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PubMed2004

Pioglitazone in the management of diabetes mellitus after transplantation.

Type 2 diabetes mellitus is a common problem in patients after solid organ transplantation. We studied the safety and efficacy of pioglitazone therapy in this setting. Ten patients with diabetes mellitus treated with insulin or glyburide after transplantation were studied after the addition of the thiazolidinedione pioglitazone. Serum creatinine, HBA1C, total daily insulin dose, tacrolimus dose, tacrolimus level and prednisone dose were followed for a mean of 242 days and compared to the corresponding values measured before the initiation of pioglitazone. The addition of pioglitazone caused no significant changes in serum creatinine or mean tacrolimus dose, and caused decreases in HBA1C (8.36%+/- 1.5% pre-pioglitazone, 7.08%+/- 1.5% post-pioglitazone, p = 0.018) and total daily insulin dose (125.1 +/- 28.1 units pre-pioglitazone, 80.6 +/- 22.8 units post-pioglitazone, p = 0.002). Our preliminary study suggests that pioglitazone is a safe and effective oral agent for the management of diabetes mellitus after transplantation.

Adult↗
PubMed2006

Limited therapeutic efficacy of pioglitazone on progression of hepatic fibrosis in rats.

AIM: Peroxisome proliferator activated receptor gamma (PPARgamma) agonists have been shown to prevent hepatic fibrosis in rodents. We evaluated the therapeutic antifibrotic potential of the PPARgamma agonist pioglitazone on established hepatic fibrosis. METHODS: Repeated injections of carbon tetrachloride (CCl4), a choline deficient diet, or bile duct ligation (BDL) were used to induce hepatic fibrosis in rats. Pioglitazone treatment was introduced at various time points. Therapeutic efficacy was assessed by comparison of the severity of hepatic fibrosis in pioglitazone treated versus untreated fibrotic controls. RESULTS: When introduced after two weeks of CCl4, pioglitazone reduced hepatic fibrosis, OH proline content, hepatic mRNA expression of collagen type I, and profibrotic genes, as well as the number of activated alpha smooth muscle actin positive hepatic stellate cells, compared with rats receiving CCl4 only, with no significant change in necroinflammation. When pioglitazone treatment was initiated after five weeks of CCl4, no antifibrotic effect was observed. Similarly, pioglitazone was associated with a reduced severity of fibrosis induced by a choline deficient diet when introduced early, while delayed treatment with pioglitazone remained ineffective. In contrast, pioglitazone failed to interrupt progression of fibrosis due to BDL, irrespective of the timing of its administration. CONCLUSION: In rats, the therapeutic antifibrotic efficacy of pioglitazone is limited and dependent on the type of injury, duration of disease, and/or the severity of fibrosis at the time of initiation of treatment.

Animals↗
PubMed2003

Pioglitazone inhibits LOX-1 expression in human coronary artery endothelial cells by reducing intracellular superoxide radical generation.

