Diabetes Drugs - Thiazolidinediones: pioglitazone

Question 1

Thiazolidinediones: pioglitazone

Common Indications?

Answer 1

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.

Question 2

Thiazolidinediones: pioglitazone

Mechanism of Action?

Answer 2

• 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.
• However, they cause weight gain, which can increase insulin resistance

Question 3

Thiazolidinediones: pioglitazone

Important Adverse Effects?

Answer 3

• 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• Troglitazone was withdrawn from the market due to liver toxicity.

Question 4

Thiazolidinediones: pioglitazone

Warnings?

Answer 4

• 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.

Question 5

Thiazolidinediones: pioglitazone

Practical Prescribing?

Answer 5

• Pioglitazone is only available for oral administration.
• A typical starting dose is 15–30 mg once daily with breakfast, increased to a maximum of 45 mg daily depending on response.
• Pioglitazone is a long-term treatment that in general should be stopped or changed only if adverse effects are intolerable or new contraindications develop.
• Can be taken with or without food

Question 6

Thiazolidinediones: pioglitazone

Monitoring?

Answer 6

• Monitor efficacy by measuring glycated haemoglobin (HbA1c) before and 3–6 months after commencing treatment to determine blood glucose control.
• Treatment should be stopped and alternatives considered if there is no fall in HbA1c.
• For safety, liver enzymes should be measured prior to and during therapy.
• Treatment should not be started if baseline transaminase levels are increased and may need to be discontinued if values are persistently elevated during treatment.