Mg Of Pioglitazone Research Articles

Efficacy and Safety of Pioglitazone Add-on in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Metformin and Dapagliflozin: A Multicenter, Randomized, Double-blind, and Placebo-controlled Study

PurposeThe purpose of this study was to determine the efficacy and safety profile of pioglitazone compared with placebo (PBO) in patients with type 2 diabetes (T2D) inadequately controlled with metformin and dapagliflozin. MethodsIn this prospective, multicenter, randomized, double-blind, PBO-controlled trial, 366 patients with T2D who did not meet glycemic targets (7.0% ≤ glycosylated hemoglobin [HbA1c] ≤ 10.5%), despite treatment with metformin ≥1000 mg and dapagliflozin 10 mg, received either a PBO, 15 mg of pioglitazone daily (PIO15), or 30 mg of pioglitazone daily (PIO30). The primary end point was the mean change in HbA1c from baseline at 24 weeks across the groups. FindingsFor the 366 participants (PBO, n = 124; PIO15, n = 118; PIO30, n = 124), the mean age was 55.6 years and mean duration of diabetes was 8.7 years, with a baseline HbA1c of 7.9%. After 24 weeks, HbA1c reduced significantly in the PIO15 and PIO30 groups from baseline, with intergroup differences of −0.38% and −0.83%, respectively, compared with the PBO group. The proportion of patients with HbA1c levels <7% was significantly higher in the PIO15 and PIO30 groups than in the PBO group. The adverse event rates did not significantly differ across the groups, indicating favorable safety profiles for triple combination therapy using metformin, dapagliflozin, and pioglitazone. ImplicationsThe addition of pioglitazone as a third oral antidiabetic medication is an appropriate option for patients with T2D inadequately controlled with metformin and dapagliflozin based on the resulting significant efficacy in glycemic control and favorable safety profile. ClinicalTrials.gov identifier: NCT04885712.

Pioglitazone-induced alterations of purine metabolism in healthy male subjects.

Pioglitazone is class of thiazolidinediones that activates peroxisome proliferator-activated receptors (PPARs) in adipocytes to improve glucose metabolism and insulin sensitivity and has been used as a treatment for type 2 diabetes. However, the underlying mechanisms of associated pioglitazone-induced effects remain unclear. Our study aimed to investigate endogenous metabolite alterations associated with pioglitazone administration in healthy male subjects using an untargeted metabolomics approach. All subjects received 30 mg of pioglitazone once daily in the assigned sequence and period. Urine samples were collected before pioglitazone administration and for 24 h after 7 days of administration. A total of 1465 compounds were detected and filtered using a coefficient of variance below 30% and 108 metabolites were significantly altered upon pioglitazone administration via multivariate statistical analysis. Fourteen significant metabolites were identified using authentic standards and public libraries. Additionally, pathway analysis revealed that metabolites from purine and beta-alanine metabolisms were significantly altered after pioglitazone administration. Further analysis of quantification of metabolites from purine metabolism, revealed that the xanthine/hypoxanthine and uric acid/xanthine ratios were significantly decreased at post-dose. Pioglitazone-dependent endogenous metabolites and metabolic ratio indicated the potential effect of pioglitazone on the activation of PPAR and fatty acid synthesis. Additional studies involving patients are required to validate these findings.

Pioglitazone in spontaneous subarachnoid hemorrhage: study protocol of a multicenter, double-blind, randomized trial (PSSH).

