Thiazolidinediones

Key examples

• Pioglitazone

 

Common indications

Type 2 diabetes mellitus:

• As a single agent in overweight patients where metformin is contraindicated or not tolerated.
• Added as a second agent to metformin or a sulphonylurea where blood glucose control is inadequate on one drug and the metformin/sulphonylurea combination is contraindicated or not tolerated.
• Added as a third agent with metformin and a sulphonylurea where blood glucose control is inadequate as an alternative to starting insulin.

 

Mechanisms of action

• Thiazolidinediones are insulin sensitisers. 
• They lower blood glucose by activating the gamma subclass of nuclear peroxisome proliferator-activated receptors (PPARγ). 
• This induces genes which enhance insulin action in skeletal muscle, adipose tissue and the liver, with increased peripheral glucose uptake and utilisation and reduced hepatic gluconeogenesis. 
• Thiazolidinediones do not stimulate pancreatic insulin secretion, hence do not cause hypoglycaemia. 
• They cause weight gain, which can increase insulin resistance.

 

Important adverse effects

• Adverse effects of pioglitazone include gastrointestinal upset, anaemia and minor neurological effects such as dizziness, headache and disturbed vision. 
• More serious side effects include oedema and cardiac failure, particularly where pioglitazone is prescribed with insulin. 
• Pioglitazone is associated with a small increase in the risk of bladder cancer and an increase in bone fractures in women. 
• Idiosyncratic reactions include severe liver toxicity. 
• Pioglitazone is the only thiazolidinedione currently available for prescription in the UK. 
• The marketing authorisation (license) for rosiglitazone has been suspended as cardiovascular risk associated with this drug appears greater than its potential benefits. 
• Troglitazone was withdrawn from the market due to liver toxicity.

 

Warnings

• Pioglitazone should be avoided or prescribed with caution in people at increased risk of serious adverse effects. 
• It is contraindicated in people with heart failure and should be used with caution in cardiovascular disease. 
• It is contraindicated if there is known bladder cancer or macroscopic haematuria and should be used with caution in people with risk factors for bladder cancer (e.g. smoking, occupational exposure, prior pelvic irradiation). 
• Careful consideration should be given when prescribing pioglitazone for elderly patients, who tend to have increased risk of cardiac disease, bladder cancer and bone fractures. 
• Pioglitazone is extensively metabolised in the liver and can cause liver toxicity, so should be used with caution in hepatic impairment.

 

Important interactions

• Pioglitazone is usually prescribed in combination with other antidiabetic drugs, which increases the risk of adverse effects, e.g. hypoglycaemia and cardiac failure. 
• There are no other significant drug interactions.