Pioglitazone
Encyclopedia
Pioglitazone is a prescription drug of the class thiazolidinedione
(TZD) with hypoglycemic
(antihyperglycemic, antidiabetic) action.
Pioglitazone is marketed as trademarks Actos in the USA, Canada, the UK and Germany, Glustin in Europe,"Glizone" and "Pioz" in India by Zydus CND and USV respectively and Zactos in Mexico by Takeda Pharmaceuticals. Actos was the tenth-best selling drug in the U.S. in 2008, with sales exceeding $2.4 billion. Its cardiovascular safety profile compares favorably with rosiglitazone
(Avandia), which was withdrawn after concerns about an increased risk of cardiac events, but pioglitazone has subsequently been found to be associated with bladder tumors and has been withdrawn in some countries.
peroxisome proliferator-activated receptor gamma (PPAR-γ
) and to a lesser extent PPAR-α
. It modulates the transcription of the insulin
-sensitive genes involved in the control of glucose and lipid metabolism
in the muscle
, adipose tissue
, and the liver
. As a result, pioglitazone reduces insulin resistance
in the liver and peripheral tissues; increases the expense of insulin-dependent glucose; decreases withdrawal of glucose from the liver; reduces quantity of glucose, insulin and glycated hemoglobin in the bloodstream. Although not clinically significant, pioglitazone decreases the level of triglycerides and increases that of high-density lipoproteins (HDL) without changing low-density lipoproteins (LDL) and total cholesterol in patients with disorders of lipid metabolism, although statin
s are the drug of choice for this.
More recently, pioglitazone and other active TZDs have been shown to bind to the outer mitochondrial membrane
protein mitoNEET
with affinity comparable to that of pioglitazone for PPARγ.
(previously known as non-insulin-dependent diabetes mellitus, NIDDM) in monotherapy and in combination with a sulfonylurea
, metformin
, or insulin
. Pioglitazone has also been used to treat non-alcoholic steatohepatitis (fatty liver), but this use is presently considered experimental. Pioglitazone has also been found to reduce the risk of conversion from prediabetes
to diabetes mellitus type 2
by 72%.
and diabetic ketoacidosis
. Its safety in pregnancy, lactation
(breastfeeding) and people under 18 is not established.
Given previous experiences with the related drug troglitazone
, acute diseases of the liver are regarded as a contraindication for pioglitazone.
Pioglitazone and all other drugs of its class (Thiazolidinediones) are absolutely contraindicated in patients with heart failure.
compared with those given metformin or glyburide. The information was based on data from the ADOPT trial. Following release of this statement, Takeda also admitted that pioglitazone has similar implications for female patients.
The risk of hypoglycemia
is low in the absence of other drugs that lower blood glucose.
Pioglitazone can cause fluid retention and peripheral edema
. As a result, it may precipitate congestive heart failure (which worsens with fluid overload in those at risk). It may cause anemia
. Mild weight gain is common due to increase in subcutaneous adipose tissue
. In studies, patients on pioglitazone had an increased proportion of upper respiratory tract infection, sinusitis, headache, myalgia and tooth problems.
On July 30, 2007 an Advisory Committee of the Food and Drug Administration concluded that the use of rosiglitazone for the treatment of type 2 diabetes was associated with a greater risk of "myocardial ischemic events" when compared to placebo, but when compared to other diabetes drugs, there was no increased risk. Pioglitazone is currently being reviewed. A meta-analysis
released subsequently showed that pioglitazone reduced the number of ischemic cardiac events rather than increase the risk, but increases CHF.
The PERISCOPE study compared pioglitazone with glimepiride
in diabetics; atherosclerotic plaque
volume was measured and followed over time. Glimepiride therapy had highly significant progression of plaque volume over time of 0.73 percent. In comparison, pioglitazone had a -0.16 percent regression in plaque volume. This is the first study to show that diabetic therapy slowed progression of atherosclerosis
. Therapy with pioglitazone raised HDL
, and lowered triglyceride
and hsCRP; these are all beneficial effects on risk factors for coronary artery disease, however to date, no oral anti-diabetic drug has been shown to reduce the risk of cardiovascular complications. Chronic administration of the drug has led to occasional instances of cholestatic hepatitis, reversible upon drug discontinuation.
