Pioglitazone combined with atorvastatin promotes plaque stabilization in a rabbit model

Objective It is not yet clear whether plaque inflammation and cardiovascular events are reduced further when pioglitazone and atorvastatin are combined. Our study aimed to determine whether pioglitazone combined with atorvastatin can restrain the progression of atherosclerosis and promote plaque stabilization in a rabbit model Method and Result Thirty rabbits were randomly divided into an atherosclerosis group, an atorvastatin group, and an atorvastatin plus pioglitazone group. The atherosclerosis model was induced using balloon injury and feeding a high-fat diet. Plasma samples were then used to analyze glucose, triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), high-sensitivity C-reactive protein (hs-CRP), and matrix metalloproteinase-9 (MMP-9). The area percentage of atherosclerotic plaques was analyzed by hematoxylin-eosin staining. The relative reductions in TG and LDL-C and the increase in HDL-C levels were significantly greater in the combination therapy group than in the atorvastatin monotherapy group (TG: −33.60 ± 7.17% vs −24.16 ± 8.04%, p < 0.001; LDL-C: −42.89 ± 1.63% vs −37.13 ± 1.35%, p < 0.001; and HDL-C: 25.18 ± 5.53% vs 10.43 ± 6.31%, p < 0.001). The relative reductions in hs-CRP and MMP-9 levels were significantly greater in the combination therapy group than in the atorvastatin monotherapy group (−69.38 ± 1.06% vs-53.73 ± 1.92%, p < 0.001; −32.77 ± 2.49% vs −13.36 ± 1.66%, p < 0.001). The area percentage of atherosclerotic plaques was significantly smaller in the atorvastatin group (47.75%, p < 0.05) and in the atorvastatin plus pioglitazone group (22.57%, p < 0.05) than in the atherosclerosis group (84.08%, p < 0.05) Conclusion We can thus conclude that the combination treatment of atorvastatin and pioglitazone provided additive benefits on inflammatory parameters and lipid metabolism. Pioglitazone combined with atorvastatin can further restrain the progression of atherosclerosis and promote plaque stabilization in a rabbit model.

Combination of pioglitazone and clomiphene citrate versus clomiphene citrate alone for infertile women with the polycystic ovarian syndrome

Background Anovulation is one of the common causes of infertility. Polycystic ovary syndrome (PCOS) is the most common disorder with chronic Anovulation. To the best of our knowledge, insulin resistance relates significantly to PCOS. Therefore administration of insulin-sensitizing drugs such as pioglitazone can be used for ovulation stimulation in PCO patients. Methods After obtaining approval from the Ethics Committee of Mashhad University of Medical Sciences, 61 patients with PCOS were enrolled in the study based on inclusion/ exclusion criteria. Patients were divided into two groups. The first group received 30 mg (mg) of pioglitazone daily from the second day of the menstrual period. The second one received a placebo. 150 mg clomiphene citrate was administered from the third to the seventh day of the menstrual cycle. Vaginal sonography was performed in all women, and in cases with the mature follicle, intrauterine insemination was conducted after human chorionic gonadotropin injection. Ovary stimulation and pregnancy rate were compared between groups. Results There were no differences between groups regard to demographic characteristics and infertility type. Body mass index was higher in the pioglitazone group (28.3 ± 3.8 versus 26.2 ± 3.5, P value = 0.047). The size of the follicle was not significantly different between groups (2.2 ± 1.4 versus 1.3 ± 1.1, P value = 0.742). pregnancy rate [4 (12.9%) versus 4 (13.3%), P value = 1] had no differences between groups. Conclusion Although the number of follicles was higher in the pioglitazone group, our study showed no differences in ovary stimulation and pregnancy rate.

Pioglitazone Inhibits Diabetes-Induced Atrial Mitochondrial Oxidative Stress and Improves Mitochondrial Biogenesis, Dynamics, and Function Through the PPAR-γ/PGC-1α Signaling Pathway

