Metformin Initiation and Titration

Metformin is the usual first-line oral drug in type 2 diabetes. It lowers hepatic glucose output and improves insulin sensitivity, does not cause hypoglycaemia on its own, is weight neutral, is cheap, and has long-term safety data. Gastrointestinal intolerance is the main limit, and lactic acidosis is rare but serious.

Kidney threshold. Metformin is cleared unchanged by the kidney. Its use is set by eGFR.

Vitamin B12. Long-term use lowers vitamin B12 in a proportion of patients.

Indications. Type 2 diabetes, prediabetes with high risk, gestational diabetes (second-line to insulin in some practice), and polycystic ovary syndrome (off-label).

Contraindications. eGFR under 30 mL/min/1.73 m2, acute kidney injury, severe sepsis, shock, hypoxia, acute heart failure, decompensated cirrhosis, active heavy alcohol use, and diabetic ketoacidosis.

Formulation. Immediate-release tablets 500 mg, 850 mg and 1 g. Modified-release tablets help patients with gastrointestinal intolerance.

Adults. - Start 500 mg orally once daily with the evening meal for 1 week. - Increase by 500 mg weekly to 500 mg twice daily, then 1 g twice daily. - Usual maximum is 2 g daily; some labels allow up to 3 g daily, with little added effect over 2 g. - Modified-release: start 500 mg once daily with the evening meal, increase by 500 mg weekly to a maximum of 2 g once daily.

Kidney function. - eGFR 45 or more: full dose. - eGFR 30 to 44: do not start; if already taking it, maximum 1 g daily. - eGFR under 30: stop.

Contrast and procedures. Withhold metformin at the time of iodinated contrast if eGFR is 30 to 60 or contrast is given intra-arterially, and restart 48 hours later once kidney function is confirmed stable. Withhold on the day of surgery in major procedures with fasting.

Gastrointestinal intolerance. Slow the titration, take with food, switch to modified-release, or accept a lower dose of 1 to 1.5 g daily.

Special groups. - Liver disease: avoid in decompensated cirrhosis and active alcohol misuse. - Pregnancy: may continue in type 2 diabetes or polycystic ovary syndrome; insulin is added when targets are missed. - Breastfeeding: compatible. - Older adults: reduce dose as eGFR falls; stop in frailty with poor intake. - Children from 10 years with type 2 diabetes: 500 mg orally once daily with a meal, increased weekly to a maximum of 2 g daily.

Monitoring. eGFR before starting, then every 6 to 12 months, or every 3 to 6 months when eGFR is under 60. Vitamin B12 every 2 to 3 years, or sooner if neuropathy, anaemia or macrocytosis appears.

Sick-day rule. Withhold during vomiting, diarrhoea, fever, dehydration or acute illness, and restart after 24 to 48 hours of normal eating and drinking.

Stopping. Stop for eGFR under 30, lactic acidosis, acute kidney injury, or decompensated liver disease.

Lactic acidosis. Suspect with malaise, myalgia, abdominal pain, tachypnoea, and a lactate over 5 mmol/L with pH under 7.35. Treat in intensive care with supportive care and consider renal replacement.

Referral and escalation. Seek specialist input for intolerance at low doses, B12 deficiency with neurological signs, or eGFR falling under 45.