Thiazolidinedione
Encyclopedia
The thiazolidinediones also known as glitazones, are a class of medication
s used in the treatment of diabetes mellitus type 2
. They were introduced in the late 1990s.
s (peroxisome proliferator-activated receptors), a group of receptor
molecules inside the cell nucleus
, specifically PPARγ (gamma). The ligand
s for these receptors are free fatty acid
s (FFAs) and eicosanoid
s. When activated, the receptor migrates to the DNA
, activating transcription
of a number of specific gene
s.
Genes upregulated by PPARγ can be found in the main article on peroxisome proliferator-activated receptor
s.
By activating PPARγ:
TZDs also increase the synthesis of certain proteins involved in fat and glucose metabolism, which reduces levels of certain types of lipids, and circulating free fatty acids. TZDs generally decrease triglycerides and increase high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Although the increase in LDL-C may be more focused on the larger LDL particles, which may be less atherogenic, the clinical significance of this is currently unknown. Nonetheless, rosiglitazone, a certain glitazone, was suspended from allowed use by medical authorities in Europe, as it has been linked to an increased risk of heart attack and stroke.
Chemically, the members of this class are derivatives of the parent compound thiazolidinedione, and include:
Experimental agents include MCC-555, an antidiabetic agent
, rivoglitazone
, and the early non-marketed thiazolidinedione ciglitazone
.
Replacing one oxygen atom in a thiazolidinedione with an atom of sulfur gives a rhodanine
.
type 2.
It is being investigated experimentally in polycystic ovary syndrome
(PCOS), non-alcoholic steatohepatitis (NASH), psoriasis
, autism
, ovarian hyperstimulation syndrome
(by VEGF inhibition in granulosa cell
s) and other conditions.
Several forms of lipodystrophy
cause insulin resistance, which has responded favorably to thiazolidinediones. There are some indications that thiazolidinediones provide some degree of protection against the initial stages of breast carcinoma development.
has led to concerns of the other thiazolidinediones also increasing the incidence of hepatitis
and potential liver failure, an approximately 1 in 20,000 individual occurrence with troglitazone. Because of this, the FDA recommends two to three month checks of liver enzymes for the first year of thiazolidinedione therapy to check for this rare but potentially catastrophic complication. To date, 2008, the newer thiazolidinediones, rosiglitazone
and pioglitazone
have been free of this problem.
The main side effect of all thiazolidinediones is water retention, leading to edema
, generally a problem in less than 5% of individuals, but a big problem for some and potentially, with significant water retention, leading to a decompensation of potentially previously unrecognized heart failure. Therefore, thiazolidinediones should be prescribed with both caution and patient warnings about the potential for water retention/weight gain, especially in patients with decreased ventricular function (NYHA
grade III or IV heart failure).
Though recent studies have shown there may be an increased risk of coronary heart disease
and heart attacks with rosiglitazone, pioglitazone
treatment, in contrast, has shown significant protection from both micro- and macro-vascular cardiovascular events and plaque
progression. These studies led to a period of Food and Drug Administration advisories (in February 2007) that, along with scientific publications and media exposure, were associated with a substantial decrease in rosiglitazone use. Despite a class-level FDA advisory, pioglitazone use was not similarly affected.
Preliminary data from a 10-year epidemiological study from Takeda Pharmaceutical Company
indicated a possible link between pioglitazone
(Actos) and bladder cancer
. The findings prompted the FDA
to order safety reviews for the drug in September 2010.
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
s used in the treatment of 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...
. They were introduced in the late 1990s.
Mechanism of action
Thiazolidinediones or TZDs act by activating PPARPeroxisome proliferator-activated receptor
In the field of molecular biology, the peroxisome proliferator-activated receptors are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes...
s (peroxisome proliferator-activated receptors), a group of receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
molecules inside the cell nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
, specifically PPARγ (gamma). The ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
s for these receptors are free fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
s (FFAs) and eicosanoid
Eicosanoid
In biochemistry, eicosanoids are signaling molecules made by oxidation of twenty-carbon essential fatty acids, ....
s. When activated, the receptor migrates to the DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, activating transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
of a number of specific gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s.
Genes upregulated by PPARγ can be found in the main article on peroxisome proliferator-activated receptor
Peroxisome proliferator-activated receptor
In the field of molecular biology, the peroxisome proliferator-activated receptors are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes...
s.
By activating PPARγ:
- Insulin resistanceInsulin resistanceInsulin 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...
is decreased - AdipocyteAdipocyteHowever, in some reports and textbooks, the number of fat cell increased in childhood and adolescence. The total number is constant in both obese and lean adult...
differentiation is modified - VEGFVascular endothelial growth factorVascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
-induced angiogenesisAngiogenesisAngiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
is inhibited - LeptinLeptinLeptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...
levels decrease (leading to an increased appetiteAppetiteThe appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...
) - Levels of certain interleukinInterleukinInterleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...
s (e.g. IL-6) fall - AdiponectinAdiponectinAdiponectin is a protein which in humans is encoded by the ADIPOQ gene.- Structure :...
levels rise
TZDs also increase the synthesis of certain proteins involved in fat and glucose metabolism, which reduces levels of certain types of lipids, and circulating free fatty acids. TZDs generally decrease triglycerides and increase high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Although the increase in LDL-C may be more focused on the larger LDL particles, which may be less atherogenic, the clinical significance of this is currently unknown. Nonetheless, rosiglitazone, a certain glitazone, was suspended from allowed use by medical authorities in Europe, as it has been linked to an increased risk of heart attack and stroke.
