II. Indications

  1. Oral Hypoglycemic for Type II Diabetes Mellitus
    1. Second line agent (although falling out of favor in 2012 due to risks)
    2. Add to other Oral Hypoglycemic agents
  2. Diabetes with coronary Vasospastic Angina pectoris
    1. Murakami (1999) Am J Cardiol 84:92-4 [PubMed]
  3. Insulin Resistance Syndromes (experimental)
    1. Polycystic Ovary Syndrome
  4. Psoriasis (experimental)
    1. Thiazolidinediones activate PPARs
      1. Peroxisome proliferator-activated receptors (PPARs)
    2. PPARs have antiinflammatory activity in Psoriasis
      1. Ellis (2000) Arch Dermatol 136(5):609-16 [PubMed]

III. Contraindications

  1. Liver disease (ALT > 2.5x upper limit of normal)
  2. CHF NYA Class III or Class IV Heart Failure
  3. Osteoporosis
  4. Bladder Cancer

IV. Precautions

  1. CHF exacerbation risk (and contraindicated for NYHA Class III or IV) for ALL Glitazones (FDA Black Box warning)

V. Mechanism

  1. Thiazolidinedione derivative
  2. Primary Mechanism: Increases peripheral tissue Insulin sensitivity
  3. Secondary Mechanism: Decreases hepatic Glucose production
  4. Acts at liver, skeletal muscle and fat cells
  5. Activates peroxisome proliferator activated receptors
    1. Receptors known as PPARS
    2. Reduces Insulin Resistance
    3. May independently reduce cardiovascular risk
    4. Increases Glucose uptake
    5. Decreases hepatic Glucose output
  6. Shifts fat deposition from visceral to subcutaneous
  7. Decreases free Fatty Acid levels

VI. Adverse Effects

  1. Hepatotoxicity and Liver Failure
    1. Associated with Troglitazone use
    2. Troglitazone removed from U.S. market in March 2000
    3. Rosiglitazone and Pioglitazone may also cause this
    4. Follow Liver Function Tests closely
      1. Especially follow in first year
    5. References
      1. May (2002) Ann Intern Med 136:449-52 [PubMed]
  2. Fluid retention
    1. Congestive Heart Failure risk (see below)
    2. Peripheral Edema (in 3-5% of patients)
    3. Moderate weight gain (1-3 kg)
    4. Mild Anemia
  3. Variable lipid effects
    1. Pioglitazone (Actos)
      1. Lowers Triglycerides by 9-12%
      2. Raises HDL Cholesterol by 12-19%
    2. Rosiglitazone (Avandia):
      1. RAISES Triglycerides by 15%
      2. Raises HDL Cholesterol by 8-19%
      3. Raises LDL Cholesterol
    3. References
      1. (2005) Prescriber's Letter 12(8):43
  4. Risks of adverse effects compounded with Insulin
    1. Weight gain (3-4 kg)
    2. Edema (8-10% of cases)
    3. Congestive Heart Failure
      1. Observe patients with CHF risk closely
    4. Hypoglycemia risk
  5. Decrease Bone Density (Osteoporosis risk)
    1. Class effect
    2. Odds Ratio approaches 2.5 for Glitazone use >8 months
    3. (2008) Arch Intern Med 168:820-5 [PubMed]
  6. Cardiovascular risk
    1. Rosiglitazone (Avandia) appears to increase CAD risk
      1. No longer recommended as a first-line agent
    2. Pioglitazone (Actos) may slightly decrease CAD risk
      1. Atherosclerosis may be slowed by Actos
      2. Nissen (2008) JAMA 299(13):1561-73 [PubMed]
  7. Bladder Cancer risk
    1. Risk of up to 11 per 10,000 cases per patients taking Pioglitazone (actos) >1 year
    2. Mamtani (2012) J Natl Cancer Inst 104 (18): 1411-1421 [PubMed]

VII. Preparations: Pioglitazone

  1. Preferred of the Glitazones due to vascular disease risk increase with Rosiglitazone
  2. Protocol
    1. Discontinue if no improvement in 8-12 weeks
  3. Dosing
    1. Initial: 15 to 30 mg orally daily
    2. Maximum: 45 mg per day

VIII. Preparations: Rosiglitazone (use only with caution)

  1. Precautions
    1. Limited use now due to increased cardiovascular risk
    2. FDA has restricted further Rosiglitazone use to those with refractory Type II Diabetes on other agents
      1. FDA will loosen restrictions in 2014 based on re-analysis of RECORD Study data, but caution is still advised
      2. (2014) Presc Lett 21(1): 3
  2. Conversion to Pioglitazone
    1. Rosiglitazone 2 mg is equivalent to Pioglitazone 15 mg
    2. Rosiglitazone 4 mg is equivalent to Pioglitazone 30 mg
    3. Rosiglitazone 8 mg is equivalent to Pioglitazone 45 mg
  3. Rosiglitazone (Avandia)
    1. Initial: 4 mg PO qd (or 2 mg PO bid)
    2. Maximum: 8 mg per day (4 mg if on Insulin)

