Pioglitazone

Pioglitazone is an oral thiazolidinedione that improves insulin sensitivity in fat, muscle and liver. It lowers HbA1c by about 0.5 to 1.4% with a slow onset of 6 to 12 weeks, carries low hypoglycaemia risk, improves hepatic steatohepatitis, and reduces recurrent vascular events in some groups, but causes fluid retention, weight gain and fractures.

Classification. Thiazolidinedione, PPAR-gamma agonist with weak PPAR-alpha activity. Tablets 15, 30 and 45 mg; fixed-dose combinations with metformin, glimepiride and alogliptin exist.

Mechanism. Activates the nuclear receptor PPAR-gamma, changing transcription of genes for glucose transport and lipid handling. Fat shifts from liver and muscle into subcutaneous adipose tissue, and adiponectin rises.

Pharmacodynamics. Lowers fasting glucose, insulin and free fatty acids. Triglycerides fall and HDL cholesterol rises, with little effect on LDL cholesterol. Renal sodium retention causes plasma volume expansion.

Pharmacokinetics. Bioavailability over 80%; peak about 2 hours; over 99% protein bound. Metabolised mainly by CYP2C8, with some CYP3A4, to active metabolites. Parent half-life 3 to 7 hours; total active moiety 16 to 24 hours. Excreted mainly in bile and faeces, with 15 to 30% in urine.

Type 2 diabetes, adults.

• Start 15 to 30 mg orally once daily, with or without food.
• Increase in 15 mg steps no sooner than every 4 to 12 weeks, because full effect takes up to 12 weeks.
• Maximum 45 mg once daily. No loading dose.
• Review at 3 to 6 months; stop when HbA1c reduction is under 0.5% (5.5 mmol/mol).

With insulin.

• 15 to 30 mg once daily. Reduce insulin by 10 to 25% if hypoglycaemia occurs. Watch closely for oedema and heart failure, which are more frequent in this combination.

Metabolic dysfunction-associated steatohepatitis (unlicensed).

• 30 mg once daily, increased to 45 mg once daily, in patients with or without diabetes when steatohepatitis is confirmed. Specialist use.

Secondary prevention after ischaemic stroke or TIA with insulin resistance (unlicensed).

• Start 15 mg once daily and titrate to 45 mg once daily. Benefit on recurrent stroke and myocardial infarction is offset by fractures, weight gain and oedema; specialist decision.

Adjustments.

• Kidney: no dose change; fluid retention is more troublesome in advanced kidney disease and on dialysis.
• Liver: do not start if ALT is more than 2.5 times the upper limit of normal from active liver disease; labels advise against use in hepatic impairment except under specialist direction for steatohepatitis.
• Strong CYP2C8 inhibitors (gemfibrozil): maximum 15 mg daily.
• Older adults: start 15 mg.
• Weight: no weight-based dosing.

Contraindications. Heart failure: any history of heart failure in most labels, and NYHA class III to IV in others. Current or previous bladder cancer, or uninvestigated macroscopic haematuria. Diabetic ketoacidosis. Hepatic impairment from active liver disease. Type 1 diabetes.

Boxed-warning-level risk. Fluid retention can cause or worsen heart failure. Stop at once if heart failure develops.

Other adverse effects.

• Weight gain of 2 to 4 kg from fat and fluid; peripheral oedema in about 5%, more with insulin.
• Distal limb fractures, mainly in women.
• Bladder cancer: a small possible increase with long duration and high cumulative dose. Assess age, smoking, occupational exposure and haematuria before starting.
• Macular oedema with reduced vision.
• Hepatotoxicity is rare; anaemia from haemodilution.
• Ovulation may resume in anovulatory premenopausal women.

Major interactions.

• Gemfibrozil doubles to triples exposure; cap at 15 mg.
• Rifampicin roughly halves exposure.
• Insulin and NSAIDs add to fluid retention.
• Sulphonylureas and insulin increase hypoglycaemia risk.

Special groups.

• Pregnancy: avoid; use insulin. Advise contraception in premenopausal women.
• Breastfeeding: avoid.
• Children: not licensed.
• Older adults: weigh fracture and heart failure risk; start 15 mg.
• Kidney and liver impairment: no dose change for kidney disease, though oedema is harder to manage; avoid in active liver disease.
• East Africa: an inexpensive non-hypoglycaemic option where SGLT2 inhibitors and GLP-1 receptor agonists are unaffordable. Rifampicin during TB treatment lowers effect. Screen for heart failure, which is common from hypertensive and rheumatic heart disease.

Administration. Once daily at a consistent time, with or without food.

Baseline. HbA1c, ALT, weight, assessment for heart failure and oedema, urinalysis for haematuria, bladder cancer risk factors, fracture risk.

Monitoring.

• HbA1c at 3 months and 6 months, then every 6 months.
• Weight and oedema at each visit; investigate rapid weight gain of 2 kg or more in a week.
• ALT periodically and with symptoms of liver injury.
• Urinalysis if haematuria is reported; visual symptoms prompt eye review.

Stopping thresholds. Stop with heart failure, ALT more than 3 times the upper limit of normal with jaundice or persisting on repeat testing, macroscopic haematuria pending investigation, macular oedema or inadequate HbA1c response at 6 months.

Referral and escalation. Admit new heart failure. Refer macroscopic haematuria to urology and visual loss to ophthalmology.