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Query: CAS:111025-46-8 (Pioglitazone)
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A central finding of the UKPDS was that in type 2 diabetic patients, tight glycemic control with HbA1c targets as close to the normal range as possible must be achieved to further reduce diabetes related-complications, -mortality, and -cardiovascular disease, highlighting the need for new, optimized treatment strategies. With a focus on clinical efficacy, this paper discusses the results from the 20 major therapeutical trials published in the years 1997-1999, that evaluated the new insulinsensitizing thiazolidinediones Rosiglitazone and Pioglitazone and the new insulin-releasing potassium channel blockers Repaglinide and Nateglinide. While for Nateglinide, promising, but only preliminary data is available at current, Rosiglitazone, Pioglitazone, and Repaglinide have been shown appropriate for both mono- and combination therapy with current standard drug treatment of type 2 diabetes. Similar to the known, older antidiabetic drugs, the new agents discussed have comparable blood glucose lowering potentials with a dose-related capacity of 0.5 to 1.5% HbA1c reduction. These beneficial effects were both seen in drug-naive patients previously treated with diet only and in combination therapies where patients had previous antidiabetic standard drug treatment suggesting effectiveness of glitazones and glinides also in more advanced stages of the disease. Problems with adverse effects appeared minor although long-range implications of weight gain, edema, lowering of hemoglobin, increase of total cholesterol for the glitazones, and hypoglycemia for glinides warrant further consideration. What becomes clear from the variety of most recent mono- and combination treatment studies with as much as five different classes of antidiabetic drugs is that individually tailored therapies that recognize quality of life parameters and target the predominant features of metabolic pathology (such as early postprandial versus fasting hyperglycemia, degree of insulin resistance, progressive loss of 1-cell function) may become a feasible goal in the future.
Exp Clin Endocrinol Diabetes 2000
PMID:Clinical efficacy of new thiazolidinediones and glinides in the treatment of type 2 diabetes mellitus. 1092 9

Urinary endothelin (ET)-1 excretion is present in non-insulin dependent diabetes (NIDDM) patients with microalbuminuria, and an increase in circulating ET-1 precedes the microalbuminuric phase of renal injury related to diabetes. The aim of the present study was to determine whether various drugs alter urinary ET-1 levels and urinary albumin excretion (UAE) in NIDDM patients with microalbuminuria. Forty-five NIDDM patients with microalbuminuria were randomly assigned to three groups: those treated with pioglitazone at 30 mg/day (n=15), those treated with glibenclamide at 5 mg/day (n=15), and those treated with voglibose at 0.6 mg/day (n=15). Patients received these drugs for 3 months. UAE, urinary ET-1, and plasma ET-1 levels were measured in these patients before and after treatment. Before treatment, UAE, urinary ET-1, and plasma ET-1 levels differed little among the three groups. UAE in the 45 NIDDM patients (156.2+/-42.8 microg/min) was greater than that in 30 healthy controls (8.2+/-2.6 microg/min) (P<.001). Urinary ET-1 levels in the NIDDM patients (8.7+/-1.3 ng/g urinary creatinine (UC)) were significantly higher than that in the controls (2.4+/-0.2 ng/g UC) (P<.01). Plasma ET-1 levels, however, in the NIDDM patients (1.3+/-0.4 pg/ml) did not differ significantly from the levels in healthy controls (1.0+/-0.6 pg/ml). Pioglitazone but no glibenclamide or voglibose reduced UAE from 142.8+/-42.2 to 48. 4+/-18.2 microg/min (P<.01) and urinary ET-1 levels from 8.6+/-1.3 to 3.4+/-0.5 ng/g UC (P<.01). These data suggest pioglitazone to be effective in reducing UAE and urinary ET-1 concentrations in NIDDM patients with microalbuminuria.
J Diabetes Complications
PMID:Comparative effects of pioglitazone, glibenclamide, and voglibose on urinary endothelin-1 and albumin excretion in diabetes patients. 1111 86

Tumor necrosis factor (TNF)-alpha is one of the candidate mediators of insulin resistance associated with obesity, a major risk factor for the development of type 2 diabetes. The insulin resistance induced by TNF-alpha is antagonized by thiazolidinediones (TZDs), a new class of insulin-sensitizing drugs. The aim of the current study was to dissect the mechanism whereby pioglitazone, one of the TZDs, ameliorates TNF-alpha-induced insulin resistance in 3T3-L1 adipocytes. Pioglitazone restored insulin-stimulated 2-deoxyglucose (DOG) uptake, which was reduced by TNF-alpha, with concomitant restorations in tyrosine phosphorylation and protein levels of insulin receptor (IR) and insulin receptor substrate (IRS)-1, as well as association of the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase with IRS-1 and PI 3-kinase activity. Adenovirus-mediated gene transfer of either wild-type human peroxisome proliferator-activated receptor (PPAR)-gamma2 or a mutant carrying a replacement at the consensus mitogen-activated protein kinase phosphorylation site (hPPAR-gamma2-S112A) promoted adipogenesis of 3T3-L1 fibroblasts and restored TNF-alpha-induced decrease of triglyceride in adipocytes as effectively as pioglitazone. Overexpression of the PPAR-gamma proteins in TNF-alpha-treated adipocytes restored protein levels of IR/IRS-1, but did not improve insulin-stimulated tyrosine phosphorylation of IR/IRS-1 or insulin-stimulated 2-DOG uptake. These results indicate that the ability of pioglitazone to restore insulin-stimulated tyrosine phosphorylation of IR/IRS-1, which is necessary for amelioration of TNF-alpha-induced insulin resistance, may be independent of the adipogenic activity of PPAR-gamma that regulates protein levels of IR/IRS-1.
Diabetes 2001 May
PMID:Pioglitazone ameliorates tumor necrosis factor-alpha-induced insulin resistance by a mechanism independent of adipogenic activity of peroxisome proliferator--activated receptor-gamma. 1133 12

