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Evaluation of the Pharmacokinetic Interaction Between Lobeglitazone and Dapagliflozin at Steady State.
Jang, K, Jeon, JY, Moon, SJ, Kim, MG
Clinical therapeutics. 2020;(2):295-304
Abstract
PURPOSE Coadministration of lobeglitazone and dapagliflozin is expected to result in a blood glucose-lowering effect, followed by a gradual increase, in clinical usage; however, combining drugs could cause negative interactions. This study aimed to evaluate the effect of the coadministration of lobeglitazone and dapagliflozin on their individual pharmacokinetic properties at steady state in healthy male volunteers in the fasted state. METHODS This study consisted of 2 parts, each of which was a randomized, open-labeled, multiple-dose, 2-way crossover study in 20 healthy male volunteers in each part. Blood samples were taken periodically over a 48-h period after dosing to derive total plasma lobeglitazone and dapagliflozin pharmacokinetic properties; safety profile was evaluated throughout the study. FINDINGS When the pharmacokinetic properties of dapagliflozin were evaluated following its administration alone and in combination with lobeglitazone, point estimate and 90% CI of the geometric mean ratio of dapagliflozin AUCτ were entirely within the conventional bioequivalence range of 80%-125%. However, although it was not clinically meaningful, its Css,max was ~8% lower in subjects receiving multiple doses of dapagliflozin and lobeglitazone than that in those administered dapagliflozin alone. The pharmacokinetic properties of lobeglitazone were evaluated following its administration alone and in combination with dapagliflozin. The geometric mean ratios and 90% CIs of the lobeglitazone Css,max and AUCτ were within the conventional bioequivalence range of 80%-125%. IMPLICATIONS Coadministration of lobeglitazone and dapagliflozin had no apparent clinically relevant effects on the pharmacokinetic properties of either drug. Based on these findings, it is anticipated that lobeglitazone and dapagliflozin can be coadministered without dose adjustment. ClinicalTrials.gov identifier: NCT03616392.
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Insulin secretion predicts the response to therapy with exenatide plus pioglitazone, but not to basal/bolus insulin in poorly controlled T2DM patients: Results from the Qatar study.
Abdul-Ghani, M, Migahid, O, Megahed, A, Singh, R, Kamal, D, DeFronzo, RA, Jayyousi, A
Diabetes, obesity & metabolism. 2018;(4):1075-1079
Abstract
The present study aims to identify predictors for response to combination therapy with pioglitazone plus exenatide vs basal/bolus insulin therapy in T2DM patients who are poorly controlled with maximum/near-maximum doses of metformin plus a sulfonylurea. Participants in the Qatar study received a 75-g OGTT with measurement of plasma glucose, insulin and C-peptide concentration at baseline and were then randomized to receive either treatment with pioglitazone plus exenatide or basal/bolus insulin therapy for one year. Insulin secretion measured with plasma C-peptide concentration during the OGTT was the strongest predictor of response to combination therapy (HbA1c ≤ 7.0%) with pioglitazone plus exenatide. A 54% increase in 2-hour plasma C-peptide concentration above the fasting level identified subjects who achieved the glycaemic goal (HbA1c < 7.0%) with 82% sensitivity and 79% specificity. Only baseline HbA1c was a predictor of response to basal/bolus insulin therapy. Thus, the increment in 2-hour plasma C-peptide concentration above the fasting level provides a useful tool to identify poorly controlled T2DM patients who can achieve glycaemic control without insulin therapy, and thereby, can be used to individualize antihyperglycaemic therapy in poorly controlled T2DM patients.
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Rationale, Design, and Baseline Characteristics of Beijing Prediabetes Reversion Program: A Randomized Controlled Clinical Trial to Evaluate the Efficacy of Lifestyle Intervention and/or Pioglitazone in Reversion to Normal Glucose Tolerance in Prediabetes.
Luo, Y, Paul, SK, Zhou, X, Chang, C, Chen, W, Guo, X, Yang, J, Ji, L, Wang, H
Journal of diabetes research. 2017;:7602408
Abstract
Background. Patients with prediabetes are at high risk for diabetes and cardiovascular disease (CVD). No study has explored whether intervention could revert prediabetes to normal glycemic status as the primary outcome. Beijing Prediabetes Reversion Program (BPRP) would evaluate whether intensive lifestyle modification and/or pioglitazone could revert prediabetic state to normoglycemia and improve the risk factors of CVD as well. Methods. BPRP is a randomized, multicenter, 2 × 2 factorial design study. Participants diagnosed as prediabetes were randomized into four groups (conventional/intensive lifestyle intervention and 30 mg pioglitazone/placebo) with a three-year follow-up. The primary endpoint was conversion into normal glucose tolerance. The trial would recruit 2000 participants (500 in each arm). Results. Between March 2007 and March 2011, 1945 participants were randomized. At baseline, the individuals were 53 ± 10 years old, with median BMI 26.0 (23.9, 28.2) kg/m2 and HbA1c 5.8 (5.6, 6.1)%. 85% of the participants had IGT and 15% had IFG. Parameters relevant to glucose, lipids, blood pressure, lifestyle, and other metabolic markers were similar between conventional and intensive lifestyle intervention group at baseline. Conclusion. BPRP was the first study to determine if lifestyle modification and/or pioglitazone could revert prediabetic state to normoglycemia in Chinese population. Major baseline parameters were balanced between two lifestyle intervention groups. This trial is registered with www.chictr.org.cn: ChiCTR-PRC-06000005.
