Effects of the peroxisome proliferator-activated receptor (PPAR)-γ agonist pioglitazone on renal and hormonal responses to salt in diabetic and hypertensive individuals 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. Rapid communication: inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes. Effect of the insulin sensitizer pioglitazone on insulin resistance, hyperandrogenism, and ovulatory dysfunction in women with polycystic ovary syndrome. 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. Adjuvant pioglitazone for unremitted depression: Clinical correlates of treatment response Does pioglitazone improve depression through insulin-sensitization? Results of a randomized double-blind metformin-controlled trial in patients with polycystic ovarian syndrome and comorbid depression Pioglitazone improves insulin sensitivity through reduction in muscle lipid and redistribution of lipid into adipose tissue. Pioglitazone Improves Insulin Sensitivity Among Nondiabetic Patients With a Recent Transient Ischemic Attack or Ischemic Stroke Effect of pioglitazone versus insulin glargine on cardiac size, function, and measures of fluid retention in patients with type 2 diabetes Pioglitazone and the risk of cardiovascular events in patients with Type 2 diabetes receiving concomitant treatment with nitrates, renin-angiotensin system blockers, or insulin: results from the PROactive study (PROactive 20). Fenofibrate and pioglitazone improve endothelial function and reduce arterial stiffness in obese glucose tolerant men. A long-term comparison of pioglitazone and gliclazide in patients with Type 2 diabetes mellitus: a randomized, double-blind, parallel-group comparison trial. Responses of serum androgen and insulin resistance to metformin and pioglitazone in obese, insulin-resistant women with polycystic ovary syndrome. The Effect of a Thiazolidinedione Drug, Troglitazone, on Glycemia in Patients with Type 2 Diabetes Mellitus Poorly Controlled with Sulfonylurea and Metformin: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial Effect of pioglitazone compared with metformin on glycemic control and indicators of insulin sensitivity in recently diagnosed patients with type 2 diabetes. Beneficial effect of pioglitazone on the outcome of catheter ablation in patients with paroxysmal atrial fibrillation and type 2 diabetes mellitus.
Aims /hypothesisGlitazones are powerful insulin sensitisers prescribed for the treatment of type 2 diabetes . Their use is , however , associated with fluid retention and an increased risk of congestive heart failure . We previously demonstrated that pioglitazone increases proximal sodium reabsorption in healthy volunteers . This study examines the effects of pioglitazone on renal sodium h and ling in individuals prone to insulin resistance , i.e. those with diabetes and /or hypertension . Methods In this double-blind r and omised placebo-controlled four-way crossover study , we examined the effects of pioglitazone ( 45 mg daily during 6 weeks ) or placebo on renal , systemic and hormonal responses to changes in sodium intake in 16 individuals , eight with type 2 diabetes and eight with hypertension . Results Pioglitazone was associated with a rapid increase in body weight and an increase in diurnal proximal sodium reabsorption , without any change in renal haemodynamics or in the modulation of the renin – angiotensin aldosterone system to changes in salt intake . A compensatory increase in brain natriuretic peptide levels was observed . In spite of sodium retention , pioglitazone dissociated the blood-pressure response to salt and abolished salt sensitivity in salt-sensitive individuals . Conclusions /interpretationPioglitazone increases diurnal proximal sodium retention in diabetic and hypertensive individuals . These effects cause fluid retention and may contribute to the increased incidence of congestive heart failure with glitazones . Trial registration : Clinical Trial.gov NCT01090752 Funding : Hypertension Research Foundation 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 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 Polycystic ovary syndrome ( PCOS ) is characterized by hyper and rogenism , chronic anovulation , and insulin resistance ; long-term consequences include diabetes mellitus type 2 . The aim of this r and omized , double-blind , controlled trial was to investigate whether the thiazolidinedione derivative pioglitazone diminishes insulin resistance and hyper and rogenism and enhances ovulation rates in women with PCOS . Forty premenopausal women with PCOS were r and omly allocated to treatment with either pioglitazone ( 30 mg/d ) or placebo for periods of 3 months . Administration of pioglitazone result ed in a remarkable decline in both fasting serum insulin levels ( P < 0.02 ) and the area under the insulin response curve after an oral glucose load ( P < 0.02 ) . This represented an increase in insulin sensitivity and a decrease in insulin secretion ( P < 0.05 ) . Furthermore , pioglitazone increased serum SHBG ( P < 0.05 ) , result ing in a significant decrease in the free and rogen index ( P < 0.05 compared with placebo ) . Treatment with pioglitazone was also associated with higher ovulation rates ( P < 0.02 ) . Thus , pioglitazone significantly improved insulin sensitivity , hyper and rogenism , and ovulation rates in women with PCOS , thereby providing both metabolic and reproductive benefits 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 Previous studies suggest that insulin-sensitizing agents could play a significant role in the treatment of major depression , particularly depression in patients with documented insulin resistance or those who are resistant to st and ard psychopharmacological approaches . This study aim ed to assess the effects on depressive symptoms with adjuvant treatment with the PPARγ-agonist pioglitazone .  Patients ( N=37 ) with non-psychotic , non-remitting depression receiving st and ard psychiatric regimens for depression were r and omized across an insulin sensitivity spectrum in a 12-week double blind , r and omized controlled trial of pioglitazone or placebo . Improvement in depression was associated with improvement in glucose metabolism but only in patients with insulin resistance . An age effect was also shown in that response to pioglitazone was more beneficial in younger aged patients . Study findings suggest differential improvement in depression severity according to both glucose metabolic status and level of depression at baseline . A greater underst and ing of the reciprocal links between depression and IR may lead to a dramatic shift in the way in which depression is conceptualized and treated , with a greater focus on treating and /or preventing metabolic dysfunction Thiazolidinediones have shown beneficial effects in short-term treatment of depression . However , it is unclear whether the antidepressant efficacy of these agents is related to their insulin-sensitizing action . We conducted the present study to compare the antidepressant efficacy of pioglitazone with another insulin-sensitizer , metformin , in obese patients with concomitant polycystic ovarian syndrome ( PCOS ) and major depressive disorder ( MDD ) . In a six-week double-blind study , 50 patients with PCOS and MDD ( DSM-IV-TR criteria ) with Hamilton depression rating scale ( HDRS ) score of < 20 , r and omly received pioglitazone ( 15 mg twice daily ; PO ) or metformin ( 750 mg twice daily ; PO ) . Assessment was done using HDRS ( weeks 0 , 3 , 6 ) together with fasting Insulin , glucose , and lipid profile , liver enzymes , homeostatic model assessment of insulin resistance ( HOMA-IR ) , anthropometric measures , and serum and rogens ( weeks 0 and 6 ) . Pioglitazone was superior to metformin in reducing HDRS scores at the end of the study [ 38.3 % versus 8.3 % reduction from baseline scores , F(1 , 37 ) = 73.513 , P<0.001 ] . Changes from baseline in HOMA-IR values at week 6 were not significantly different between the two groups ( P = 0.888 ) . Baseline ( but not follow-up ) HDRS and HOMA-IR values were significantly correlated ( r = 0.393 , P = 0.012 ) . In multiple regression analysis , treatment with pioglitazone independent of HOMA-IR values predicted greater score reduction on HDRS at week 6 ( st and ardized beta = 0.801 , P<0.001 ) . Biochemical and hormonal profile did not differ between the two groups at week 6 . Metformin was associated with higher frequency of gastrointestinal side effects ( P = 0.014 ) . In summary , we showed that pioglitazone improved depression with mechanisms largely unrelated to its insulin-sensitizing action ( registration number : I RCT 201106081556N23 ) Patients