Describe metformin with its mechanism, uses, adverse effects and contraindications.

Mechanism of Action

Metformin is taken up into hepatocytes by the OCT1 transporter → It inhibits mitochondrial complex I, so the cellular amp:ATP ratio rises → amp-activated protein kinase (AMPK) is activated → Hepatic gluconeogenesis is suppressed — the principal effect → Peripheral glucose uptake by muscle increases, and intestinal absorption falls → It is an "antihyperglycaemic", not a "hypoglycaemic" — it lowers a raised glucose but does not drive it below normal, because it does not stimulate insulin release

Pharmacokinetics and Uses

• Not metabolised and not protein-bound; excreted unchanged by the kidney — which is the entire basis of its contraindications
• Uses — type 2 diabetes (first-line, alone or in any combination, including with insulin); polycystic ovary syndrome, where it reduces insulin resistance and restores ovulation; and prevention of progression from prediabetes, particularly in the young and obese
• Advantages — cheap, effective, weight-neutral or slightly weight-reducing, no hypoglycaemia, and the longest safety record of any oral agent

Adverse Effects

• Gastrointestinal — the commonest: nausea, anorexia, metallic taste, abdominal discomfort and diarrhoea, in up to a third. Reduced by starting at a low dose, taking it with food, increasing slowly, and using the extended-release preparation. Most tolerance develops within weeks
• Vitamin B12 deficiency — from impaired ileal absorption, in up to 30% with long-term use; causes macrocytosis and can worsen or mimic diabetic neuropathy. Levels should be checked periodically, and certainly in any patient with neuropathy
• Lactic acidosis — rare (about 3 per 100,000 patient-years) but with a mortality approaching 50%. Metformin inhibits hepatic lactate clearance, so acidosis occurs when the drug accumulates or when lactate production rises. Presents with vomiting, abdominal pain, hyperventilation, hypotension and a high anion gap metabolic acidosis; treated with supportive care and haemodialysis, which removes both the drug and the acid
• Does not cause hypoglycaemia alone, though it can contribute when combined with insulin or a sulphonylurea

Contraindications and When to Withhold

• EGFR below 30 — absolute contraindication; the dose is reduced between 30 and 45 and it is not started below 45
• Withhold before iodinated contrast and restart only after renal function is confirmed stable at 48 hours
• Withhold during any acute illness with dehydration, hypoxia or sepsis — vomiting, diarrhoea, severe infection, myocardial infarction, decompensated cardiac failure
• Withhold before surgery and during the perioperative period
• Avoid in significant hepatic impairment and in alcohol excess, both of which impair lactate handling

Applied Aspects

• Teach "sick day rules" at the first prescription — stop metformin if unable to eat and drink normally, and restart when recovered; this prevents most cases of lactic acidosis
• Do not abandon metformin for gastrointestinal upset without trying the measures — low starting dose, with food, slow titration, extended-release form; a great many patients are switched to a more expensive and less proven drug unnecessarily
• Check B12 in any long-term user with neuropathy or macrocytosis, rather than assuming the neuropathy is diabetic
• Continue metformin when insulin is started in type 2 diabetes; it reduces the insulin dose needed and limits weight gain
• Metformin is on the WHO essential medicines list and costs very little, which makes it the appropriate foundation of diabetes care in India regardless of what newer agents can do
• There is no dose adjustment for age alone — only for renal function, which is what actually determines accumulation