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`
`StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.
`Thiazolidinediones
`Julie S. Eggleton; Ishwarlal Jialal.
`
`Author Information and Affiliations
`
`Last Update: February 20, 2023.
`
`Continuing Education Activity
`Thiazolidinediones are medications used to manage and treat type 2 diabetes mellitus. These
`medications may be acting as a nuclear transcription regulator and an insulin sensitizer. This
`activity illustrates the indications, mechanism of action, and contraindications for
`thiazolidinediones as valuable agents for managing type 2 diabetes.
`Objectives:
`
`Identify the mechanism of action of thiazolidinediones.
`
`Describe the potential adverse effects of thiazolidinediones.
`
`Outline appropriate monitoring for the toxicity of thiazolidinediones.
`
`Review the importance of collaboration and coordination among the interprofessional team
`and how it can enhance patient care with thiazolidinedione therapy to improve patient
`outcomes for patients who have diabetes.
`
`Access free multiple choice questions on this topic.
`
`Indications
`The use of thiazolidinediones, also called "glitazones," in managing type 2 diabetes can help with
`glycemic control and insulin resistance. There are two thiazolidinediones, rosiglitazone, and
`pioglitazone, currently approved by the FDA as monotherapy or combined with metformin or
`sulfonylureas to manage type 2 diabetes mellitus. These medications should be in conjunction
`with lifestyle modifications such as diet, exercise, and weight reduction. Thiazolidinediones may
`also be used to treat polycystic ovarian syndrome, as these may lead to improved endothelial
`function, improved ovulation, and reduction of insulin resistance.[1] Pioglitazone specifically
`reduces hepatic fat and may improve liver fibrosis in patients with nonalcoholic steatohepatitis
`(NASH); however, additional variables and risks require assessment in NASH patients.[2][3] The
`most significant advantage of TZDs is that they do not cause hypoglycemia as monotherapy and
`are not contraindicated in patients with renal disease.
`
`Mechanism of Action
`Thiazolidinediones (TZDs) are insulin sensitizers that act on intracellular metabolic pathways to
`enhance insulin action and increase insulin sensitivity in critical tissues.[4] TZDs also increase
`adiponectin levels, decrease hepatic gluconeogenesis, and increase insulin-dependent glucose
`uptake in muscle and fat. Adiponectin, a cytokine secreted by fat tissue, increases insulin
`sensitivity, and fatty acid oxidation increases with TZD therapy.[1][5][6][7]
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`TZDs function by regulating gene expression through binding to peroxisome proliferator-
`activated receptor-gamma (PPAR-gamma), a nuclear transcription regulator.[6] Peroxisome
`proliferator-activated receptors (PPARs) are a family of ligand-activated transcription factors of
`nuclear hormone receptors that regulate energy homeostasis. The genes activated by the PPAR-
`gamma subtype are present in muscle, fat, and liver, regulating glucose metabolism, fatty acid
`storage, and adipocyte differentiation.[8] The binding of TZD will induce a conformational
`change to alter gene expression of numerous pathways involved in metabolism regulation,
`including lipoprotein lipase, glucokinase, fatty acyl-CoA synthase, and others.[9] PPAR-gamma
`agonists improve insulin resistance by increasing adiponectin, GLUT4 expression, and opposing
`the effect of TNF-alpha in adipocytes. Increased GLUT 4 expression will increase glucose
`uptake in adipocytes and skeletal muscle cells in response to insulin.[8]
`
`In addition to their function in glycemic control and improvement of insulin resistance, TZDs
`potentially have anti-inflammatory and anti-cancer properties. There is evidence that TZDs may
`slow the progression of medial intimal thickening and decrease coronary intimal hyperplasia.
`Research has shown additional beneficial effects on endothelial function, atherogenesis,
`fibrinolysis, and ovarian steroidogenesis. Some studies demonstrated that activation of PPAR-
`gamma receptors could induce cancer cell apoptosis. However, these mechanisms are still under
`investigation due to conflicting studies and possible confounders.[1]
`
`Administration
`Thiazolidinediones (TZDs) are taken orally once daily, with or without food. Before initiating
`treatment and periodically during therapy, LFTs and HbA1C levels require monitoring. Maximal
`glucose-lowering effects of TZDs are not seen for six weeks to 6 months due to a delayed onset
`of action via modification of gene expression. For type 2 diabetes management, TZDs should be
`used in combination with lifestyle modifications and can be used in conjunction with biguanides,
`sulfonylureas, and insulin injectables.[4][10]
`
`Dosing for treatment of T2DM:
`
`Pioglitazone: Initial 15 to 30 mg PO with a meal once a day; may increase the dose by 15
`mg with careful monitoring to 45 mg once a day. The maximum dose is 45 mg.
