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Lobeglitazone and pioglitazone as add-ons to metformin for patients with type 2 diabetes: a 24-week, multicentre, randomized, double-blind, parallel-group, active-controlled, phase III clinical trial with a 28-week extension.
Jin, SM, Park, CY, Cho, YM, Ku, BJ, Ahn, CW, Cha, BS, Min, KW, Sung, YA, Baik, SH, Lee, KW, et al
Diabetes, obesity & metabolism. 2015;(6):599-602
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Abstract
We aimed to compare the efficacy and safety of lobeglitazone and pioglitazone as add-ons to metformin in patients with type 2 diabetes. Patients who were inadequately controlled by metformin were randomized and treated once daily with either lobeglitazone (0.5 mg, n = 128) or pioglitazone (15 mg, n = 125) for 24 weeks, with a 28-week extension trial of lobeglitazone treatment in patients who consented. The primary endpoint was the change in glycated haemoglobin (HbA1c) concentration from baseline to week 24. At week 24, the mean change from baseline in HbA1c was -0.74% for the lobeglitazone group and -0.74% for the pioglitazone group, with a mean difference of 0.01% [95% confidence interval (CI) of difference, -0.16 to 0.18]. The effects of lobeglitazone on lipid variables and the adverse events associated with lobeglitazone were similar to those observed with pioglitazone. Lobeglitazone was not inferior to pioglitazone as an add-on to metformin in terms of their efficacy and safety.
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Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone.
Forst, T, Guthrie, R, Goldenberg, R, Yee, J, Vijapurkar, U, Meininger, G, Stein, P
Diabetes, obesity & metabolism. 2014;(5):467-77
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Abstract
AIM: The efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, was evaluated in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and pioglitazone. METHODS In this randomized, double-blind, phase 3 study, patients (N = 342) received canagliflozin 100 or 300 mg during a 26-week, placebo-controlled, core period and a 26-week, active-controlled extension in which placebo-treated patients were switched to sitagliptin 100 mg. Efficacy comparisons for canagliflozin versus placebo at week 26 are reported, with no comparisons versus sitagliptin at week 52 (sitagliptin used to maintain double-blind and control for safety). Safety data are reported for canagliflozin and placebo/sitagliptin. RESULTS Canagliflozin 100 and 300 mg significantly lowered haemoglobin A1c (HbA1c) compared with placebo at week 26 (-0.89%, -1.03% and -0.26%; p < 0.001); reductions with canagliflozin 100 and 300 mg were maintained at week 52 (-0.92% and -1.03%). Relative to placebo, both canagliflozin doses significantly reduced body weight (-2.5 and -3.5 kg), fasting plasma glucose and systolic blood pressure (BP) at week 26 (p < 0.05 for all), with reductions maintained at week 52. Overall adverse event (AE) incidence over 52 weeks was 69.9, 76.3 and 76.5% with canagliflozin 100 and 300 mg and placebo/sitagliptin; AE-related discontinuation and serious AE rates were low. Incidences of genital mycotic infections and AEs related to osmotic diuresis and volume depletion were higher with canagliflozin than placebo/sitagliptin. CONCLUSION Canagliflozin improved glycaemic control, reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM on metformin and pioglitazone over 52 weeks.
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Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial.
Kovacs, CS, Seshiah, V, Swallow, R, Jones, R, Rattunde, H, Woerle, HJ, Broedl, UC, ,
Diabetes, obesity & metabolism. 2014;(2):147-58
Abstract
AIMS: This study investigated the efficacy and tolerability of empagliflozin as add-on to pioglitazone ± metformin in patients with type 2 diabetes (T2DM). METHODS Patients with HbA1c ≥7 and ≤10% were randomized and treated with once daily empagliflozin 10 mg (n = 165), empagliflozin 25 mg (n = 168) or placebo (n = 165) as add-on to pioglitazone ± metformin for 24 weeks. Endpoints included changes from baseline in HbA1c (primary endpoint), fasting plasma glucose (FPG) and body weight at week 24. RESULTS Adjusted mean ± standard error changes in HbA1c were -0.6 ± 0.07% and -0.7 ± 0.07% with empagliflozin 10 mg and 25 mg, respectively, vs. -0.1 ± 0.07% with placebo (both p < 0.001). More patients with HbA1c ≥7% at baseline achieved HbA1c <7% with empagliflozin 10 mg (23.8%) and 25 mg (30.0%) vs. placebo (7.7%) (both p < 0.001). FPG decreased with empagliflozin (-0.94 mmol/l for 10 mg and -1.22 mmol/l for 25 mg) and increased with placebo (+0.36 mmol/l; both p < 0.001). Adjusted mean ± standard error changes in weight were -1.62 ± 0.21 kg and -1.47 ± 0.21 kg with empagliflozin 10 mg and 25 mg, respectively, vs. +0.34 ± 0.21 kg with placebo (both p < 0.001). Similar proportions of patients reported adverse events with empagliflozin (67.3-71.4%) and placebo (72.7%). Confirmed hypoglycaemia was reported by 1.2-2.4% of patients on empagliflozin and 1.8% on placebo. CONCLUSION Empagliflozin 10 mg and 25 mg once daily for 24 weeks as add-on to pioglitazone ± metformin reduced HbA1c, FPG and weight and were well tolerated in patients with T2DM.
