Pioglitazone

See Also

Indications

Pioglitazone is preferred of the Glitazones
1. Vascular disease risk increase with Rosiglitazone
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
Diabetes with coronary Vasospastic Angina pectoris
1. Murakami (1999) Am J Cardiol 84:92-4 [PubMed]
Insulin Resistance Syndromes (experimental)
1. Polycystic Ovary Syndrome
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]

Contraindications

Type 1 Diabetes Mellitus
Liver disease (ALT > 2.5x upper limit of normal)
CHF NYA Class III or Class IV Heart Failure
Osteoporosis or Osteopenia
Bladder Cancer

Precautions

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

Mechanism

Thiazolidinedione derivative
Primary mechanism: Increases peripheral tissue Insulin sensitivity
Secondary mechanism: Decreases hepatic Glucose production
Acts at liver, skeletal Muscle and fat cells
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
Shifts fat deposition from visceral to subcutaneous
Decreases free Fatty Acid levels

Medications

Pioglitazone (Actos) 15 mg, 30 mg, 45 mg

Dosing

Protocol
1. Discontinue if no improvement in diabetes control within 8 to 12 weeks
Dosing
1. Start: 15 to 30 mg orally daily for the first 3 months
2. Maximum: 45 mg per day

Adverse Effects

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]
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
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
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
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]
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]
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]

Pharmacokinetics

Hepatic metabolism by Cytochrome P450: CYP2C8

Monitoring

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

Efficacy

Lowers Hemoglobin A1C 0.5 to 1.5%
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]

Safety

Unknown Safety in pregnancy
Avoid in Lactation

Resources

Pioglitazone (DailyMed)
1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5e36173a-2b5f-4ed7-bf81-6e79d78df0c4

References