Pioglitazone Group Research Articles

Effects of Different Types of Oral Glucose-Lowering Drugs on Hepatic Fat Accumulation and Liver Function in Japanese Subjects with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease—A Randomized, Open-Label, 3-Arm Active-Control Study

Objective: In this study, we compared the effects of different types of oral hypoglycemic agents on NAFLD in subjects with T2DM. Methods: We conducted a randomized, open-label, 3-arm active-control trial in subjects with T2DM and NAFLD. A total of 98 subjects were randomly allocated either to dapagliflozin (SG, n=32), pioglitazone (TZ, n=33) or glimepiride (SU, n=33) group, and the subjects took these drugs for 28 weeks. The primary endpoint was a change of liver-to-spleen (L/S) ratio on CT. Results: Baseline characteristics in the three groups were similar in various clinical parameters. SG, TZ and SU ameliorated glycemic control similarly. Body weight and visceral fat area (VFA) were significantly decreased only in SG group. Serum adiponectin level was increased in TZ group compared to other two groups. SG and TZ, but not SU, significantly increased L/S ratio and decreased ALT level, and the effects of SG and TZ on those parameters were comparable. In simple correlation analysis with all subjects, change of L/S ratio was negatively correlated with alteration of BMI, VFA, HbA1c and serum insulin, and positively associated with change of adiponectin level. Multiple linear regression analysis revealed that the decrease in VFA and the increase in adiponectin level contributed to improve NAFLD in subjects with T2DM. In addition, the common factor which improved NAFLD in all groups was reduced VFA. On the other hand, there were also some differences among three groups about which factors were correlated with the change of L/S ratio. Conclusions: The present study showed the decreased VFA and increased adiponectin independently contributed to improve NAFLD in patients with T2DM. Furthermore, dapagliflozin and pioglitazone, exerted equivalent beneficial effects on NAFLD in subjects with T2DM, although the two drugs have different mechanism of action. Disclosure T. Kinoshita: None. M. Shimoda: Speaker's Bureau; Self; AstraZeneca. Research Support; Self; Taisho Pharmaceutical Co., Ltd. S. Nakanishi: Speaker's Bureau; Self; Sanofi. T. Mune: None. K. Kaku: Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation, MSD K.K.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Ono Pharmaceutical Co., Ltd.. Advisory Panel; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Speaker's Bureau; Self; Taisho Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceuticals, Japan Inc., Kowa Pharmaceuticals, Japan Inc.. Advisory Panel; Self; Astellas, Japan Inc. H. Kaneto: Research Support; Self; Sanofi, Novo Nordisk Inc., Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K., Takeda Pharmaceuticals U.S.A., Inc., Ono Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Astellas Pharma US, Inc..

Modulation of brain insulin signaling in Alzheimer’s disease: New insight on the protective role of green coffee bean extract

Objective: Alzheimer's disease (AD), a neurodegenerative disorder, involves brain insulin signaling cascades and insulin resistance (IR). Because of limited treatment options, new treatment strategies are mandatory. Green coffee bean extract (GCBE) was reported to attenuate IR and improve brain energy metabolism. We aimed to investigate the possible use of GCBE as a prophylactic strategy to delay the onset of AD or combined with pioglitazone (PIO) as a strategy to retard the progression of AD.Methods: Rats received 10% fructose in drinking water for 18 weeks to induce AD. GCBE-prophylactic group received GCBE for 22 weeks started 4 weeks prior to fructose administration. The PIO group treated with PIO for 6 weeks started on week 12 of fructose administration. The GCBE+PIO group received GCBE for 22 weeks started 4 weeks prior to fructose administration and treated with PIO for the last 6 weeks of fructose administration.Results: Pretreatment with GCBE, either alone or combined with PIO, alleviated IR-induced AD changes. GCBE improved cognition, decreased serine phosphorylation of insulin receptor substrate, increased phosphoinositol-3 kinase (PI3K) activity and protein kinase B (Akt) gene expression, decreased glycogen synthase kinase-3β (GS3Kβ) gene expression and Tau hyperphosphorylation.Discussion: GCBE exerted neuroprotective effects against IR-induced AD mediated by alleviating IR and modulating brain insulin signaling cascade.