Background: Oxidative stress contributes to adverse atrial remodeling in diabetes mellitus. This remodeling can be prevented by the PPAR-γ agonist pioglitazone via its antioxidant and anti-inflammatory effects. In this study, we examined the molecular mechanisms underlying the protective effects of pioglitazone on atrial remodeling in a rabbit model of diabetes.Methods: Rabbits were randomly divided into control, diabetic, and pioglitazone-treated diabetic groups. Echocardiographic, hemodynamic, and electrophysiological parameters were measured. Serum PPAR-γ levels, serum and tissue oxidative stress and inflammatory markers, mitochondrial morphology, reactive oxygen species (ROS) production rate, respiratory function, and mitochondrial membrane potential (MMP) levels were measured. Protein expression of the pro-fibrotic marker TGF-β1, the PPAR-γ coactivator-1α (PGC-1α), and the mitochondrial proteins (biogenesis-, fusion-, and fission-related proteins) was measured. HL-1 cells were transfected with PGC-1α small interfering RNA (siRNA) to determine the underlying mechanisms of pioglitazone improvement of mitochondrial function under oxidative stress.Results: The diabetic group demonstrated a larger left atrial diameter and fibrosis area than the controls, which were associated with a higher incidence of inducible atrial fibrillation (AF). The lower serum PPAR-γ level was associated with lower PGC-1α and higher NF-κB and TGF-β1 expression. Lower mitochondrial biogenesis (PGC-1α, NRF1, and TFAM)-, fusion (Opa1 and Mfn1)-, and fission (Drp1)-related proteins were detected. Mitochondrial swelling, higher mitochondrial ROS, lower respiratory control rate, and lower MMP were observed. The pioglitazone group showed a reversal of structural remodeling and a lower incidence of inducible AF, which were associated with higher PPAR-γ and PGC-1α. The pioglitazone group had lower NF-κB and TGF-β1 expression levels, whereas biogenesis-, fusion-, and fission-related protein expression was higher. Further, mitochondrial structure and function were improved. In HL-1 cells, PGC-1α siRNA transfection blunted the effect of pioglitazone on Mn-SOD protein expression and MMP collapse in H2O2-treated cells.Conclusion: Diabetes mellitus induces adverse atrial structural, electrophysiological remodeling, and mitochondrial damage and dysfunction. Pioglitazone prevented these abnormalities through the PPAR-γ/PGC-1α pathway.

Effective Reduction of Inflammatory and Coagulation Factors using Sitagliptin in Type 2 Diabetes

Introduction: There are different drug-based treatments (i.e., oral or injective) for patients with type 2 diabetes. Pioglitazone and sitagliptin, among oral agents, can affect blood glucose control and lipid profile. Objectives: The purpose of the current investigation was the assessment of the effects of adding sitagliptin or pioglitazone (as the third drug) to the combined metformin-sulfonylurea treatment on glycemic control, inflammatory factors, and lipid profile. Methods: This clinical trial was carried out on 125 patients with type 2 diabetes undergoing metformin-glibenclamide treatment. The patients were randomly divided into three groups, namely the sitagliptin group receiving 100 mg of sitagliptin for 3 months (n=45), pioglitazone group receiving 30 mg of pioglitazone for 3 months (n=40), and control group (n=40). After the interventions, the anthropometric indices, glycated hemoglobin A1c level, lipid profile, fibrinogen, and high-sensitivity C-reactive protein (hs-CRP) were compared among the study groups. Results: The sitagliptin group demonstrated significantly lower levels of hs-CRP (0.53±0.26 mg/L) and fibrinogen (314.08±48.09 mg/dL), compared to those reported for the pioglitazone and control groups. In contrast, significantly lower triglyceride levels (115.02±32.92 mg/dL) and significantly higher high-density lipoprotein cholesterol (51.57±11.14 mg/dL) were observed in the pioglitazone group in comparison to those reported for the sitagliptin and control groups. Conclusion: The results of the present study suggest that sitagliptin reduces the levels of fibrinogen and hs-CRP. Nevertheless, pioglitazone has a more significant effect on the improvement of the lipid profile, compared to sitagliptin and combined metformin-sulfonylurea treatments.

THE RS1801282 PPARG POLYMORPHISM DEPENDENT METABOLIC EFFECTS OF PIOGLITAZONE IN PATIENTS WITH OBESITY AND CONCOMITANT NAFLD

The aim: to investigate the metabolic effects of different treatment options in patients with obesity and concomitant non-alcoholic fatty liver disease (NAFLD) based on the presence of CG and GG genotypes PPARG rs1801282 (Pro12Ala) polymorphism in Ukrainians. Materials and methods: 123 patients with NAFLD in combination with obesity 1, 2, 3 classes were included in the motivational weight loss program (5 visits, 3 months). The case group was treated with pioglitazone 15 mg / day, while the control group received only a program. Ultrasound steatometry, anthropometric and laboratory tests before and after treatment, genetic testing rs1801282 polymorphism in PPARG gene were performed. Results: the carriers of CG and GG genotypes PPARG rs1801282 polymorphism had less high stimulated insulin levels compared with groups of different genotypes (p<0.001). It was found pioglitazone effectiveness with significant difference in dynamics of CAP reduction (p<0.001) regardless of polymorphism. Dynamics of BMI decrease was the lowest in control group CC carries – –2.81 (–3.23; –2.39) kg (p<0.001) compared among other groups. Subjects from pioglitazone group with rs1801282 polymorphism carrying of CG and GG genotypes had significant differences in dynamics of fasting С-peptide decrease, serum uric acid reduction – –1.31 (–1.50; –1.13) µg/L and -165.3 (–182.80; –147.80) µmol/L (p<0.001) respectively compared among other groups. Conclusions: Better reduction of metabolic parameters during pioglitazone treatment of patients with obesity and concomitant NAFLD appears to be associated with carrying of CG and GG genotypes PPARG rs1801282 polymorphism.