On June 9, 2011 the French Agency for the Safety of Health Products decided to withdraw pioglitazone in regards to high risk of bladder cancer
On June 10, 2011 Germany's Federal Institute for Drugs and Medical Devices
also advised doctors not to prescribe the medication until further investigation of the cancer risk had been conducted.
On June 15, 2011 the U.S. FDA
announced that pioglitazone use for more than one year may be associated with an increased risk of bladder cancer, and that the information about this risk will be added to the Warnings and Precautions
section of the label for pioglitazone-containing medicines. The patient Medication Guide for these medicines will also be revised to include information on the risk of bladder cancer
.
s or insulin
reciprocally exponentiate risk of hypoglycemia
. Therapy with pioglitazone increased risk for pregnancy in those taking oral contraception.
as Duetact (tablets containing 30 mg pioglitazone and either 2 or 4 mg of glimepiride).
Thiazolidinedione
The thiazolidinediones , also known as glitazones, are a class of medications used in the treatment of diabetes mellitus type 2. They were introduced in the late 1990s.- Mechanism of action :...
(TZD) with hypoglycemic
Anti-diabetic drug
Anti-diabetic medications treat diabetes mellitus by lowering glucose levels in the blood. With the exceptions of insulin, exenatide, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents...
(antihyperglycemic, antidiabetic) action.
Pioglitazone is marketed as trademarks Actos in the USA, Canada, the UK and Germany, Glustin in Europe,"Glizone" and "Pioz" in India by Zydus CND and USV respectively and Zactos in Mexico by Takeda Pharmaceuticals. Actos was the tenth-best selling drug in the U.S. in 2008, with sales exceeding $2.4 billion. Its cardiovascular safety profile compares favorably with rosiglitazone
Rosiglitazone
Rosiglitazone is an antidiabetic drug in the thiazolidinedione class of drugs. It works as an insulin sensitizer, by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin...
(Avandia), which was withdrawn after concerns about an increased risk of cardiac events, but pioglitazone has subsequently been found to be associated with bladder tumors and has been withdrawn in some countries.
Pharmacology
Pioglitazone selectively stimulates the nuclear receptorNuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
peroxisome proliferator-activated receptor gamma (PPAR-γ
Peroxisome proliferator-activated receptor gamma
Peroxisome proliferator-activated receptor gamma , also known as the glitazone receptor, or NR1C3 is a type II nuclear receptor that in humans is encoded by the PPARG gene.Two isoforms of PPARG are detected in the human and in the mouse: PPAR-γ1 and...
) and to a lesser extent PPAR-α
Peroxisome proliferator-activated receptor alpha
Peroxisome proliferator-activated receptor alpha , also known as NR1C1 , is a nuclear receptor protein that in humans is encoded by the PPARA gene.- Function :...
. It modulates the transcription of the insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
-sensitive genes involved in the control of glucose and lipid metabolism
Lipid metabolism
Lipid metabolism refers to the processes that involve the intercourse and degradation of lipids.The types of lipids involved include:* Bile salts* Cholesterols* Eicosanoids* Glycolipids* Ketone bodies* Fatty acids - see also fatty acid metabolism...
in the muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
, adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
, and the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
. As a result, pioglitazone reduces insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
in the liver and peripheral tissues; increases the expense of insulin-dependent glucose; decreases withdrawal of glucose from the liver; reduces quantity of glucose, insulin and glycated hemoglobin in the bloodstream. Although not clinically significant, pioglitazone decreases the level of triglycerides and increases that of high-density lipoproteins (HDL) without changing low-density lipoproteins (LDL) and total cholesterol in patients with disorders of lipid metabolism, although statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
s are the drug of choice for this.