Role of Wnt4/β-catenin, Ang II/TGFβ, ACE2, NF-κB, and IL-18 in attenuating renal ischemia/reperfusion-induced injury in rats treated with Vit D and pioglitazone

Renal ischemia-reperfusion injury (I/RI) remains a critical clinical situation. Several evidence revealed the potential reno-protective effects of Vitamin D and/or pioglitazone, on renal I/RI. This study addresses the possible involvement of the Wnt4/β-catenin signaling, p-S536NF-κBp65, PPARγ, Ang II/TGF-β, and ACE2 as potential effectors to vitamin D and pioglitazone-mediated renoprotective effects. Two sets of Sprague-Dawley rats (n = 30 rat each), were randomized into sham, I/R, Vit D "alfacalcidol" (5 ng/kg/day), pioglitazone (5 mg/kg/day), and Vit D + pioglitazone groups. In all groups renal biochemical parameters, as well as inflammatory and structural profiles were assessed, besides the expression/contents of Wnt4/β-catenin and pS536-NF-κBp65. All treatments started 7 days before I/RI and animals were killed 24 h after I/RI in the first set, while those in the 2nd set continued their treatments for 14 days. After 24 h, all pre-treatments impeded theI/R effect on neutrophils recruitment, p-S536NF-κBp65, IL-18, NGAL, caspase-3, AngII, ACE-2, PPARγ and TGF-β, besides the expression of Wnt4 and ACE-2 with notable reflection on histological changes. Two weeks after I/RI, except a marked up regulation in Wnt4 expression and a striking elevation in the β-catenin content, the magnitude of the injurious events was relatively less pronounced, an effect that was mostly augmented by the different treatments. The current study pledges a promising and novel reno-protective role of the administration of Vit D and pioglitazone entailing a potential involvement of ICAM-1, MPO, NF-κB, Ang II, ACE2, TGFβ, and a modulation of Wnt4/β-catenin pathway.

Yiqi Yangyin and Huatan Quyu granule can improve skeletal muscle energy metabolism in a type 2 diabetic rat model by promoting the AMPK/SIRT/PGC-1α signalling pathway

Abstract Objective To investigate how Yiqi Yangyin and Huatan Quyu granule (YYHQ) improves skeletal muscle insulin resistance in a type 2 diabetic rat model and to discover whether the molecular mechanism is related to the promotion of the AMPK/SIRT/PGC-1α signalling pathway. Methods Rats were randomly divided into 4 groups: the normal group, the model group, the YYHQ granule group, and the pioglitazone group. The type 2 diabetic rat model was established by feeding a high-fat diet for 5 weeks along with a single intraperitoneal injection of 30 mg/kg streptozotocin (STZ). After modelling successfully, the appropriate drug was intragastrically administered to diabetic rats for 2 weeks, once per day. The YYHQ granule group was given a dose of 4.8 g/kg body weight per day, the pioglitazone group was given a dose of 1.35 mg/kg body weight per day. The doses for both groups were equivalent to the clinical equivalent dose based on a previous study. Other groups were gavaged with the same amount of saline water. Body weight, food intake, water intake, urine volume and grip strength were recorded weekly. The fasting blood glucose(FBG) was determined weekly using blood glucose test strips. The related glucose and lipid metabolism indexes, e.g., fasting insulin (Fins), glycated haemoglobin (GHb), HOMA-IR, ISI, triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and free fatty acid (FFA), were determined using biochemical method. The mRNA expression levels of adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), carnitine palmitoyl transterase-1 (CPT-1), Sirtuin 1 (SIRT1), and Sirtuin 3 (SIRT3) were assessed using quantitative real-time PCR (qRT-PCR). The protein expression levels of creatine kinase (CK), Ca2+ ATPase, α-Actin, AMPK, PGC-1α and CPT-1 were determined using enzyme-linked immunosorbent assay method (ELISA). Results Body weight decreased significantly (P .05). The levels of FBG, Fins, GHb, HOMA-IR and ISI were improved significantly (P .05). Further results indicated that YYHQ granule significantly decreased the mRNA expression of AMPK, PGC-1α, CPT-1, SIRT1 and SIRT3 in skeletal muscle (P .05). Conclusion The possible molecular mechanism of YYHQ granule improving skeletal muscle insulin resistance in a type 2 diabetic rat model may be related to the stimulation of energy metabolism in skeletal muscle via the AMPK/SIRT/PGC-1α signalling pathway.