OBJECTIVE: LOX-1, a novel lectin-like receptor for oxidized LDL (ox-LDL), is expressed in response to ox-LDL, angiotensin II (Ang II), tumor necrosis factor (TNF)-alpha, and other stress stimuli. It is highly expressed in atherosclerotic tissues. Peroxisome proliferator-activated receptor (PPAR)-gamma ligands, such as pioglitazone, exert antiatherosclerotic effects. This study examined the regulation of LOX-1 expression in human coronary artery endothelial cells (HCAECs) by pioglitazone. METHODS AND RESULTS: Fourth generation HCAECs were treated with ox-LDL, Ang II, or TNF-alpha with or without pioglitazone pretreatment. All 3 stimuli upregulated LOX-1 expression (mRNA and protein). Pioglitazone, in a concentration-dependent manner, reduced LOX-1 expression (P<0.01 versus ox-LDL, Ang II, or TNF-alpha alone). Ox-LDL, Ang II, and TNF-alpha each enhanced intracellular superoxide radical generation, and pioglitazone pretreatment reduced superoxide generation (P<0.01 versus ox-LDL, Ang II, or TNF-alpha). Furthermore, all 3 stimuli upregulated the expression of the transcription factors nuclear factor-kappaB and activator protein-1 (determined by electrophoretic mobility shift assay), and pioglitazone pretreatment reduced this expression (P<0.01 versus ox-LDL, Ang II, or TNF-alpha). To determine the biological significance of pioglitazone-mediated downregulation of LOX-1, we studied monocyte adhesion to ox-LDL-treated HCAECs. Pioglitazone reduced the adhesion of monocytes to activated HCAECs in a fashion similar to that produced by antisense to LOX-1 mRNA. CONCLUSIONS: These observations suggest that the PPAR-gamma ligand pioglitazone reduces intracellular superoxide radical generation and subsequently reduces the expression of transcription factors, expression of the LOX-1 gene, and monocyte adhesion to activated endothelium. The salutary effect of PPAR-gamma ligands in atherogenesis may involve the inhibition of LOX-1 and the adhesion of monocytes to endothelium.

Angiotensin II↗
PubMed2003

Pioglitazone prevents hypertension and reduces oxidative stress in diet-induced obesity.

The objective of this study was to determine the effect of pioglitazone on blood pressure (BP) and oxidative balance in obese, hypertensive, Sprague-Dawley rats and to identify some of the molecular mechanisms involved. After 12 weeks of a moderately high-fat diet, rats diverged into obesity-prone (OP) and obesity-resistant (OR) groups (n=6 per group). At the end of the diet, peroxisome proliferator activated receptor-gamma (PPARgamma) mRNA expression and activity in the renal cortex and medulla of OP rats were significantly lower compared with that in OR rats. Pioglitazone treatment increased PPARgamma expression and activity in OP rats, suggesting a possible direct ligand-related effect of pioglitazone. As opposed to the untreated OP group, which showed moderate hypertension (systolic BP=159+/-5.3 mm Hg) after 12 weeks, pioglitazone-treated rats were normotensive (systolic BP=123.9+/-2.7 mm Hg). Insulin production was reduced by 2-fold in the OP group treated with pioglitazone. Urinary isoprostanes and renal lipid peroxides were also reduced in OP rats treated with pioglitazone compared with untreated counterparts. Also, expression of p47phox and gp91phox, both increased in OP versus OR rats, was reduced in the former by pioglitazone treatment. In addition, pioglitazone treatment increased nitrate/nitrite excretion and expression of renal endothelial and neuronal nitric oxide synthase. Collectively, the results show that pioglitazone treatment prevented hypertension and renal oxidative stress both by reducing free-radical production and by increasing nitric oxide production/availability.

Animals↗
PubMed2001

Pioglitazone: a review of Japanese clinical studies.

Pioglitazone, a new thiazolidinedione agent,has been shown to increase insulin sensitivity in clinical trials. Pioglitazone HCI was rapidly absorbed within one hour, achieved peak concentrations at 2-3 h, and was eliminated from serum at 24-36 h. Pioglitazone demonstrated dose-dependent pharmacokinetics. Food did not significantly affect the pharmacokinetic profile of pioglitazone. The pharmacokinetic profile of sulfonylurea agents was not significantly altered by concurrent administration with pioglitazone. Pharmacokinetic studies in healthy volunteers and in patients with type 2 diabetes indicated that pioglitazone may be administered once daily. In patients with type 2 diabetes, pioglitazone as monotherapy and in combination with sulfonylureas or an alpha-glucosidase inhibitor significantly reduced fasting blood glucose, HbA1c, triglycerides, and free fatty acids, and significantly increased HDL-cholesterol. Pioglitazone demonstrated either minor increases or decreases in cholesterol with no adverse effect on LDL-cholesterol. No patients experienced jaundice or ALT elevations > or = three times the upper limit of normal. Adverse events were mild and transient; all subjects returned to their baseline health status or laboratory tests upon withdrawal from, or completion of, the studies. Based upon these preliminary studies, full-scale clinical investigations were conducted in Japan, the United States, and Europe. As a result, in many countries pioglitazone has gained approval for use in patients with type 2 diabetes.

