Sulphonylureas

Key examples

• Gliclazide

 

Common indications

• Type 2 diabetes mellitus: 
• As a single agent to control blood glucose and reduce complications where metformin is contraindicated or not tolerated. 
• In combination with metformin (and/or other hypoglycaemic agents) where blood glucose is not adequately controlled on a single agent.

 

Mechanisms of action

• Sulphonylureas lower blood glucose by stimulating pancreatic insulin secretion. 
• They block ATP-dependent K+ channels in pancreatic β-cell membranes, causing depolarisation of the cell membrane and opening of voltage-gated Ca2+ channels. This increases intracellular Ca2+ concentrations, stimulating insulin secretion. 
• Sulphonylureas are only effective in patients with residual pancreatic function. 
• As insulin is an anabolic hormone, stimulation of insulin secretion by sulphonylureas is associated with weight gain. Weight gain increases insulin resistance and can worsen diabetes mellitus in the long term.

 

Important adverse effects

• Dose-related side effects such as gastrointestinal upset (nausea, vomiting, diarrhoea, constipation) are usually mild and infrequent. 
• Hypoglycaemia is a potentially serious adverse effect, which is more likely with high treatment doses, where drug metabolism is reduced (see Warnings) or where other hypoglycaemic medications are prescribed (see Important interactions). Sulphonylurea-induced hypoglycaemia may last for many hours and, if severe, should be managed in hospital. 
• Rare hypersensitivity reactions include hepatic toxicity (e.g. cholestatic jaundice), drug hypersensitivity syndrome (rash, fever, internal organ involvement) and haematological abnormalities (e.g. agranulocytosis).

 

Warnings

• Gliclazide is metabolised in the liver and has a plasma half-life of 10–12 hours. Unchanged drug and metabolites are excreted in the urine. A dose reduction may therefore be required in patients with hepatic impairment and blood glucose should be monitored carefully in patients with renal impairment. 
• Sulphonylureas should be prescribed with caution for people at increased risk of hypoglycaemia, including those with hepatic impairment (reduced gluconeogenesis), malnutrition, adrenal or pituitary insufficiency (lack of counter-regulatory hormones) and the elderly.

 

Important interactions

• Risk of hypoglycaemia is increased by co-prescription of other antidiabetic drugs including metformin, thiazolidinediones (e.g. pioglitazone) and insulin. 
• The efficacy of sulphonylureas is reduced by drugs that elevate blood glucose, e.g. prednisolone, thiazide and loop diuretics.