Effects of low-intensity pulsed ultrasound and pioglitazone on chondrocytes in osteoarthritis

Objective To investigate any protective effect of low-intensity pulsed ultrasound (LIPUS) and pioglitazone on chondrocytes in osteoarthritic patients using the pathway from peroxisome proliferator-activated γreceptor (PPARγ) to nuclear factor kappa B (NF-κB) to inducible nitric oxide synthase (iNOS). Methods Normal chondrocytes of 24 healthy adult New Zealand white rabbits were extracted and divided into a normal group, a lipopolysaccharide (LPS) group, a LIPUS group (LPS+ LIPUS) and a pioglitazone group (LPS+ pioglitazone), each of 6 using a random number table. Each group was given the intervention their names implies. The levels of tumor necrosis factor-α (TNF-α), leptin (LEP) and nitric oxide (NO) in the chondrocytes were detected using enzyme-linked immune sorbent assays. The expression of type II collagen (COL2) in the chondrocytes of each groups was detected using immunocytochemistry and fluorescent staining. The mRNA and protein expressions of PPARγ, NF-κB and iNOS were detected using reverse transcription polymerase chain reactions and western blotting respectively. Results Compared with the LPS group, the average level of TNF-α, LEP and NO in the LIPUS and pioglitazone groups was significantly lower, with the levels in the pioglitazone group significantly lower than in the LIPUS group. Compared with the LPS group, COL2 expression in the LIPUS group was significantly greater. The mRNA and protein expressions of PPARγ in the chondrocytes in the LIPUS and pioglitazone groups were significantly higher than those in the LPS group. Compared with the LPS group, the mRNA and protein expressions of NF-κB and iNOS in the pioglitazone and LIPUS groups were significantly lower, with the pioglitazone group′s levels significantly below those of the LIPUS group. Conclusion LIPUS and pioglitazone may promote anti-inflammatory action and COL2 synthesis in chondrocytes through the PPARγ/ NF-κB/iNOS pathway and play a protective role, at least in rabbits. Key words: Ultrasound; Pioglitazone; Osteoarthritis; Lipopolysaccharides

Remission of hyperglycemia after withdrawal of oral antidiabetic drugs in Japanese patients with early-stage type 2 diabetes.

Aims/IntroductionTo assess whether intervention with oral antidiabetic drug in Japanese patients with the early stage of type 2 diabetes could provide a significant remission of the disease process.Materials and MethodsPatients with diabetes duration <5 years were randomized to the lifestyle modification (LFS), pioglitazone (PIO) or sulfonylurea (SU) treatment group. In phase 1 as the on‐treatment period and in phase 2 as the off‐treatment period, the duration that glycated hemoglobin (HbA1c) was maintained at less than the target was compared among groups.ResultsA total of 278 patients were assigned to LFS (n = 84), PIO (n = 101) and SU (n = 93), and 212 patients completed phase 1. The number of patients that dropped out because of HbA1c elevation was larger in the LFS group, and the duration of HbA1c being maintained at <7.9% was longer in the SU group than the other groups. The duration of HbA1c being maintained at <7.4% in phase 2 was significantly shorter in the SU group than in the other groups. The proportion of patients who achieved HbA1c <6.9% or 6.2% at the end of phase 1 was obviously less in the LFS group than other groups. The duration of HbA1c being maintained at <6.2% in phase 2 was longer in the PIO group than other groups, although not significant statistically. An increase in serum adiponectin and decreases in high‐sensitivity C‐reactive protein and homeostatic model assessment of insulin resistance were shown in patients treated with PIO, but not LFS and SU, in phase 1, but were canceled in the drug‐off phase 2 period.Conclusions PIO treatment provided a prolonged remission of hyperglycemia after stopping the dosage in patients with the early stage of type 2 diabetes.

Effect of pioglitazone on cardiometabolic profiles and safety in patients with type 2 diabetes undergoing percutaneous coronary artery intervention: a prospective, multicenter, randomized trial.

Pioglitazone has superior antiatherosclerotic effects compared with other classes of antidiabetic agents, and there is substantial evidence that pioglitazone improves cardiovascular (CV) outcomes. However, there is also a potential risk of worsening heart failure (HF). Therefore, it is clinically important to determine whether pioglitazone is safe in patients with type 2 diabetes mellitus (T2DM) who require treatment for secondary prevention of CV disease, since they have an intrinsically higher risk of HF. This prospective, multicenter, open-label, randomized study investigated the effects of pioglitazone on cardiometabolic profiles and CV safety in T2DM patients undergoing elective percutaneous coronary intervention (PCI) using bare-metal stents or first-generation drug-eluting stents. A total of 94 eligible patients were randomly assigned to either a pioglitazone or conventional (control) group, and pioglitazone was started the day before PCI. Cardiometabolic profiles were evaluated before PCI and at primary follow-up coronary angiography (5-8months). Pioglitazone treatment reduced HbA1c levels to a similar degree as conventional treatment (pioglitazone group 6.5 to 6.0%, P<0.01; control group 6.5 to 5.9%, P<0.001), without body weight gain. Levels of high-molecular weight adiponectin increased more in the pioglitazone group than the control group (P<0.001), and the changes were irrespective of baseline glycemic control. Furthermore, pioglitazone significantly reduced plasma levels of natriuretic peptides and preserved cardiac systolic and diastolic function (assessed by echocardiography) without incident hospitalization for worsening HF. The incidence of clinical adverse events was also comparable between the groups. These results indicate that pioglitazone treatment before and after elective PCI may be tolerable and clinically safe and may improve cardiometabolic profiles in T2DM patients.