Introduction: Spontaneous subarachnoid hemorrhage (SAH), is a disorder that may be fatal and is primarily caused by a ruptured brain aneurysm. Despite significant leaps forward in the methods to produce aneurysms, the long-term outcomes did not much improve. Pioglitazone is a medication that has been authorized by the FDA as an agonist for the peroxisome proliferator-activated receptor-gamma (PPARγ). Pioglitazone or PPARγ has neuroprotective benefits in animal experiments both during and after traumatic brain injury (TBI) and SAH. Nevertheless, the treatment impact of Pioglitazone on humans is still unknown at this time. As a result, we will conduct a randomized, double-blind, placebo-controlled trial to explore the impact of pioglitazone on SAH. Methods/Design: This trial will recruit 400 patients with SAH from four Chinese hospitals. These patients will be equally and randomly assigned to Pioglitazone and placebo control groups for up to 30 days. Scores on the modified Rankin scale (mRS) are the primary outcomes. The secondary outcomes are a 30-day all-cause mortality rate, 6months of Montreal cognitive assessment (Mo-CA), delayed cerebral ischemia, the requirement for intensive care, the incidence of sepsis, etc. All serious adverse events (SAEs) were recorded during the hospital. Every primary and safety analysis was conducted based on the intention-to-treat technique. The participants were given either a matching placebo or 15mg of pioglitazone, with dose titrated to a target of 45mg daily. Data on the therapeutic use of pioglitazone after SAH will be provided as a consequence of the findings of this experiment. In addition, this pilot trial is the first to prospectively investigate the effectiveness and safety of pioglitazone in patients with SAH. Ethics and dissemination: Ethics approval was obtained from the Medical Ethics Committee of 904th Hospital of Joint Logistic Support Force of PLA (Wuxi Taihu Hospital, approval No. 20220701). The findings of the trial will be presented at conferences, discussed in relevant patient groups, and published in peer-reviewed journals. Clinical Trial Registration: clinicaltrials.gov, identifier ChiCTR2200062954.

Effect of pioglitazone on proteinuria and cardiovascular events in patients with diabetic nephropathy

Introduction: Slowing the progression of diabetes to DN has established a great deal of interest in recent years. Objectives: Considering the enormous costs of managing patients with diabetes and the lack of similar studies on the Iranian population, the present study aimed at investigating the effect of pioglitazone on the progression of DN and the prevalence of cardiovascular events. Patients and Methods: The present prospective study was undertaken on 55 patients with type 2 diabetes who were divided into two groups. The group 1 patients received 30 mg of pioglitazone daily in addition to other blood sugar-controlling drugs. Patients in the group 2 recieved other anti-diabetic medications. During a six-month follow-up period, proteinuria and the occurrence of cardiovascular events were assessed. Results: The 24-hour urinary proteinuria decreased within the group 1 and these intragroup differences were significant (P&lt;0.001) during six months of follow-up compared to month two. There was no significant difference in the ratio of cardiovascular events in the group 1 compared to the group 2. Conclusion: Adding 30 mg of pioglitazone to other blood sugar-lowering medications could lower proteinuria in individuals with type 2 diabetes; however, it had no impact on the risk of cardiovascular events.

Validated stability-indicating RP-HPLC method for simultaneous estimation of candesartan and pioglitazone in human plasma

Objective: The focus of this study was to establish a simple, robust, and validated RP-column approach to analyze Candesartan and Pioglitazone in a bilayer tablet dosage form. To broaden patient compliance in conditions such as diabetes and hypertension, a combination of drugs is often prescribed. As a result, a bilayer tablet containing a fixed-dose combination of 8 mg of Candesartan and 15 mg of Pioglitazone was developed. Both drugs were analyzed and chromatographically separated using the liquid chromatography technique. Methodology: waters 2695 with a quaternary pump and Inertsil C18 column mobile phase as buffer: acetonitrile (60:40) and flow rate of 1ml per minute and detection at 220nm was used for performing Chromatography. Results: Internal standard, Candesartan, and Pioglitazone eluted with retention times of 2.208, 2.569, and 3.553 minutes, respectively. There was no interference found between the peaks. With a correlation value of 0.999, the approach is verified across a linear range of 0.5 µg/ml – 20.0µg/ml for Candesartan and 0.08 µg/ml – 3.2 µg/ml for Pioglitazone. 6 samples at LLOQ level were analyzed for accuracy and precision and found to be in limit and all the analytes were stable at 28 °C and -80 °C in human plasma.

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.