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Add on DPP-4 inhibitor alogliptin alone or in combination with pioglitazone improved β-cell function and insulin sensitivity in metformin treated PCOS.
Jensterle, M, Goricar, K, Janez, A
Endocrine research. 2017;(4):261-268
Abstract
PURPOSE Impaired β-cell function remains unaddressed in PCOS. The aim of the study was to evaluate whether dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin (ALO) alone or in combination with pioglitazone (PIO) improves β-cell function along with insulin resistance (IR) in metformin (MET) treated obese women with PCOS with persistent IR. MATERIALS AND METHODS In 12-week randomized study, ALO 25 mg QD (n=15) or ALO 25 mg QD and PIO 30 mg QD (n=15) was added to MET 1000 mg BID in PCOS women (aged 34.4 ± 6.5 years, BMI 39.0 ± 4.9 kg/m2, HOMA-IR 4.82 ± 2.52, mean ± SD). Model derived parameters of glucose homeostasis from the meal tolerance test (MTT) were determined. The ability of the β-cell function was assessed by the adaptation index (AI). RESULTS MET-ALO and MET-ALO-PIO resulted in a significant decrease of HOMA-IR (by 1.6±2.3 (p=0.039) and 2.9±3.3 (p=0.001), respectively) and an increase in insulin sensitivity (IS) after meal ingestion (oral glucose IS) by 31.4±97.5 ml·min-1·m-2 (p=0.007) vs 39.0±58.1 ml·min-1·m-2 (p=0.039), respectively. AI across the entire group was significantly improved from 329.6±200.6 to 442.5±303.9 (p=0.048). CONCLUSIONS ALO alone and in combination with PIO improved IR along with dynamic IS and meal related β-cell function when added to MET treated PCOS.
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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.
Schmitz, JM, Green, CE, Hasan, KM, Vincent, J, Suchting, R, Weaver, MF, Moeller, FG, Narayana, PA, Cunningham, KA, Dineley, KT, et al
Addiction (Abingdon, England). 2017;(10):1861-1868
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Abstract
BACKGROUND AND AIMS 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. DESIGN Two-arm double-blind randomized controlled proof-of-concept pilot trial of PIO or placebo (PLC). SETTING Single-site out-patient treatment research clinic in Houston, TX, USA. PARTICIPANTS 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. INTERVENTION Study medication was dispensed at thrice weekly visits along with once-weekly cognitive behavioral therapy for 12 weeks. MEASUREMENTS 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). FINDINGS 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. CONCLUSIONS 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.
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Effect of pioglitazone on insulin resistance, progression of atherosclerosis and clinical course of coronary heart disease.
Skochko, OV, Kaidashev, IP
Wiadomosci lekarskie (Warsaw, Poland : 1960). 2017;(5):881-890
Abstract
INTRODUCTION Pioglitazone, a medication of thiazolidinedione group, is capable of triggering the peroxisome proliferator-activated receptors (PPAR-γ). Activation of receptor PPAR-γ regulates carbohydrate and lipid metabolism, immune and inflammatory responses in heart tissues. THE AIM Our aim was to study the effect of pioglitazone on insulin resistance, the clinical course of atherosclerosis and coronary heart disease (CHD). MATERIALS AND METHODS The study included 43 patients with coronary artery disease. Patients were divided into the main group - 20 patients, in whom pioglitazone (Pioglar, Ranbaxy, India) was included in the combined therapy at a dose of 15 mg 1 time per day in the morning, and the comparison group - 23 patients receiving standard complex drug therapy over 6 months. Patients underwent clinical examination, ultrasound of neck vessels, study of carbohydrate and lipid metabolism. RESULTS Joining pioglitazone to standard therapy resulted in the reduction of systolic (p<0.05) and diastolic (p<0.05) blood pressure; decrease in the duration of pain attacks (p<0.05); reduction in the frequency of angina attacks (p<0.05); regression of atherosclerosis of the carotid vessels (p<0.05), decrease in the thickness of the intima-media complex (p<0.05). The decline in oral glucose tolerance test (p<0.05), hyperglycemic factor (p<0.05), total cholesterol (p<0.05), and low density lipoproteins (p<0.05) were observed, as well as increased high-density lipoprotein (p<0.05). CONCLUSION Long-term treatment with pioglitazone at low doses against the background of standard therapy contributes to functional and clinical condition of patients, promotes the prevention of atherosclerosis and reduction of insulin resistance, thereby improving the clinical manifestations of coronary heart disease.