Cardiovascular Outcomes in Patients with Previous Myocardial Infarction and Mild Diabetes Mellitus Following Treatment with Pioglitazone -Reports from the Japan Working Group for the Assessment Whether Pioglitazone Protects Dm Patients Against Re-Infarction (Ppar Study)-

Background: Secondary prevention in patients with myocardial infarction (MI) is critically important to prevent ischaemic heart failure and reduce social burden. Pioglitazone improves vascular dysfunction and prevents coronary atherosclerosis, mainly via anti-inflammatory and antiatherogenic effects by enhancing adiponectin production in addition to antihyperglycemic effects, thus suggesting that pioglitazone attenuates cardiovascular events in patients with mild (HbA1c levels < 6·5%) diabetes mellitus (DM). Therefore, we evaluated the effects of pioglitazone on cardiovascular events in patients with both previous MI and mild DM. Methods: In this multicentre, prospective, randomised, open, blinded-endpoint trial of PPAR study, we randomly assigned 630 patients with mild DM with a history of MI to undergo either DM therapy with (pioglitazone group) or without (control group) pioglitazone. DM was diagnosed using the 75-g oral glucose tolerance test, and mild DM was defined if HbA1c level was < 6·5%. The primary endpoint was the composite of cardiovascular death and hospitalisation caused by acute MI, unstable angina, coronary revascularisation (including percutaneous coronary intervention and cardiac bypass surgery), and stroke. HbA1C levels were 5·9 and 5·8% (p = 0.71) at baseline and 6·0 and 5·8% (p < 0.01) at 2 years for the control and pioglitazone groups, respectively. Findings: The primary endpoint was observed in 14·2% and 14·1% patients in the control and pioglitazone groups during two years, respectively; the incidence of MI and stroke was 0·3% and 2·2% and 1·0% and 0·3%, respectively. Post-hoc analyses of the 7-year observation period showed that these trends became clearer. Interpretation: Pioglitazone could not reduce the occurrence of cardiovascular events in patients with mild DM and previous MI. This result contradicts the results of the IRIS trial that pioglitazone decreased cardiovascular events in stroke patients or the results of the PROactive trial that pioglitazone decreased cardiovascular events in patients with moderate DM and macrovascular disease. Funding: The Grants of Japan Heart Foundation for PPAR study. Conflict of Interest: Dr. Asakura reports grants from Acterion Pharmaceutical Japan, grants from Boehringer Ingelheim Japan, Inc., personal fees from Otsuka Pharmaceutical Co., Ltd., personal fees from Sanofi K.K., personal fees from Bayer Yakuhin, Ltd., personal fees from MSD K.K., personal fees from Takeda Pharmaceutical Company Limited., personal fees from ONO PHARMACEUTICAL CO., LTD., personal fees from Mitsubishi Tanabe Pharma Corporation, personal fees from DAIICHI SANKYO COMPANY, LIMITED , personal fees from Pfizer Japan Inc., personal fees from Astellas Amgen Biopharma, outside the submitted work. Dr. Kim has nothing to disclose. Dr. Asanuma reports grants from Japan Heart Foundation, during the conduct of the study; grants from Japan Society For The Promotion Of Science (Grants-in-Aid For Scientific Research), grants from Novartis Pharmaceuticals Corporation, grants from Mitsubishi Tanabe Pharma Corporation, personal fees from Otsuka Pharmaceutical Co,Ltd, personal fees from Kyowa Hakko Kirin Co, Ltd, personal fees from Daiichi Sankyo Company, Limited, outside the submitted work. Dr. Hamasaki has nothing to disclose. Dr. Nakama has nothing to disclose. Dr. Tsukahara reports grants from Japan Heart Foundation, during the conduct of the study. Dr. Higashino reports grants from Japan Heart Foundation, during the conduct of the study. Dr. Ishikawa reports grants from Japan Heart Foundation during the conduct of the study. Dr. Koba reports grants from Japan Heart Foundation during the conduct of the study; grants from Daiichi Sankyo Company, Ltd, personal fees from MSD K.K. outside the submitted work. Ethical Approval Statement: The study was performed following the principles of the Declaration of Helsinki and the Japanese ethical guidelines for clinical research.