Clinical Trials as Topic↗
PubMed2006

Glimepiride versus pioglitazone combination therapy in subjects with type 2 diabetes inadequately controlled on metformin monotherapy: results of a randomized clinical trial.

OBJECTIVE: To compare the effect of add-on glimepiride or pioglitazone in subjects with type 2 diabetes inadequately controlled on metformin monotherapy. RESEARCH DESIGN AND METHODS: Multicenter, randomized, parallel-group, open-label, forcedtitration study involving 203 adults with poorly controlled type 2 diabetes (A1C 7.5-10%) on metformin monotherapy. Subjects were randomized to receive glimepiride or pioglitazone, titrated to the maximum dose for 26 weeks. Subjects were evaluated for A1C changes, fasting plasma glucose (FPG), insulin, C-peptide, and lipid levels. Safety outcomes and diabetes-related healthcare resource utilization were also evaluated. RESULTS: Both treatment groups achieved similar and significant mean decreases from baseline to endpoint (week 26) in A1C (p = 0.0001) and FPG (p < 0.05). Glimepiride therapy, however, resulted in a more rapid decline in A1C levels at weeks 6, 12, and 20 vs. pioglitazone (p < 0.05). A mean A1C < or = 7% was reached faster in the glimepiride group (median, 80-90 days vs. 140-150 days [p = 0.024]). Total and LDL cholesterol were significantly higher with pioglitazone treatment than with glimepiride at endpoint (p < 0.05). Glimepiride treatment was associated with an increased risk of hypoglycemia and pioglitazone with higher rate of peripheral edema. Healthcare resource utilization was similar between groups, but total healthcare costs were significantly lower for glimepiride versus pioglitazone over the course of the study, driven largely by drug costs. The use of fasting C-peptide concentration > or = 0.27 nmol/L in the inclusion criteria was a potential limitation as it may have included those patients with an improved probability for glimepiride or pioglitazone response. In addition, a larger patient population would have provided a greater degree of data applicability. CONCLUSIONS: In patients with type 2 diabetes inadequately controlled on metformin monotherapy, add-on glimepiride or pioglitazone results in similar overall improvements in glycemic control. Compared with pioglitazone, glimepiride is associated with faster glycemic control, lower total and LDL cholesterol levels and reduced short-term healthcare costs.

Adolescent↗
PubMed2006

A fixed-dose combination of pioglitazone and metformin: A promising alternative in metabolic control.

BACKGROUND: When type 2 diabetes is managed with glucose-lowering monotherapy, glycemic control ultimately deteriorates due to the inability of the beta-cell to overcome insulin resistance. Combining drugs with different complementary mechanisms of action improves long-term glycemic control and may lower the risk of vascular complications. A fixed-dose combination of pioglitazone (a thiazolidinedione) and metformin has been approved for use in the US (Actoplus met) and in Europe (Competact). SCOPE: This review (based upon MEDLINE and EMBASE searches from January 1990 to April 2006) discusses the potential benefits of co-formulating metformin and pioglitazone with respect to compliance and targeting glycemia, as well as other metabolic parameters. FINDINGS: Pioglitazone increases insulin sensitivity, while metformin reduces hepatic gluconeogenesis and improves peripheral glucose uptake. Both agents reduce hyperglycemia and hyperinsulinemia, and appear to protect beta-cell function. Their similar pharmacokinetic time profiles have facilitated a co-formulation bioequivalent to their separate administration. In randomized studies, pioglitazone and metformin administered separately provided significantly better glycemic control than metformin monotherapy or metformin plus gliclazide. Pioglitazone and metformin have complimentary benefits on diabetic dyslipidemia; pioglitazone primarily improves high-density lipoprotein cholesterol and triglyceride levels (to a greater extent than rosiglitazone does), while metformin mainly improves total cholesterol. Pioglitazone and metformin also modulate other atherosclerosis biomarkers, including inflammatory mediators, coagulation thrombosis components, and carotid intima media thickness. Together, these pleiotropic effects have the potential to confer a reduced risk of cardiovascular disease in patients with type 2 diabetes. Pioglitazone and metformin are well tolerated in combination, with low rates of hypoglycemia, and the convenience of a single tablet may be expected to aid dosing compliance. CONCLUSION: The co-formulation of pioglitazone and metformin is a rational approach that maximizes the established, complimentary benefits of these agents, while potentially improving compliance.