Pioglitazone Is Associated with Lower Major Adverse Cardiovascular and Cerebrovascular Events than DPP4-Inhibitors in Diabetic Patients with End-Stage Renal Disease: A Taiwan Nationwide Cohort Study, 2006–2016

While pioglitazone reduces insulin resistance and hepatic gluconeogenesis effectively in patients with type 2 diabetes mellitus (T2DM), these benefits remained controversial in patients with end stage renal disease (ESRD). We compared major adverse cardiac cerebrovascular events (MACCEs) and mortality (overall, infection-related, and MACCE-related) of pioglitazone to that of dipeptidyl peptidase 4 inhibitors (DPP4-inhibitors) in patients with T2DM and ESRD. From Taiwan’s national health insurance research database (NHIRD), 647 pioglitazone users and 6080 DPP4-inhibitors users between 1 April 2006 and 31 December 2016 were followed from the 91th date after the ESRD certification until the study outcomes, independently; withdraw from the NHI program, death, or 31 December 2017, whichever came first. After weighting, risks of MACCEs (10.48% vs. 12.62% per person-years, hazard ratio (HR): 0.85, 95% (CI): 0.729–0.985) and all-cause mortality (12.86% vs. 13.22% per person-years, (HR): 0.88, 95% (CI): 0.771–0.995) are significantly lower in pioglitazone group. Subgroup analysis found lower MACCEs risk in the pioglitazone users without insulin therapy (6.44% vs. 10.04% (HR): 0.59, 95% (CI): 0.42–0.82) and lower MACCEs related death (2.76% vs. 3.84% (HR): 0.61, 95% (CI): 0.40–0.95) in the pioglitazone group with dyslipidemia, when comparing with DPP4-inhibitors users. Pioglitazone is associated with lower all-cause mortality and MACCEs in diabetic patients with ESRD, compared to DPP4-inhibitors. These benefits were even more significant in the non-insulin users and patients with dyslipidemia.

COMPARATIVE STUDY OF SITAGLIPTINAND PIOGLITAZONE AS ADDONTHERAPY OVER PLASMA GLUCOSE LEVEL IN TYPE 2 DIABETES MELLITUS PATIENTS : AN OBSERVATIONAL COHORT STUDY

Background: Type 2 diabetes mellitus (DM) is a progressive chronic disorder and sustained control of plasma glucose is essential to prevent complications. Pioglitazoneofthiazolidinedionesand sitagliptin of Dipeptidyl peptidase-4 inhibitors (DPP4I) have recently been used as add-on therapy to control type 2 DM. The aim of this study was to compare the plasma glucose and glycocelatedHb% level of both the group who had poor glycemic control with Metformin and sulfonylurea. MATERIAL AND METHODS: In this observational cohort study, 100 patients with uncontrolled type 2 DM on 2000 mg/day of Metformin and 4 mg/day of Glimepiride were enrolled. The patients were randomly allocated into two groups with fifty each. One group received two divided doses of pioglitazone (30 mg/day) and the other received two divided doses of sitagliptin (100 mg/day) as the third medication. Plasma glucose fasting and 2 hours after drug and meal along with HbA1c were assessed before and after three months of treatment. Results: Fasting plasma glucose level in the sitagliptin group was higher than the pioglitazone group; however, this difference was not statistically significant (130.30 ± 30.29 versus 124.58 ± 46.84, p=0.212). Significantdifferences were not observed in HbA1c (7.20±0.96 versus 7.43±0.99, p=0.563) and plasma glucose 2 hours after meal (194.56±66.22 versus 198.58±51.5, p=0.946) after treatment withsitagliptin and pioglitazone among the two groups. Mean weight in the sitagliptin group was lower compared to the pioglitazone group after treatment, however, this difference was not statistically significant (p=0.824). Conclusion: Both the molecule as third agent had similar efficacy in glycemic control. Sitagliptin is better choice to add-on therapy in obese overweight patients.

