title: Plasma BNP levels in the treatment of type 2 diabetes with pioglitazone. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. A Comparison of Lipid and Glycemic Effects of Pioglitazone and Rosiglitazone in Patients With Type 2 Diabetes and Dyslipidemia Safety and efficacy of low-dose pioglitazone (7.5 mg/day) vs. standard-dose pioglitazone (15 mg/day) in Japanese women with type 2 diabetes mellitus. A long-term comparison of pioglitazone and gliclazide in patients with Type 2 diabetes mellitus: a randomized, double-blind, parallel-group comparison trial.
abstract: We monitored the change in plasma ANP and BNP levels ( as markers for left ventricular dysfunction ( LVD ) ) in DM2 patients treated with pioglitazone ( Pio ) for 4 weeks . Thirty DM2 patients with no sign of heart failure were treated with Pio ( 15 mg/day ) , and their plasma ANP ( normal levels < or=43 pg/ml ) and BNP levels ( normal levels < or=18.4 pg/ml ) were examined . We also examined those levels in  no drug-treatment group ( n = 10 ) as well as buformine  treatment group ( n = 10 ) . Among these groups , there were no significant differences in clinical profiles related to DM control . Pio treatment was terminated when BNP ( above 100 pg/ml ) and ANP levels ( above 50 pg/ml ) suggested the left ventricular dysfunction ( LVD ) . The patients ( n = 12 ) whose BNP levels reached to the LVD-positive levels showed the basal BNP levels above the normal upper limit ( 18 pg/ml ) , while the rest of subjects ( n = 18 ) whose basal BNP levels within normal limits did not showed the LVD-positive levels in the Pio-treatment . On the other h and basal ANP levels did not predict the development to LVD . In conclusion , BNP levels are suggested to be a good marker of Pio-induced LVD , and the Pio treatment of DM2 patients with BNP levels above the normal limit should be carefully carried out by monitoring BNP levels BACKGROUND No pharmacologic therapy has conclusively proved to be effective for the treatment of nonalcoholic steatohepatitis , which is characterized by insulin resistance , steatosis , and necroinflammation with or without centrilobular fibrosis . Pioglitazone is a thiazolidinedione that ameliorates insulin resistance and improves glucose and lipid metabolism in type 2 diabetes mellitus . METHODS We r and omly assigned 55 patients with impaired glucose tolerance or type 2 diabetes and liver biopsy-confirmed nonalcoholic steatohepatitis to 6 months of treatment with a hypocaloric diet  ( a reduction of 500 kcal per day in relation to the calculated daily intake required to maintain body weight ) plus pioglitazone ( 45 mg daily ) or a hypocaloric diet plus placebo . Before and after treatment , we assessed hepatic histologic features , hepatic fat content by means of magnetic resonance spectroscopy , and glucose turnover during an oral glucose tolerance test ( [14C]glucose given with the oral glucose load and [3H]glucose given by intravenous infusion ) . RESULTS Diet plus pioglitazone , as compared with diet plus placebo , improved glycemic control and glucose tolerance ( P<0.001 ) , normalized liver aminotransferase levels as it decreased plasma aspartate aminotransferase levels ( by 40 % vs. 21 % , P=0.04 ) , decreased alanine aminotransferase levels ( by 58 % vs. 34 % , P<0.001 ) , decreased hepatic fat content ( by 54 % vs. 0 % , P<0.001 ) , and increased hepatic insulin sensitivity ( by 48 % vs. 14 % , P=0.008 ) . Administration of pioglitazone , as compared with placebo , was associated with improvement in histologic findings with regard to steatosis ( P=0.003 ) , ballooning necrosis ( P=0.02 ) , and inflammation ( P=0.008 ) . Subjects in the pioglitazone group had a greater reduction in necroinflammation ( 85 % vs. 38 % , P=0.001 ) , but the reduction in fibrosis did not differ significantly from that in the placebo group ( P=0.08 ) . Fatigue and mild lower-extremity edema developed in one subject who received pioglitazone ; no other adverse events were observed . CONCLUSIONS In this proof-of-concept study , the administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis . Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone . ( Clinical Trials.gov number , NCT00227110 [ Clinical Trials.gov ] . ) OBJECTIVE Published reports suggest that pioglitazone and rosiglitazone have different effects on lipids in patients with type 2 diabetes . However , these previous studies were either retrospective chart review s or clinical trials not rigorously controlled for concomitant glucose- and lipid-lowering therapies . This study examines the lipid and glycemic effects of pioglitazone and rosiglitazone . RESEARCH DESIGN AND METHODS We enrolled subjects with a diagnosis of type 2 diabetes ( treated with diet alone or oral monotherapy ) and dyslipidemia ( not treated with any lipid-lowering agents ) . After a 4-week placebo washout period , subjects r and omly assigned to the pioglitazone arm ( n = 400 ) were treated with 30 mg once daily for 12 weeks followed by 45 mg once daily for an additional 12 weeks , whereas subjects r and omly assigned to rosiglitazone  ( n = 402 ) were treated with 4 mg once daily followed by 4 mg twice daily for the same intervals . RESULTS Triglyceride levels were reduced by 51.9 + /- 7.8 mg/dl with pioglitazone , but were increased by 13.1 + /- 7.8 mg/dl with rosiglitazone ( P < 0.001 between treatments ) . Additionally , the increase in HDL cholesterol was greater ( 5.2 + /- 0.5 vs. 2.4 + /- 0.5 mg/dl ; P < 0.001 ) and the increase in LDL cholesterol was less ( 12.3 + /- 1.6 vs. 21.3 + /- 1.6 mg/dl ; P < 0.001 ) for pioglitazone compared with rosiglitazone , respectively . LDL particle concentration was reduced with pioglitazone and increased with rosiglitazone ( P < 0.001 ) . LDL particle size increased more with pioglitazone ( P = 0.005 ) . CONCLUSIONS Pioglitazone and rosiglitazone have significantly different effects on plasma lipids independent of glycemic control or concomitant lipid-lowering or other antihyperglycemic therapy . Pioglitazone compared with rosiglitazone is associated with significant improvements in triglycerides , HDL cholesterol , LDL particle concentration , and LDL particle size It is well known that pioglitazone , a potent thiazolidinedione , improves metabolic control . However , weight gain or peripheral edema may be of major clinical concern when using this agent . The purpose of our study was to prospect ively evaluate the effects of low-dose pioglitazone ( 7.5 mg/day ) on metabolic control , weight gain and the incidence of edema compared with a st and ard dose of pioglitazone ( 15.0 mg/day ) in patients with type 2 diabetes mellitus ( T2DM ) . Ninety-five Japanese female patients ( mean age 58.4 + /- 10.4 years ) with newly diagnosed T2DM were selected for this study . They were r and omly divided into the following 2 groups according to therapy regimens , and examined every month for 6 months after diagnosis . Group A consisted of 54 patients treated with low-dose pioglitazone orally ; Group B , the control-group , consisted of 41 patients treated with st and ard-dose pioglitazone orally . The incidence of peripheral edema was significantly much lower in group A ( 2/54 ) than in group B ( 11/41 ) ( p = 0.0014 ) . In addition , % change of body weight during the 6-month treatment in group A was significantly less than that in group B ( p < 0.0001 ) . On the other h and , the % change of biochemical parameters including HbA1c did not differ significantly between group A and group B , although glucose and lipid control significantly improved from baseline in both groups . Our results demonstrate the safety and efficacy of low-dose pioglitazone , suggesting that it could be another good choice of treatment for Japanese women with T2DM 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
target: 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
background: 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 .