Are physicians neglecting the risk of heart failure in diabetic patients who are receiving sulfonylureas? Lessons from the TOSCA.IT trial.

Are physicians neglecting the risk of heart failure in diabetic patients who are receiving sulfonylureas? Lessons from the TOSCA.IT trial.

Electroacupuncture Mitigates Skeletal Muscular Lipid Metabolism Disorder Related to High-Fat-Diet Induced Insulin Resistance through the AMPK/ACC Signaling Pathway.

The aim of this work is to investigate the effect of electroacupuncture (EA) on insulin sensitivity in high-fat diet (HFD) induced insulin resistance (IR) rats and to evaluate expression of AMPK/ACC signaling components. Thirty-two male Sprague-Dawley rats were randomized into control group, HFD group, HFD+Pi (oral gavage of pioglitazone) group, and HFD+EA group. Acupuncture was subcutaneously applied to Zusanli (ST40) and Sanyinjiao (SP6). For Zusanli (ST40) and Sanyinjiao (SP6), needles were connected to an electroacupuncture (EA) apparatus. Fasting plasma glucose was measured by glucose oxidase method. Plasma fasting insulin (FINS) and adiponectin (ADP) were determined by ELISA. Triglyceride (TG) and cholesterol (TC) were determined by Gpo-pap. Proteins of adiponectin receptor 1 (adipoR1), AMP-activated Protein Kinase (AMPK), and acetyl-CoA carboxylase (ACC) were determined by Western blot, respectively. Compared with the control group, HFD group exhibits increased levels of FPG, FINS, and homeostatic model assessment of insulin resistance (HOMA-IR) and decreased level of ADP and insulin sensitivity index (ISI). These changes were reversed by both EA and pioglitazone. Proteins of adipoR1 and AMPK were decreased, while ACC were increased in HFD group compared to control group. Proteins of these molecules were restored back to normal levels upon EA and pioglitazone. EA can improve the insulin sensitivity of insulin resistance rats; the positive regulation of the AMPK/ACC pathway in the skeletal muscle may be a possible mechanism of EA in the treatment of IR.

Safety profile of second-line agents as add-on to oral monotherapy or dual therapy in uncomplicated type 2 diabetes in South Indian population

Background: Nowadays, there is an abundance of many therapeutic options available for the management of type 2 diabetes mellitus (DM). Hence, shifting the trend toward personalized treatment that focuses on the differences among different classes of pharmacological agents with regard to the mechanism of action, efficacy, and most important - the safety. Most of the clinical guidelines reconcile the risk-benefit ratio of the individual therapies. Moreover, there is limited evidence comparing the efficacy and safety of second-line drugs in combination therapies. It becomes crucial to rationalize the combination therapies with respect to attainment of glycemic targets, reduction in the short- and long-term complications and providing a better quality of life. In clinical practice, optimal treatment of type 2 DM must take into account the various comorbidities and adverse drug reactions (ADRs). Aims and Objective: The aims of the study were to assess the ADRs associated with second-line antidiabetic drugs when used as add-on agent in uncomplicated type 2 DM. Materials and Methods: Patients aged ≥18 years of age, diagnosed as uncomplicated type 2 DM who were previously receiving at least one oral antidiabetic drug (metformin or sulfonylurea) or dual-combination therapy (metformin+sulfonylurea) and for the first-time initiated on a second-line add-on agent, i.e., pioglitazone or dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin/vildagliptin) or α-glucosidase inhibitor (voglibose) or insulin (pre-mixed insulin [30% regular/70% NPH]) were included in the study. The ADRs associated with second-line agents were assessed based on hypoglycemic events, weight changes, frequency of ADRs, liver and renal function tests, and medical events reported. Results: A total of 240 patients (mean age 56.79 ± 11.73 years) were prescribed one of four different class of hypoglycemic agents. Overall, the median weight gain of 1.5 kg was observed in the insulin group, with no change of median weight in DPP-4 inhibitor group; while pioglitazone and voglibose group demonstrated a median weight loss of 1 and 0.5 kg, respectively, at the end of 6 months. The maximum number of hypoglycemic episodes was reported in insulin treatment group, i.e., 33; while least with DPP-4 inhibitor, i.e., 12. Out of 274 ADRs, the most common were gastrointestinal adverse effects, i.e., 30.66% and least were the dermatological ADRs (5.11%). Conclusion: Henceforth, DPP-4 inhibitor add-on group was found to be safest in terms of least hypoglycemic episodes and side effects when used as add-on therapy.