THIOZOLIDINEDIONES IN THE TREATMENT OF PATIENTS WITH EXTENSIVE PSORIASIS AND CONCOMITANT ALIMENTARY OBESITY

Psoriasis is one of the most common chronic recurrent systemic autoimmune multifactorial diseases, affected the skin, joints, internal organs and systems of the body. Despite the significant prevalence of psoriasis and a large number of studies devoted this problem there is still no single view on the pathogenesis of this dermatosis. To clear up the pathogenesis of psoriasis, it seems to be reasonable to focus on the common comorbidities or multimorbidities, which may occur in the course of psoriasis, as this issue is still insufficiently studied. Recent reports have proven the evidences of indisputable link between psoriasis and obesity. The scientific literature extensively covers the issues of identical pathogenetic mechanisms of inflammatory processes in psoriasis and obesity. Given the current data on the role of systemic inflammation underlying the development of both psoriasis and obesity, the study of molecular mechanisms of its development and in particularly the role of proinflammatory nuclear transcription factors, thiazolidinediones have been found out as pathogenetically justified medicine of choice for the therapy of these diseases. In this study, we determined the effectiveness of using 30 mg of pioglitazone daily for 6 months in the course of treatment for patients with extensive psoriasis vulgaris of moderate severity, who were also diagnosed as having concomitant grade І-ІІ alimentary obesity that was supported by clinical and immunological findings evidenced of systemic inflammation. Analyzing the results obtained, we have found out the prolonged therapy with pioglitazone leads to a decrease in systemic inflammation and contributes to a milder recurrent course of psoriasis.

APPLICATION OF PIOGLITAZONE IN THE COMPREHENSIVE TREATMENT OF PSORIATIC PATIENTS WITH CONCOMITANT ALIMENTARY OBESITY

Psoriasis is one of the most common chronic recurrent systemic autoimmune multifactorial diseases, in which the skin, joints, internal organs and systems of the body are involved in the pathological process. Despite the significant prevalence of psoriasis and a large number of studies on this problem, there is still no single view on the pathogenesis of this dermatosis. To objectively understand the pathogenesis of psoriasis, it is necessary to take into account the insufficiently studied comorbidity of this pathology. Recently, an indisputable link between psoriasis and obesity has been proven. The scientific literature widely covers the issue of identical pathogenetic mechanisms of inflammatory processes in psoriasis and obesity. Given the current data on the role of systemic inflammation underlying the development of both psoriasis and obesity, the study of molecular mechanisms of its development and taking into account the role of proinflammatory nuclear transcription factors, thiazolidinediones are the pathogenetically justified drugs of choice for treatment of these diseases. In this study, we determined the effectiveness of using 15 mg of pioglitazone once a day for 6 months in the treatment of patients with extensive psoriasis vulgaris of moderate severity and concomitant grade І-ІІ alimentary obesity by clinical and immunological examination of systemic inflammation. Analyzing the results of the study, it was found that long-term use of pioglitazone, even in small doses, led to a decrease in systemic inflammation and contributed to a milder course of psoriasis in recurrence of the disease.

Comparative Efficacy of Lobeglitazone Versus Pioglitazone on Albuminuria in Patients with Type 2 Diabetes Mellitus.

IntroductionThe aim of this analysis was to evaluate the efficacy of lobeglitazone on albuminuria at 24 weeks of follow-up in patients with type 2 diabetes mellitus (T2DM) compared with pioglitazone using data from a randomized, double-blinded phase III trial.MethodsIn the phase III trial, patients who were inadequately controlled with metformin received 0.5 mg of lobeglitazone or 15 mg of pioglitazone for 24 weeks. Post hoc, exploratory analysis was used to investigate mean changes from baseline in the urine albumin–creatinine ratio (UACR) between the lobeglitazone (N = 104) and pioglitazone (N = 101) treatment groups.ResultsAfter 24 weeks of treatment, UACR was slightly decreased in the lobeglitazone group (− 4.3 mg/g creatinine [Cr]) compared to baseline and slightly increased in the pioglitazone group (5.2 mg/g Cr), with no change in the estimated glomerular filtration rate in either group; this difference was not statistically significant (P = 0.476). The incidence of new-onset microalbuminuria (2.4%) and the progression of albuminuria by > 1 stage (2.9%) in the lobeglitazone group were lower than the respective values in the pioglitazone group (6.8 and 6.1%, respectively). Of the patients in the lobeglitazone group, 50% exhibited regression to normoalbuminuria, compared to 39.3% of the patients in the pioglitazone. In subjects in the lobeglitazone group with micro- and macroalbuminuria, UACR tended to be more decreased and HbA1c was more reduced compared to those with normoalbuminuria (P = 0.014).ConclusionLobeglitazone had a tendency to improve albuminuria in patients with T2DM and had comparable effects on albuminuria as pioglitazone which has demonstrated beneficial effects.Trial RegistrationClinicalTrials.gov identifier, NCT01106131.Electronic Supplementary MaterialThe online version of this article (10.1007/s13300-020-00948-1) contains supplementary material, which is available to authorized users.