`
`Rosiglitazone: Initial 4 mg PO once a day. If inadequate response after 8 to 12 weeks, may
`increase the dose to 8 mg PO once a day or 4 mg twice a day.
`
`Adverse Effects
`There are several undesirable side effects to thiazolidinediones, particularly with long-term use.
`The risks versus benefits require discussion with patients, and alternative first-line agents
`attempted before using TZDs.
`Edema and Congestive Heart Failure
`
`TZDs have been shown to cause dose-related fluid retention in up to 20% of patients. Methods of
`fluid retention include PPAR-gamma receptors in the distal nephron and insulin-activated
`epithelial sodium channels in the collecting tubules. PPAR-gamma activation stimulates sodium
`reabsorption, acting at the same site as aldosterone. Patients with preexisting edema or
`concomitant insulin therapy are at higher risk of edema and should start on the lowest available
`dose.[1][4][11] In most patients, fluid retention will respond to diuretics such as thiazides or
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`spironolactone if the edema is mild or loop diuretics for severe cases. Furthermore, lower doses
`of 15 and 30 mg a day decreases the risk of edema and weight gain.
`
`There are reports of an increase in intravascular volume to the point of congestive heart failure.
`Thus TZDs should be used with caution in patients with diastolic dysfunction or a history of
`CHF. The risk of heart failure and death is higher in rosiglitazone than pioglitazone.[12]
`Weight Gain
`
`Adipocytes have the highest concentration of PPAR-gamma receptors in the body. The
`mechanism behind the weight gain is due to a combination of factors. TZDs upregulate PPAR-
`gamma receptors in the central nervous system, leading to increased feeding. TZD agents expand
`adipose tissue mass via the maturation of preadipocytes into mature adipocytes and increase fat
`storage by increasing free fatty acid movement into cells. Additionally, fluid retention can
`increase weight.[4][13] Fat gain occurs primarily in the subcutaneous tissues, sparing the visceral
`area. As with edema and CHF, weight gain becomes exacerbated by concomitant insulin use, but
`the risk decreases when using metformin and lower doses of TZDs.
`Fractures
`
`Several studies have demonstrated an increased fracture risk and decreased bone density in
`patients taking TZDs compared to those taking insulin or other oral agents such as sulfonylureas.
`Proposed mechanisms for this include PPAR-gamma activation and insulin-like growth factor
`down-regulation, which diverts the differentiation of osteoblasts into adipocytes and leads to
`bone loss.[1][14] These fractures appear to be more likely in the distal extremities (forearm,
`wrist, ankle, foot, tibia) than the axial skeleton (hip, pelvis, femur). The fracture risk is further
`increased by additional risk factors, such as postmenopausal females or patients concurrently
`taking glucocorticoids or proton pump inhibitors (PPIs).[15][16][17]
`Bladder Cancer
`
`Pioglitazone has, in some studies, shown correlations with an increased risk of bladder cancer.
`This effect varies in a duration-dependent and dose-dependent fashion. Also, most recent
`analyses do not support an increased risk. In contrast, rosiglitazone was not associated with an
`increased risk of bladder cancer in any analysis, suggesting the risk is drug-specific and not a
`class effect.[18]
`
`Hepatotoxicity
`
`Troglitazone, the original PPAR-gamma activator, was removed from the market primarily due to
`hepatotoxicity. However, the other agents, rosiglitazone and pioglitazone, have rarely been linked
`to acute liver injury.[5][10] Baseline and routine monitoring of alanine aminotransferase levels
`and monitoring for clinical symptoms of liver injury are recommended.[19][20][21]
`Diabetic Macular Edema
`
`Combination TZD and insulin therapy have correlated with an increased incidence of diabetic
`macular edema at 1-year and 10-year follow-up. However, more studies are underway to evaluate
`confounding factors and define the frequency of this adverse event.[22][23]
`Increased Ovulation and Teratogenic Effects
`
`Patients with polycystic ovarian syndrome have shown an increased ovulation rate when using
`TZD and other insulin sensitizers. This effect may result in ovulation in some premenopausal,
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`anovulatory women, leading to improved rates of spontaneous pregnancy. However, TZDs have
`also been shown to have some teratogenic potential by decreasing fetal maturation.
`Premenopausal women should use contraception if they are not trying to conceive and switch to
`another insulin sensitizer, such as metformin, after conception.[24]
`
`Contraindications
`When considering management for T2DM, primary interventions should be lifestyle changes
`such as diet, exercise, and weight reduction. First-line monotherapy should be metformin or
`sulfonylureas due to their favorable side effect profiles. However, TZDs may be used as
`monotherapy or as combination therapy when first-line medications are contraindicated. TZDs
`may be necessary for high-risk hypoglycemic patients; however, the contraindications require
`evaluation before starting treatment.