Effects of pioglitazonetreatment on blood leptin levels in patients with type2 diabetes.

Aims/IntroductionThe aim of the present study was to carry out a meta‐analysis of randomized controlled trials (RCTs) that investigated the effects of pioglitazone on blood leptin levels in patients with type 2 diabetes.Materials and MethodsLiterature searches were carried out using Medline, the Cochrane Controlled Trials Registry and ClinicalTrials.gov, and RCTs that investigated the effects of pioglitazone on blood leptin levels in patients with type 2 diabetes were selected. Standardized mean differences and 95% confidence intervals were calculated.ResultsA total of 10 RCTs met the eligibility criteria and were included in the meta‐analysis. Significantly lower blood leptin levels were observed in the pioglitazone group (standardized mean difference −0.58, 95% confidence interval −1.12 to −0.05%, P = 0.03) than in the placebo group. There was no significant difference in blood leptin levels observed between the pioglitazone and oral antidiabetic drug groups (standardized mean difference −0.01, 95% confidence interval −0.20 to 0.19%, P = 0.93).ConclusionsThere was a significant difference in blood leptin levels between the pioglitazone and placebo groups. However, relatively few RCTs were included in the study, and there was a high level of statistical heterogeneity; we believe that this could have affected the results.

Inflammatory Response Modulation through a PPARγ Agonist during Surgically Induced Visceral Ischemia in an Animal Model

Ischemia/reperfusion (I/R) injury represents one of the most severe complications in vascular surgery where cross-clamping of the aorta and subsequent visceral ischemia are a recurrent issue. The literature describes a family of nuclear receptors, that is, peroxisome proliferator-activated receptors (PPARs), in particular PPARγ isoform, which are important modulators of vascular inflammation resulting from I/R injury. The aim of our study is to evaluate how PPARγ agonist administration could reduce local and systemic inflammatory response after I/R injury during aortic supraceliac clamping in animal model. Our model includes 16 rats divided as follows: 8 rats in the placebo control group (PlacG) were operated on without having been administered of any drugs during the preoperative period, whereas the 8 rats in the pioglitazone group (PioG) were pretreated with pioglitazone. Renal and visceral ischemias were induced in the rats by supraceliac aortic clamping. Rats were sacrificed after surgery, and then, we collected blood samples to measure serum levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) and one of the kidneys and a segment of the liver to perform histological analysis. Considering both cytokines in the PioG, there has been a negative trend in serum concentrations, whereas in the PlacG, we observed an increasing trend. The high standard deviation observed in our study is mainly due to the small population of the cohort. Histologic examination of the kidney showed more severe damage in the placebo group as compared to the PioG with more evident differences in tubular and tubulointerstitial scores. Our observations show that administering pioglitazone can partially reduce secondary inflammatory response in the ischemic insult especially in endothelial and perivascular tissues.

Effect of pioglitazone on inflammation and calcification in atherosclerotic rabbits : An 18F-FDG-PET/CT in vivo imaging study.

We developed an atherosclerotic rabbit model and tested pioglitazone as adrug intervention for early vascular calcification. Positron emission tomography/computed tomography (PET/CT) was used to evaluate inflammation and therapeutic effects. We randomly divided 20 male New Zealand white rabbits into apioglitazone-treated group (n= 10) and acontrol group (n= 10). Atherosclerosis was induced via ahigh-cholesterol diet and endothelial denudation. The animals were maintained on ahyperlipidemic diet for 16weeks after surgery, and the treatment group received pioglitazone daily. Serum samples were obtained at 8 and 18 weeks postoperatively to assess high-sensitivity C‑reactive protein (hs-CRP) and matrix metalloproteinase-9 (MMP-9) concentrations. Sixteen rabbits underwent amid-stage PET/CT scan at week8, and 11 rabbits underwent an end-stage PET/CT scan at week18. PET/CT parameters, including the mean standardized uptake value (SUVmean) and maximum standardized uptake value (SUVmax), were measured and documented. There were significantly lower hs-CRP and MMP-9 levels in the pioglitazone group at week18 (p< 0.01). At the end of the 8thweek, no significant between-group differences in SUVmean and SUVmax were observed. From week8 to week18, the SUVmean and SUVmax decreased in the pioglitazone group but the SUVmean increased in the control group, with significant between-group differences at the end of the 18th week (p< 0.01). Histopathological examination of aortas in the control and pioglitazone groups revealed significantly smaller plaque area, macrophage density, and tissue calcification area in the latter group. Pioglitazone affects early vascular microcalcification, and pioglitazone-induced changes can be assessed using 18F-FDG-PET/CT.

