride . This effect is independent from blood glucose control and may be attributed to peroxisome proliferator-activated receptor gamma activation AIM Prediabetes is an independent risk factor for future stroke . However , no effective treatment has yet been established for the recurrence of stroke in patients with prediabetes . Here we investigated the effects of pioglitazone , a potent peroxisome proliferator-activated receptor-gamma agonist , for the reduction of recurrent stroke in patients with prediabetes . METHODS Participants were patients who had a symptomatic ischemic stroke or transient ischemic attack ( TIA ) without a history of type 2 diabetes mellitus and who were diagnosed to have IGT or newly diagnosed diabetes by a 75-g oral glucose tolerance test . These patients were r and omized to either receive or not receive pioglitazone . The primary endpoint was a recurrence of ischemic stroke . RESULTS A total of 120 patients were enrolled in the study . Sixty-three patients received pioglitazone and 57 were enrolled in the control group that did not receive pioglitazone . The majority of patients ( 68.3 % ) were prescribed 15 mg of pioglitazone , while the remaining patients ( 31.7 % ) were treated with 30 mg of pioglitazone . Over a median follow-up period of 2.8 years , treatment with pioglitazone was found to be associated with a lower rate of the primary endpoint ( recurrence of stroke ) than that observed in the control group [ event rate=4.8 % pioglitazone vs 10.5 % control , hazard ratio=0.62 , 95 % confidence interval 0.13 - 2.35 , p=0.49 ] . However , differences were not statistically significant . CONCLUSIONS While this study was too underpowered to determine the effect of pioglitazone , the result failed to show beneficial effects in patients of ischemic stroke or TIA with impaired glucose tolerance and newly diagnosed diabetes There have been increasing evidence s that thiazolidinediones , peroxisome proliferator-activated receptor gamma ( PPARgamma ) agonists , may have some antiatherogenic actions . We have previously reported that troglitazone has a potent inhibitory effect on common carotid arterial intima-media thickness ( IMT ) in subjects with type 2 diabetes . However , some studies suggested a possibility that PPARgamma activators may have protoatherogenic actions , raising concern about their detrimental effects in diabetic subjects . In the present study , we investigated the effect of treatment with pioglitazone , another PPARgamma agonist , on IMT in a total of 106 Japanese subjects with type 2 diabetes .  Pioglitazone ( 30 mg daily ) was administered for 6 months in 53 patients . Compared to control group ( n = 53 ) , the group given pioglitazone showed a significant decrease in IMT as early as 3 months after the administration . The decrease in IMT was also found after 6 months ( IMT change : -0.084[SE 0.023 ] mm vs. control 0.022[SE 0.006 ] mm , P < 0.001 ) , although the difference between those after 3 and 6 months did not reach any statistical significance . These findings indicate that thiazolidinediones cause an inhibition of early atherosclerotic process PPARgamma activation
Further , in a cohort study of patients with type 2 diabetes , pioglitazone therapy was associated with a statistically significant decrease in the risk of all-cause mortality .
Despite these beneficial effects , the meta- analysis showed that pioglitazone therapy had higher risks of heart failure , bone fractures , edema and weight gain .
The low-dose pioglitazone therapy may show the same degree of improvements in glucose and lipid metabolism , fatty liver , insulin resistance , and adiponectin as the st and ard- and high-dose pioglitazone therapy .
Furthermore , the low-dose pioglitazone therapy may also show less adverse effects on weight gain , edema and heart failure as compared with the st and ard- and high-dose pioglitazone therapy
Pioglitazone is one of thiazolidinedione derivatives , which stimulates nuclear peroxisome proliferator-activated receptor gamma and improves glucose and lipid metabolism and insulin sensitivity .
A recent systematic review and meta- analysis showed that pioglitazone therapy was associated with a lower risk of major adverse cardiovascular events in patients with pre-diabetes and diabetes .