Ефективність застосування піоглітазону в комплексному лікуванні хворих на псоріаз із супутнім аліментарним ожирінням

Relevance. Psoriasis is the common chronic genetically determined autoimmune polyetiological inflammatory disease with impaired epidermal proliferation, provoked by exogenous and endogenous factors, and manifested by erythematous and scaly elements, papules and plaques. Despite the significant prevalence of psoriasis and a large number of studies on this problem, there is still no single view on the pathogenesis of this dermatosis. To objectively understand the pathogenesis of psoriasis, it is necessary to take into account the insufficiently studied comorbidity of this pathology. Recently, an indisputable link between psoriasis and obesity has been proven. The scientific literature widely covers the issue of identical pathogenetic mechanisms of inflammatory processes in psoriasis and obesity. Given the current data on the role of systemic inflammation underlying the development of both psoriasis and obesity, the study of molecular mechanisms of its development and taking into account the role of proinflammatory nuclear transcription factors, thiazolidinediones are the pathogenetically justified drugs of choice for treatment of these diseases. The objective. To determine the effectiveness of the use of 45 mg of pioglitazone 1 time per day for 26 weeks in the complex treatment of patients with widespread psoriasis vulgaris of moderate severity with concomitant alimentary obesity of I–II degrees. Materials and research methods. Clinical and immunological studies of indicators of systemic inflammation. Results. the use of 45 mg pioglitazone for 26 weeks led to a decrease in systemic inflammation in terms of IL-33 by 83.7%, IL-6 by 72%, uch-CRP by 76.8% and the PASI index by 46.8% with repeated relapse diseases. Conclusions. Long-term use of 45 mg of pioglitazone in the complex treatment of patients with widespread psoriasis vulgaris of moderate severity with concomitant alimentary obesity of I–II degrees proved to be effective and contributed to a milder course of psoriasis with repeated relapse of the disease.

The effects of PPAR-γ agonist pioglitazone on hippocampal cytokines, brain-derived neurotrophic factor, memory impairment, and oxidative stress status in lipopolysaccharide-treated rats.

Objective(s):The aim of current study was to evaluate improving effects of pioglitazone as an agonist of peroxisome proliferator-activated receptor gamma (PPARγ), on brain-derived neurotrophic factor (BDNF) and cytokines as well as tissue oxidative damage criteria in the hippocampus in a rat model of lipopolysaccharide (LPS) induced memory impairment.Materials and Methods:The rats were classified and treated as follows (10 rats per group): (1) vehicle, (2) vehicle before LPS (1 mg/kg, 120 min before memory tests), (3-5) pioglitazone 10, 20 or 30 mg/kg 30 min before LPS. Finally, the hippocampal tissues were collected for biomedical analyses.Results:In the Morris water maze test, the LPS group, had a longer latency to find the platform while they spent a shorter time in the target quadrant in the probe trial. In the passive avoidance test, the animals of the LPS group had shorter delay times to enter the dark compartment than those of the control group. Treatment with 20 and 30 mg of pioglitazone corrected these parameters. In the hippocampus of LPS group interleukin-6, tumor necrosis factor-α, nitric oxide metabolites, and malondialdehyde were higher while thiol, BDNF, and IL-10 concentrations and the activities of catalase (CAT) and superoxide dismutase (SOD) were lower than the control group. Treatment by both doses of 20 and 30 mg of pioglitazone corrected the biochemical parameters in the hippocampus.Conclusion:The current findings revealed that pioglitazone protected the rats from learning and memory impairment induced by LPS. The effects were associated with improvement of cytokines, oxidative stress criteria, and BDNF.

