![Thiazolidinedione functional group](https://upload.wikimedia.org/wikipedia/commons/3/3d/Thiazolidinedione_functional_group.svg)
The thiazolidinediones , abbreviated as TZD, also known as glitazones after the
prototypical drug In pharmacology and pharmaceutics, a prototype drug is an individual drug that represents a drug class – group of medications having similar chemical structures, mechanism of action and mode of action. Prototypes are the most important, and typica ...
ciglitazone
Ciglitazone ( INN) is a thiazolidinedione. Developed by Takeda Pharmaceuticals in the early 1980s, it is considered the prototypical compound for the thiazolidinedione class.
Ciglitazone was never used as a medication, but it sparked interest in ...
,
are a class of
heterocyclic compounds
A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis, properties, and ...
consisting of a five-membered C
3NS ring. The term usually refers to a family of drugs used in the treatment of
diabetes mellitus type 2
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...
that were introduced in the late 1990s.
Mechanism of action
Thiazolidinediones or TZDs act by activating
PPAR
In the field of molecular biology, the peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the reg ...
s (peroxisome proliferator-activated receptors), a group of
nuclear receptors
In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of specif ...
, specific for ''
PPARγ
Peroxisome proliferator- activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone reverse insulin resistance
receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II nuclear receptor functioning as a tran ...
'' (PPAR-gamma, PPARG). They are thus the PPARG agonists subset of
PPAR agonist
PPAR agonists are drugs which act upon the peroxisome proliferator-activated receptor. They are used for the treatment of symptoms of the metabolic syndrome, mainly for lowering triglycerides and blood sugar.
Classification
PPAR-alpha and PPAR-g ...
s. The endogenous
ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
s for these receptors are free
fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...
s (FFAs) and
eicosanoid
Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub-c ...
s. When activated, the receptor binds to
DNA in complex with the
retinoid X receptor
The retinoid X receptor (RXR) is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9-''cis''-13,14-dihydroretinoic acid, which is likely to be the major e ...
(RXR), another nuclear receptor, increasing
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
of a number of specific
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
s and decreasing transcription of others. The main effect of expression and repression of specific genes is an increase in the storage of fatty acids in adipocytes, thereby decreasing the amount of fatty acids present in circulation. As a result, cells become more dependent on the oxidation of
carbohydrates
In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or may ...
, more specifically
glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
, in order to yield energy for other cellular processes.
PPARγ transactivation
![Transactivation upload](https://upload.wikimedia.org/wikipedia/commons/3/3b/Transactivation_upload.svg)
The activated PPAR/RXR
heterodimer
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
binds to peroxisome proliferator
hormone response element Response elements are short sequences of DNA within a gene promoter or enhancer region that are able to bind specific transcription factors and regulate transcription of genes.
Under conditions of stress, a transcription activator protein binds ...
s upstream of target genes in complex with a number of
coactivators such as
nuclear receptor coactivator 1
The nuclear receptor coactivator 1 (''NCOA1'') is a transcriptional coregulatory protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA1 is recruited to DNA promotion sites by l ...
and
CREB binding protein
Cyclic adenosine monophosphate Response Element Binding protein Binding Protein (CREB-binding protein), also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the ''CREBBP'' gene in humans, located on chromosome 16p13.3. CBP has intrin ...
, this causes upregulation of genes (for a full list see
PPARγ
Peroxisome proliferator- activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone reverse insulin resistance
receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II nuclear receptor functioning as a tran ...
):
*
Insulin resistance
Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin.
Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...
is decreased
*
Adipocyte
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
differentiation is modified
*
VEGF
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
-induced
angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
is inhibited
*
Leptin
Leptin (from Ancient Greek, Greek λεπτός ''leptos'', "thin" or "light" or "small") is a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate Energy homeostasis, energy balance by inhib ...
levels decrease (leading to an increased
appetite
Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to regu ...