Cardiovascular Diseases↗
PubMed2002

Effects of pioglitazone in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study.

Hypertension is often associated with insulin resistance, dyslipidemia and obesity, which indicate a prediabetic state and increased risk of cardiovascular disease. Pioglitazone treatment of patients with type 2 diabetes reduces insulin resistance and improves lipid profiles. The present double-blind placebo-controlled study is the first study to report effects of pioglitazone in non-diabetic patients with arterial hypertension. Following a one week run-in, 60 patients were randomized to receive either pioglitazone (45 mg/day) or placebo for 16 weeks. Insulin sensitivity (M-value) increased by 1.2 +/- 1.7 mg/min/kg with pioglitazone compared with 0.4 +/- 1.4 mg/min/kg (P = 0.022) with placebo. HOMA index was decreased (-22.5 +/- 45.8) by pioglitazone but not by placebo (+0.8 +/- 26.5; P < 0.001). Decreases in fasting insulin and glucose were significantly (P = 0.002 and P = 0.004, respectively) greater with pioglitazone than placebo. Body weight did not change significantly with either treatment. HDL-cholesterol was increased and apolipoprotein B was decreased to a significantly greater extent with pioglitazone. There was a significantly (P = 0.016) greater decrease from baseline in diastolic blood pressure with pioglitazone. These changes would suggest improved glucose metabolism and a possible reduction in risk of cardiovascular disease with pioglitazone treatment of non-diabetic patients with arterial hypertension.

Apolipoproteins B↗
PubMed2004

Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a double-blind, randomized trial.

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.

Adult↗
PubMed2003

Analysis of the relationship between the Pro12Ala variant in the PPAR-gamma2 gene and the response rate to therapy with pioglitazone in patients with type 2 diabetes.

OBJECTIVE: To investigate the influence of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) gene variants on the response rate to therapy with the thiazolidinedione (TZD) pioglitazone, because in vitro studies have suggested that genetic variants of the PPAR-gamma gene may influence the drug efficacy of TZD. RESEARCH DESIGN AND METHODS: A total of 131 patients were treated in an open-label, randomized, multicenter study with pioglitazone (45 mg o.d.) during a course of >or=26 weeks. Response to the pioglitazone therapy was defined by either a >20% decrease in fasting plasma glucose or a >15% decrease in HbA(1c) values after 26 weeks of pioglitazone treatment. We evaluated the association between the PPAR-gamma genotype and the response rate to pioglitazone treatment. RESULTS: The Pro12Ala and the Pro12Pro variants in the PPAR-gamma gene are not associated with the response rate to pioglitazone treatment in patients with type 2 diabetes. However, we identified initial fasting plasma glucose level >11.0 mmol/l, HbA(1c) value >9.0%, BMI >32 kg/m(2), and fasting C-peptide concentrations at baseline >2.5 pmol/l as predominant confounding factors for the responder frequency to pioglitazone treatment. CONCLUSIONS: The Pro12Ala variant in the PPAR-gamma gene does not affect the therapy efficacy of pioglitazone, suggesting that the drug-treatment response is independent from pharmacogenetic effects between PPAR-gamma and its ligand pioglitazone. Whether the Ala12Ala genotype plays a role in the response rate to TZD therapy remains to be determined.

Aged↗
PubMed2004

One-year glycemic control with a sulfonylurea plus pioglitazone versus a sulfonylurea plus metformin in patients with type 2 diabetes.

