Thiazolidinedione

Aka: Thiazolidinedione, Glitazone, Troglitazone, Rezulin

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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. Type 1 Diabetes Mellitus
  2. Liver disease (ALT > 2.5x upper limit of normal)
  3. CHF NYA Class III or Class IV Heart Failure
  4. Osteoporosis or Osteopenia
  5. 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. Medications: Pioglitazone

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

VII. Medications: 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)

VIII. 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 when combined 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. Fracture Risk and Decreased 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]

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)

XI. Efficacy

  1. Lowers Hemoglobin A1C 0.5 to 1.5%
  2. Delays Insulin need when added to Metformin, Sulfonylureas
    1. Aljabri (2004) Am J Med 116:230-5 [PubMed]
    2. Dailey (2004) Am J Med 116:223-9 [PubMed]

XII. References

  1. (1999) Med Lett Drugs Ther 41(1059):71-3 [PubMed]
  2. Krische (2000) West J Med 173:54-7 [PubMed]
  3. Schwartz (1998) N Engl J Med 338:861-6 [PubMed]
  4. Saltiel (1996) Diabetes 45:1661-9 [PubMed]
  5. Vaughan (2024) Am Fam Physician 109(4): 333-42 [PubMed]

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Related Studies

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
Derived from the NIH UMLS (Unified Medical Language System)

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
Derived from the NIH UMLS (Unified Medical Language System)

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
Derived from the NIH UMLS (Unified Medical Language System)

Related Topics in Pharmacology

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