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P Brunetti - One of the best experts on this subject based on the ideXlab platform.
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a long term comparison of Pioglitazone and gliclazide in patients with type 2 diabetes mellitus a randomized double blind parallel group comparison trial
Diabetic Medicine, 2005Co-Authors: B Charbonnel, Guntram Schernthaner, D R Matthews, M Hanefeld, P BrunettiAbstract:Aims This study compared the effects of Pioglitazone and gliclazide on metabolic control in drug-naive patients with Type 2 diabetes mellitus. Methods A total of 1270 patients with Type 2 diabetes were randomized in a parallel-group, double-dummy, double-blind study. Patients with poorly controlled Type 2 diabetes (HbA1c 7.5–11%), despite dietary advice, received either Pioglitazone up to 45 mg once daily or gliclazide up to 160 mg two times daily. Primary efficacy endpoint was change in HbA1c from baseline to the end of the study. Secondary efficacy endpoints included change in fasting plasma glucose, fasting plasma insulin and plasma lipids. At selected centres, oral glucose tolerance tests were performed and C-peptide and pro-insulin levels were measured. Results Mean HbA1c values decreased by the same amount in the two treatment groups from baseline to week 52 [Pioglitazone: −1.4%; gliclazide: −1.4%; (90% CI: −0.18 to 0.02)]. A significantly greater mean reduction in fasting plasma glucose was observed in the Pioglitazone group (2.4 mmol/l) than in the gliclazide group [2.0 mmol/l; treatment difference −0.4 mmol/l in favour of Pioglitazone; P = 0.002; (95% CI: −0.7 to −0.1)]. Improvements in high-density lipoprotein cholesterol (HDL-C) and total cholesterol/HDL-C were greater with Pioglitazone than with gliclazide (P < 0.001). The frequencies of adverse events were comparable between the two treatment groups, but more hypoglycaemic events were reported for gliclazide, whereas twice as many patients reported oedema with Pioglitazone than with gliclazide. Conclusions Pioglitazone monotherapy was equivalent to gliclazide in reducing HbA1c, with specific differences between treatments in terms of mechanism of action, plasma lipids and adverse events.
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efficacy and safety of Pioglitazone versus metformin in patients with type 2 diabetes mellitus a double blind randomized trial
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Guntram Schernthaner, B Charbonnel, D R Matthews, M Hanefeld, P BrunettiAbstract:Pioglitazone increases the insulin sensitivity of peripheral tissues and may provide an alternative first-line treatment for type 2 diabetes. This study compared metabolic control in drug-naive type 2 diabetes patients given either Pioglitazone or metformin. Eleven hundred and ninety-nine patients with poorly controlled type 2 diabetes mellitus [glycosylated hemoglobin (HbA1c), 7.5-11%; normal, 4.3-6.1%] were randomized to receive either Pioglitazone (< or =45 mg/d) or metformin (< or =850 mg, three times daily). HbA1c, fasting plasma glucose (FPG), insulin levels, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol, triglycerides, free fatty acids, and urinary albumin/creatinine ratio were measured. Mean HbA1c decreased in both treatment groups from baseline to wk 52 (-1.4% and -1.5%). Significantly greater mean reductions in FPG were observed in the Pioglitazone group (-45.0 mg/dl; -2.5 mmol/liter) than in the metformin (-39.6 mg/dl; -2.2 mmol/liter) group (P = 0.016). Favorable changes in triglycerides and HDL-C were more pronounced with Pioglitazone. Although low density lipoprotein cholesterol and TC levels increased with Pioglitazone, TC/HDL-C ratios decreased similarly with both treatments. The urinary albumin/creatinine ratio was reduced by 19% with Pioglitazone treatment, but remained unchanged with metformin therapy (-1%; P = 0.002). There was an increase in body weight of 1.9 kg in the Pioglitazone group and a decrease of 2.5 kg in the metformin group. The overall frequency of adverse events was similar between treatment groups, but adverse event profiles were different between treatment groups. HbA1c reduction is similar after Pioglitazone and metformin monotherapies, but differences in FPG, plasma lipids, and adverse effects between the two compounds may influence decision-making in individual prescribers.
