Metformin

Metformin is a biguanide primarily used to treat type 2 diabetes mellitus. It improves glucose tolerance through several actions (detailed below). Unlike sulphonylureas, it doesn't cause hypoglycemia or weight gain, making it the first-line treatment—especially for overweight patients. Metformin is also used to treat polycystic ovarian syndrome and non-alcoholic fatty liver disease.

Mechanism of action: • Activates AMP-activated protein kinase (AMPK) • Increases insulin sensitivity • Decreases hepatic gluconeogenesis • May reduce gastrointestinal carbohydrate absorption

Adverse effects: • Gastrointestinal upset is common (nausea, anorexia, diarrhea)—intolerable in 20% of patients • Reduced vitamin B12 absorption—rarely clinically significant • Lactic acidosis with severe liver disease or renal failure • Note: Metformin-induced lactic acidosis is now known to be rare, though it remains an important exam topic

Contraindications: • Chronic kidney disease: NICE guidelines recommend dose review if creatinine >130 µmol/l (or eGFR <45 ml/min) and discontinuation if creatinine >150 µmol/l (or eGFR <30 ml/min) • Conditions causing tissue hypoxia (risk of lactic acidosis): recent myocardial infarction, sepsis, acute kidney injury, severe dehydration • Iodine-containing X-ray contrast media (e.g., peripheral arterial angiography, coronary angiography, intravenous pyelography [IVP]): increased risk of contrast nephropathy—discontinue metformin on procedure day and for 48 hours after • Alcohol abuse (relative contraindication)

Starting metformin: • Gradually titrate dose to minimize gastrointestinal side effects • Consider modified-release metformin if standard formulation causes unacceptable side effects

Sulfonylureas

work by increasing pancreatic insulin secretion and hence are only effective if functional B-cells are present. On a molecular level they bind to an ATP-dependent K+ (KATP) channel on the cell membrane of pancreatic beta cells.

Common adverse effects

• hypoglycaemic episodes (more common with long-acting preparations such as chlorpropamide)
• weight gain

Rarer adverse effects

• hyponatraemia secondary to syndrome of inappropriate ADH secretion
• bone marrow suppression
• hepatotoxicity (typically cholestatic)
• peripheral neuropathy

Sulfonylureas should be avoided in breastfeeding and pregnancy.