More recently, pioglitazone and other active TZDs have been shown to bind to the outer mitochondrial membrane
Outer mitochondrial membrane
thumb|300px|Mitochondria structure :1) [[Inner membrane]]2) Outer membrane3) [[Crista]]4) [[Matrix |Matrix]]The outer mitochondrial membrane, which encloses the entire organelle, has a protein-to-phospholipid ratio similar to the eukaryotic plasma membrane...
protein mitoNEET
CDGSH iron sulfur domain
The CDGSH iron sulfur domain are a group of iron-sulfur clusters and a unique 39 amino acid CDGSH domain [C-X-C-X2--X3-P-X-C-D-G--H]....
with affinity comparable to that of pioglitazone for PPARγ.
Indications and usage
Pioglitazone is used for the treatment of diabetes mellitus type 2Diabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...
(previously known as non-insulin-dependent diabetes mellitus, NIDDM) in monotherapy and in combination with a sulfonylurea
Sulfonylurea
Sulfonylurea derivatives are a class of antidiabetic drugs that are used in the management of diabetes mellitus type 2. They act by increasing insulin release from the beta cells in the pancreas.-First generation:* Carbutamide...
, metformin
Metformin
Metformin is an oral antidiabetic drug in the biguanide class. It is the first-line drug of choice for the treatment of type 2 diabetes, in particular, in overweight and obese people and those with normal kidney function. Its use in gestational diabetes has been limited by safety concerns...
, or insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
. Pioglitazone has also been used to treat non-alcoholic steatohepatitis (fatty liver), but this use is presently considered experimental. Pioglitazone has also been found to reduce the risk of conversion from prediabetes
Prediabetes
Prediabetes is the state in which some but not all of the diagnostic criteria for diabetes are met. It is often described as the “gray area” between normal blood sugar and diabetic levels. While in this range, patients are at risk for not only developing type 2 diabetes, but also for cardiovascular...
to diabetes mellitus type 2
Diabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...
by 72%.
Contraindication
Pioglitazone cannot be used in patients with a known hypersensitivity to pioglitazone, other thiazolidinediones or any of components of its pharmaceutical forms. It is ineffective and possibly harmful in diabetes mellitus type 1Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
and diabetic ketoacidosis
Diabetic ketoacidosis
Diabetic ketoacidosis is a potentially life-threatening complication in patients with diabetes mellitus. It happens predominantly in those with type 1 diabetes, but it can occur in those with type 2 diabetes under certain circumstances...
. Its safety in pregnancy, lactation
Lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, however it predates mammals. In humans the process of feeding milk is called breastfeeding or nursing...
(breastfeeding) and people under 18 is not established.
Given previous experiences with the related drug troglitazone
Troglitazone
Troglitazone is an anti-diabetic and antiinflammatory drug, and a member of the drug class of the thiazolidinediones. It was developed by Daiichi Sankyo Co.. In the United States, it was introduced and manufactured by Parke-Davis in the late 1990s, but turned out to be associated with an...
, acute diseases of the liver are regarded as a contraindication for pioglitazone.
Pioglitazone and all other drugs of its class (Thiazolidinediones) are absolutely contraindicated in patients with heart failure.
Side effects
A press release by GlaxoSmithKline in February 2007 noted that there is a greater incidence of fractures of the upper arms, hands and feet in female diabetics given rosiglitazoneRosiglitazone
Rosiglitazone is an antidiabetic drug in the thiazolidinedione class of drugs. It works as an insulin sensitizer, by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin...
compared with those given metformin or glyburide. The information was based on data from the ADOPT trial. Following release of this statement, Takeda also admitted that pioglitazone has similar implications for female patients.
The risk of hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
is low in the absence of other drugs that lower blood glucose.
Pioglitazone can cause fluid retention and peripheral edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
. As a result, it may precipitate congestive heart failure (which worsens with fluid overload in those at risk). It may cause anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
. Mild weight gain is common due to increase in subcutaneous adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
. In studies, patients on pioglitazone had an increased proportion of upper respiratory tract infection, sinusitis, headache, myalgia and tooth problems.