Pioglitazone is Associated with Lower Major Adverse Cardiovascular and Cerebrovascular Events than DPP4-Inhibitors in Diabetic Patients with End-Stage Renal Disease: A Taiwan Nationwide Cohort Study, 2006-2016

While pioglitazone reduces insulin resistance and hepatic gluconeogenesis effectively in patients with T2DM, these benefits remained controversial in patients with ESRD. We compared MACCEs and mortality (overall, infection-related, and MACCE-related) of pioglitazone to that of DPP4-inhibitors in patients with T2DM and ESRD. From Taiwan&rsquo;s national health insurance database, 647 pioglitazone users and 6080 DPP4-inhibitors users between April 1st, 2006 and December 31th, 2016 were followed from the 91th date after the ESRD certification till study outcomes, independently; withdraw from the NHI program, death, or Dec. 31th, 2017. After weighting, risks of MACCEs (10.48% vs 12.62% per person-years, [HR]: 0.85, 95% [CI]: 0.729&ndash;0.985) and all-cause mortality (12.86% vs 13.22% per person-years, [HR]: 0.88, 95% [CI]: 0.771&ndash;0.995) are significantly lower in pioglitazone group. Subgroup analysis found lower MACCEs risk in the pioglitazone users without insulin therapy (6.44% vs 10.04% [HR]: 0.59, 95% [CI]: 0.42&ndash;0.82) and lower MACCEs related death (2.76% vs 3.84% [HR]: 0.61, 95% [CI]: 0.40&ndash;0.95) in the pioglitazone group with dyslipidemia, when comparing with DPP4-inhibitors users. Pioglitazone is associated with lower all-cause mortality and MACCEs in diabetic patients with ESRD, compared to DPP4-inhibitors. These benefits were further significant in the non-insulin users and patients with dyslipidemia.

A Triple-Blind Randomized Controlled Trial on Impacts of Pioglitazone on Oxidative Stress Markers in Diabetic Kidney Transplant Recipients

Background: Oxidative stress as a major mediator of adverse outcomes in kidney transplant recipients who are prone to oxidative stress-mediated injury by pre-transplant and post-transplant conditions. Objectives: The purpose of this study was to assess the effects of Pioglitazone on oxidative stress biomarkers and blood glucose control in diabetic patients receiving insulin after kidney transplantation. Methods: In a triple-blind randomized placebo-controlled trial, sixty-two kidney transplanted diabetic patients (40 men and 24 women) were followed for 4 months after randomly assigned to the placebo group and Pioglitazone group (30 mg/d). All of the patients continued their insulin therapy irrespective of the group that they were assigned to evaluate the effects of the addition of pioglitazone on blood glucose and oxidative stress biomarkers, Malondialdehyde (MDA) and total protein carbonyls (TPC) serum levels. Results: At baseline, there were no statistically significant differences in glycemic control levels and oxidative markers between the two groups. After 4 months of intervention, a significant improvement occurred in Hemoglobin A1c (HBA1c) in the Pioglitazone group. The changes of HBA1c during 4 months of follow up in the Pioglitazone group show improvement in glucose control were as HBA1c in the placebo group increased by 0.3% (P = 0.0001). Moreover, at the end of the study, the MDA level was significantly lower in the Pioglitazone group (P < 0.0001, 1.22 - 3.90). Regarding the serum level of TPC, the changes were not statistically different at baseline and also at the end of the study between two groups. Conclusions: Administration of Pioglitazone in addition to insulin in diabetic kidney transplant patients not only improved glycemic control (evidenced by HBA1c) but also significantly decreased oxidative stress markers such as MDA.

Differential Impact of Insulin Sensitizers vs. Anti-Androgen on Serum Leptin Levels in Vitamin D Replete PCOS Women: A Six Month Open Labeled Randomized Study

Women with PCOS are linked to insulin resistance, inflammation, and vitamin D (VD) deficiency. The study endeavors to comprehend the differential impact of insulin sensitizers vs. anti-androgen on serum leptin levels among women with PCOS rendered vitamin D replete with high VD oral supplement. This was open-labeled randomized study that screened 180 eligible women presenting to Endocrine clinic with oligomenorrhea or features of hyperandrogenism. Ninety-nine women who furnished written informed consent and fulfilled the Rotterdam 2003 criteria for diagnosis of PCOS were randomized into 3 drug treatment arms to receive either spironolactone (50 mg/d; n=30), metformin (1000 mg/d; n=30) or pioglitazone (30 mg/d; n=30). These women were also administered oral VD (4000 IU/day) in addition to the allocated drug for a period of 6 months. Detailed history, clinical examination, and laboratory evaluation was carried out at baseline and 6 months after intervention. Number of menstrual cycles/year increased while as Ferriman–Gallwey score, blood glucose, HOMA-IR, and plasma insulin levels significantly decreased in all the three arms with better outcomes in spironolactone and pioglitazone arms (p<0.05). Similarly, serum leptin levels superiorly improved in spironolactone and pioglitazone group. Pioglitazone group showed better efficacy in lowering serum total testosterone (p<0.05). Co-supplementation of high dosage VD with spironolactone or pioglitazone are more effective in reducing plasma leptin levels than metformin, and thus might prove to be better therapeutic strategies for women with PCOS.