)
* Levels of certain
interleukin
Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...
s (e.g. IL-6) fall
*
Antiproliferative
Cytostasis (cyto – cell; stasis – stoppage) is the inhibition of cell growth and multiplication. Cytostatic refers to a cellular component or medicine that inhibits cell division.
Cytostasis is an important prerequisite for structured multic ...
action
*
Adiponectin
Adiponectin (also referred to as GBP-28, apM1, AdipoQ and Acrp30) is a protein hormone and adipokine, which is involved in regulating glucose levels as well as fatty acid breakdown. In humans it is encoded by the ''ADIPOQ'' gene and it is produced ...
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.
PPARγ transrepression
![PPAR transrepression](https://upload.wikimedia.org/wikipedia/commons/9/96/PPAR_transrepression.svg)
Binding of PPARγ to coactivators appears to reduce the levels of coactivators available for binding to pro-inflammatory transcription factors such as
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
; this causes a decrease in transcription of a number of pro inflammatory genes, including various interleukins and tumour necrosis factors.
Members of the class
![Thiazolidinedione and rhodanine](https://upload.wikimedia.org/wikipedia/commons/d/d7/Thiazolidinedione_and_rhodanine.svg)
Chemically, the members of this class are derivatives of the parent compound thiazolidinedione, and include:
*
Pioglitazone
Pioglitazone, sold under the brand name Actos among others, is an anti-diabetic medication used to treat type 2 diabetes. It may be used with metformin, a sulfonylurea, or insulin. Use is recommended together with exercise and diet. It is not re ...
(Actos), France and Germany have suspended its sale after a study suggested the drug could raise the risk of bladder cancer.
*
Rosiglitazone
Rosiglitazone (trade name Avandia) is an antidiabetic drug in the thiazolidinedione class. It works as an insulin sensitizer, by binding to the PPAR in fat cells and making the cells more responsive to insulin. It is marketed by the pharmaceutica ...
(Avandia), which was put under selling restrictions in the US and withdrawn from the market in Europe due to some studies suggesting an increased risk of cardiovascular events. Upon re-evaluation of new data in 2013, the FDA lifted the restrictions.
*
Lobeglitazone
Lobeglitazone (trade name Duvie, Chong Kun Dang) is an antidiabetic drug in the thiazolidinedione class of drugs. As an agonist for both PPARα and PPARγ, it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and ma ...
(Duvie), approved for use in Korea
Experimental, failed and non-marketed agents include:
*
Ciglitazone
Ciglitazone ( INN) is a thiazolidinedione. Developed by Takeda Pharmaceuticals in the early 1980s, it is considered the prototypical compound for the thiazolidinedione class.
Ciglitazone was never used as a medication, but it sparked interest in ...
*
Darglitazone
Darglitazone (previously known as CP 86325-2) is a member of the class of drugs and an agonist of Peroxisome proliferator-activated receptor gamma, peroxisome proliferator-activated receptor-γ (PPAR-γ), an orphan member of the nuclear receptor ...
*
Englitazone
*
Netoglitazone
Netoglitazone (also called MCC-555) is a hypoglycemic agent belonging to the thiazolidinedione
The thiazolidinediones , abbreviated as TZD, also known as glitazones after the prototypical drug ciglitazone, are a class of heterocyclic comp ...
*
Rivoglitazone
Rivoglitazone (INN) is a thiazolidinedione derivative undergoing research for use in the treatment of type 2 diabetes.
It is being developed by Daiichi Sankyo
is a global pharmaceutical company and the second-largest pharmaceutical company in ...
*
Troglitazone
Troglitazone is an antidiabetic and anti-inflammatory drug, and a member of the drug class of the thiazolidinediones. It was prescribed for people with diabetes mellitus type 2.
It was patented in 1983 and approved for medical use in 1997. It ...
(Rezulin), withdrawn due to increased incidence of drug-induced
hepatitis
Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pa ...
.
* Balaglitazone (DRF-2593) - developed by
Dr Reddy's Laboratories
Dr. Reddy's Laboratories is an Indian multinational Pharmaceutical industry, pharmaceutical company based in Hyderabad. The company was founded by Kallam Anji Reddy, who previously worked in the mentor institute Indian Drugs and Pharmaceutica ...