Hansjuergen Woerle - One of the best experts on this subject based on the ideXlab platform.
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Linagliptin and Pioglitazone combination therapy versus monotherapy with linagliptin or Pioglitazone: A randomised, double-blind, parallel-group, multinational clinical trial.
Diabetes & vascular disease research, 2016Co-Authors: Michael A. Nauck, Sanjay Patel, Maximiliano Di Domenico, Maureen Kobe, Robert Toorawa, Hansjuergen WoerleAbstract:Linagliptin plus Pioglitazone single-pill combinations were evaluated. Patients (n = 936) with insufficient glycaemic control, despite lifestyle interventions, were randomised for 30 weeks to either monotherapy with linagliptin 5 mg; Pioglitazone 15, 30 or 45 mg; or single-pill combination with linagliptin 5 mg plus Pioglitazone 15, 30 or 45 mg. An extension (⩽54 weeks) planned to evaluate linagliptin plus Pioglitazone 30 or 45 mg single-pill combinations was not completed due to a protocol amendment. Adjusted mean (95% confidence interval) differences in HbA1c change from baseline at week 30 for linagliptin plus Pioglitazone 15, 30 and 45 mg were −0.17% (−0.41, 0.07), −0.37% (−0.60, −0.14) and −0.41% (−0.64, −0.18) versus Pioglitazone monotherapies, respectively, and −0.44% (−0.67, −0.20), −0.68% (−0.91, −0.44) and −0.89% (−1.12, −0.66) versus linagliptin monotherapy, respectively. Single-pill combinations were generally well tolerated. Hypoglycaemia frequency was ⩽1.5% per group. Linagliptin plus piogli...
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Pharmacokinetics of Empagliflozin and Pioglitazone After Coadministration in Healthy Volunteers.
Clinical Therapeutics, 2015Co-Authors: Sreeraj Macha, Uli C Broedl, Michaela Mattheus, Sabine Pinnetti, Hansjuergen WoerleAbstract:Abstract Purpose The aim was to investigate the effects of coadministration of the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin with the thiazolidinedione Pioglitazone. Methods In 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. Findings Pioglitazone exposure (C max and AUC) increased when coadministered with empagliflozin versus monotherapy in study 1. The geometric mean ratio (GMR) for Pioglitazone C max at steady state (C max,ss ) and for AUC during the dosing interval at steady state (AUC τ,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 C max,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 AUC τ,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. Implications These 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).
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efficacy and safety of initial combination therapy with linagliptin and Pioglitazone in patients with inadequately controlled type 2 diabetes a randomized double blind placebo controlled study
Diabetes Obesity and Metabolism, 2011Co-Authors: R Gomis, Hansjuergen Woerle, R M Espadero, Russell Jones, Klaus DugiAbstract:Aims: To compare the efficacy, safety and tolerability of linagliptin or placebo administered for 24 weeks in combination with Pioglitazone in patients with type 2 diabetes mellitus (T2DM) exhibiting insufficient glycaemic control (HbA1c 7.5–11.0%). Methods: Patients were randomized to receive the initial combination of 30 mg Pioglitazone plus 5 mg linagliptin (n = 259) or Pioglitazone plus placebo (n = 130), all once daily. The primary endpoint was change from baseline in HbA1c after 24 weeks of treatment, adjusted for baseline HbA1c and prior antidiabetes medication. Results: After 24 weeks of treatment, the adjusted mean change (±s.e.) in HbA1c with the initial combination of linagliptin plus Pioglitazone was −1.06% (±0.06), compared with −0.56% (±0.09) for placebo plus Pioglitazone. The difference in adjusted mean HbA1c in the linagliptin group compared with placebo was −0.51% (95% confidence interval [CI] −0.71, −0.30; p < 0.0001). Reductions in fasting plasma glucose (FPG) were significantly greater for linagliptin plus Pioglitazone than with placebo plus Pioglitazone; −1.8 and −1.0 mmol/l, respectively, equating to a treatment difference of −0.8 mmol/l (95% CI −1.2, −0.4; p < 0.0001). Patients taking linagliptin plus Pioglitazone, compared with those receiving placebo plus Pioglitazone, were more likely to achieve HbA1c of <7.0% (42.9 vs. 30.5%, respectively; p = 0.0051) and reduction in HbA1c of ≥0.5% (75.0 vs. 50.8%, respectively; p < 0.0001). β-cell function, exemplified by the ratio of relative change in adjusted mean HOMA-IR and disposition index, improved. The proportion of patients that experienced at least one adverse event was similar for both groups. Hypoglycaemic episodes (all mild) occurred in 1.2% of the linagliptin plus Pioglitazone patients and none in the placebo plus Pioglitazone group. Conclusion: Initial combination therapy with linagliptin plus Pioglitazone was well tolerated and produced significant and clinically meaningful improvements in glycaemic control. This combination may offer a valuable additive initial treatment option for T2DM, particularly where metformin either is not well tolerated or is contraindicated, such as in patients with renal impairment.