OBJECTIVE: The goal was to assess the 1-year efficacy and safety of the addition of pioglitazone or metformin to existing sulfonylurea (SU) therapy in patients with inadequately controlled type 2 diabetes. RESEARCH DESIGN AND METHODS: In this multicenter, double-blind study, patients were randomized to receive either pioglitazone 15 mg (n = 319) or metformin 850 mg (n = 320) and up to 45 mg/day and 2,550 mg/day, respectively. The primary efficacy endpoint was HbA(1c) at week 52. Fasting plasma glucose, insulin, and lipid profiles were also measured. RESULTS: HbA(1c) was reduced by 1.20% in the SU plus pioglitazone group and 1.36% in the SU plus metformin group, and fasting plasma glucose was reduced by 2.2 and 2.3 mmol/l in the respective groups. Fasting insulin levels were also reduced (pioglitazone arm -1.3 micro IU/ml; metformin arm -0.8 micro IU/ml). There were no significant between-treatment differences in these three parameters. Pioglitazone addition to SU significantly reduced triglycerides (-16 vs. -9%; P = 0.008) and increased HDL cholesterol (14 vs. 8%; P < 0.001) compared with metformin addition. LDL cholesterol was increased 2% by the addition of pioglitazone and decreased 5% by the addition of metformin to SU (P < 0.001). Urinary albumin-to-creatinine ratio was reduced by 15% in the SU plus pioglitazone group and increased 2% in the SU plus metformin group (P = 0.017). Both combinations were well tolerated with no evidence of hepatic or cardiac toxicity in either group. CONCLUSIONS: Clinically equivalent improvements in glycemic control were observed for both combinations. Compared with metformin plus SU, addition of pioglitazone to SU resulted in a reduction of the urinary albumin-to-creatinine ratio, a small but significant rise in LDL cholesterol, and significantly greater improvements in triglyceride levels and HDL cholesterol levels. Metformin plus SU was associated with a significant reduction in LDL cholesterol. SU plus pioglitazone is an effective and well-tolerated combination regimen that may provide additional beneficial effects for patients with type 2 diabetes.

Adult↗
PubMed2004

The effect of pioglitazone on peroxisome proliferator-activated receptor-gamma target genes related to lipid storage in vivo.

OBJECTIVE: Pioglitazone is a member of the thiazolidinediones (TZDs), insulin-sensitizing agents used to treat type 2 diabetes. The aim of this study was to define the effect of pioglitazone on the expression of genes related to carbohydrate and lipid metabolism in subcutaneous fat obtained from type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Forty-eight volunteers with type 2 diabetes were divided into two groups treated for 12 weeks with placebo or pioglitazone (30 mg/day). The expression of several genes was quantified by real-time RT-PCR. RESULTS: Pioglitazone treatment increased the expression of genes involved in glycerol-3-phosphate synthesis. The mRNA expression of PEPCK-C and glycerol-3-phosphate dehydrogenase (GPDH) increased (P < 0.01) in patients treated with pioglitazone. There was no difference in glycerol kinase (GyK) mRNA levels. The expression of genes that regulate fatty acid availability in adipocytes, including lipoprotein lipase (LPL) and acetyl-CoA synthetase (ACS), was higher (P < 0.01) in pioglitazone-treated patients. Pioglitazone stimulated (P < 0.0001) expression of c-Cbl-associated protein (CAP), whereas tumor necrosis factor-alpha, leptin, resistin, angiopoietin like-4, and 11-beta-hydroxysteroid dehydrogenase type 1 (11beta HSD 1) were not affected by pioglitazone. The baseline peroxisome proliferator-activated receptor (PPAR)-gamma1 mRNA was significantly correlated with mRNA for LPL, CAP, ACS, 11beta HSD 1, GyK, fatty acid synthase, leptin, and GPDH, whereas PPAR-gamma2 mRNA was correlated with CAP, PEPCK-C, leptin, and GPDH. CONCLUSIONS: Treatment with pioglitazone increased body weight, and this is associated with upregulation of some, but not all, genes previously demonstrated as "TZD responsive" in subcutaneous fat. The results suggest that TZDs might increase body weight through the upregulation of genes facilitating adipocyte lipid storage in vivo.

