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Pioglitazone is an oral antidiabetic agent and a member of the group of drugs known as thiazolidinediones, also called 'insulin sensitizers'. Pioglitazone specifically targets insulin resistance, which is thought to be central to the development of type 2 diabetes, as well as dyslipidemia and hypertension in patients with diabetes mellitus.

  Troglitazone was the first thiazolidinedione approved, but it was withdrawn from the US market due to the risk of idiosyncratic hepatotoxicity. Currently, two thiazolidinediones are available commercially in the United States - pioglitazone and rosiglitazone.

Rare cases of hepatic failure have been reported during post-marketing experience with both; periodic monitoring of hepatic enzymes is recommended. Pioglitazone therapy results in improvements in glycemic control as indicated by significant reductions in fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c). The glucose lowering effect of pioglitazone appears to last for at least one year based on an open-label extension study.

Pioglitazone is administered once daily and is approved as monotherapy or in combination with insulin, metformin, or a sulfonylurea. When pioglitazone is used in combination with other oral antidiabetic agents or insulin, reductions in FPG and HbA1c are significantly greater than when any agent is used alone. The risk of heart failure, edema, and/or weight gain is increased with thiazolidinedione therapy and this risk is further increased when combined with insulin; monitor patients receiving combined therapy closely for signs or symptoms of congestive heart failure. In a study of patients with type 2 diabetes, the addition of pioglitazone to existing diabetes therapy resulted in a reduction in the secondary composite endpoint of all-cause mortality, non-fatal myocardial infarction, and stroke (HR 0.84, 95% CI 0.72—0.98, p=0.027); however, the occurrence of the primary composite endpoint of all-cause mortality, non-fatal MI, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle was not different. More patients in the pioglitazone treatment group suffered from heart failure (11% vs. 8%, p<0.0001), heart failure not requiring hospitalization (5% vs. 3%, p=0.003), and heart failure requiring hospitalization (6% vs. 4%, p=0.007).

Furthermore, 562 patients receiving pioglitazone versus 341 patients receiving placebo reported edema, and an increase in mean body weight was significantly higher in those patients treated with pioglitazone (3.6 kg vs. -0.4kg, p<0.0001). It is unclear whether those patients receiving insulin plus pioglitazone experienced more heart failure, edema, or weight gain compared with patients taking pioglitazone without insulin. Similarly, in a meta-analyses of four, long-term clinical trials of patients taking pioglitazone (n=8554) verus placebo or other antidiabetic agents (n=7836), it was found that the risk of death, myocardial infarction, or stroke was decreased in favor of pioglitazone (HR 0.82, 95% CI 0.72—0.95, P=0.005); it should be noted that the risk of heart failure was also significantly increased (HR 1.41, 95% CI 1.14—1.76, P=0.002). These findings are in contrast to two meta-analyses reviewing patients taking rosiglitazone, where the risk of myocardial infarction was increased. 

The two drugs affect lipid parameters differently, with pioglitazone causing an overall improved lipid profile and decreasing atherogenic risk, which may partially explain the disparity in the cardiovascular safety findings of these 2 drugs. The FDA is currently reviewing the cardiovascular safety of the thiazolidinedione class of drugs; a black box warning regarding heart failure was added to labeling of both drugs in August 2007. Final FDA approval for pioglitazone was granted in July 1999.

Mechanism of Action: Pioglitazone is an oral thiazolidinedione used in the treatment of type 2 diabetes mellitus. Its primary action is enhancement of insulin sensitivity in adipose tissue, skeletal muscle, and the liver. Clinically, pioglitazone decreases plasma glucose concentrations, insulin concentrations, and glycosylated hemoglobin. Additional favorable metabolic effects include decreased hepatic glucose output, lower free fatty acid concentrations, and improved lipid profiles. In addition, preliminary evidence suggests that the thiazolidinediones may preserve beta cell function, a key component in the development of type 2 diabetes mellitus in patients with insulin resistance.

Unlike oral sulfonylureas, pioglitazone does not stimulate insulin secretion. All oral agents used in the management of type 2 diabetes mellitus, including pioglitazone, are ineffective in patients with insulin deficiency (e.g., type 1 diabetes mellitus).

The mechanisms of pioglitazone are complex and not fully understood.

Pioglitazone is a highly selective and potent agonist for the peroxisome proliferator activated receptor (PPAR-gamma) that regulates the transcription of a number of insulin responsive genes.

