Pharm
Thiazolidinedione
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Thiazolidinedione
, Glitazone, Troglitazone, Rezulin
See Also
Type II Diabetes Medications
Rosiglitazone
Pioglitazone
Indications
Oral Hypoglycemic
for
Type II Diabetes Mellitus
Second line agent (although falling out of favor in 2012 due to risks)
Add to other
Oral Hypoglycemic
agents
Diabetes with coronary
Vasospastic Angina
pectoris
Murakami (1999) Am J Cardiol 84:92-4 [PubMed]
Insulin Resistance Syndrome
s (experimental)
Polycystic Ovary Syndrome
Psoriasis
(experimental)
Thiazolidinediones activate PPARs
Peroxisome proliferator-activated receptors (PPARs)
PPARs have antiinflammatory activity in
Psoriasis
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
Receptors known as PPARS
Reduces
Insulin Resistance
May independently reduce
Cardiovascular Risk
Increases
Glucose
uptake
Decreases hepatic
Glucose
output
Shifts fat deposition from visceral to subcutaneous
Decreases free
Fatty Acid
levels
Medications
Pioglitazone
Preferred of the Glitazones due to vascular disease risk increase with
Rosiglitazone
Protocol
Discontinue if no improvement in diabetes control within 8 to 12 weeks
Dosing
Initial: 15 to 30 mg orally daily
Maximum: 45 mg per day
Medications
Rosiglitazone
(use only with caution)
Precautions
Limited use now due to increased
Cardiovascular Risk
FDA has restricted further
Rosiglitazone
use to those with refractory
Type II Diabetes
on other agents
FDA will loosen restrictions in 2014 based on re-analysis of RECORD Study data, but caution is still advised
(2014) Presc Lett 21(1): 3
Conversion to
Pioglitazone
Rosiglitazone
2 mg is equivalent to
Pioglitazone
15 mg
Rosiglitazone
4 mg is equivalent to
Pioglitazone
30 mg
Rosiglitazone
8 mg is equivalent to
Pioglitazone
45 mg
Rosiglitazone
(
Avandia
)
Initial: 4 mg PO qd (or 2 mg PO bid)
Maximum: 8 mg per day (4 mg if on
Insulin
)
Adverse Effects
Hepatotoxicity and
Liver
Failure
Associated with Troglitazone use
Troglitazone removed from U.S. market in March 2000
Rosiglitazone
and
Pioglitazone
may also cause this
Follow
Liver Function Test
s closely
Especially follow in first year
References
May (2002) Ann Intern Med 136:449-52 [PubMed]
Fluid retention
Congestive Heart Failure
risk (see below)
Peripheral Edema
(in 3-5% of patients)
Moderate weight gain (1-3 kg)
Mild
Anemia
Variable lipid effects
Pioglitazone
(
Actos
)
Lowers
Triglyceride
s by 9-12%
Raises
HDL Cholesterol
by 12-19%
Rosiglitazone
(
Avandia
):
RAISES
Triglyceride
s by 15%
Raises
HDL Cholesterol
by 8-19%
Raises
LDL Cholesterol
References
(2005) Prescriber's Letter 12(8):43
Risks of adverse effects (compounded when combined with
Insulin
)
Weight gain (3-4 kg)
Edema
(8-10% of cases)
Congestive Heart Failure
Observe patients with CHF risk closely
Hypoglycemia
risk
Fracture
Risk and Decreased Bone Density (
Osteoporosis
risk)
Class effect
Odds Ratio
approaches 2.5 for Glitazone use >8 months
(2008) Arch Intern Med 168:820-5 [PubMed]
Cardiovascular Risk
Rosiglitazone
(
Avandia
) appears to increase CAD risk
No longer recommended as a first-line agent
Pioglitazone
(
Actos
) may slightly decrease CAD risk
Atherosclerosis may be slowed by
Actos
Nissen (2008) JAMA 299(13):1561-73 [PubMed]
Bladder Cancer
risk
Risk of up to 11 per 10,000 cases per patients taking
Pioglitazone
(actos) >1 year
Mamtani (2012) J Natl Cancer Inst 104 (18): 1411-1421 [PubMed]
Pharmacokinetics
Hepatic metabolism by
Cytochrome P450
: CYP2C8
Monitoring
Liver Function Test
s
Initial: Baseline and in 6-12 weeks
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
,
Sulfonylurea
s
Aljabri (2004) Am J Med 116:230-5 [PubMed]
Dailey (2004) Am J Med 116:223-9 [PubMed]
References
(1999) Med Lett Drugs Ther 41(1059):71-3 [PubMed]
Krische (2000) West J Med 173:54-7 [PubMed]
Schwartz (1998) N Engl J Med 338:861-6 [PubMed]
Saltiel (1996) Diabetes 45:1661-9 [PubMed]
Vaughan (2024) Am Fam Physician 109(4): 333-42 [PubMed]
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