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Effects of rosiglitazone on serum paraoxonase activity and metabolic parameters in patients with type 2 diabetes mellitus.
Atamer, Y, Atamer, A, Can, AS, Hekimoğlu, A, Ilhan, N, Yenice, N, Koçyiğit, Y
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas. 2013;(6):528-32
Abstract
Human serum paraoxonase contributes to the anti-atherogenic effect of high-density lipoprotein cholesterol (HDL-C) and has been shown to protect both low-density lipoprotein cholesterol (LDL-C) and HDL-C against lipid peroxidation. We investigated the effects of rosiglitazone on paraoxonase activity and metabolic parameters in patients with type 2 diabetes mellitus [50 patients (30 males, 20 females); mean ± SD age: 58.7 ± 9.2 years, body mass index: 28.2 ± 4.1'kg/m2], in whom glucose control could not be achieved despite treatment with metformin, sulphonylurea, and/or insulin. The patients were given 4'mg/day rosiglitazone for 3 months in addition to their usual treatment. Serum paraoxonase activity, malondialdehyde, homocysteine, and lipid profile were measured at the time of initiation and at the end of therapy with rosiglitazone. After rosiglitazone therapy, serum levels of HDL-C, apolipoprotein A-1, and paraoxonase activity increased significantly (P<0.05) and malondialdehyde, homocysteine, lipoprotein(a), and glucose levels decreased significantly (P<0.05), but no significant changes in levels of total cholesterol and apolipoprotein B were observed. Triglyceride levels also increased significantly (P<0.05). Rosiglitazone treatment led to an improvement in glycemic control and to an increase in paraoxonase activity and HDL-C levels. Although rosiglitazone showed favorable effects on oxidant/antioxidant balance and lipid profile, further studies are needed to determine the effect of rosiglitazone on cardiovascular risk factors and cardiovascular morbidity and mortality.
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Clinical effect of addition of beraprost sodium to pioglitazone treatment on the blood glucose levels in patients with type 2 diabetes mellitus.
Chen, T, Kusunoki, M, Sato, D, Tsutsui, H, Nakamura, T, Miyata, T, Oshida, Y
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2013;(10):624-7
Abstract
In recent years, the number of patients with type 2 diabetes mellitus caused by insulin resistance has continued to increase in Japan. Insulin resistance is considered to be closely related to the risk of cardiovascular diseases and atherosclerotic diseases, represented by arteriosclerosis obliterans (ASO). Therefore, improvement of insulin resistance is one of the important strategies in the treatment of type 2 diabetes mellitus. At present, α-glucosidase inhibitors, incretin-related drugs, and thiazolidinediones are among the most important oral hypoglycemic drugs used to improve insulin resistance. In this study, the effect of beraprost sodium, a prostaglandin I2 derivative, in the treatment of type 2 diabetes mellitus was investigated. In type 2 diabetic patients with ASO who were under treatment with pioglitazone, additional treatment with beraprost sodium exerted a significant synergistic effect in reducing the serum HbA1c levels as compared to treatment with pioglitazone alone. This result indicates that concomitant administration of pioglitazone and beraprost sodium may be useful in the treatment of diabetes -mellitus.
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PPAR-γ2 and PTPRD gene polymorphisms influence type 2 diabetes patients' response to pioglitazone in China.