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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.
Vaccaro, O, Masulli, M, Nicolucci, A, Bonora, E, Del Prato, S, Maggioni, AP, Rivellese, AA, Squatrito, S, Giorda, CB, Sesti, G, et al
The lancet. Diabetes & endocrinology. 2017;(11):887-897
Abstract
BACKGROUND 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. METHODS 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. FINDINGS 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. INTERPRETATION 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. FUNDING Italian Medicines Agency, Diabete Ricerca, and Italian Diabetes Society.
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Does enhanced insulin sensitivity improve sleep measures in patients with obstructive sleep apnea: a randomized, placebo-controlled pilot study.
Liu, A, Kim, SH, Ariel, D, Abbasi, F, Lamendola, C, Cardell, J, Xu, S, Patel, S, Tomasso, V, Mojaddidi, H, et al
Sleep medicine. 2016;:57-60
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BACKGROUND High fasting insulin levels have been reported to predict development of observed apneas, suggesting that insulin resistance may contribute to the pathogenesis of obstructive sleep apnea (OSA). The aim of this study was to determine whether enhancing insulin sensitivity in individuals with OSA would improve sleep measures. PATIENTS/METHODS Insulin-resistant, nondiabetic individuals with untreated OSA were randomized (2:1) to pioglitazone (45 mg/day) or placebo for eight weeks in this single-blind study. All individuals had repeat measurements pertaining to sleep (overnight polysomnography and functional outcomes of sleep questionnaire) and insulin action (insulin suppression test). RESULTS A total of 45 overweight/obese men and women with moderate/severe OSA were randomized to pioglitazone (n = 30) or placebo (n = 15). Although insulin sensitivity increased 31% among pioglitazone-treated compared with no change among individuals receiving placebo (p <0.001 for between-group difference), no improvement in quantitative or qualitative sleep measurements was observed. CONCLUSIONS Pioglitazone administration increased insulin sensitivity in otherwise untreated individuals with OSA, without any change in polysomnographic sleep measures over an eight-week period. These findings do not support a causal role for insulin resistance in the pathogenesis of OSA.
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Effects of ethinylestradiol-cyproterone acetate vs. pioglitazone-flutamide-metformin on plasma FGF21 levels in adolescent girls with androgen excess.
Díaz, M, Gallego-Escuredo, JM, de Zegher, F, Villarroya, F, Ibáñez, L
Diabetes & metabolism. 2016;(3):196-9
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Pioglitazone treatment enhances the sympathetic nervous system response to oral carbohydrate load in obese individuals with metabolic syndrome.
Straznicky, NE, Grima, MT, Sari, CI, Eikelis, N, Lambert, GW, Nestel, PJ, Richards, K, Dixon, JB, Schlaich, MP, Lambert, EA
Metabolism: clinical and experimental. 2015;(7):797-803
Abstract
CONTEXT Insulin resistance is associated with blunted sympathetic nervous system (SNS) response to carbohydrate ingestion which may contribute to postprandial hypotension and impaired body weight homeostasis. OBJECTIVE This study was conducted to examine the effects of pharmacological insulin sensitization on whole-body norepinephrine kinetics during a standard 75-g oral glucose tolerance test (OGTT) in obese, insulin resistant subjects with metabolic syndrome. METHODS Un-medicated individuals (n=42, mean age 56±0.8 yrs, body mass index 34±0.6 kg/m(2)) were randomised to 12-weeks pioglitazone (PIO, 15 mg for 6 weeks, then 30 mg daily) or placebo using a double-blind, parallel group design. Whole-body norepinephrine kinetics (arterial norepinephrine concentration, calculated spillover and clearance rates), spontaneous cardiac baroreflex sensitivity, heart rate and blood pressure were measured at times 0, 30, 60, 90 and 120 minutes during OGTT. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp (M) and Matsuda index. RESULTS PIO increased clamp derived glucose utilisation by 35% (P<0.001) and there were concurrent reductions in inflammatory status and plasma triglycerides (P<0.05). Fasting norepinephrine kinetic parameters were unaltered. PIO treatment was associated with lower plasma insulin incursions, greater reduction in diastolic blood pressure and enhanced baroreflex sensitivity during OGTT (P all <0.05). The overall norepinephrine spillover response (AUC(0-120)) increased significantly in the PIO group (group × time interaction, P=0.04), with greatest increment at 30 minutes post-glucose (101±38 ng/min at baseline versus 241±48 ng/min post treatment, P=0.04) and correlated with percent improvement in M. CONCLUSIONS PIO enhances the early postprandial SNS response to carbohydrate ingestion.