with insulin resistance often manifest increased intramyocellular lipid ( IMCL ) along with increased visceral adipose tissue . This study was design ed to determine whether the insulin sensitizer drugs pioglitazone and metformin would improve glucose intolerance and insulin sensitivity by decreasing IMCL . In this study , 23 generally healthy subjects with impaired glucose tolerance were r and omized to receive either pioglitazone 45 mg/day or metformin 2,000 mg/day for 10 wk . Before and after treatment , we measured insulin sensitivity and abdominal subcutaneous and visceral adipose tissue with CT scanning . In addition , muscle biopsies were performed for measurement of IMCL and muscle oxidative enzymes . After treatment with pioglitazone , 2-h glucose fell from 9.6 mmol/l ( 172 mg/dl ) to 6.1 mmol/l ( 119 mg/dl ) , whereas there was no change in 2-h glucose with metformin . With pioglitazone treatment , there was a 65 % increase in insulin sensitivity along with a 34 % decrease in IMCL ( both P < or = 0.002 ) . This decrease in IMCL was not due to increased muscle lipid oxidation , as there were no changes in muscle lipid oxidative enzymes . However , pioglitazone result ed in a 2.6-kg weight gain along with a significant decrease in the visceral-to-subcutaneous adipose tissue ratio . In contrast , metformin treatment result ed in no change in insulin sensitivity , IMCL , oxidative enzymes , or adipose tissue volumes .  Pioglitazone improved glucose tolerance and insulin sensitivity by reducing IMCL . This reduction in IMCL was not due to an increase in muscle lipid oxidation but to a diversion of lipid from ectopic sites into subcutaneous adipose tissue Background and Purpose — The aim of this study was to determine the effectiveness of pioglitazone compared with placebo for improving insulin sensitivity among nondiabetic patients with a recent transient ischemic attack ( TIA ) or nondisabling ischemic stroke and impaired insulin sensitivity . Methods — Eligible subjects were men and women > 45 years of age who had no history of diabetes , fasting glucose < 7.0 mmol/L , and impaired insulin sensitivity according to an index calculated from insulin and glucose blood levels obtained during an oral glucose tolerance test . Eligible subjects were r and omized to pioglitazone 45 mg/d or placebo . After 3 months of therapy , the glucose tolerance test was repeated . Results — Between July 2000 and June 2001 , we performed oral glucose tolerance tests on 75 patients with no history of diabetes , among whom 36 ( 50 % ) were found to have impaired insulin sensitivity and fasting glucose < 7.0 mmol/L. Among these 36 , 20 consented to the trial . Patients assigned to pioglitazone ( n=10 ) and placebo ( n=10 ) were similar in insulin sensitivity , age , obesity , and index event ( stroke compared with TIA ) , but patients assigned to pioglitazone were less likely to be male ( 4 compared with 9 ) . The mean proportional increase in insulin sensitivity was 62 % among patients assigned to pioglitazone compared with a −1 % decline among patients assigned to placebo ( P = 0.0006 ) . Mean C-reactive protein concentration declined from 0.30 to 0.20 mg/L among patients assigned to pioglitazone and increased from 0.41 to 0.45 mg/L among patients assigned to placebo ( P = 0.06 for comparison of mean change ) . Conclusions — Pioglitazone is effective for improving insulin sensitivity among patients with recent TIA or stroke and impaired insulin sensitivity Background Both insulin and thiazolidinediones ( TZDs ) are effective in the treatment of hyperglycaemia and amelioration of insulin resistance in type 2 diabetes but have side effects including weight gain and fluid retention . The use of TZDs has been further hampered by the risk of adverse cardiovascular events including heart failure . The present study evaluated the effect of pioglitazone or insulin glargine on cardiac function and size as well as on surrogate markers of fluid retention such as weight , haemoglobin and natriuretic peptides . Methods Thirty patients with inadequate glycaemic control on metformin and sulfonylurea were r and omised to receive  add-on therapy with insulin glargine or pioglitazone for 26 weeks . Echocardiographic data and blood sample s were collected from the two groups before the start of the treatment and after 