Pei, Q, Huang, Q, Yang, GP, Zhao, YC, Yin, JY, Song, M, Zheng, Y, Mo, ZH, Zhou, HH, Liu, ZQ
Acta pharmacologica Sinica. 2013;(2):255-61
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Abstract
AIM: To investigate the influence of peroxisome proliferator-activated receptor γ2 (PPAR-γ2) gene polymorphism rs1801282 and protein tyrosine phosphatase receptor type D (PTPRD) gene polymorphism rs17584499 on the occurrence of type 2 diabetes and pioglitazone efficacy in a Chinese Han population. METHODS One hundred ninety seven type 2 diabetes patients and 212 healthy controls were enrolled. Among them, 67 type 2 diabetes patients were administered pioglitazone (30 mg/d, po) for 3 months. All the subjects were genotyped for genetic variants in PPAR-γ2 and PTPRD using MALDI-TOF mass spectrometry. Fasting plasma glucose, postprandial plasma glucose, glycated hemoglobin, serum triglyceride, total cholesterol, low-density and high-density lipoprotein-cholesterol were determined. RESULTS The PPAR-γ2 gene rs1801282 polymorphism was significantly associated with type 2 diabetes susceptibility (OR=0.515, 95% CI 0.268-0.990) and the PTPRD gene rs17584499 polymorphism was also significantly associated with type 2 diabetes (OR=1.984, 95% CI 1.135-3.469) in a dominant model adjusted for age, gender and BMI. After pioglitazone treatment for 3 months, the type 2 diabetes patients with PPAR-γ2 rs1801282 CG genotypes significantly showed higher differential values of postprandial plasma glucose and serum triglyceride compared with those with rs1801282 CC genotype. The patients with PTPRD rs17584499 CT+TT genotypes showed significantly lower differential value of postprandial plasma glucose compared to those with rs17584499 CC genotype. CONCLUSION Diabetes risk alleles in PPAR-γ2 (rs1801282) and PTPRD (rs17584499) are associated with pioglitazone therapeutic efficacy.
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Influence of CYP2C8*2 on the pharmacokinetics of pioglitazone in healthy African-American volunteers.
Aquilante, CL, Wempe, MF, Spencer, SH, Kosmiski, LA, Predhomme, JA, Sidhom, MS
Pharmacotherapy. 2013;(9):1000-7
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Abstract
STUDY OBJECTIVES To determine the influence of the Cytochrome P450 (CYP) 2C8*2 polymorphism on pioglitazone pharmacokinetics in healthy African-American volunteers. DESIGN Prospective, open-label, single-dose pharmacokinetic study. SETTING University of Colorado Hospital Clinical and Translational Research Center. PARTICIPANTS Healthy African-American volunteers between 21 and 60 years of age were enrolled in the study based on CYP2C8 genotype: CYP2C8*1/*1 (9 participants), CYP2C8*1/*2 (7 participants), and CYP2C8*2/*2 (1 participant). INTERVENTION Participants received a single 15-mg dose of pioglitazone in the fasted state, followed by a 48-hour pharmacokinetic study. MEASUREMENTS AND MAIN RESULTS Plasma concentrations of pioglitazone and its M-III (keto) and M-IV (hydroxy) metabolites were compared between participants with the CYP2C8*1/*1 genotype and CYP2C8*2 carriers. Pioglitazone area under the plasma concentration-time curve (AUC)0-∞ and half-life (t1/2 ) did not differ significantly between CYP2C8*1/*1 and CYP2C8*2 carriers (AUC0-∞ 7331 ± 2846 vs 10431 ± 5090 ng*h/ml, p=0.15, t1/2 7.4 ± 2.7 vs 10.5 ± 4.0 h, p=0.07). M-III and M-IV AUC0-48 also did not differ significantly between genotype groups. However, the M-III:pioglitazone AUC0-48 ratio was significantly lower in CYP2C8*2 carriers than CYP2C8*1 homozygotes (0.70 ± 0.15 vs 1.2 ± 0.37, p=0.006). Similarly, CYP2C8*2 carriers had a significantly lower M-III:M-IV AUC0-48 ratio than participants with the CYP2C8*1/*1 genotype (0.82 ± 0.26 vs 1.22 ± 0.26, p=0.006). CONCLUSION These data suggest that CYP2C8*2 influences pioglitazone pharmacokinetics in vivo, particularly the AUC0-48 ratio of M-III:parent drug, and the AUC0-48 ratio of M-III:M-IV. Larger studies are needed to further investigate the impact of CYP2C8*2 on the pharmacokinetics of CYP2C8 substrates in individuals of African descent.
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Serum A-FABP is increased and closely associated with elevated NT-proBNP levels in type 2 diabetic patients treated with rosiglitazone.
Zhou, M, Bao, Y, Lu, J, Zhou, J, Jia, W
PloS one. 2011;(10):e27032
Abstract
BACKGROUND Adipocyte fatty acid-binding protein (A-FABP) has been shown to play important roles in the development of metabolic syndrome, diabetes, and cardiovascular diseases. In this study we investigated the possible role of A-FABP in the development of cardiac dysfunction related to rosiglitazone treatment. METHODOLOGY/PRINCIPAL FINDINGS A total of 84 patients with newly diagnosed type 2 diabetes were treated with rosiglitazone for 48 weeks. Circulating A-FABP and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were determined at baseline and repeated at 24 and 48 weeks. After the 48-week rosiglitazone treatment period, serum levels of both A-FABP and NT-proBNP increased progressively and significantly (P<0.01). Serum levels of A-FABP were demonstrated to be positively correlated with gender and waist circumference both at baseline and the end of the study, and with age, body mass index (BMI), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and NT-proBNP at 48 weeks (all P<0.05). In addition, changes in A-FABP were significantly and positively correlated with changes in NT-proBNP (r = 0.239, P = 0.039). Furthermore, multiple stepwise regression analysis showed that the changes in A-FABP were independently and positively associated with changes in NT-proBNP after adjusting for confounding factors (β = 0.320, P = 0.007). CONCLUSIONS/SIGNIFICANCE Rosiglitazone-mediated increase of A-FABP is closely associated with the elevation of NT-proBNP, a well-established marker of cardiac dysfunction. The findings of our study imply that A-FABP may mediate the cross-talk between heart and adipose tissue.