Body Composition↗
PubMed2005

Comparison of effect of pioglitazone with metformin or sulfonylurea (monotherapy and combination therapy) on postload glycemia and composite insulin sensitivity index during an oral glucose tolerance test in patients with type 2 diabetes.

OBJECTIVE: Pioglitazone, metformin, and gliclazide lower HbA(1c) and fasting plasma glucose in patients with type 2 diabetes. We compared the effects of these three drugs, used as monotherapy and in combination, on postload glycemia and composite insulin sensitivity index (CISI) in these patients. RESEARCH DESIGN AND METHODS: Postload glycemia and CISI were analyzed for 940 patients who had oral glucose tolerance tests (OGTTs) in four multicenter, randomized, double-blind, double-dummy, parallel group clinical trials (pioglitazone versus metformin, pioglitazone versus gliclazide, pioglitazone plus sulfonylurea versus metformin plus sulfonylurea, and pioglitazone plus metformin versus gliclazide plus metformin). Plasma glucose and insulin were determined during the 3-h OGTT performed at baseline and after 1 year of therapy. Incremental area under the curve for glucose was the surrogate for postload glycemia. CISI was calculated using the formula {10,000/ radical of [(fasting glucose x fasting insulin) x (mean glucose x mean insulin)]} during the OGTT. RESULTS: In monotherapy, pioglitazone reduced postload glycemia and enhanced CISI more than metformin and gliclazide. In combination therapy, pioglitazone plus sulfonylurea reduced postload glycemia and increased CISI more than metformin plus sulfonylurea. Pioglitazone plus metformin also decreased postload glycemia and increased CISI more than gliclazide plus metformin. CONCLUSIONS: Pioglitazone improves postload glycemia and CISI more than metformin or gliclazide when used as monotherapy or in combination therapy in patients with type 2 diabetes.

Adult↗
PubMed2005

A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia.

OBJECTIVE: Published reports suggest that pioglitazone and rosiglitazone have different effects on lipids in patients with type 2 diabetes. However, these previous studies were either retrospective chart reviews or clinical trials not rigorously controlled for concomitant glucose- and lipid-lowering therapies. This study examines the lipid and glycemic effects of pioglitazone and rosiglitazone. RESEARCH DESIGN AND METHODS: We enrolled subjects with a diagnosis of type 2 diabetes (treated with diet alone or oral monotherapy) and dyslipidemia (not treated with any lipid-lowering agents). After a 4-week placebo washout period, subjects randomly assigned to the pioglitazone arm (n = 400) were treated with 30 mg once daily for 12 weeks followed by 45 mg once daily for an additional 12 weeks, whereas subjects randomly assigned to rosiglitazone (n = 402) were treated with 4 mg once daily followed by 4 mg twice daily for the same intervals. RESULTS: Triglyceride levels were reduced by 51.9 +/- 7.8 mg/dl with pioglitazone, but were increased by 13.1 +/- 7.8 mg/dl with rosiglitazone (P < 0.001 between treatments). Additionally, the increase in HDL cholesterol was greater (5.2 +/- 0.5 vs. 2.4 +/- 0.5 mg/dl; P < 0.001) and the increase in LDL cholesterol was less (12.3 +/- 1.6 vs. 21.3 +/- 1.6 mg/dl; P < 0.001) for pioglitazone compared with rosiglitazone, respectively. LDL particle concentration was reduced with pioglitazone and increased with rosiglitazone (P < 0.001). LDL particle size increased more with pioglitazone (P = 0.005). CONCLUSIONS: Pioglitazone and rosiglitazone have significantly different effects on plasma lipids independent of glycemic control or concomitant lipid-lowering or other antihyperglycemic therapy. Pioglitazone compared with rosiglitazone is associated with significant improvements in triglycerides, HDL cholesterol, LDL particle concentration, and LDL particle size.