, discontinued during 2010-11 phase III trials as no better than available molecules.
AS-605240 48450-29-7Replacing one oxygen atom in a thiazolidinedione with an atom of sulfur gives a
rhodanine
Rhodanine is a 5-membered heterocyclic organic compound possessing a thiazolidine core. It was discovered in 1877 by Marceli Nencki who named it ''"Rhodaninsaure"'' in reference to its synthesis from ammonium rhodanide (known as ammonium thiocya ...
.
Uses
The only approved use of the thiazolidinediones is in
diabetes mellitus
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
type 2. According to a 2014
Cochrane systematic review of four
randomized controlled trial
A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical te ...
s, PPARγ-agonists may be effective in preventing further
stroke
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
s in those who have already had a stroke or a
transient ischemic attack
A transient ischemic attack (TIA), commonly known as a mini-stroke, is a minor stroke whose noticeable symptoms usually end in less than an hour. TIA causes the same Symptoms of stroke, symptoms associated with strokes, such as weakness or numbn ...
(TIA) and may stabilize
atherosclerotic plaques
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no sy ...
in the
carotid arteries
In anatomy, the left and right common carotid arteries (carotids) (Entry "carotid"
in
polycystic ovary syndrome
Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and no ...
(PCOS),
non-alcoholic steatohepatitis
Non-alcoholic fatty liver disease (NAFLD), also known as metabolic (dysfunction) associated fatty liver disease (MAFLD), is excessive fat build-up in the liver without another clear cause such as alcohol use. There are two types; non-alcoholic ...
(NASH),
psoriasis
Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...
,
autism
The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
,
ovarian hyperstimulation syndrome
Ovarian hyperstimulation syndrome (OHSS) is a medical condition that can occur in some women who take fertility medication to stimulate egg growth, and in other women in very rare cases. Most cases are mild, but rarely the condition is severe and c ...
(by VEGF inhibition in
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 (called an oocyte or egg) in the ovary of mammals.
Structure and function
In the primordial ovarian follicle, an ...
s), lichen planopilaris, and other conditions.
[Clinical Trials for Rosiglitazone]
- from ClinicalTrials.gov, a service of the U.S. National Institutes of Health
The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
Several forms of
lipodystrophy
Lipodystrophy syndromes are a group of genetic or acquired disorders in which the body is unable to produce and maintain healthy fat tissue. The medical condition is characterized by abnormal or degenerative conditions of the body's adipose tissue. ...
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
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipple, ...
development.
Evidence was emerging in 2008 that
vitamin E
Vitamin E is a group of eight fat soluble compounds that include four tocopherols and four tocotrienols. Vitamin E deficiency, which is rare and usually due to an underlying problem with digesting dietary fat rather than from a diet low in vitami ...
with thiazolidinediones is effective in the treatment of
non-alcoholic steatohepatitis
Non-alcoholic fatty liver disease (NAFLD), also known as metabolic (dysfunction) associated fatty liver disease (MAFLD), is excessive fat build-up in the liver without another clear cause such as alcohol use. There are two types; non-alcoholic ...
due to their combined antioxidant and insulin sensitizing effects, producing histological improvements in
steatosis
Steatosis, also called fatty change, is abnormal retention of fat (lipids) within a cell or organ. Steatosis most often affects the liver – the primary organ of lipid metabolism – where the condition is commonly referred to as fatty liver disea ...
severity.
Side effects and contraindications
The withdrawal of
troglitazone
Troglitazone is an antidiabetic and anti-inflammatory drug, and a member of the drug class of the thiazolidinediones. It was prescribed for people with diabetes mellitus type 2.
It was patented in 1983 and approved for medical use in 1997. It ...
has led to concerns of the other thiazolidinediones also increasing the incidence of
hepatitis
Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pa ...