PPAR receptors can be found in key targets for insulin action including adipose tissue, skeletal muscle, and the liver. Pioglitazone is more potent than troglitazone with a 10 to 15 fold higher binding affinity for the PPAR-gamma receptor. Rosiglitazone is even more potent than pioglitazone with a 100 to 200 fold higher binding affinity for the PPAR-gamma receptor when compared to troglitazone. The clinical significance of this is unknown. Activation of the PPAR-gamma receptor enhances insulin sensitivity through several mechanisms. First, expression of the glucose transporter GLUT4 is increased in adipose tissue resulting in improved glucose utilization in skeletal muscle and the liver. Second, insulin sensitivity is enhanced by the lowering of plasma free fatty acid concentrations and shifting the storage of free fatty acids from non-adipose cells to adipocytes. Finally, the release of adipocytokines such as tumor necrosis factor alfa, resistin, and adiponectin is regulated to promote insulin sensitivity. Furthermore, thiazolidinedione-mediated receptor activation promotes adipogenesis and the differentiation of adipocytes causing a favorable redistribution of fat from visceral to subcutaneous stores. Subcutaneous adipocytes tend to be less lipolytic and more insulin sensitive. These effects contribute to the overall improved metabolic effects associated with thiazolidinedione use including insulin sensitivity peripherally.

Pioglitazone decreases serum triglyceride concentrations and increases serum HDL cholesterol; increases and decreases in serum LDL cholesterol have been described. In two randomized clinical trials, the overall lipid profile of patients receiving pioglitazone improved. In the first study, which was 24 weeks in duration, patients receiving 45 mg of pioglitazone/day experienced a decrease in triglycerides of 12%, an increase in HDL cholesterol of 14.9%, an increase in LDL cholesterol of 15.7%, and an increase in total cholesterol of 5.7% (P<0.05 compared to baseline for all parameters). A second randomized clinical trial of 12 months in duration demonstrated significant improvements in all lipid parameters including a 22.4% reduction in triglycerides, a 15% increase in HDL cholesterol, a 12% decrease in LDL cholesterol, and a 11% decrease in total cholesterol (P<0.05 compared to baseline for all parameters). Furthermore, in one study, the LDL/HDL cholesterol ratio improved with pioglitazone therapy resulting in a lipid profile that was less atherogenic. In addition, the LDL cholesterol changed from small dense particles to larger and more buoyant ones. While the thiazolidinediones have been shown to have positive effects on myocardial function, blood pressure, endothelial function, fibrinolysis, microalbuminuria, and inflammation, meta-analyses of available clinical trials indicate that there may be an increased risk of myocardial infarction with another drug in this class, rosiglitazone. These effects have not been found in a clinical trial or a meta-analysis of patients taking pioglitazone. Investigations by the FDA are ongoing and will help to determine the role of thiazolidinediones in the treatment of diabetes mellitus.

Pioglitazone is administered orally. Steady-state serum concentrations are achieved within 7 days. Protein binding is extensive (> 99%), primarily to serum albumin. Binding also occurs to other serum proteins, but with lower affinity. Pioglitazone is extensively metabolized by hydroxylation and oxidation. The major hepatic cytochrome P450 enzymes involved are CYP2C8 and CYP3A4 with contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1 enzyme. In animal models of type 2 diabetes, metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglitazone) are pharmacologically active. Metabolites M-III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady state, serum concentrations of metabolites M-III and M-IV are equal to or greater than serum concentrations of pioglitazone. In both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30—50% of the total peak serum concentrations and 20—25% of the total AUC at steady state. Approximately 15—30% of the total pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. Most of an oral dose is presumed to be excreted into the bile either unchanged or as metabolites and eliminated in the feces. The mean serum half-lives of pioglitazone and its metabolites is 3—7 hours and 16—24 hours, respectively.

•Route-Specific Pharmacokinetics
Oral Route
Following oral administration, serum concentrations of pioglitazone are first measurable within 30 minutes. Peak serum concentrations occur within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption. Steady-state serum concentrations are achieved within 7 days.

•Special Populations
Hepatic Impairment
Compared with normal patients, patients with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone peak concentrations with no change in AUC values. Pioglitazone should not be initiated in patients with clinical evidence of active liver disease or ALT values > 2.5x the upper limit of normal at baseline.

Pharmacokinetic data of pioglitazone in children are not available.

Gender Differences
The mean AUC and Cmax values of pioglitazone are increased by 20—60% in females compared to males. HbA1c decreases are generally greater in females versus males; however, because therapy is individualized, dose adjustments based on gender alone is not necessary.


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Lincoff AM, Wolski K, Nicholls SJ, et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. N Eng J Med 2007;298:1180-8.

Singh S, Loke YI, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. N Engl J Med 2007;298:1189-95.

Derosa G, Cicero AFG, D'Angelo A, et al. Effects of 1 year treatment with pioglitazone or rosiglitazone added to glimepiride on lipoprotein (a) and homocysteine concentrations in patients with type 2 diabetes mellitus and metabolic syndrome: a multicenter, randomized, double-blind, controlled clinical trial. Clin Ther 2006;28:679-88.

Comment from Dr. Praveen Ramchandra: Glitazones are to be used as reserve drugs especially with older age group patients and patients with cardiovascular risk morbidity


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