26 weeks . Left ventricular end-diastolic and left atrial end-systolic volumes were quantified , weight measured and blood sample s analyzed . Results After 26 weeks of treatment , the changes in HbA1c , weight and haemoglobin were similar between the two groups . HDL increased significantly in the pioglitazone group . While there was an increase in natriuretic peptides in the pioglitazone group ( NT-proBNP 11.4 ± 19.6 to 22.8 ± 44.0 , p = 0.046 ) , the difference between the treatment groups was not significant . Left ventricular end-diastolic volume increased by 11 % and left atrial end-systolic volume by 17 % in the pioglitazone group ( Both , p < 0.05 , between treatment groups ) . There was a borderline significant increase in ejection fraction in the pioglitazone group . Conclusion This r and omised pilot- study showed that six-month treatment with pioglitazone induced significant increases in natriuretic peptides and alterations of cardiac size . These changes were not observed with insulin glargine , which also is known to induce fluid retention . Larger r and omised trials are warranted to confirm these findings BACKGROUND Patients with Type 2 diabetes mellitus ( T2DM ) are often treated with multiple glucose-lowering and cardiovascular agents . The concomitant use of nitrates , renin-angiotensin system ( RAS ) blockers , or insulin has been linked to a potential increase in myocardial ischemic risk with rosiglitazone . The PROactive data base provides an opportunity to investigate the effects of these medications on the potential macrovascular benefits reported with pioglitazone . METHODS The PROactive study was a r and omized double-blind prospect i ve trial that evaluated mortality and cardiovascular morbidity in 5238 patients with T2DM and macrovascular disease . Patients received pioglitazone or placebo in addition to their baseline glucose-lowering and cardiovascular medications . The effect of pioglitazone on composite endpoints was evaluated , including all-cause death , myocardial infa rct ion ( MI ) , and stroke , as well as safety events of edema and serious heart failure , in subgroups using nitrates , RAS blockers , or insulin at baseline . RESULTS The risk of all-cause death , MI , and stroke for pioglitazone versus placebo was similar regardless of the baseline use of nitrates , RAS blockers , or insulin , with hazard ratios ranging from 0.81 to 0.87 . Similar results were obtained for the other composite endpoints analyzed . There were no significant interactions between baseline medication subgroups and treatment . The increased risk of edema and serious heart failure was consistent across the baseline medication subgroups . CONCLUSIONS This post hoc analysis did not reveal an increased risk of macrovascular events with pioglitazone in patients receiving nitrates , RAS blockers , or insulin . Rather , all patients realized the same trend towards benefit with pioglitazone , and adverse events of edema and heart failure were predictable Obesity is a low grade inflammatory state associated with premature cardiovascular morbidity and mortality . Along with traditional risk factors the measurement of endothelial function , insulin resistance , inflammation and arterial stiffness may contribute to the assessment of cardiovascular risk . We conducted a r and omised placebo controlled trial to assess the effects of 12 weeks treatment with a PPAR alpha agonist ( fenofibrate ) and a PPAR gamma agonist ( pioglitazone ) on these parameters in obese glucose tolerant men .  Arterial stiffness was measured using augmentation index and pulse wave velocity ( PWV ) . E-selectin , VCAM-1 and ICAM-1 were used as markers of endothelial function . Insulin sensitivity improved with pioglitazone treatment ( p=0.001 ) and , in keeping with this , adiponectin increased by 85.2 % ( p<0.001 ) . Pro-inflammatory cytokine levels ( TNFalpha , IL-6 and IL-1 beta ) fell with both treatments ( p<0.01 for TNFalpha and IL-1 beta , p<0.001 for IL-6 ) . VCAM-1 and ICAM-1 were reduced with both treatments ( p<0.001 for VCAM-1 , p<0.05 for ICAM-1 ) and E-selectin improved with pioglitazone treatment ( p=0.05 ) . Both treatments result ed in a fall in augmentation index . PWV fell by 17.4 % with fenofibrate treatment ( p<0.001 ) and 16.3 % with pioglitazone treatment ( p<0.001 ) . Pioglitazone and