Use of pioglitazone is associated with a small increased risk of bladder cancer. Healthcare professionals should be aware of new warnings and precautions for use in at risk patients article date: august 2011 pioglitazone actos▼ is an oral treatment for type 2 diabetes, either on its own or combined with other oral antidiabetic agents or insulin. The potential risk of bladder cancer with pioglitazone was first identified at the time of licensing, observed in male rats in an animal toxicity study that supported the initial licence application. The marketing authorisation licence holder committed to investigate the risk further in animal studies and observational studies in human use. The european medicines agency’s ema committee for medicinal products for human use chmp has reviewed the results of these studies and other relevant data regularly. After an increase in healthcare professional reports of bladder cancer suspected to be associated with pioglitazone, in march 2011 the ema initiated a further european wide review to investigate this safety signal.

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Whether the increased risk occurs early in treatment or only after prolonged exposure remains unclear. Chmp stated that the small increased risk could be reduced by appropriate patient selection. Advice for healthcare professionals: patients with active bladder cancer or with a history of bladder cancer, and those with uninvestigated haematuria, should not receive pioglitazone prescribers should review the safety and efficacy of pioglitazone in individuals after 3–6 months of treatment to ensure that only patients who are deriving benefit continue to be treated. When reporting please provide as much information as possible, including information about medical history, any concomitant medication, onset, and treatment dates.

It is crucial at this point to perform a risk ndash benefit analysis to determine what role pioglitazone should play in our current treatment of type 2 diabetes and where the future of this class of drugs is headed. Clinical data currently available indicate that pioglitazone is an effective and generally well tolerated treatment option for use in patients with type 2 diabetes. The full terms of this license are available at and incorporate the creative commons attribution non commercial unported, v3.0 license. Non commercial uses of the work are permitted without any further permission from dove medical press limited, provided the work is properly attributed.

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For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our terms. Type 2 diabetes t2d is a progressive disorder with a consistent and steady increase in glycosylated hemoglobin hba₁ c over time associated with enhanced risk of micro and macrovascular complications and a substantial reduction in life expectancy. There are three major pathophysiologic abnormalities associated with t2d: impaired insulin secretion, excessive hepatic glucose output, and insulin resistance in skeletal muscle, liver, and adipose tissue. These defects have been treated in clinical praxis by use of oral insulin secretagogues sulfonylureas/glinides or insulin, biguanides, and thiazolidinediones tzds respectively.

Pioglitazone hcl is an insulin sensitizer in the tzd family and glimepiride is an insulin secretagogue in the su family. This article reviews mechanisms of action and clinical data behind the use of these two commonly used oral hypoglycemic agents with documented efficacy and good safety profile of once daily administration, alone or in combination with insulin or metformin, in the management of t2d in terms of glycemic and non glycemic effects, tolerability and side effects, and impact on vascular health. Studies were obtained from searches of databases medline, cochrane database of systematic reviews, and cochrane central register of controlled trials, using search terms type 2 diabetes, pioglitazone, glimepiride, sulfonylureas, and thiazolidinediones limiting for english language.

Thiazolidinediones tzds are agonists of peroxisome proliferator activated receptors x003b3 ppar x003b3 lehmann et al 1995 henry 1997 , which are nuclear receptors, composed of three major isoforms x003b1 , x003b2 / x003b4 , and x003b3 . Ppar x003b3 is a transcription factor, when activated by tzds, promoting transcription of insulin sensitive genes involved in fatty acid and glucose uptake and lipogenesis and thereby enhance or partially mimic selective actions of insulin saltiel and olefsky 1996 . Ppar x003b3 is also essential for normal adipocyte differentiation and proliferation lemberger et al 1996 . Ppar x003b3 is expressed in key target tissues for insulin action, most abundantly in adipose tissue but also in skeletal muscle, liver, pancreatic x003b2 cells, vascular endothelium, and macrophages dubois et al 20 willson et al 2001 . The glucose lowering effect of tzds is attributed to increased peripheral glucose disposal nolan et al 1994 miyazaki et al 2001a. B miyazaki et al 2002a and decreased hepatic glucose output miyazaki et al 2001a .

Tzds have been shown to cause redistribution of fat from hepatic and visceral adipose tissue to subcutaneous adipose tissue miyazaki et al 2002a shadid and jensen 2003 rasouli et al 2005 smith et al 2005 , and in this way possibly saving tissues such as liver, skeletal muscle, and pancreatic x003b2 cells from lipotoxicity. Two tzds are currently approved for treatment of hyperglycemia in t2d, rosiglitazone and pioglitazone, which are both potent and highly selective agonists for ppar x003b3 , being very similar in mechanism of action, effect on hyperglycemia, and side effect profiles. It is important to keep in mind that these drugs need insulin as a co factor for ppar agonism feinglos and bethel 1998 , and if used at late stages of t2d, when insulinopenia has already developed, the full effect cannot be expected. Pioglitazone has in addition shown some minor activation of ppar x003b1 forman et al 1995 lehmann et al 1995 . Ppar x003b1 activation is also known to have anti inflammatory effects and preventive effect on arteriosclerosis rubins et al 19 duez et al 2002 . They exert their insulin releasing effect mainly by inhibiting atp sensitive potassium channels. In the pancreatic x003b2 cell this action induces depolarization of the cell membrane, allowing an influx of calcium in the cell.

The insulin release is not modified by plasma glucose and the su action can thus induce hypoglycemia. It is, however, also evident that sus have insulin releasing effects independent of atp sensitive potassium channels. Tolbutamide, glibenclamide, and glipizide were shown to increase insulin secretion in human x003b2 cells also when the membrane of the x003b2 cell was voltage clamped and thus ca flux was unaffected eliasson et al 1996 . It was also suggested that this action was mediated by protein kinase c pkc , since the stimulatory action of tolbutamide was abolished by a pkc inhibitor. Recent studies of rat x003b2 cells have shown that glibenclamide inhibits activity of carnitine palmitoyltransferase 1 cpt 1 which in turn switches fatty acid catabolism to synthesis of pkc activating lipids and cpt 1 may thus play a major role in su mediated insulin release lehtihet et al 2003 . In this context it is also interesting to note that it was shown long ago hellman et al 1984 that glibenclamide accumulates in the x003b2 cell during chronic treatment.

Atp sensitive potassium channels are not specific to the pancreatic x003b2 cell but found in a variety of cells throughout the human organism. These cells include vascular smooth muscle cells quayle et al 1997 vascular endothelium, cardiac myocytes nichols and lederer 1991 and some brain neurons yamada et al 2001 . Atp sensitive potassium channels are also found on the inner membranes of mitochondria dahlem et al 2004 .