Members of the class
- RosiglitazoneRosiglitazoneRosiglitazone 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 put under selling restrictions in the US and withdrawn from the market in Europe due to an increased risk of cardiovascular events. - PioglitazonePioglitazonePioglitazone is a prescription drug of the class thiazolidinedione with hypoglycemic 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...
(Actos), France and Germany have suspended the sale of the diabetes drug Actos after a study suggested the drug, also known as pioglitazone, could raise the risk of bladder cancer. - TroglitazoneTroglitazoneTroglitazone 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...
(Rezulin), which was withdrawn from the market due to an increased incidence of drug-induced hepatitisHepatitisHepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
.
Experimental agents include MCC-555, an antidiabetic agent
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...
, rivoglitazone
Rivoglitazone
Rivoglitazone is a thiazolidinedione undergoing research for use in the treatment of type 2 diabetes.It is being developed by Daiichi Sankyo Co....
, and the early non-marketed thiazolidinedione ciglitazone
Ciglitazone
Ciglitazone is a thiazolidinedione. Developed by Takeda Pharmaceuticals in the early 1980s, it is considered the prototypical compound for the thiazolidinedione class....
.
Replacing one oxygen atom in a thiazolidinedione with an atom of sulfur gives a rhodanine
Rhodanine
Rhodanine is an organic compound derived from thiazolidine. Rhodanine can be prepared by the reaction of carbon disulfide, ammonia, and chloroacetic acid....
.
Uses
The only approved use of the thiazolidinediones is in diabetes mellitusDiabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
type 2.
It is being investigated experimentally in polycystic ovary syndrome
Polycystic ovary syndrome
Polycystic ovary syndrome is one of the most common female endocrine disorders. PCOS is a complex, heterogeneous disorder of uncertain aetiology, but there is strong evidence that it can to a large degree be classified as a genetic disease....
(PCOS), non-alcoholic steatohepatitis (NASH), psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
, autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
, ovarian hyperstimulation syndrome
Ovarian hyperstimulation syndrome
Ovarian hyperstimulation syndrome is a complication from some forms of fertility medication. Most cases are mild, but a small proportion are severe.-Causative medications:...
(by VEGF inhibition in granulosa cell
Granulosa cell
A granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete in the ovary of mammals.-Anatomy and function:...
s) and other conditions.
Several forms of lipodystrophy
Lipodystrophy
Lipodystrophy is a medical condition characterized by abnormal or degenerative conditions of the body's adipose tissue. A more specific term, lipoatrophy is used when describing the loss of fat from one area...
cause insulin resistance, which has responded favorably to thiazolidinediones. There are some indications that thiazolidinediones provide some degree of protection against the initial stages of breast carcinoma development.
Side effects and contraindications
The withdrawal of troglitazoneTroglitazone
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...
has led to concerns of the other thiazolidinediones also increasing the incidence of hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
and potential liver failure, an approximately 1 in 20,000 individual occurrence with troglitazone. Because of this, the FDA recommends two to three month checks of liver enzymes for the first year of thiazolidinedione therapy to check for this rare but potentially catastrophic complication. To date, 2008, the newer thiazolidinediones, 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...
and pioglitazone
Pioglitazone
Pioglitazone is a prescription drug of the class thiazolidinedione with hypoglycemic 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...
have been free of this problem.
The main side effect of all thiazolidinediones is water retention, leading to 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...
, generally a problem in less than 5% of individuals, but a big problem for some and potentially, with significant water retention, leading to a decompensation of potentially previously unrecognized heart failure. Therefore, thiazolidinediones should be prescribed with both caution and patient warnings about the potential for water retention/weight gain, especially in patients with decreased ventricular function (NYHA
New York Heart Association Functional Classification
The New York Heart Association Functional Classification provides a simple way of classifying the extent of heart failure. It places patients in one of four categories based on how much they are limited during physical activity; the limitations/symptoms are in regards to normal breathing and...
grade III or IV heart failure).
Though recent studies have shown there may be an increased risk of coronary heart disease
Coronary heart disease
Coronary artery disease is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients. It is sometimes also called coronary heart disease...
and heart attacks with rosiglitazone, pioglitazone
Pioglitazone
Pioglitazone is a prescription drug of the class thiazolidinedione with hypoglycemic 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...
treatment, in contrast, has shown significant protection from both micro- and macro-vascular cardiovascular events and plaque
Atheroma
In pathology, an atheroma is an accumulation and swelling in artery walls that is made up of macrophage cells, or debris, that contain lipids , calcium and a variable amount of fibrous connective tissue...
progression. These studies led to a period of Food and Drug Administration advisories (in February 2007) that, along with scientific publications and media exposure, were associated with a substantial decrease in rosiglitazone use. Despite a class-level FDA advisory, pioglitazone use was not similarly affected.
Preliminary data from a 10-year epidemiological study from Takeda Pharmaceutical Company
Takeda Pharmaceutical Company
is the largest pharmaceutical company in Japan and Asia and a top 15 pharmaceutical company. The company has over 19,000 employees worldwide and achieved $15.7 billion USD in revenue during the 2008 fiscal year...
indicated a possible link between pioglitazone
Pioglitazone
Pioglitazone is a prescription drug of the class thiazolidinedione with hypoglycemic 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...
(Actos) and 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...
. The findings prompted the 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...
to order safety reviews for the drug in September 2010.