Pioglitazone Therapy in Patients With Stroke and Prediabetes

In the Insulin Resistance Intervention After Stroke (IRIS) randomized clinical trial, pioglitazone, an insulin-sensitizing agent, reduced the risk for recurrent stroke or myocardial infarction (MI) among patients with insulin resistance. However, insulin resistance is not commonly measured in clinical practice. To analyze the effects of pioglitazone in patients with good adherence as well as intention-to-treat effects of pioglitazone in patients with prediabetes in the IRIS trial. The IRIS trial was a randomized multicenter clinical trial in patients with prior stroke or transient ischemic attack as well as insulin resistance but not diabetes. Patients were enrolled from February 2005 to January 2013, and the median follow-up was 4.8 years. The post hoc analyses reported here were performed from June to September 2018. Per American Diabetes Association criteria, prediabetes was defined as having a hemoglobin A1c level of 5.7% to 6.4% or fasting plasma glucose level of 100 mg/dL to 125 mg/dL (to convert to mmol/L, multiply by 0.0555). Good adherence was defined as taking 80% or more of the protocol dose. Fasting glucose and hemoglobin A1c, used to define prediabetes, and adherence of 80% or higher, stipulated in the protocol as defining good adherence, were prespecified subgroups in the analysis plan. Participants were randomized to 15 mg of pioglitazone, with dose titrated to target of 45 mg daily, or matching placebo. The primary outcome was recurrent stroke or MI. Secondary outcomes included stroke, acute coronary syndrome, stroke/MI/hospitalization for heart failure, and progression to diabetes. Among 3876 participants analyzed in the IRIS trial, 2885 were included in this analysis (1456 in the pioglitazone cohort and 1429 in the placebo cohort). The mean (SD) age of patients was 64 (11) years, and 974 (66.9%) and 908 (63.5%) of patients were men in the pioglitazone and placebo cohort, respectively. In the prediabetic population with good adherence (644 of 1456 individuals [44.2%] in the pioglitazone group and 810 of 1429 [56.7%] in the placebo group), the hazard ratios (95% CI) were 0.57 (0.39-0.84) for stroke/MI, 0.64 (0.42-0.99) for stroke, 0.47 (0.26-0.85) for acute coronary syndrome, 0.61 (0.42-0.88) for stroke/MI/hospitalization for heart failure, and 0.18 (0.10-0.33) for progression to diabetes. There was a nonsignificant reduction in overall mortality, cancer, and hospitalization, a slight increase in serious bone fractures, and an increase in weight gain and edema. Intention-to-treat results also showed significant reduction of events but to a lesser degree. Hazard ratios (95% CI) were 0.70 (0.56-0.88) for stroke/MI, 0.72 (0.56-0.92) for stroke, 0.72 (0.52-1.00) for acute coronary syndrome, 0.78 (0.63-0.96), for stroke/MI/hospitalization for heart failure, and 0.46 (0.35 to 0.61) for progression to diabetes. Pioglitazone may be effective for secondary prevention in patients with stroke/transient ischemic attack and with prediabetes, particularly in those with good adherence. ClinicalTrials.gov identifier: NCT00091949.