fenofibrate treatment of obese , glucose tolerant men reduces inflammation , improves markers of endothelial function and reduces arterial stiffness . These results suggest that treatment with PPAR agonists has potential to reduce the incidence of premature cardiovascular disease associated with obesity AIMS This study compared the effects of pioglitazone and gliclazide on metabolic control in drug-naive patients with Type 2 diabetes mellitus . METHODS A total of 1270 patients with Type 2 diabetes were r and omized in a parallel-group , double-dummy , double-blind study . Patients with poorly controlled Type 2 diabetes ( HbA1c 7.5 - 11 % ) , despite dietary advice , received either pioglitazone up to 45 mg once daily or gliclazide up to 160 mg two times daily . Primary efficacy endpoint was change in HbA1c from baseline to the end of the study . Secondary efficacy endpoints included change in fasting plasma glucose , fasting plasma insulin and plasma lipids . At selected centres , oral glucose tolerance tests were performed and C-peptide and pro-insulin levels were measured . RESULTS Mean HbA1c values decreased by the same amount in the two treatment groups from baseline to week 52 [ pioglitazone : -1.4 % ; gliclazide : -1.4 % ; ( 90 % CI : -0.18 to 0.02 ) ] . A significantly greater mean reduction in fasting plasma glucose was observed in the pioglitazone group ( 2.4 mmol/l ) than in the gliclazide group [ 2.0 mmol/l ; treatment difference -0.4 mmol/l in favour of pioglitazone ; P = 0.002 ; ( 95 % CI : -0.7 to -0.1 ) ] . Improvements in high-density lipoprotein cholesterol ( HDL-C ) and total cholesterol/HDL-C were greater with pioglitazone than with gliclazide ( P < 0.001 ) . The frequencies of adverse events were comparable between the two treatment groups , but more hypoglycaemic events were reported for gliclazide , whereas twice as many patients reported oedema with pioglitazone than with gliclazide . CONCLUSIONS Pioglitazone monotherapy was equivalent to gliclazide in reducing HbA1c , with specific differences between treatments in terms of mechanism of action , plasma lipids and adverse events Severe insulin resistance is a key abnormality in obese women with polycystic ovary syndrome ( PCOS ) . The purpose of this study was to evaluate whether pioglitazone decreases insulin resistance ( IR ) and hyper and rogenism to the same extent as metformin in obese women with PCOS who have not received any previous treatment . Fifty-two women with PCOS were r and omly allocated to receive either pioglitazone ( 30 mg/d , n = 25 ) or metformin ( 850 mg three times daily , n = 27 ) and were assessed before and after 6 months . Body weight , body mass index , and waist to hip ratio increased significantly ( P < /= 0.05 ) after pioglitazone treatment but not after metformin treatment . Fasting serum insulin concentration ( P < 0.001 for both drugs ) and the area under the insulin curve during a 2-h oral glucose tolerance test decreased after pioglitazone ( P < 0.002 ) or metformin ( P < 0.05 ) treatment . IR ( homeostasis model of assessment -IR index ) decreased and insulin sensitivity ( elevation of the quantitative insulin sensitivity check index and the fasting glucose to insulin ratio ) increased ( P < /= 0.008 ) after treatment with either drug . Hirsutism ( P < 0.05 ) and serum concentrations of free testosterone ( P < 0.02 ) and and rostenedione ( P < 0.01 ) declined to a similar extent after treatment with the drugs . Treatment with pioglitazone or metformin was associated with the occurrence of pregnancy ( n = 5 and n = 3 , respectively ) . These results suggest that pioglitazone is as effective as metformin in improving insulin sensitivity and hyper and rogenism , despite an increase in body weight , body mass index , and the waist to hip ratio associated with pioglitazone Persistent hyperglycemia secondary to insulin resistance and eventual insufficient insulin secretory capacity is the hallmark of type 2 diabetes mellitus . Resistance to insulin-stimulated glucose uptake is present in most patients with this disease ( 1 ) . Treatment is aim ed at reducing blood glucose levels to normal or near-normal values ( 2 , 3 ) . Diet and exercise are the first treatments of choice for patients with type 2 diabetes mellitus . However , as many as 95 % of those with newly diagnosed diabetes do not