IX. Pharmacokinetics

  1. Hepatic metabolism by Cytochrome P450: CYP2C8

X. Monitoring

  1. Liver Function Tests
    1. Initial: Baseline and in 6-12 weeks
    2. Later: Every 6 months
  2. Do not start medication if LFTs > 2.5x normal
  3. Stop medication if LFTs >3x normal
  4. Follow weight for weight gain (esp. if CHF risk)

XII. Cost

  1. Expensive! (Up to $175 to $192 per month)

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Cost: Medications

avandia (on 1/1/2016 at Medicaid.Gov Survey of pharmacy drug pricing)
AVANDIA 4 MG TABLET $4.80 each
pioglitazone (on 8/17/2016 at Medicaid.Gov Survey of pharmacy drug pricing)
PIOGLITAZONE HCL 15 MG TABLET Generic $0.14 each
PIOGLITAZONE HCL 30 MG TABLET Generic $0.19 each
PIOGLITAZONE HCL 45 MG TABLET Generic $0.22 each
PIOGLITAZONE-GLIMEPIRIDE 30-4 Generic $12.33 each
PIOGLITAZONE-METFORMIN 15-500 Generic $1.51 each
PIOGLITAZONE-METFORMIN 15-850 Generic $1.61 each
actos (on 7/6/2016 at Medicaid.Gov Survey of pharmacy drug pricing)
ACTOS 15 MG TABLET Generic $0.14 each
ACTOS 30 MG TABLET Generic $0.19 each
ACTOS 45 MG TABLET Generic $0.22 each

Ontology: pioglitazone (C0071097)

Definition (NCI_NCI-GLOSS) A drug that is used to treat type 2 diabetes and is being studied in the prevention of head and neck cancer. It may be able to stop leukoplakia (a condition affecting the mouth ) from developing into cancer. It is a type of thiazolidinedione.
Definition (NCI) An orally-active thiazolidinedione with antidiabetic properties and potential antineoplastic activity. Pioglitazone activates peroxisome proliferator-activated receptor gamma (PPAR-gamma), a ligand-activated transcription factor, thereby inducing cell differentiation and inhibiting cell growth and angiogenesis. This agent also modulates the transcription of insulin-responsive genes, inhibits macrophage and monocyte activation, and stimulates adipocyte differentiation.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C060836
SnomedCT 326058001, 395828009
LNC LP171629-1
English 5-(4-(2-(5-ethyl-2-pyridyl)ethoxy)benzyl)-2,4-thiazolidinedione, pioglitazone, pioglitazone [Chemical/Ingredient], PIOGLITAZONE, Pioglitazone (product), Pioglitazone (substance), Pioglitazone
Spanish pioglitazona (producto), pioglitazona (sustancia), pioglitazona

Ontology: troglitazone (C0245514)

Definition (NCI) An orally-active thiazolidinedione with antidiabetic and hepatotoxic properties and potential antineoplastic activity. Troglitazone activates peroxisome proliferator-activated receptor gamma (PPAR-gamma), a ligand-activated transcription factor, thereby inducing cell differentiation and inhibiting cell growth and angiogenesis. This agent also modulates the transcription of insulin-responsive genes, inhibits macrophage and monocyte activation, and stimulates adipocyte differentiation. (NCI04)
Definition (PDQ) An orally-active thiazolidinedione with antidiabetic and hepatotoxic properties and potential antineoplastic activity. Troglitazone activates peroxisome proliferator-activated receptor gamma (PPAR-gamma), a ligand-activated transcription factor, thereby inducing cell differentiation and inhibiting cell growth and angiogenesis. This agent also modulates the transcription of insulin-responsive genes, inhibits macrophage and monocyte activation, and stimulates adipocyte differentiation. Check for "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=42706&idtype=1" active clinical trials or "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=42706&idtype=1&closed=1" closed clinical trials using this agent. ("http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C1522" NCI Thesaurus)
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C057693
SnomedCT 109085002, 386967007
English 2,4-Thiazolidinedione, 5-((4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)phenyl)methyl)-, 5-(4-((6-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzyl)-2,4-thiazolidinedione), troglitazone, 5-[4-[(6-Hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]benzyl]-2,4-thiazolidinedione, 5-[[4-[4(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy]phenyl]methyl\-2,4-thiazolidinedione, troglitazone [Chemical/Ingredient], 5-((4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)phenyl)methyl)-2,4-Thiazolidinedione, Troglitazone, Troglitazone (product), Troglitazone (substance), TROGLITAZONE
Spanish troglitazona (producto), troglitazona (sustancia), troglitazona