Effects of pioglitazone on mnemonic hippocampal function: A blood oxygen level–dependent functional magnetic resonance imaging study in elderly adults

IntroductionMitochondrial dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD). Accordingly, drugs that positively influence mitochondrial function are being evaluated in delay-of-onset clinical trials with at-risk individuals. Such ongoing clinical research can be advanced by developing a better understanding of how these drugs affect intermediate brain phenotypes associated with both AD risk and pathophysiology. MethodsUsing a randomized, parallel-group, placebo-controlled design in 55 healthy elderly volunteers, we explored the effects of oral, low-dose pioglitazone, a thiazolidinedione with promitochondrial effects, on hippocampal activity measured with functional magnetic resonance imaging during the encoding of novel face–name pairs. ResultsCompared with placebo, 0.6 mg of pioglitazone (but not 2.1 mg, 3.9 mg, or 6.0 mg) administered daily for 14 days was associated with significant increases in right hippocampal activation during encoding of novel face–name pairs at day 7 and day 14, relative to baseline. DiscussionOur exploratory analyses suggest that low-dose pioglitazone has measurable effects on mnemonic brain function associated with AD risk and pathophysiology.

The Low-Dose (7.5 mg/day) 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. 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. To find out the efficacy and safety of the low-dose (7.5 mg/day) pioglitazone therapy, we reviewed the dose-response of pioglitazone on favorable effects and adverse effects due to pioglitazone, by searching the reports on effects of daily dose of 7.5 mg and/or 15 mg and/or 30 mg of pioglitazone. 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 standard- 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 standard- and high-dose pioglitazone therapy.

Pharmacokinetics of Empagliflozin and Pioglitazone After Coadministration in Healthy Volunteers

PurposeThe aim was to investigate the effects of coadministration of the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin with the thiazolidinedione pioglitazone. MethodsIn study 1, 20 healthy volunteers received 50 mg of empagliflozin alone for 5 days, followed by 50 mg of empagliflozin coadministered with 45 mg of pioglitazone for 7 days and 45 mg of pioglitazone alone for 7 days in 1 of 2 treatment sequences. In study 2, 20 volunteers received 45 mg of pioglitazone alone for 7 days and 10, 25, and 50 mg of empagliflozin for 9 days coadministered with 45 mg of pioglitazone for the first 7 days in 1 of 4 treatment sequences. FindingsPioglitazone exposure (Cmax and AUC) increased when coadministered with empagliflozin versus monotherapy in study 1. The geometric mean ratio (GMR) for pioglitazone Cmax at steady state (Cmax,ss) and for AUC during the dosing interval at steady state (AUCτ,ss) when coadministered with empagliflozin versus administration alone was 187.89% (95% CI, 166.35%–212.23%) and 157.97% (95% CI, 148.02%–168.58%), respectively. Because an increase in pioglitazone exposure was not expected, based on in vitro data, a second study was conducted with the empagliflozin doses tested in Phase III trials. In study 2, pioglitazone exposure decreased marginally when coadministered with empagliflozin. The GMR for pioglitazone Cmax,ss when coadministered with empagliflozin versus administration alone was 87.74% (95% CI, 73.88%–104.21%) with empagliflozin 10 mg, 90.23% (95% CI, 66.84%–121.82%) with empagliflozin 25 mg, and 89.85% (95% CI, 71.03%–113.66%) with empagliflozin 50 mg. The GMR for pioglitazone AUCτ,ss when coadministered with empagliflozin versus administration alone was 90.01% (95% CI, 77.91%–103.99%) with empagliflozin 10 mg, 88.98% (95% CI, 72.69%–108.92%) with empagliflozin 25 mg, and 91.10% (95% CI, 77.40%–107.22%) with empagliflozin 50 mg. The effects of empagliflozin on pioglitazone exposure are not considered to be clinically relevant. Empagliflozin exposure was unaffected by coadministration with pioglitazone. Empagliflozin and pioglitazone were well tolerated when administered alone or in combination. In study 1, adverse events were reported in 1 of 19 participants on empagliflozin 50 mg alone, 4 of 20 on pioglitazone alone, and 5 of 18 on combination treatment. In study 2, adverse events were reported in 8 of 20 participants on pioglitazone alone, 10 of 18 when coadministered with empagliflozin 10 mg, 5 of 17 when coadministered with empagliflozin 25 mg, and 6 of 16 when coadministered with empagliflozin 50 mg. ImplicationsThese results indicate that pioglitazone and empagliflozin can be coadministered without dose adjustments. EudraCT identifiers: 2008-006087-11 (study 1) and 2009-018089-36 (study 2).

