Sulfonylureas

Mechanism of Action  

Sulfonylureas stimulate insulin secretion from pancreatic β-cells, therefore are only effective when there is some residual pancreatic β-cell activity present. 

They work by binding to and blocking ATP-sensitive potassium channels on pancreatic beta cells, causing accumulation of intracellular potassium and depolarisation of the cell. This leads to opening of calcium channels, calcium influx into the cell, and subsequently insulin release through exocytosis. 

Additionally, glimepiride increases glucose transport molecules on the plasma membranes of muscle and fat cells, enhancing glucose uptake and utilisation.

Aydintay, Public domain, via Wikimedia Commons

Fig 1: Sulfonylureas, mechanism of action

Cautions and Contraindications

Renal and hepatic impairment 

Renal impairment increases the risk of hypoglycaemia.
If use is necessary:

• Tolbutamide (short-acting) and gliclazide (mainly hepatic metabolism) are preferred.
• Insulin is recommended in severe impairment.

Hepatic impairment increases hypoglycaemia risk, particularly with glipizide.

Adverse Effects

One of the most clinically relevant side effects of sulfonylureas is hypoglycaemia, which is defined as a blood sugar level below 4mmol/L.

By TeachMeSeries Ltd (2026)

Fig 2: Risk factors for and symptoms of hypoglycaemia

Other side effects:

• Gastrointestinal: transient diarrhoea with glibenclamide
• Hepatic impairment
• Skin: rash, angioedema, itching, photosensitivity, stevens-johnson syndrome (glibenclamide)
• Blood: leucopenia, thrombocytopenia, agranulocytosis, pancytopenia, haemolytic anaemia
• Electrolytes: hyponatraemia (gliclazide, glipizide)

Interactions 

• Beta blockers – mask signs of hypoglycaemia such as tremor (interaction is applicable to all antidiabetic agents)
• Medications that may reduce efficacy of sulfonylureas include: 
  • Medications that may antagonise the blood glucose lowering effects of sulfonylureas: danazol, chlorpromazine, glucocorticoids, diuretics, oestrogens and progesterones 
• Colesevelam reduces absorption of glibenclamide, glimepiride and glipizide – take 4 hours before or after colesevelam (take 4 hours before for glimepiride)
• Sulfonylureas are metabolised by CYP2C9, therefore CYP2C9 inducers such as rifampicin and St John’s wort may reduce the plasma concentration of sulfonylureas 
• Medications that may enhance the blood glucose lowering effects of sulfonylureas include:
  • Alcohol, anabolic steroids, ACE-inhibitors, chloramphenicol, cimetidine, coumarins, MAOIs, NSAIDs, testosterone, tetracyclines and trimethoprim
• Highly protein bound drugs may displace glibenclamide (99% bound to albumin) from plasma proteins and therefore potentiate the hypoglycemic effect e.g. phenytoin, NSAIDs, oral anticoagulants
• Sulfonylureas are metabolised by CYP2C9 therefore CYP2C9 inhibitors such as fluconazole and miconazole may increase the plasma concentration of sulfonylureas 
  • Miconazole use is contraindicated with gliclazide & glipizide
• Tolbutamide transiently increases plasma concentrations of phenytoin and fosphenytoin

References 

1. Sulfonylureas | Prescribing information | Diabetes – type 2 | CKS | NICE
2. AMGLIDIA 0.6 mg/mL oral suspension with 5 mL oral syringe – Summary of Product Characteristics (SmPC) – (emc)
3. Gliclazide 80 mg Tablets – Summary of Product Characteristics (SmPC) – (emc)
4. Glimepiride 1 mg tablets – Summary of Product Characteristics (SmPC) – (emc)
5. Minodiab 5mg Tablets – Summary of Product Characteristics (SmPC) – (emc)
6. Tolbutamide Tablets BP 500 mg – Summary of Product Characteristics (SmPC) – (emc)
7. Didari E, Sarhangi N, Afshari M, Aghaei Meybodi HR, Hasanzad M. A pharmacogenetic pilot study of CYP2C9 common genetic variant and sulfonylureas therapeutic response in type 2 diabetes mellitus patients. J Diabetes Metab Disord. 2021 Sep 14;20(2):1513-1519. doi: 10.1007/s40200-021-00894-0. PMID: 34900803; PMCID: PMC8630254