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Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase-4 inhibitor linagliptin and Pioglitazone in healthy volunteers.
International journal of clinical pharmacology and therapeutics, 2010Co-Authors: Eva Ulrike Graefe-mody, Hansjuergen Woerle, Arne Ring, Arvid Jungnik, Klaus DugiAbstract:Objective: Co-administration of the dipeptidyl peptidase-4 inhibitor linagliptin (BI 1356) with Pioglitazone may improve glycemic control in patients with Type 2 diabetes due to their complementary mechanisms of action. This study aimed to investigate any potential pharmacokinetic interaction between linagliptin and Pioglitazone, a CYP 2C8 substrate. Methods: 20 (10 male and 10 female) healthy subjects, between 22 and 65 years of age with a BMI range of ≥ 18.5 and ≤ 29.9 kg/m 2 , took part in this single center open-label, randomized, two-way cross-over study. The subjects were administered linagliptin 10 mg/day and/or Pioglitazone 45 mg/day until steady state was reached. Results: Co-administration of Pioglitazone did not significantly affect linagliptin C max,ss (geometric mean ratio (GMR) 107.3; 90% confidence interval (CI); 92.3 ― 124.8) or AUC τ,ss (GMR 113.4; 90% CI 103.0 ― 124.9). Co-administration of linagliptin did not significantly affect Pioglitazone AUC τ,ss (GMR 94.4; 90% CI 87.1 -102.2), but reduced C max,ss by 14% (GMR 85.6; 90% CI 78.1 ― 93.8). As expected, linagliptin and Pioglitazone were well tolerated, whether administered alone or concomitantly. There were no reported serious adverse events. The investigator defined 5 adverse events as drug-related with linagliptin, and 4 with Pioglitazone. Conclusions: Linagliptin and Pioglitazone have no clinically relevant pharmacokinetic interaction and may be co-administered without dose adjustment. These data further confirm that linagliptin is not an inhibitor of CYP 2C8 in vivo. As the pharmacokinetic profiles of linagliptin and Pioglitazone are similar in Type 2 diabetes patients and healthy subjects, it is reasonable to assume that they may be administered together to Type 2 diabetes patients without dose adjustment.
S E Cohen - One of the best experts on this subject based on the ideXlab platform.