achieve adequate blood glucose control after a 3-month dietary intervention ( 4 ) , and initiation with oral antidiabetes therapy is then advocated . On the basis of patient profile and level of glycemic control , first-line monotherapy typically begins with sulfonylurea ( an insulin secretagogue ) or metformin , which inhibits hepatic gluconeogenesis ( 5 ) . When monotherapy fails to achieve optimal glycemic control , these agents are frequently prescribed in combination ( 6 ) . However , many patients continue to experience suboptimal control , resisting health professionals ' ultimate recommendation to begin insulin injection therapy ( 7 - 9 ) . Thiazolidinediones are a class of peroxisome proliferator-activated receptor- drugs that , unlike sulfonylureas and metformin , stimulate increased peripheral glucose disposal and reduce insulin resistance in the muscle , liver , and adipose tissue ( 10 - 15 ) . Studies have shown that troglitazone used as monotherapy or in combination with sulfonylurea and insulin improves glucose control ( 16 - 18 ) . The addition of an insulin-sensitizing agent , such as troglitazone , to complement the insulin-stimulatory and hepatic glucosesuppressive effects of sulfonylurea and metformin has been considered an attractive therapeutic alternative to insulin . However , whether a thiazolidinedione would be efficient at a stage of the disease when -cell secretion is failing ( 19 ) remains to be demonstrated . The current trial ( which was completed before troglitazone was withdrawn from the U.S. market because of hepatotoxicity ) was conducted to determine whether the addition of a thiazolidinedione , troglitazone , could decrease hemoglobin A1c levels and thereby delay or eliminate the need for insulin treatment in patients who did not achieve adequate glucose control despite combined therapy with sulfonylurea and metformin . Methods Patients This multicenter study was conducted at 16 sites in Canada . Study participants were required to be at least 40 years of age and to have type 2 diabetes mellitus according to the National Diabetes Data Group criteria ( 20 ) . Inadequate glycemic control was defined as having a hemoglobin A1c level of at least 0.085 ( 8.5 % ) despite undergoing at least 8 weeks of stable treatment with maximum tolerable doses of oral sulfonylurea and metformin .  Patients treated with less than 20 mg of glyburide and less than 1500 mg of metformin  were included only if documentation of intolerance to higher doses was available . Patients were ineligible if they had previously received long-term insulin treatment ( 3 days of treatment was allowed ) or were currently using fenfluramine or glucocorticoids ( these patients were excluded because of the negative effects of these drugs on insulin sensitivity ) . Patients were also ineligible if they had any of the following : serum creatinine concentration greater than 180 mol/L ( 2.0 mg/dL ) , alanine aminotransferase ( ALT ) level more than 2 times the upper limit of normal , uncontrolled hypertension , anemia , symptomatic angina , cardiac insufficiency , body mass index greater than 40 kg/m2 , or active cancer within 5 years of screening . Contraceptive use was required for women of childbearing potential . Patient volunteers gave written informed consent to participate in the study . An ethics committeeinstitutional review board at each study center approved the protocol . Study Design Patients were recruited if they had received a diagnosis of type 2 diabetes mellitus and were currently taking maximum-dose sulfonylurea and metformin . Patients at each study site who met the inclusion criteria were invited to participate . Upon acceptance , they entered a 4-week lead-in period and received placebo in addition to their current regimen of sulfonylurea and metformin . Patients were then r and omly assigned to receive , in a double-blind fashion , troglitazone , 400 mg/d , or a matching placebo of similar appearance and taste once daily for 24 weeks , in addition to current treatment with sulfonylurea and metformin . R and om assignment of patients occurred sequentially , following a single computer-generated r and omization schedule for the entire study with a block size of four . Medication was packaged according to the r and omization schedule and was allocated to centers in blocks of