Ontology: rosiglitazone (C0289313)

Definition (NCI_NCI-GLOSS) The active ingredient in a drug that helps control the amount of glucose (sugar) in the blood and is being studied in the prevention and treatment of some types of cancer. Rosiglitazone stops cells from growing and may prevent the growth of new blood vessels that tumors need to grow. It is a type of thiazolidinedione and a type of antiangiogenesis agent.
Definition (NCI) An agent belonging to the glitazone class of antidiabetic agents with antihyperglycemic and anti-inflammatory activities. In addition to its selective affinity for peroxisome proliferator-activated receptor (PPAR) gamma and its ability to lower blood glucose levels, rosiglitazone also exerts anti-inflammatory activity through its ability to inhibit nuclear factor-kappaB (NF-KB) activity and increase I-kappaB levels. In addition, rosiglitazone may cause fluid retention and may worsen congestive heart failure. This agent is also associated with an increased risk of heart attacks.
Definition (CSP) peroxisome proliferator activated receptor agonist; reduces lipid availability; improves insulin action and glucoregulation.
Definition (PDQ) An orally-active thiazolidinedione with antidiabetic properties and potential antineoplastic activity. Rosiglitazone activates peroxisome proliferator-activated receptor gamma (PPAR-gamma), a ligand-activated transcription factor, thereby inducing cell differentiation and inhibiting cell growth and angiogenesis. This agent also modulates the transcription of insulin-responsive genes, inhibits macrophage and monocyte activation, and stimulates adipocyte differentiation. Check for "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=37793&idtype=1" active clinical trials or "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=37793&idtype=1&closed=1" closed clinical trials using this agent. ("http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C2583" NCI Thesaurus)
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C089730
SnomedCT 326053005, 395869000
LNC LP171637-4
English 5-((4-(2-methyl-2-(pyridinylamino)ethoxy)phenyl)methyl)-2,4-thiazolidinedione-2-butenedioate, rosiglitazone, rosiglitazone [Chemical/Ingredient], 2,4-Thiazolidinedione, 5-004-02-((((methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-, ROSIGLITAZONE, Rosiglitazone (product), Rosiglitazone (substance), Rosiglitazone, ROS
Spanish rosiglitazona (producto), rosiglitazona (sustancia), rosiglitazona

Ontology: Rezulin (C0701265)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C057693
English Rezulin, rezulin, Parke Davis brand of troglitazone, Warner-Lambert brand of troglitazone

Ontology: Actos (C0875954)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C060836
English Actos, pioglitazone (Actos), actos, acto, Eli Lilly brand of pioglitazone hydrochloride, Takeda brand of pioglitazone hydrochloride

Ontology: Avandia (C0875967)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C089730
English Avandia, rosiglitazone maleate (Avandia), avandia, Glaxo Wellcome brand of rosiglitazone maleate, GlaxoSmithKline brand of rosiglitazone maleate, SmithKline Beecham brand of rosiglitazone maleate

Ontology: Thiazolidinediones (C1257987)

Definition (MSH) THIAZOLES with two keto oxygens. Members are insulin-sensitizing agents which overcome INSULIN RESISTANCE by activation of the peroxisome proliferator activated receptor gamma (PPAR-gamma).
Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
MSH D045162
SnomedCT 109086001, 372568004
Swedish Tiazolidinedioner
Czech thiazolidinediony, glitazony
Finnish Tiatsolidiinidionit
Russian TIAZOLIDINEDIONY, ТИАЗОЛИДИНЕДИОНЫ
English thiazolidinediones, thiazolidinediones (medication), Thiazolidinediones [Chemical/Ingredient], glitazone, glitazones, thiazolidinedione, Glitazones, Thiazolidinedione (product), Thiazolidinedione (substance), Thiazolidinedione, Thiazolidinediones
Japanese チアゾリジンジオン類, チアゾリジンジオン
Italian Glitazoni, Tiazolidinedioni
Spanish tiazolidinadiona (producto), tiazolidinediona (producto), tiazolidinediona, Tiazolidindionas, tiazolidinadiona (sustancia), tiazolidinadiona, tiazolidinediona (sustancia), Tiazolidinedionas
Polish Tiazolidinedionu pochodne, Tiazolidinediony
French Glitazones, Thiazolidine-diones, Thiazolidinediones
German Thiazolidindione
Portuguese Tiazolidinedionas