Aged↗
PubMedDate not supplied

Substitution of pioglitazone for troglitazone in patients with type 2 diabetes.

OBJECTIVE: To evaluate the clinical utility of pioglitazone therapy in patients who previously received troglitazone. METHODS: We undertook an observational study involving patients with type 2 diabetes, who were originally treated with troglitazone and subsequently converted to pioglitazone therapy. Drug efficacy was evaluated by comparing baseline hemoglobin A1c (HbA1c) levels, weight, blood pressure, and lipid profiles (during troglitazone treatment) with corresponding values 6 months after final pioglitazone dose titration. Drug safety was evaluated by review of hepatic enzyme levels and documented reports of side effects. RESULTS: The study cohort consisted of 316 patients in whom pioglitazone therapy was initiated after they had received troglitazone for at least 1 year. Discontinuation of pioglitazone treatment subsequently occurred in 43 patients; in 7 additional patients, no follow-up occurred. We found no significant difference between baseline and follow-up mean HbA1c values. Aspartate aminotransferase levels did not significantly change after 6 months of pioglitazone therapy; however, alanine aminotransferase levels increased by a statistically significant 3.8 U/L (95% confidence interval, 2.6 to 4.9). Pioglitazone treatment was discontinued because of edema in 29 of the 309 evaluable patients (9.4%). CONCLUSION: Pioglitazone was as effective as troglitazone in maintaining HbA1c levels. The hepatic safety of pioglitazone was also demonstrated.

Aged↗
PubMed2001

[Pharmacological effects of a thiazolidinedione derivative, pioglitazone].

Pioglitazone, a thiazolidinedione derivative, was developed from our basic research on diabetic animal models and our chemical research on lipid-lowering agents. In clinical studies, pioglitazone at doses of 15-45 mg/man/day produced 1.0-1.6% reduction in HbA1c for 6 months. Moreover, pioglitazone produced about 14% reduction in plasma triglyceride levels and 4-11% increase in HDL-cholesterol(HDL-C) levels without the significant changes in total cholesterol and LDL-C levels. Although the exact molecular mechanism of reducing insulin resistance still remains obscure, pioglitazone normalizes abnormalities in the cellular insulin signal transduction. This effect seems to be due to the inhibitory action of pioglitazone on TNF-alpha production, which is one of the factors responsible for insulin resistance. Pioglitazone is a potent agonist for the peroxisome proliferator activated receptor(PPAR)-gamma, that is related to differentiation of adipocytes, and the relationship between TNF-alpha production and PPAR-gamma has been reported. Therefore, the agonistic activity of pioglitazone on PPAR-gamma may be involved in the mechanism for reducing insulin resistance. Recently, it was demonstrated that pioglitazone is also an agonist of PPAR-alpha, which plays a central role in lipid metabolism through enhancing the synthesis of apo AI, apo AII and reverse cholesterol transporters, such as fatty acid transporter molecules, and SR-B1 and ABCA1 reverse cholesterol transport receptors. Therefore, these findings suggest that pioglitazone has a benefit for prevention of both diabetic micro-angiopathy and macro-angiopathy.

Animals↗
PubMed2005

Pioglitazone, rosiglitazone, and rosiglitazone + metformin: new drugs. Glitazone + oral antidiabetic combination: inadequately evaluated.