Effects of pioglitazone on cognitive function in patients with a recent ischaemic stroke or TIA: a report from the IRIS trial

IntroductionPatients with cerebrovascular disease are at increased risk for cognitive dysfunction. Modification of vascular risk factors, including insulin resistance, could improve poststroke cognitive function.MethodsIn the Insulin Resistance Intervention after Stroke...

Targeting Pioglitazone Hydrochloride Therapy After Stroke or Transient Ischemic Attack According to Pretreatment Risk for Stroke or Myocardial Infarction

ImportanceThere is growing recognition that patients may respond differently to therapy and that the average treatment effect from a clinical trial may not apply equally to all candidates for a therapy.ObjectiveTo determine whether, among patients with an ischemic stroke or transient ischemic attack and insulin resistance, those at higher risk for future stroke or myocardial infarction (MI) derive more benefit from the insulin-sensitizing drug pioglitazone hydrochloride compared with patients at lower risk.Design, Setting, and ParticipantsA secondary analysis was conducted of the Insulin Resistance Intervention After Stroke trial, a double-blind, placebo-controlled trial of pioglitazone for secondary prevention. Patients were enrolled from 179 research sites in 7 countries from February 7, 2005, to January 15, 2013, and were followed up for a mean of 4.1 years through the study’s end on July 28, 2015. Eligible participants had a qualifying ischemic stroke or transient ischemic attack within 180 days of entry and insulin resistance without type 1 or type 2 diabetes. InterventionsPioglitazone or matching placebo.Main Outcomes and MeasuresA Cox proportional hazards regression model was created using baseline features to stratify patients above or below the median risk for stroke or MI within 5 years. Within each stratum, the efficacy of pioglitazone for preventing stroke or MI was calculated. Safety outcomes were death, heart failure, weight gain, and bone fracture.ResultsAmong 3876 participants (1338 women and 2538 men; mean [SD] age, 63 [11] years), the 5-year risk for stroke or MI was 6.0% in the pioglitazone group among patients at lower baseline risk compared with 7.9% in the placebo group (absolute risk difference, –1.9% [95% CI, –4.4% to 0.6%]). Among patients at higher risk, the risk was 14.7% in the pioglitazone group vs 19.6% for placebo (absolute risk difference, –4.9% [95% CI, –8.6% to 1.2%]). Hazard ratios were similar for patients below or above the median risk (0.77 vs 0.75; P = .92). Pioglitazone increased weight less among patients at higher risk but increased the risk for fracture more.Conclusions and RelevanceAfter an ischemic stroke or transient ischemic attack, patients at higher risk for stroke or MI derive a greater absolute benefit from pioglitazone compared with patients at lower risk. However, the risk for fracture is also higher.Trial Registrationclinicaltrials.gov Identifier: NCT00091949

Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial

The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes. TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50-75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2-3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15-45 mg) or a sulfonylurea (5-15 mg glibenclamide, 2-6 mg glimepiride, or 30-120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856. Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74-1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p<0·0001). Moderate weight gain (less than 2 kg, on average) occurred in both groups. Rates of heart failure, bladder cancer, and fractures were not significantly different between treatment groups. In this long-term, pragmatic trial, incidence of cardiovascular events was similar with sulfonylureas (mostly glimepiride and gliclazide) and pioglitazone as add-on treatments to metformin. Both of these widely available and affordable treatments are suitable options with respect to efficacy and adverse events, although pioglitazone was associated with fewer hypoglycaemia events. Italian Medicines Agency, Diabete Ricerca, and Italian Diabetes Society.

Pioglitazone can improve adhesion of bone marrow-derived endothelial progenitor cells from rat model of metaboic syndrome and its mechanism exploration