Takeda has a relatively long history in diabetes research. Pioglitazone, a thiazolidinedione derivative, was developed from our basic research on diabetic animal models in the 1960s and our chemical research on lipid-lowering agents in the 1970s. Pioglitazone reduced plasma glucose, triglyceride and insulin levels in obese-diabetic animal models with insulin resistance in liver and/or peripheral tissues, but did not decrease normoglycemia in normal rats and aged dogs or hyperglycemia in insulin-deficient streptozocin-induced diabetic rats and impaired-insulin-secretory Goto-Kakizaki rats. The ED50 of plasma glucose-lowering action was 0.5 mg/kg/day in Wistar fatty rats. These findings clearly indicate that pioglitazone works in animals with insulin resistance and has a quite different mechanism from sulfonylureas and insulin itself. Although the exact mechanism of pioglitazone still remains obscure, pioglitazone normalized abnormalities in the cellular signal transduction of insulin. These effects seem 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 of reduction of insulin resistance. The clinical data clearly demonstrated that pioglitazone, at clinical doses of 15-45 mg/day, decreased plasma glucose, HbA1c and triglyceride, increased plasma HDL-cholesterol, but did not alter total cholesterol and LDL-cholesterol levels. These findings suggest that pioglitazone has a benefit for prevention of cardiovascular diseases in addition to diabetic complications.
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PMID:[Insulin resistance-reducing effect of a new thiazolidinedione derivative, pioglitazone]. 1141 43

Thiazolidinediones are a powerful and clinically important new class of oral antidiabetic agents that act by improving insulin sensitivity. Troglitazone is the prototype drug in this class but was withdrawn from the market in March 2000 due to its association with idiosyncratic hepatotoxicity. Currently two thiazolidinediones, rosiglitazone and pioglitazone, are U.S. Food and Drug Administration (FDA) approved for treatment of type 2 diabetes. These agents bind to and activate peroxisome proliferator-activator receptor gamma (PPAR-gamma) and work by altering the expression of genes involved in glucose uptake, glucose disposal, and lipid metabolism. The drugs differ in receptor binding and potency due to differences in their side chain moieties. These agents are rapidly absorbed from the gastrointestinal tract and are metabolized mainly in the liver. Rosiglitazone is FDA approved for monotherapy and for use in combination therapy with metformin or sulfonylureas. Pioglitazone is FDA approved for monotherapy as well as for use in combination therapy with metformin, insulin, or sulfonylureas. These drugs may also cause significant changes in plasma lipid concentrations, and improved insulin sensitivity may improve ovulatory function and fertility in women with polycystic ovary syndrome. The most serious side effect of the thiazolidinediones is hepatotoxicity. Although rosiglitazone and pioglitazone were not associated with hepatotoxicity in premarketing clinical trials, there were two recent case reports of idiosyncratic hepatotoxicity in patients treated with rosiglitazone. In addition, these agents may be associated with edema and some hematological changes. The purpose of this review is to provide an overview of the two currently approved thiazolidinediones and to suggest an approach for their safe and rational use.
Diabetes Technol Ther 2000
PMID:Thiazolidinediones: a comparative review of approved uses. 1146 45

The discovery of a new class of oral antidiabetic drugs was stimulated by difficulties with the treatment currently available for patients with type 2 diabetes mellitus. Thiazolidinediones can lower blood glucose values due to their special insulin-sensitiser effect. In this way, these drugs seem to be very effective in the treatment of type 2 diabetic patients with characteristics of metabolic syndrome. The intracellular action caused by thiazolidinediones differs markedly from that of other oral antidiabetic drugs available. Apart from antihyperglycaemic effect, thiazolidinediones have further beneficial effects in experimental diabetes which require corroboration by clinical studies. Troglitazone was the first drug which reached the market. Unfortunately, this drug was withdrawn soon due to its hepatotoxicity. Rosiglitazone proved to be much safer in clinical studies. Pioglitazone is being tested nowadays in clinical studies. Thiazolidinediones have been already listed among oral antidiabetic drugs in international therapeutical guidelines. Nevertheless, further clinical studies and experiences are needed to determine the final exact indication of thiazolidinediones for the treatment of type 2 diabetic patients.
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PMID:[Thiazolidinediones--a new class of oral antidiabetic drugs]. 1149 46

