Thiazolidinediones

Thiazolidinediones (glitazones) are oral insulin sensitisers. Pioglitazone is the only member in general use; rosiglitazone is withdrawn or restricted in most regions because of cardiovascular concern, and troglitazone was withdrawn for hepatotoxicity. They reduce insulin resistance in fat, muscle and liver without causing hypoglycaemia when used alone.

Mechanism. They activate the nuclear receptor PPAR-gamma, which promotes adipocyte differentiation, increases subcutaneous fat storage, lowers circulating free fatty acids and raises adiponectin. Hepatic fat and glucose output fall, and peripheral glucose uptake rises.

Pharmacokinetics. Pioglitazone is well absorbed, highly protein bound and metabolised by CYP2C8 (and CYP3A4) to active metabolites. Half-life is 3 to 7 hours (16 to 24 hours with metabolites). Full glycaemic effect takes 6 to 12 weeks. HbA1c falls by 0.5 to 1.4%.

Pioglitazone. 15, 30 and 45 mg tablets, once daily with or without food.

Rosiglitazone. Associated with higher myocardial infarction risk in analyses of the early studies; not used in most regions.

Versus other oral agents. Durable glycaemic control, a fall in triglycerides and a rise in HDL cholesterol, and a benefit in fatty liver disease. These are offset by fluid retention, weight gain and fractures.

• Type 2 diabetes add-on: start 15 mg daily, increase to 30 mg after 4 to 12 weeks if tolerated, maximum 45 mg daily. When combined with insulin, use 15 to 30 mg and reduce the insulin dose by 10 to 25% if hypoglycaemia occurs.
• Metabolic dysfunction-associated steatotic liver disease with type 2 diabetes: pioglitazone 30 to 45 mg daily improves liver histology (off-label use).
• Insulin resistance after ischaemic stroke or transient ischaemic attack: pioglitazone reduces recurrent stroke and myocardial infarction in non-diabetic insulin-resistant patients; use is limited by side effects.
• Best candidates: marked insulin resistance, fatty liver, intolerance of metformin, and absence of heart failure, osteoporosis or bladder disease.

Special groups. Pregnancy: avoid; pioglitazone can restore ovulation in anovulatory women, so contraception is needed. Breastfeeding: avoid. Children: not used. Older adults: avoid in heart failure risk, frailty and osteoporosis. Kidney impairment: no adjustment, but fluid retention is more likely. Liver impairment: avoid if alanine aminotransferase is over 2.5 times the upper limit of normal.

Adverse effects. Fluid retention and peripheral oedema (4 to 6%, higher with insulin), heart failure, weight gain of 2 to 4 kg, distal fractures in women (about 1.5-fold risk), anaemia (dilutional), macular oedema and, with long exposure, a possible small increase in bladder cancer.

Contraindications. Heart failure of any grade, active or past bladder cancer, unexplained macroscopic haematuria, severe hepatic impairment, diabetic ketoacidosis and pregnancy.

Interactions. Gemfibrozil raises pioglitazone exposure about 3-fold, so the dose is limited to 15 mg daily. Rifampicin lowers levels. Insulin increases oedema and heart failure risk.

Monitoring. Weight and oedema at each visit in the first 3 months, liver enzymes at baseline and periodically, HbA1c every 3 months, and bone health in postmenopausal women. Stop for jaundice, new breathlessness or oedema, or haematuria.

Referral and escalation. New heart failure, haematuria, jaundice, or a low-trauma fracture.