Effects of Pioglitazone for Secondary Stroke Prevention in Patients with Impaired Glucose Tolerance and Newly Diagnosed Diabetes: The J-SPIRIT Study.

Prediabetes is an independent risk factor for future stroke. However, no effective treatment has yet been established for the recurrence of stroke in patients with prediabetes. Here we investigated the effects of pioglitazone, a potent peroxisome proliferator-activated receptor-gamma agonist, for the reduction of recurrent stroke in patients with prediabetes. Participants were patients who had a symptomatic ischemic stroke or transient ischemic attack (TIA) without a history of type 2 diabetes mellitus and who were diagnosed to have IGT or newly diagnosed diabetes by a 75-g oral glucose tolerance test. These patients were randomized to either receive or not receive pioglitazone. The primary endpoint was a recurrence of ischemic stroke. A total of 120 patients were enrolled in the study. Sixty-three patients received pioglitazone and 57 were enrolled in the control group that did not receive pioglitazone. The majority of patients (68.3%) were prescribed 15 mg of pioglitazone, while the remaining patients (31.7%) were treated with 30 mg of pioglitazone. Over a median follow-up period of 2.8 years, treatment with pioglitazone was found to be associated with a lower rate of the primary endpoint (recurrence of stroke) than that observed in the control group [event rate=4.8% pioglitazone vs 10.5% control, hazard ratio=0.62, 95% confidence interval 0.13-2.35, p=0.49]. However, differences were not statistically significant. While this study was too underpowered to determine the effect of pioglitazone, the result failed to show beneficial effects in patients of ischemic stroke or TIA with impaired glucose tolerance and newly diagnosed diabetes.

Effects of Low Dose Pioglitazone on Restenosis and Coronary Atherosclerosis in Diabetic Patients Undergoing Drug Eluting Stent Implantation

PurposeThiazolidinediones are insulin-sensitizing agents that reduce neointimal proliferation and the adverse clinical outcomes associated with percutaneous coronary intervention (PCI) in patients with diabetes mellitus (DM). There is little data on whether or not low dose pioglitazone reduces adverse clinical outcomes.Materials and MethodsThe study population included 121 DM patients with coronary artery disease and they were randomly assigned to 60 patients taking 15 mg of pioglitazone daily in addition to their diabetic medications and 61 patients with placebo after the index procedure with drug-eluting stents (DESs). The primary end points were rate of in-stent restenosis (ISR) and change in atheroma volume and in-stent neointimal volume. The secondary end points were all-cause death, myocardial infarction (MI), stent thrombosis and re-PCI.ResultsThere were no statistical differences in the clinical outcomes and the rate of ISR between the two groups [all-cause death; n=0 (0%) in the pioglitazone group vs. n=1 (1.6%) in the control group, p=0.504, MI; n=2 (3.3%) vs. n=1 (1.6%), p=0.465, re-PCI; n=6 (10.0%) vs. n=6 (9.8%), p=0.652, ISR; n=4 (9.3%) vs. n=4 (7.5%), p=1.000, respectively]. There were no differences in changes in neointimal volume, percent neointimal volume, total plaque volume and percent plaque volume between the two groups on intravascular ultrasonography (IVUS) study.ConclusionOur study demonstrated that low dose pioglitazone does not reduce rate of ISR, neointimal volume nor atheroma volume in DM patients who have undergone PCI with DESs, despite the limitations of the study.

