Rosiglitazone

Rosiglitazone is an oral thiazolidinedione and a selective PPAR-gamma agonist. It lowers HbA1c by about 1% but carries the class risks of fluid retention, heart failure and fractures, raises LDL cholesterol and has concerns about myocardial ischaemia. Its marketing authorisation was suspended in Europe, and pioglitazone is preferred when a thiazolidinedione is needed.

Classification. Thiazolidinedione. Tablets 2, 4 and 8 mg where marketed.

Mechanism. Activates PPAR-gamma, improving insulin sensitivity in adipose tissue, muscle and liver.

Pharmacodynamics. Slow onset over 8 to 12 weeks. Raises HDL and LDL cholesterol, with LDL rising more than with pioglitazone; little effect on triglycerides.

Pharmacokinetics. Bioavailability about 99%; peak about 1 hour; 99.8% protein bound. Metabolised mainly by CYP2C8, with some CYP2C9, to inactive metabolites excreted mostly in urine. Half-life 3 to 4 hours.

Type 2 diabetes, adults (where licensed).

• Start 4 mg orally daily as a single dose or 2 mg twice daily.
• Increase to 8 mg daily after 8 to 12 weeks if response is inadequate.
• Maximum 8 mg daily. No loading dose. Review at 3 to 6 months and stop when HbA1c reduction is under 0.5%.

Combination use. May be combined with metformin or a sulphonylurea. Combination with insulin or nitrates is not advised.

Adjustments.

• Kidney: no dose change.
• Liver: do not start if ALT is more than 2.5 times the upper limit of normal or with active liver disease.
• Gemfibrozil: roughly doubles exposure; avoid or reduce dose.
• Older adults: start 4 mg daily; weigh fracture and heart failure risk.
• Weight: no weight-based dosing.

Contraindications. Heart failure (NYHA class III to IV in all labels; any heart failure in some); acute coronary syndrome; active liver disease; diabetic ketoacidosis; type 1 diabetes.

Boxed-warning-level risk. Causes or worsens heart failure. Product labels carry warnings on myocardial ischaemia; avoid in established ischaemic heart disease, especially with nitrates or insulin.

Other adverse effects. Weight gain, oedema, anaemia from haemodilution, distal fractures in women, macular oedema, raised LDL cholesterol, rare hepatotoxicity, ovulation in anovulatory women.

Major interactions. Gemfibrozil and other CYP2C8 inhibitors raise levels; rifampicin lowers them; insulin, NSAIDs and nitrates add risk.

Special groups.

• Pregnancy and breastfeeding: avoid; use insulin.
• Children: not licensed.
• Older adults: avoid where alternatives exist.
• East Africa: rarely stocked; switch patients found on it to pioglitazone or another class.

Administration. Once or twice daily, with or without food.

Baseline. HbA1c, ALT, lipid profile, weight, heart failure and ischaemic heart disease assessment.

Monitoring.

• HbA1c every 3 months until stable.
• Weight, oedema and heart failure symptoms at each visit.
• ALT periodically; lipids after 3 months.

Stopping thresholds. Stop with heart failure, ischaemic chest pain, ALT more than 3 times the upper limit of normal with jaundice or on repeat testing, macular oedema, or inadequate response at 6 months.

Referral and escalation. Admit new heart failure or suspected acute coronary syndrome. Most patients still on rosiglitazone need review to change class.