Pioglitazone is a thiazolidinedione that increases insulin sensitivity in target tissues. It is well-absorbed, with a mean absolute bioavailability of 83% and reaching maximum concentrations in around 1.5 hours. It is metabolised by the hepatic cytochrome P450 enzyme system. However, unlike troglitazone, studies have provided no evidence to suggest that pioglitazone administration leads to inhibition or induction of any of the P450 isoenzymes involved in drug metabolism. Therefore pioglitazone may have lower potential for drug interaction. The half-life is about 9 hours but two active metabolites mainly contribute to the extended glucose-lowering effects. It is administered once daily without regard to meals. The pharmacokinetics are not significantly altered in Type 2 diabetes, renal or hepatic insufficiency or in the elderly. In placebo-controlled clinical studies, pioglitazone effectively improved glycaemic control in people with Type 2 diabetes as evidenced by significant reductions in HbA1c and fasting plasma glucose, whether used as monotherapy or in combination with sulphonylurea, metformin or insulin. Pioglitazone also had a beneficial effect on the abnormal lipid profile seen in Type 2 diabetes. Compared with placebo, pioglitazone significantly reduced serum triglycerides and increased high density lipoprotein cholesterol with no change in low density lipoprotein or total cholesterol.
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PMID:Pharmacokinetics and clinical efficacy of pioglitazone. 1159 40

Thiazolidinediones, such as pioglitazone, are synthetic ligands for peroxisome proliferator-activated receptors (PPARs). They alter the transcription of genes influencing carbohydrate and lipid metabolism, resulting in changed amounts of protein synthesis and, therefore, metabolic changes. Pioglitazone improves glycaemic control in people with Type 2 diabetes by improving insulin sensitivity through its action at PPAR gamma 1 and PPAR gamma 2, and affects lipid metabolism through action at PPAR alpha. The results of these interactions include increases in glucose transporters 1 and 4, lowered free fatty acids, enhanced insulin signalling, reduced tumour necrosis factor alpha (TNF alpha) and remodelling of adipose tissue. Together, these can increase glucose uptake and utilisation in the peripheral organs and decrease gluconeogenesis in the liver, thereby reducing insulin resistance.
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PMID:Pioglitazone: mechanism of action. 1159 39

1. The effects of combined treatment with pioglitazone.HCl and metformin on diabetes and obesity were investigated in Wistar fatty rats, which are hyperglycaemic and hypertriglyceridaemic and have higher plasma levels of total ketone bodies than lean rats. 2. Plasma glucose was significantly decreased when pioglitazone.HCl or metformin was administered alone and combined treatment accentuated this decrease. The administration of pioglitazone.HCl, but not metformin, also decreased plasma levels of triglyceride and total ketone bodies. 3. The glycogen content of skeletal muscle was not increased by pioglitazone.HCl or metformin alone, but was increased by combined treatment (P=0.003, ANOVA). 4. Pioglitazone.HCl produced increased food intake and bodyweight in hyperphagic Wistar fatty rats; however, concurrent administration of metformin significantly ameliorated these pioglitazone.HCl-induced increases. 5. These results indicate that combined treatment with pioglitazone.HCl and metformin induces a marked hypoglycaemic effect accompanied by a reduction in plasma levels of total ketone bodies and prevention of excessive bodyweight gain in Wistar fatty rats. These favourable effects suggest that the combination would be beneficial in treating patients with type 2 diabetes.
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PMID:Effects of combined pioglitazone and metformin on diabetes and obesity in Wistar fatty rats. 1198 34

Type 2 diabetes mellitus remains a significant burden to the Canadian healthcare system. Over 2 million Canadians have diabetes, with 85 to 90% having type 2 diabetes. Insulin resistance is a major pathophysiological mechanism in the development of type 2 diabetes. Insulin resistance can be defined as an impaired biological response to the metabolic and/or mitogenic effects of either exogenous or endogenous insulin. As a consequence of insulin resistance, type 2 diabetes is characterised by decreased glucose transport and utilisation at the level of muscle and adipose tissue and increased glucose production by the liver. The traditional oral agents used to treat type 2 diabetes clearly do not address the underlying insulin resistance responsible for the development of diabetes. Thiazolidinediones (TZDs) represent a relatively new class of oral hypoglycaemic medications that have been shown to reverse some of the metabolic processes believed responsible for the development of insulin resistance and, ultimately, type 2 diabetes. Research has demonstrated that TZDs activate peroxisome proliferator activator receptors, in particular, the gamma-receptor isoform. Pioglitazone is a TZD that reduces plasma glucose levels by increasing peripheral glucose utilisation and decreasing hepatic glucose production. Clinical studies with pioglitazone have demonstrated the following: absolute reductions in glycosylated haemoglobin of 0.8 to 2.6%; reductions in fasting plasma glucose of 1.7 to 4.4 mmol/L; an increase in high density lipoprotein cholesterol of 8.7 to 12.6%; and a decrease in triglycerides of 18.2 to 26.0%, with no significant effects on low density lipoprotein or total cholesterol.
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PMID:New solutions for type 2 diabetes mellitus: the role of pioglitazone. 1203 79


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