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 enzyme
Liver function tests (LFTs or LFs), also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin ti ...
s for the first year of thiazolidinedione therapy to check for this rare but potentially catastrophic complication. To date, 2008, the newer thiazolidinediones,
rosiglitazone
Rosiglitazone (trade name Avandia) is an antidiabetic drug in the thiazolidinedione class. It works as an insulin sensitizer, by binding to the PPAR in fat cells and making the cells more responsive to insulin. It is marketed by the pharmaceutica ...
and
pioglitazone
Pioglitazone, sold under the brand name Actos among others, is an anti-diabetic medication used to treat type 2 diabetes. It may be used with metformin, a sulfonylurea, or insulin. Use is recommended together with exercise and diet. It is not re ...
have been free of this problem.
The main side effect of all thiazolidinediones is water retention, leading to
edema
Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...
, 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
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
. 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 The New York Heart Association (NYHA) 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 limitati ...
grade III or IV heart failure).
Though older studies suggested there may be an increased risk of
coronary heart disease
Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pla ...
and heart attacks with rosiglitazone,
pioglitazone
Pioglitazone, sold under the brand name Actos among others, is an anti-diabetic medication used to treat type 2 diabetes. It may be used with metformin, a sulfonylurea, or insulin. Use is recommended together with exercise and diet. It is not re ...
treatment, in contrast, has shown significant protection from both micro- and macro-vascular cardiovascular events and
plaque
Plaque may refer to:
Commemorations or awards
* Commemorative plaque, a plate or tablet fixed to a wall to mark an event, person, etc.
* Memorial Plaque (medallion), issued to next-of-kin of dead British military personnel after World War I
* Pla ...
progression.
These studies led to a period of Food and Drug Administration advisories (2007 - 2013) that, aided by extensive media coverage, led to a substantial decrease in rosiglitazone use. In November 2013, the FDA announced it would remove the usage restrictions for rosiglitazone in patients with coronary artery disease. The new recommendations were largely based on the reasoning that prior meta-analyses leading to the original restrictions were not designed to assess cardiac outcomes and, thus, not uniformly collected or adjudicated. In contrast, one of the largest trials (RECORD trial) that was specifically designed to assess cardiac outcomes found no increased risk of
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
with rosiglitazone use, even after independent re-evaluation for FDA review.
A 2013
meta-analysis
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...
concluded that use of
pioglitazone
Pioglitazone, sold under the brand name Actos among others, is an anti-diabetic medication used to treat type 2 diabetes. It may be used with metformin, a sulfonylurea, or insulin. Use is recommended together with exercise and diet. It is not re ...
is associated with a slightly higher risk of
bladder cancer
Bladder cancer is any of several types of cancer arising from the tissues of the urinary bladder. Symptoms include blood in the urine, pain with urination, and low back pain. It is caused when epithelial cells that line the bladder become mali ...
compared to the general population. The authors of the same analysis recommended that other blood sugar lowering agents be considered in people with other risk factors for bladder cancer such as
cigarette smoking
Tobacco smoking is the practice of burning tobacco and ingesting the resulting smoke. The smoke may be inhaled, as is done with cigarettes, or simply released from the mouth, as is generally done with pipes and cigars. The practice is believed ...
, family history, or exposure to certain forms of
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
.
A 2020 Cochrane systematic review did not find enough evidence of reduction of all-cause mortality, serious adverse events, cardiovascular mortality, non-fatal
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
, non-fatal
stroke
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
or
end-stage renal disease
Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vom ...
when comparing
metformin
Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. ...
monotherapy to Thiazolidinedione for treatment of
type 2 diabetes
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...
.
Thiazolidinediones reduce
bone mineral density
Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to optica ...
and increase the risk of fractures in women, possibly as a result of biasing the differentiation of
bone marrow stromal cells
Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...
away from
osteoblast
Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...
differentiation and toward
adipocyte
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
formation.
Thiazolidinediones increase expression of
angiotensin-converting enzyme 2 (ACE2). It is hypothesized that this increases the chance of serious infection with the
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
virus, which causes
COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was COVID-19 pandemic in Hubei, identified in Wuhan, China, in December ...
.
References
{{PPAR modulators