(1) When single-agent therapy provides inadequate glycaemic control for patients with type 2 diabetes, most guidelines recommend metformin in combination with a glucose-lowering sulphonylurea as standard treatment, despite the lack of any proven impact on morbidity or mortality. Other options include switching to insulin or abandoning the target of strict glycaemic control. (2) Pioglitazone and rosiglitazone are approved for use in combination with a glucose-lowering sulphonylurea when metformin is poorly tolerated or contraindicated, and in combination with metformin in overweight patients. (3) A fixed-dose combination containing 1 or 2 mg of rosiglitazone plus 500 mg of metformin (hydrochloride) was launched onto the French market in October 2004. (4) The indication for rosiglitazone was extended to include its use as triple-agent therapy in combination with metformin and a glucose-lowering sulphonylurea. (5) No clinical trials assessing effects on mortality or morbidity have evaluated rosiglitazone or pioglitazone in combination with other oral antidiabetic drugs. (6) Several trials have compared the glucose-lowering effects of dual-agent therapy using rosiglitazone or pioglitazone plus a glucose-lowering sulphonylurea or metformin versus dual-agent therapy with metformin and a glucose-lowering sulphonylurea. (7) These clinical trials indicate that in terms of HbA1c level, dual-agent therapy based on rosiglitazone or pioglitazone is about as effective as combination therapy with metformin plus a glucose-lowering sulphonylurea. (8) The main known adverse effect of pioglitazone and rosiglitazone is water-sodium retention, which can provoke oedema and haemodilution anaemia, and can aggravate or reveal heart failure. (9) Pioglitazone has a positive effect on the lipid profile, whereas rosiglitazone increases the LDL-cholesterol level. (10) Dual-agent therapy with pioglitazone and a sulphonylurea causes more weight gain than metformin plus a sulphonylurea. (11) Several trials have assessed triple-agent regimens containing a glitazone. Three placebo-controlled double-blind trials have tested pioglitazone (one trial, nearly 300 patients) or rosiglitazone (two trials, about 1200 patients) for 12 to 26 weeks in patients whose glycaemia was poorly controlled by dual-agent therapy with a sulphonylurea plus metformin. The glycated haemoglobin level fell by 0.3% to 1.1% (in absolute values), depending on the trial and the dosage, but at a cost of the usual adverse effects such as weight gain, anaemia and oedema. Three unblinded trials have compared oral triple-agent regimens containing glitazone versus insulin plus metformin, alone or in combination with a glucose-lowering sulphonylurea; the treatment including glitazone was no more effective in terms of the glycated haemoglobin level, but was associated with an increase in adverse effects and dropouts. (12) Given the limited clinical data available in early 2005, pioglitazone and rosiglitazone have no place in the management of type 2 diabetes.

Clinical Trials as Topic↗
PubMed2002

Metabolic efficacy and safety of once-daily pioglitazone monotherapy in patients with type 2 diabetes: a double-blind, placebo-controlled study.

Pioglitazone is a novel oral anti-diabetic agent belonging to the thiazolidinedione class. Pioglitazone has been shown to be effective and well tolerated in the treatment of patients with type 2 diabetes, as it reduces insulin resistance and improves glycaemic control and abnormal lipid profiles. This double-blind, randomised, placebo-controlled study was conducted for further evaluation of the efficacy and tolerability of once-daily administration of pioglitazone monotherapy alongside dietary measures in patients with type 2 diabetes. Following a 10-week washout period, 251 patients received one of three treatment regimens for 26 weeks: placebo + diet (n = 84), pioglitazone 15 mg once-daily + diet (n = 89), or pioglitazone 30 mg once-daily + diet (n = 78). Pioglitazone, both 15 and 30 mg/day, in addition to dietary control, was associated with significant reductions (vs. placebo) in mean levels of both glycosylated haemoglobin (HbA 1C ) and fasting blood glucose (FBG). HbA 1C was reduced by 0.92 % and 1.05 %, respectively, and FBG was reduced by 34.3 and 36.0 mg/dl, respectively, compared with the control group. Pioglitazone at 15 and 30 mg/day significantly reduced postprandial blood glucose levels at all visits (- 163 and - 165 mg/dl/hour, respectively) compared with an increase of 47.7 mg/dl/hour on placebo. The profile and frequency of adverse events were similar in all treatment groups. These results indicate that pioglitazone monotherapy together with dietary control is both effective and safe in patients with type 2 diabetes.

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