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Effect of pretreatment with pioglitazone on reperfusion injury in diabetic patients with acute myocardial infarction.
Kataoka, Y, Yagi, N, Kokubu, N, Kasahara, Y, Abe, M, Otsuka, Y
Circulation journal : official journal of the Japanese Circulation Society. 2011;(8):1968-74
Abstract
BACKGROUND Pioglitazone (PIO) is a new class of anti-diabetic agent with an anti-inflammatory effect. In the experimental studies, pretreatment with PIO before ischemia/reperfusion reduced ischemia-reperfusion injury and myocardial infarct size. However, the clinical efficacy of this therapy in patients with acute myocardial infarction (AMI) remains unknown. METHODS AND RESULTS Three hundred and nineteen diabetic patients with ST-segment elevation AMI, treated with bare metal stent within 24h from the onset of AMI were examined. Myocardial blush grade, ST-segment resolution, peak creatine kinase (CK) level, and left ventricular ejection fraction (LVEF) were compared between PIO group (pretreatment with PIO [+]; n=26) and non-PIO group (pretreatment with PIO [-]; n=293). The PIO group showed a significantly higher incidence of blush score ≥ 2 and complete ST-segment resolution (blush score ≥ 2; 38% vs. 71%, P=0.04, ST-segment resolution; 44% vs. 71%, P=0.04). Besides, slow flow/no-reflow phenomenon and reperfusion arrhythmia did not occur in this group. Better improvement of LVEF and lower peak CK level was observed in this group, although these were not statistically significant (LVEF 48% vs. 41%, P=0.10, peak CK level 2,041 vs. 3,207, P=0.06). CONCLUSIONS Pretreatment with PIO in diabetic patients with AMI resulted in better myocardial perfusion with less reperfusion injury.
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Fat redistribution preferentially reflects the anti-inflammatory benefits of pioglitazone treatment.
Moon, JH, Kim, HJ, Kim, SK, Kang, ES, Lee, BW, Ahn, CW, Lee, HC, Cha, BS
Metabolism: clinical and experimental. 2011;(2):165-72
Abstract
Thiazoledinedione is known to have an anti-inflammatory effect besides a hypoglycemic effect. We investigated changes in high-sensitivity C-reactive protein (hsCRP), a proinflammatory marker, after pioglitazone treatment in association with the resulting changes in various metabolic and anthropometric parameters. A total of 93 type 2 diabetes mellitus patients (47 men and 46 women; mean age, 50.0 ± 10.8 years) who were being treated with a stable dose of sulfonylurea or metformin were enrolled in the study. Pioglitazone (15 mg/d) was added to their treatment regimen for 12 weeks, and metabolic and anthropometric measurements were taken before and after pioglitazone treatment. Pioglitazone treatment for 12 weeks decreased serum hsCRP levels (0.83 [1.14] to 0.52 [0.82] mg/L, P < .001) and improved glycemic control (fasting glucose, P < .001; glycosylated hemoglobin, P < .001) and lipid profiles (triglyceride, P = .016; high-density lipoprotein cholesterol, P < .001). Between responders and nonresponders to the hsCRP-lowering effect of pioglitazone, there were significant differences in baseline hsCRP levels and changes in the postprandial glucose and the ratio of visceral fat thickness (VFT) to subcutaneous fat thickness (SFT) (P = .004, .011, and .001, respectively). The percentage change in hsCRP levels after treatment was inversely correlated with baseline hsCRP levels (r = -0.497, P < .001) and directly correlated with the change in postprandial glucose (r = 0.251, P = .021), VFT (r = 0.246, P = .030), and VFT/SFT ratio (r = 0.276, P = .015). Logistic regression analysis revealed that the hsCRP-lowering effect of pioglitazone was affected by baseline hsCRP levels (odds ratio [OR] = 7.929, P = .007) as well as changes in postprandial 2-hour glucose (OR = 0.716, P = .025) and VFT/SFT ratio (OR = 0.055, P = .009). In conclusion, treatment with pioglitazone produced an anti-inflammatory effect, decreasing serum hsCRP levels; and a decrease in the VFT/SFT ratio was independently and most strongly associated with the hsCRP-decreasing effect. These results suggest that abdominal fat redistribution preferentially reflects the anti-inflammatory benefits of pioglitazone treatment.