Drug Summary – Pioglitazone

(Refer to Drug review - Pioglitazone for optional full text and references)

Mode of action	Agonist of nuclear receptors called peroxisome proliferator-activated receptor-gamma (PPARγ). Leads to increased transcription of proteins that augment the post-receptor actions of insulin resulting in improved insulin sensitivity and ß-cell function
Glycaemic efficacy and indications	Good efficacy as monotherapy, dual therapy and triple therapy (± 1% HbA1C reduction); similar efficacy to metformin, SU or GLP-1RA
Cardiovascular outcome trials	PROactive study (secondary prevention) showed reductions in secondary endpoints (composite of all-cause mortality, non-fatal myocardial infarction, and stroke) by 16% Meta-analysis of RCTs also reported a significant 18% relative risk reduction in the composite outcome (death, myocardial infarction, or stroke) Increases heart failure hospitalisations because of fluid retention, but not mortality
Hypoglycaemia	Does not cause hypoglycaemia except when combined with insulin or insulin secretagogues
Weight	Causes dose-dependent weight gain (~2-4 kg) due to fluid retention and adipocyte differentiation Weight gain correlates with therapeutic response
Non-glycaemic benefits	Increases HDL-C; reduces triglycerides, reduces LDL atherogenicity, CRP and microalbuminuria; increases PAI-1 and adiponectin; reduces carotid intimamedia thickness and atheroma volume Reduces hepatic fibrosis in non-alcoholic steatohepatitis (NASH); improves ovulation and metabolic Abnormalities in polycystic ovary syndrome
Side Effects and Precautions	Can cause fluid retention, oedema, and may worsen or precipitate congestive heart failure Associated with an increase in distal long-bone fractures in women and men Possible small increase in bladder cancer
Dosing and prescribing	Start with 15 once daily in the morning; increase to 30 mg after one to three months if necessary Most patients will derive optimum benefit at this dose; do not exceed 30 mg in the primary care setting Maximum registered dose is 45 mg daily
Renal dosing	No dose adjustment is necessary, but do not use if renal disease is causing fluid retention, or when the eGFR is <30 ml/min/1.73m2
Cost of cheapest formulation	R 117.00 for 30 mg

 

(See Strength of Recommendations Taxonomy (SORT) for explanation of Grade A-C)

SEMDSA 2017 Recommendations for pioglitazone
Consider pioglitazone as initial monotherapy when metformin is contraindicated or not tolerated	A
Consider pioglitazone as add-on to metformin or other initial drug therapy, in selected patients not achieving or maintaining their glycaemic targets	A
Consider pioglitazone as a third non-insulin glucose lowering drug in selected patients not achieving or maintaining their glycaemic targets on an existing oral two-drug regimen	A
Circumstances where pioglitazone may be preferred to other treatment options: Gliclazide MR is contraindicated or not tolerated Non-alcoholic steatohepatitis is present The patient has features of severe insulin resistance There is a history of previous myocardial infarction, previous stroke or chronic kidney disease stage-3 (pioglitazone offers probable benefit for secondary prevention)	C
Circumstances where pioglitazone may not be the preferred option: Age > 75 years old (risk of congestive heart failure (CHF), fracture and bladder cancer) History of congestive heart failure History of osteoporosis History of bladder cancer, or haematuria that has not been investigated Stage-4 or worse chronic kidney disease (risk of fluid retention) Patients on insulin therapy (higher risk of fluid retention and CHF) Elevated liver enzymes (>2x ULN), which is not due to NASH	C

Caution:

Do not persist with any chosen treatment if the HbA1C has not decreased by > 0.5% after six months

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