four . Investigators , patients , and the sponsor were blinded to treatment and primary glycemic measures . After 24 weeks of double-blind treatment , an open-label phase followed in which placebo recipients began taking troglitazone , 400 mg/d , and patients previously treated with troglitazone continued to receive it for an additional 24 weeks . Fasting plasma glucose level and biochemical measures of safety , including chemistry tests ( ALT and aspartate aminotransferase levels ) , hematologic tests , and urinalysis were performed at 4-week intervals throughout the study . Hemoglobin A1c level , total plasma insulin level , and lipid levels were measured at r and omization and at 4-week intervals beginning at week 12 . Self-monitoring of  blood glucose level was encouraged , and glucose meters were provided to all patients . Symptomatic hypoglycemic events were characterized by the type of intervention required to alleviate the event and by severity ( on the basis of a self-monitored blood glucose value obtained when symptomatic hypoglycemia was present ) .  Physical examination  and  12-lead electrocardiography  were performed for each patient as additional safety assessment s before r and omization and at the end of the double-blind and open-label studies . Patients were to be withdrawn at their own discretion or if a clinician judged that their glucose levels were acutely deleterious , if they did not adhere to the protocol ( that is , if they were < 80 % adherent to the study drug regimen ) , or if they had an intolerable adverse event . A central clinical laboratory ( Medical Research Laboratories , Highl and Heights , Kentucky ) performed all biochemical measurements for all study centers . Hemoglobin A1c levels were measured by automated ion-exchange high-performance liquid chromatography ( Bio-Rad Labs , Hercules , California ) , and insulin was measured by using a two-site immunoenzymometric assay ( sensitivity , 8 pmol/L ) . Triglyceride , total cholesterol , and plasma glucose levels ( hexokinase ) were measured by using enzymatic methods with a Hitachi 747 analyzer ( Hitachi Instruments , Inc. , San Jose , California ) . High-density lipoprotein cholesterol was isolated by chemical precipitation and was measured in the same way as total cholesterol . Low-density lipoprotein cholesterol level was calculated by using the equation of Friedewald and colleagues ( 21 ) . Statistical Analysis The sample calculation was based on a two-sided t-test , with a P value less than 0.05 indicating significance . Assuming that the st and ard deviation of hemoglobin A1c level was 0.017 ( 1.7 % ) , 62 patients per treatment group were needed to detect at least a 1 % difference between troglitazone-treated patients and placebo recipients at a power of 0.9 . Assuming a 25 % loss due to dropout , our goal was to r and omly assign a minimum of 85 patients to each treatment group . The analyses of efficacy for the double-blind study were performed according to the intention-to-treat method and included all patients who received at least one dose of troglitazone or placebo and had at least one follow-up visit . The last observations for patients were carried forward to impute missing values . The safety analyses also included all patients . The analyses of efficacy for the open-label study were performed by using summary statistics inclusive of all available data for patients who entered the open-label study . Statistical analyses were performed by using SAS software , version 6.12 ( SAS Institute , Inc. , Cary , North Carolina ) . Changes in levels of hemoglobin A1c , fasting plasma glucose , insulin , triglycerides , total cholesterol , high-density lipoprotein cholesterol , and low-density lipoprotein cholesterol from r and omization to the end of the double-blind study were analyzed by using analysis of covariance , with treatment and study center as factors and the baseline value as the covariate . All statistical tests were two-sided ( = 0.05 ) . Exploratory analyses to investigate the effects of age , sex , menopausal status , and ethnicity were also conducted by using analysis of covariance , with center and treatment as factors and the baseline value as the covariate . The proportion of patients achieving American Diabetes Association glycemic control targets in the two treatment groups was