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efficacy and tolerability of vildagliptin vs Pioglitazone when added to metformin a 24 week randomized double blind study
Diabetes Obesity and Metabolism, 2007Co-Authors: Geremia B Bolli, Erika Rochotte, Francesco Dotta, S E CohenAbstract:Aim: The aim of this study was to compare the efficacy and tolerability of vildagliptin vs. Pioglitazone as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Methods: This 24-week, multicentre, double-blind, randomized, active-controlled study compared vildagliptin (100 mg daily, given as equally divided doses, n = 295) and Pioglitazone (30 mg daily, given as a single q.d. dose, n = 281) in patients with inadequate glycaemic control (A1C 7.5–11%) while receiving a stable metformin dose (≥1500 mg daily). The adjusted mean changes from baseline to study endpoint (AMΔ) in A1C, fasting plasma glucose (FPG), fasting lipids and body weight were compared by analysis of covariance. Results: When added to a stable dose of metformin (mean dose at baseline >2000 mg/day), both vildagliptin and Pioglitazone decreased A1C (AMΔ = −0.9 ± 0.1% and −1.0 ± 0.1%, respectively) from identical baseline values (8.4 ± 0.1%). The between-group difference in AMΔ A1C was 0.1 ± 0.1%, and non-inferiority of vildagliptin to Pioglitazone was established at both 0.4 and 0.3% margins for upper limit of the 95% confidence intervals. Pioglitazone decreased FPG (AMΔ = −2.1 ± 0.1 mmol/l) to a greater extent than vildagliptin (AMΔ = −1.4 ± 0.1 mmol/l), but only Pioglitazone increased body weight (AMΔ = +1.9 ± 0.2 kg: between-group difference = −1.6 ± 0.3 kg, p < 0.001). Adverse events (AEs) were reported by 60% of vildagliptin-treated patients and by 56.4% of Pioglitazone-treated patients; serious AEs were reported by 2.0 and 4.6% of patients receiving vildagliptin and Pioglitazone respectively. Mild hypoglycaemia was reported by one patient (0.3%) in the vildagliptin group and by no patients receiving Pioglitazone. Conclusions: When added to metformin, the efficacy of vildagliptin is non-inferior to that of Pioglitazone. The treatments were similarly well tolerated, but only Pioglitazone increased body weight.
Ralph A. Defronzo - One of the best experts on this subject based on the ideXlab platform.
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Rehabilitation of Pioglitazone
British Journal of Diabetes, 2015Co-Authors: Robert E J Ryder, Ralph A. DefronzoAbstract:Background In 2012 an editorial in the British Medical Journal stated that “it can confidently be assumed that Pioglitazone increases the risk of bladder cancer”.1 Yet now, the recently announced results of a 10-year study mandated by the FDA have failed to demonstrate any association between Pioglitazone and bladder cancer2 and, because of its many beneficial effects on glucose homeostasis and potential cardiovascular protective effects, the place of Pioglitazone in the treatment of diabetes warrants reconsideration. During pre-clinical studies, an excess of bladder cancers were found in male but not female rats treated with Pioglitazone.3 Of note, these bladder cancers could be prevented by acidification of the urine which prevents Pioglitazone crystal formation.4 As a result of the findings in rats, the FDA requested a 10-year study of Pioglitazone in humans to assess safety with regard to bladder cancer.5 The 8-year data have been published online6 and the 10-year results recently were made public.2 The main results of this study fail to show any association between Pioglitazone and risk of bladder cancer.7 Another large, recently reported study involving six populations, including 1.01 million diabetic individuals from six countries across the world, has come to the same conclusion.8 Previous studies suggesting a link between Pioglitazone and bladder cancer have been re-examined.7 The link between Pioglitazone and bladder cancer in many of these retrospective observational studies is likely to be explained by the fact that patients treated with Pioglitazone in the various databases were different from those not treated with Pioglitazone, with whom they were compared, i.e. the Pioglitazone-treated patients already were at higher risk of bladder cancer from other causes.7 Importantly, major risk factors for bladder cancer, i.e. smoking and proteinuria, were not available for most of these retrospective analyses. Initial concern about a potential link between Pioglitazone and bladder cancer was derived from the PROactive study, where an apparent excess of bladder cancers was observed for Pioglitazone (14) versus placebo (6, p=NS).7,9-11 The PROactive study investigators concluded that, because most of the bladder cancers occurred during the first year following initiation of Pioglitazone therapy, the drug could not plausibly be related to the development of bladder cancer.9 Further, the total numbers of bladder cancers (n=20) was small, making it difficult to draw any meaningful conclusion about the statistically insignificant difference between the treatment groups. It has been suggested that Pioglitazone might be a tumour promoter and in this way caused the excess of bladder cancer during the first year of PROactive,12 although there is no experimental evidence to support such an effect of Pioglitazone. The actual data regarding the number of months into the trial when these bladder cancer cases were diagnosed has been published: most appeared so early into the trial (two cases were diagnosed 13 and 14 days into the trial respectively, one at one month, another at three months and a fifth at four months) that they could not possibly have been related to Pioglitazone treatment.10,11 Links between Pioglitazone and bladder cancer in meta-analyses of randomised controlled trials depend entirely on inclusion of these bladder cancer cases in the first year of PROactive, which we now know could not have been related to Pioglitazone.10,11 Lastly, and most importantly, the 6-year follow up data of PROactive have been published.13 After 6 years there were 23 cases of bladder cancer in the Pioglitazone-treated group versus 22 cases in the placebo-treated group. Thus, in 2015, it is highly unlikely that there is any link between Pioglitazone and bladder cancer at all in humans.7,10,11
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Pioglitazone use in combination with insulin in the prospective Pioglitazone clinical trial in macrovascular events study (PROactive19).