On July 30, 2007 an Advisory Committee of the Food and Drug Administration concluded that the use of rosiglitazone for the treatment of type 2 diabetes was associated with a greater risk of "myocardial ischemic events" when compared to placebo, but when compared to other diabetes drugs, there was no increased risk. Pioglitazone is currently being reviewed. A meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
released subsequently showed that pioglitazone reduced the number of ischemic cardiac events rather than increase the risk, but increases CHF.
The PERISCOPE study compared pioglitazone with glimepiride
Glimepiride
Glimepiride is a medium-to-long acting sulfonylurea anti-diabetic drug. It is marketed as Amaryl by Sanofi-Aventis and GLIMY by Dr.Reddy's Labs...
in diabetics; atherosclerotic plaque
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
volume was measured and followed over time. Glimepiride therapy had highly significant progression of plaque volume over time of 0.73 percent. In comparison, pioglitazone had a -0.16 percent regression in plaque volume. This is the first study to show that diabetic therapy slowed progression of atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
. Therapy with pioglitazone raised HDL
High density lipoprotein
High-density lipoprotein is one of the five major groups of lipoproteins, which, in order of sizes, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, which enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream...
, and lowered triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
and hsCRP; these are all beneficial effects on risk factors for coronary artery disease, however to date, no oral anti-diabetic drug has been shown to reduce the risk of cardiovascular complications. Chronic administration of the drug has led to occasional instances of cholestatic hepatitis, reversible upon drug discontinuation.
On June 9, 2011 the French Agency for the Safety of Health Products decided to withdraw pioglitazone in regards to high risk of bladder cancer
Bladder cancer
Bladder cancer is any of several types of malignant growths of the urinary bladder. It is a disease in which abnormal cells multiply without control in the bladder. The bladder is a hollow, muscular organ that stores urine; it is located in the pelvis...
On June 10, 2011 Germany's Federal Institute for Drugs and Medical Devices
Federal Institute for Drugs and Medical Devices
The Federal Institute for Drugs and Medical Devices is a medical regulatory body in Germany.It operates under the Federal Ministry of Health.It is headquartered in Bonn....
also advised doctors not to prescribe the medication until further investigation of the cancer risk had been conducted.
On June 15, 2011 the U.S. FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
announced that pioglitazone use for more than one year may be associated with an increased risk of bladder cancer, and that the information about this risk will be added to the Warnings and Precautions
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
section of the label for pioglitazone-containing medicines. The patient Medication Guide for these medicines will also be revised to include information on the risk of bladder cancer
Bladder cancer
Bladder cancer is any of several types of malignant growths of the urinary bladder. It is a disease in which abnormal cells multiply without control in the bladder. The bladder is a hollow, muscular organ that stores urine; it is located in the pelvis...
.
Drug interactions
Combination with sulfonylureaSulfonylurea
Sulfonylurea derivatives are a class of antidiabetic drugs that are used in the management of diabetes mellitus type 2. They act by increasing insulin release from the beta cells in the pancreas.-First generation:* Carbutamide...
s or insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
reciprocally exponentiate risk of hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
. Therapy with pioglitazone increased risk for pregnancy in those taking oral contraception.
Formulations
Pioglitazone as Actos is supplied in oral tablets containing 15, 30 or 45 mg of pioglitazone base. It is also available in combination with metformin as ActoplusMet (tablets containing 15 mg pioglitazone and either 500 or 850 mg of metformin), Competact (tablets containing 15 mg pioglitazone and 850 mg of metformin) or in combination with glimepirideGlimepiride
Glimepiride is a medium-to-long acting sulfonylurea anti-diabetic drug. It is marketed as Amaryl by Sanofi-Aventis and GLIMY by Dr.Reddy's Labs...
as Duetact (tablets containing 30 mg pioglitazone and either 2 or 4 mg of glimepiride).