Objective To explore the effects of pioglitazone (PIO) on the migration ability of bone marrow-derived endothelial progenitor cells’ (EPCs) and the mechanism in the rat model of metaboic syndrome (MS). Methods The rat model of MS was established. Bone marrow EPCs were cultured and identified. The migration ability of EPCs in bone marrow of rats was compared among the normal control group (NC group), MS group and PIO group. EPCs cultured for 7 days were divided into 5 groups: PIO, PIO and GW9662, PIO and Wortmannin, PIO and extracellular signal -regulated kinase (ERK) channel blocker PD98059, and blank. The migration ability of EPCs was assayed. Results The migration ability of EPCs in NC was stronger than that in MS group (33.20±3.06 vs. 21.13±2.77, t=3.461, P=0.000); That was also seen beteen PIO group and MC group (27.16±2.27 vs. 21.13±2.77, t=2.909, P=0.008). PIO could improve migration of EPCs in rat model of MS. The effect disappeared when Wortmannin and GW9662 were added, but the effect didn’t disappeare when PD98059 was given (24.90±5.10 vs. 25.10±4.99, t=0.431, P=0.153). Conclusion PIO can improve the migration ability of bone-marrow-derived EPCs in rat model of MS, which may be mediated by phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signal pathway. Key words: Endothelial progenitor cell; Metabolic Syndrome; Pioglitazone; Migration; Phosphatidylinositol 3 kinase/protein kinase B

Impact of pioglitazone on bone mineral density and bone marrow fat content.

Use of the insulin sensitizer pioglitazone is associated with greater fracture incidence, although the underlying mechanisms are incompletely understood. This study aimed to assess the effect of pioglitazone treatment on femoral neck bone marrow (BM) fat content and on bone mineral density (BMD), and to establish if any correlation exists between the changes in these parameters. In this double-blind placebo-controlled clinical trial, 42 obese volunteers with metabolic syndrome were randomized to pioglitazone (45mg/day) or matching placebo for 1year. The following measurements were conducted at baseline and during the treatment: liver, pancreas, and femoral neck BM fat content (by magnetic resonance spectroscopy), BMD by DXA, abdominal subcutaneous and visceral fat, and beta-cell function and insulin sensitivity. Results were available for 37 subjects who completed the baseline and 1-year evaluations. At 12months, BM fat increased with pioglitazone (absolute change, +4.1%, p=0.03), whereas BM fat content in the placebo group decreased non-significantly (-3.1%, p=0.08) (p=0.007 for the pioglitazone-placebo response difference). Total hip BMD declined in the pioglitazone group (-1.4%) and increased by 0.8% in the placebo group (p=0.03 between groups). The change in total hip BMD was inversely and significantly correlated with the change in BM fat content (Spearman rho = -0.56, p=0.01) in the pioglitazone group, but not within the placebo group (rho = -0.29, p=0.24). Changes in BM fat with pioglitazone were predominantly observed in female vs. male subjects. Pioglitazone use for 12months compared with placebo is associated with significant increase in BM fat content at the femoral neck, accompanied by a small but significant decrease in total hip BMD.

PPAR-gamma agonist pioglitazone modifies craving intensity and brain white matter integrity in patients with primary cocaine use disorder: a double-blind randomized controlled pilot trial.

Pioglitazone (PIO), a potent agonist of PPAR-gamma, is a promising candidate treatment for cocaine use disorder (CUD). We tested the effects of PIO on targeted mechanisms relevant to CUD: cocaine craving and brain white matter (WM) integrity. Feasibility, medication compliance and tolerability were evaluated. Two-arm double-blind randomized controlled proof-of-concept pilot trial of PIO or placebo (PLC). Single-site out-patient treatment research clinic in Houston, TX, USA. Thirty treatment-seeking adults, 18 to 60 years old, with CUD. Eighteen participants (8=PIO; 10=PLC) completed diffusion tensor imaging (DTI) of WM integrity at pre-/post-treatment. Study medication was dispensed at thrice weekly visits along with once-weekly cognitive behavioral therapy for 12weeks. Measures of target engagement mechanisms of interest included cocaine craving assessed by the Brief Substance Craving Scale (BSCS), the Obsessive Compulsive Drug Use Scale (OCDUS), a visual analog scale (VAS) and change in WM integrity. Feasibility measures included number completing treatment, medication compliance (riboflavin detection) and tolerability (side effects, serious adverse events). Target engagement change in mechanisms of interest, defined as a ≥0.75 Bayesian posterior probability of an interaction existing favoring PIO over PLC, was demonstrated on measures of craving (BSCS, VAS) and WM integrity indexed by fractional anisotropy (FA) values. Outcomes indicated greater decrease in craving and greater increase in FA values in the PIO group. Feasibility was demonstrated by high completion rates among those starting treatment (21/26=80%) and medication compliance (≥ 80%). There were no reported serious adverse events for PIO. Compared with placebo, patients receiving pioglitazone show a higher likelihood of reduced cocaine craving and improved brain white matter integrity as a function of time in treatment. Pioglitazone shows good feasibility as a treatment for cocaine use disorder.