`
`There are several contraindications for using thiazolidinediones, including:
`
`Heart failure (New York Heart Association class III, IV): The American Heart Association
`and the American Diabetes Association has stated that patients with New York Heart
`Association class III, IV symptomatic heart failure should use TZD at the lowest possible
`dose or not at all due to risk of fluid retention and diastolic heart dysfunction.[12]
`
`Moderate to severe hepatic impairment: Troglitazone was removed from the market due to
`hepatoxicity. While rosiglitazone or pioglitazone have not shown the same hepatotoxic
`effects, the recommendation is still that patients undergo baseline and periodic monitoring
`of liver function. Patients with AST or ALT greater than or equal to 3 times the upper
`reference limit should discontinue TZD therapy.[25]
`
`Bladder cancer: Pioglitazone should not be used in patients with active bladder cancer. In
`patients with a history of bladder cancer, the risk of recurrence versus the benefits of
`glycemic control should merit consideration before starting pioglitazone treatment.
`Rosiglitazone has not shown similar risks of bladder cancer.[18]
`
`Pregnancy: The FDA labels TZDs as pregnancy class C with teratogenic potential, as
`PPAR-gamma is necessary for terminal differentiation of the trophoblast and placental
`vascularization. Pregnant patients should switch to another insulin sensitizer, such as
`metformin.[24]
`
`High risk of fractures: Due to increased fracture risk, patients who are at a high risk of
`fractures, such as those with a history of osteoporosis, postmenopausal women, or patients
`taking other medications that increase fracture risk (such as glucocorticoids and PPIs),
`should not start on TZD therapy.[1][14][15][16][17]
`
`Cytochromes CYP 2C8 and CYP 3A4 are necessary for the metabolism of TZDs;
`therefore, cytochrome inducers and inhibitors should be used with caution as these
`medications may affect the drug plasma levels of TZDs.
`
`Monitoring
`Before beginning TZD therapy and periodically during treatment, patients should have liver
`function tests (LFT) evaluated. If LFTs are greater than or equal to 3 times the upper limit, then
`TZD should not be started or should be discontinued. Additionally, physicians should monitor for
`clinical symptoms of hepatic injury, such as jaundice or dark urine.[10] Clinicians need to
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`monitor patients’ bodyweight to detect possible fluid overload. Signs and symptoms of fluid
`overload or heart failure, such as rapid weight gain, peripheral edema, dyspnea, S3 heart sounds,
`or decreased ejection fraction, require close monitoring. HbA1c should be monitored at least
`twice a year to assess glycemic control and consider dosage adjustments.[13][26]
`
`Enhancing Healthcare Team Outcomes
`The use of thiazolidinediones in the management of T2DM requires an interprofessional
`healthcare team. These agents can help with glycemic control and insulin resistance in patients
`with functional pancreatic beta-cells. Though they are not first-line agents, they can act
`synergistically with other oral agents and insulin. They modify gene transcription to increase
`adiponectin and insulin sensitivity, lower plasma glucose by increasing glucose utilization,
`decrease plasma fatty acids by increasing fatty acid oxidation, decrease serum triglycerides, and
`decrease visceral fat. Early use of TZDs in the course of the disease may benefit the pancreas,
`but there are many long-term dose and duration dependant adverse effects that limit their use.
`Such effects may include heart failure, weight gain, and bone density loss.
`
`When properly prescribed and carefully monitored, they can effectively reduce fasting plasma
`glucose and HbA1c levels in some patients by increasing insulin sensitivity. These adverse
`effects are why a pharmacist consult may be necessary to verify the dosing regimen, check for
`interactions, and perform medication reconciliation. To receive maximum benefit from TZDs,
`patient body weight, liver function, plasma glucose, and HbA1c levels need monitoring at
`follow-up visits; these are functions that a diabetes nurse educator can perform and keep the
`prescriber informed regarding progress. In addition to being used as adjunctive therapy for
`diabetes, they have a place in patients with steatohepatitis since they reduce liver fat in clinical
`trials. With an appropriate interprofessional team approach to thiazolidinedione therapy, patient
`outcomes for type 2 diabetes can improve with minimal adverse events. [Level 5]
`
`Review Questions
`
`Access free multiple choice questions on this topic.
`
`Comment on this article.
`
`2.
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`3.
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`
`Disclosure: Julie Eggleton declares no relevant financial relationships with ineligible companies.
`
`Disclosure: Ishwarlal Jialal declares no relevant financial relationships with ineligible companies.
`
`Copyright © 2023, StatPearls Publishing LLC.
`
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`(CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work,
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`provided that you credit the author and journal.
`
`Bookshelf ID: NBK551656 PMID: 31869120
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