The Journal of clinical endocrinology and metabolism, 2010Co-Authors: Bernard Charbonnel, Ralph A. Defronzo, Jaime A. Davidson, Ole Schmitz, Kåre I. Birkeland, Valdis Pirags, André ScheenAbstract:Objective: In this post hoc analysis, we examined insulin requirements and regimens, glycemic control, cardiovascular outcomes, and safety in the patients treated with insulin at baseline in the Prospective Pioglitazone Clinical Trial in Macrovascular Events study. Design: The Prospective Pioglitazone Clinical Trial in Macrovascular Events study was a double-blind, placebo-controlled outcome study (mean follow-up 34.5 months) in 5238 high-risk patients with type 2 diabetes randomized to Pioglitazone (force titrated to 45 mg) or placebo. One third of the total population (Pioglitazone 864; placebo 896) were receiving insulin at baseline. Results: A rapid and sustained decrease in insulin dose was observed with Pioglitazone vs. a progressive increase with placebo. By study end, the mean insulin dose was lower with Pioglitazone (42 vs. 55 U/d with placebo; P < 0.0001). The insulin regimen (number on insulin, need for multiple injections, and reduction in oral agents) had been simplified vs. placebo; neverthe...
Patrick G Sullivan - One of the best experts on this subject based on the ideXlab platform.
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Pioglitazone attenuates mitochondrial dysfunction cognitive impairment cortical tissue loss and inflammation following traumatic brain injury
Experimental Neurology, 2011Co-Authors: Andrew Sauerbeck, Jianxin Gao, Ryan D Readnower, Mei Liu, James R Pauly, Guoying Bing, Patrick G SullivanAbstract:Following traumatic brain injury (TBI) there is significant neuropathology which includes mitochondrial dysfunction, loss of cortical gray matter, microglial activation, and cognitive impairment. Previous evidence has shown that activation of the peroxisome proliferator-activated receptors (PPARs) provide neuroprotection following traumatic brain and spinal injuries. In the current study we hypothesized that treatment with the PPAR ligand Pioglitazone would promote neuroprotection following a rat controlled cortical impact model of TBI. Animals received a unilateral 1.5mm controlled cortical impact followed by administration of Pioglitazone at 10mg/kg beginning 15min after the injury and subsequently every 24h for 5days. Beginning 1day after the injury there was significant impairment in mitochondrial bioenergetic function which was attenuated by treatments with Pioglitazone at 15min and 24h (p<0.05). In an additional set of animals, cognitive function was assessed using the Morris Water Maze (MWM) and it was observed that over the course of 4days of testing the injury produced a significant increase in both latency (p<0.05) and distance (p<0.05) to the platform. Animals treated with Pioglitazone performed similarly to sham animals and did not exhibit any impairment in MWM performance. Sixteen days after the injury tissue sections through the lesion site were quantified to determine the size of the cortical lesion. Vehicle-treated animals had an average lesion size of 5.09±0.73mm(3) and treatment with Pioglitazone significantly reduced the lesion size by 55% to 2.27±0.27mm(3) (p<0.01). Co-administration of the antagonist T0070907 with Pioglitazone blocked the protective effect seen with administration of Pioglitazone by itself. Following the injury there was a significant increase in the number of activated microglia in the area of the cortex adjacent to the site of the lesion (p<0.05). Treatment with Pioglitazone prevented the increase in the number of activated microglia and no difference was observed between sham and Pioglitazone-treated animals. From these studies we conclude that following TBI Pioglitazone is capable ameliorating multiple aspects of neuropathology. These studies provide further support for the use of PPAR ligands, specifically Pioglitazone, for neuroprotection.