Biguanides

Biguanides are oral glucose-lowering agents of which metformin is the only one in clinical use; phenformin and buformin were withdrawn because of lactic acidosis. Metformin lowers fasting and postprandial glucose without causing hypoglycaemia or weight gain, and is first-line therapy for type 2 diabetes.

Mechanism. Metformin inhibits mitochondrial complex I and glycerophosphate dehydrogenase and activates AMP-activated protein kinase. This reduces hepatic gluconeogenesis, improves peripheral insulin sensitivity and increases intestinal glucose use and GLP-1 secretion.

Pharmacokinetics. Oral bioavailability 50 to 60%. Not metabolised, and cleared unchanged by renal tubular secretion through OCT2 and MATE transporters. Half-life about 6 hours, much longer in renal impairment. Reduces HbA1c by 1 to 1.5%.

Preparations. Metformin immediate release (500, 850 and 1000 mg tablets), modified release (500, 750 and 1000 mg), and oral solution.

Immediate versus modified release. Modified release is given once daily with the evening meal and causes fewer gastrointestinal effects. Efficacy is similar.

Versus other classes. Neutral on weight, low cost, no hypoglycaemia as monotherapy, and cardiovascular benefit in obese patients. It is less potent than insulin or GLP-1 receptor agonists.

• Type 2 diabetes first-line: start 500 mg once or twice daily with food, increase by 500 mg every 1 to 2 weeks to 2 g daily. Maximum 3 g daily for immediate release in some regions, though doses over 2 g add little.
• Prediabetes: used in patients under 60 with BMI over 35 kg/m2, women with prior gestational diabetes, or rising HbA1c.
• Gestational diabetes: an alternative to insulin, 500 mg to 2 g daily, crosses the placenta.
• Polycystic ovary syndrome: 1.5 to 2 g daily improves metabolic features and ovulation (unlicensed in many regions).
• Kidney function: eGFR 45 to 59 mL/min, continue and monitor 3 to 6 monthly. eGFR 30 to 44 mL/min, do not start, reduce to a maximum 1 g daily. Under 30 mL/min, stop.
• Temporary withdrawal: during dehydrating illness, sepsis, acute kidney injury and hypoxia. For iodinated contrast, stop when eGFR is under 30 mL/min, in acute kidney injury or with intra-arterial contrast, and restart after 48 hours once renal function is stable.

Special groups. Pregnancy: acceptable in gestational diabetes and polycystic ovary syndrome, though insulin is preferred in type 2 diabetes. Breastfeeding: compatible. Children: from 10 years of age. Older adults: monitor eGFR and B12. Liver impairment: avoid in severe disease and alcohol excess.

Adverse effects. Diarrhoea, nausea, abdominal pain and metallic taste in up to 25%, which are dose-related and often settle with slow titration or modified release. Vitamin B12 deficiency with long-term use. Metformin-associated lactic acidosis is rare (fewer than 10 cases in 100,000 patient-years) and tied to renal failure, sepsis, hypoxia and alcohol excess.

Contraindications. eGFR under 30 mL/min, acute decompensated heart failure, shock, severe hepatic impairment, hypoxia and acute alcohol intoxication.

Interactions. Dolutegravir raises metformin exposure by about 80%, so total metformin is limited to 1 g daily when it is co-prescribed. Cimetidine, trimethoprim and dolutegravir inhibit tubular secretion. Iodinated contrast and alcohol raise lactic acidosis risk.

Monitoring. eGFR at baseline, then annually (3 to 6 monthly if eGFR under 60 mL/min); vitamin B12 every 2 to 3 years and in neuropathy or anaemia; HbA1c every 3 months.

Referral and escalation. Suspected lactic acidosis (lactate over 5 mmol/L with pH under 7.35) is an emergency requiring stopping metformin, and haemodialysis for severe cases.