compared by using the Fisher exact test with data pooled across study centers because some centers had insufficient data . Safety variables were evaluated by using summary statistics . Role of the Funding Source Parke-Davis provided funding and facilitated the data collection and analysis for this study and approved su bmi ssion of the manuscript for publication . The authors had final authority over the decision to su bmi t the manuscript for publication . Results Patients Baseline demographic and disease-related characteristics were similar for the two treatment groups ( Table 1 ) . Two hundred patients were r and omly assigned , and 178 patients ( 92 in the troglitazone group and 86 in the placebo group ) completed the double-blind study ( Figure 1 ) . A small percentage of patients withdrew early , but these withdrawals were not concentrated at any study center and were evenly distributed across the two treatment groups . The only noted difference was in patient Pioglitazone , a thiazolidinedione , improves glycemic control primarily by increasing peripheral insulin sensitivity in patients with type 2 diabetes , whereas metformin , a biguanide , exerts its effect primarily by decreasing hepatic glucose output . In the first head-to-head , double-blind clinical trial comparing these two oral antihyperglycemic medications ( OAMs ) , we studied the effect of 32-wk monotherapy on glycemic control and insulin sensitivity in 205 patients with recently diagnosed type 2 diabetes who were naive to OAM therapy . Subjects were r and omized to either 30 mg pioglitazone or 850 mg metformin daily with titrations upward to 45 mg ( 77 % of pioglitazone patients ) and 2550 mg ( 73 % of metformin patients ) , as indicated , to achieve fasting plasma glucose levels of less than 7.0 mmol/liter ( 126 mg/dl ) . Pioglitazone was comparable to metformin in improving glycemic control as measured by hemoglobin A1C and fasting plasma glucose . At endpoint , pioglitazone was significantly more effective than metformin in improving indicators of insulin sensitivity , as determined by reduction of fasting serum insulin ( P = 0.003 ) and by analysis of homeostasis model assessment for insulin sensitivity ( HOMA-S ; P = 0.002 ) . Both OAM therapies were well tolerated . Therefore , pioglitazone and metformin are equally efficacious in regard to glycemic control , but they exert significantly different effects on insulin sensitivity due to differing mechanisms of action . The more pronounced improvement in indicators of insulin sensitivity by pioglitazone , as compared with metformin monotherapy in patients recently diagnosed with type 2 diabetes who are OAM-naive , may be of interest for further clinical evaluation AIMS Pioglitazone , one of the peroxisome proliferator-activated receptor-gamma activators , possesses anti-inflammatory and antioxidant properties . In the present study , we sought to identify the impact of pioglitazone on the outcome of catheter ablation for paroxysmal atrial fibrillation ( PAF ) . METHODS AND RESULTS We conducted a prospect i ve observational cohort study of 150 consecutive patients undergoing catheter ablation of drug-refractory PAF . All patients had a history of type 2 diabetes mellitus ( T2DM ) and were divided based on whether they received pioglitazone before ablation or not . After grouping , 51 patients treated with pioglitazone  and 99 control subjects were followed up at least 15 months after ablation . After a single ablation , sinus rhythm was maintained in 44 patients ( 86.3 % ) of the pioglitazone group vs. 70 patients ( 70.7 % ) of the control group ( P = 0.034 ) without antiarrhythmic drug during a mean follow-up of 22.9 ± 5.1 months . The second ablation was performed in 5 patients ( 9.8 % ) from the pioglitazone group and in 24 patients ( 24.2 % ) from the control group ( P = 0.034 ) . Multivariate logistic analysis showed left atrium diameter was associated with a high risk of atrial tachyarrhythmias recurrence , and treatment with renin-angiotensin system inhibitor as well as pioglitazone was associated with a reduced atrial tachyarrhythmias recurrence rate . CONCLUSION Pioglitazone improved the preservation of sinus rhythm and reduced the reablation rate in patients with PAF and T2DM after catheter ablation
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 .