Effects of low-dose pioglitazone on glucose control, lipid profiles, renin-angiotensin-aldosterone system and natriuretic peptides in diabetic patients with coronary artery disease

Pioglitazone ameliorates insulin resistance, but has an adverse effect of oedema that may result in subsequent heart failure, especially in diabetic patients with coronary artery disease. In this study, we evaluated the effects of low-dose pioglitazone on glucose control, lipid profiles, renin-angiotensin-aldosterone (RAA) system and natriuretic peptides in diabetic patients with coronary artery disease. and results: We studied 22 diabetic patients with coronary artery disease and more than 40% of left ventricular ejection fraction (LVEF). Patients were treated with 15 mg of pioglitazone for 12 weeks, in addition to their other hypoglycaemic agents. Pioglitazone significantly decreased fasting blood glucose (155.2±52.9 mg/dl to 131.1±38.4 mg/dl, p<0.01) and haemoglobin A1C (7.13±0.44 to 6.69±0.47, p<0.001). It did not affect low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, but significantly decreased triglyceride (115.6±28.8 mg/dl to 99.4±30.0 mg/dl, p<0.05) and atherogenic index of plasma (0.28±0.17 to 0.19±0.16, p<0.05). Pioglitazone did not affect plasma renin activity, plasma aldosterone, human atrial natriuretic peptide or N-terminal pro-brain natriuretic peptide. Our data suggested that low-dose pioglitazone was a safe and useful agent at least in diabetic patients with coronary artery disease and preserved LVEF.

Biochemical alterations and liver toxicity analysis with pioglitazone in healthy subjects

Pioglitazone, a member of the thiazolidinediones, is a potent, highly selective agonist for peroxisome proliferator-activated receptor gamma and is an excellent insulin sensitizer used in treating type 2 diabetes mellitus. The present study investigated the effect of pioglitazone on glucose, total cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol and high density lipoprotein (HDL) cholesterol, total proteins, albumin (ALB), alanine transaminase (ALT), and aspartate transaminase (AST) levels in 20 healthy Bengali male volunteers in a randomized, placebo-controlled study. Blood samples were collected before and 0.5–24.0 hours after a single oral dose of a 30 mg pioglitazone tablet. Plasma pioglitazone level was determined using a validated method of reverse-phase binary high-performance liquid chromatography. Blood lipid profile and levels of glucose, ALT, and AST were estimated using enzyme assay kits, plasma protein level was estimated by the biuret method, and plasma ALB level was determined colorimetrically. No significant change in blood glucose, total proteins, total cholesterol, triglyceride, HDL, and LDL levels was observed over the 24-hour assessment period, indicating no plasma biochemical alterations. There were no significant differences between baseline and 24-hour values of ALB, ALT, and AST levels, indicating a lack of liver toxicity. Our results indicate that a single dose of 30 mg of pioglitazone has no hypoglycemic or hypolipidemic effect or liver toxicity within 24 hours of treatment among healthy Bengali males.

Pioglitazone inhibits platelet function and potentiates the effects of aspirin: A prospective observation study

BackgroundThiazolidinediones (TZDs) are agonists of PPARγ and exert beneficial metabolic effects in patients with diabetes. They may also affect platelet function. ObjectivesTo characterize potential platelet inhibitory effect of pioglitazone alone and in the presence of aspirin. Methods20 normal and 20 diabetic subjects were enrolled in a prospective study. On day 1, a blood sample was obtained at baseline and a second one after ingestion of 30mg of pioglitazone. PRP was prepared and platelet aggregation and release were evaluated using ADP, collagen and arachidonic acid as agonists. Subjects returned at 6–9days later after ingesting a single 81mg dose of aspirin and a third blood sample was obtained. The subjects then again ingested 30mg of pioglitazone and a fourth and final blood sample was obtained. Platelet aggregation and release were measured. PRP was incubated with thrombin to activate platelets, and the serum was separated and assayed for thromboxane B2, TGFβ and CD40L ResultsPioglitazone alone did not affect aggregation with arachidonic acid. However, following ingestion of both aspirin and pioglitazone aggregation was significantly decreased compared to aspirin alone (P<0.0001). Pioglitazone also potentiated aspirin-induced inhibition of ATP release using either arachidonic acid or collagen. Following pioglitazone alone, TXB2 release was 32,719±3,585pg/ml which was significantly reduced compared to baseline (42,075±4,479, P=0.0004). Pioglitazone also potentiated the inhibition of TXB2 release by aspirin. ConclusionPioglitazone inhibits platelet function and potentiates the inhibitory effects of aspirin.