Metformin

Metformin is an oral biguanide and the usual first-line glucose-lowering medicine in type 2 diabetes. It lowers HbA1c by about 1 to 1.5% (11 to 16 mmol/mol), does not cause hypoglycaemia when used alone, is weight neutral or causes modest weight loss, and is cleared unchanged by the kidney, so renal function sets its dose ceiling.

Classification. Biguanide insulin sensitiser. Available as immediate-release (IR) tablets, extended-release (XR) tablets and oral solution, and in fixed-dose combinations with DPP-4 inhibitors, SGLT2 inhibitors, sulphonylureas and pioglitazone.

Mechanism. Reduces hepatic glucose output mainly by suppressing gluconeogenesis, through effects on mitochondrial redox state and complex I and activation of AMP-activated protein kinase. It also improves peripheral glucose uptake and raises endogenous GLP-1 through actions in the gut.

Pharmacodynamics. Lowers fasting glucose more than post-prandial glucose. It does not stimulate insulin secretion, which explains the low hypoglycaemia risk. Long-term follow-up in overweight people with newly diagnosed type 2 diabetes shows fewer myocardial infarctions and lower all-cause mortality.

Pharmacokinetics. Oral bioavailability 50 to 60%; peak 2 to 3 hours (IR) and about 7 hours (XR). Not protein bound and not metabolised. Excreted unchanged in urine by glomerular filtration and tubular secretion through OCT2 and MATE transporters; plasma half-life about 6 hours. Clearance falls in proportion to eGFR. It is removed by haemodialysis.

Type 2 diabetes, adults (IR).

• Start 500 mg orally once daily with the largest meal for 1 week, then 500 mg twice daily with meals.
• Titrate by 500 mg every 1 to 2 weeks to a usual maintenance of 1 g twice daily.
• Maximum 3 g daily in 2 to 3 divided doses in most labels; some markets cap IR at 2.55 g daily. Little extra glucose lowering occurs over 2 g daily.
• No loading dose. Continue long term while eGFR and tolerance allow.

Type 2 diabetes, adults (XR).

• Start 500 mg orally once daily with the evening meal.
• Increase by 500 mg every 1 to 2 weeks; maximum 2 g once daily.
• Patients with gastrointestinal intolerance of IR can switch to the same total daily dose of XR.

Type 2 diabetes, children aged 10 years and over.

• Start 500 mg orally once daily with food; increase after 10 to 15 days.
• Maximum 2 g daily in 2 to 3 divided doses. XR is not licensed for children in most markets.

Prediabetes (unlicensed in many markets).

• 500 mg daily titrated to 850 mg twice daily. Benefit is greatest in people under 60 years, with BMI 35 kg/m2 or more, or with previous gestational diabetes.

Gestational diabetes and type 2 diabetes in pregnancy.

• Start 500 mg once or twice daily with meals; titrate every 1 to 2 weeks to glucose targets.
• Usual maximum 2.5 g daily in divided doses. Add insulin when targets are not met.

Polycystic ovary syndrome (unlicensed).

• 500 mg daily titrated over 4 to 6 weeks to 1.5 to 2 g daily in divided doses, for metabolic features and menstrual irregularity in women with insulin resistance.

Antipsychotic-associated weight gain (unlicensed).

• 500 mg twice daily titrated to 1 g twice daily alongside lifestyle measures.

Dose adjustment for kidney function.

Weight and age. No weight-based adult dosing. In older adults, dose by eGFR, not by age alone.

Contraindications. eGFR under 30 mL/min/1.73 m2; diabetic ketoacidosis; acute conditions that threaten renal function or tissue oxygenation (dehydration, sepsis, shock, acute myocardial infarction, decompensated heart failure, respiratory failure); decompensated liver disease; acute alcohol intoxication or alcohol dependence.

Lactic acidosis. Rare, about 3 to 10 cases in every 100,000 patient-years, almost always with a second insult such as acute kidney injury, sepsis, hypoxia or liver failure. Suspect it with malaise, vomiting, abdominal pain, hyperventilation, lactate over 5 mmol/L and pH under 7.35. Stop metformin; haemodialysis removes the drug and corrects acidosis. Mortality is high, around 30 to 50%.

Common adverse effects. Diarrhoea, nausea, abdominal discomfort, bloating and metallic taste in up to 25%, mostly in the first weeks. Slow titration, dosing with food and XR reduce them.

Vitamin B12 deficiency. Malabsorption causes lower B12 in long-term use, with risk of anaemia and peripheral neuropathy that can be mistaken for diabetic neuropathy.

Major interactions.

• Dolutegravir raises metformin exposure through OCT2 and MATE inhibition. Start metformin low and limit the total to 1 g daily with dolutegravir; recheck glucose and adjust when either drug is started or stopped.
• Other OCT2 or MATE inhibitors raise levels: cimetidine, trimethoprim, ranolazine, vandetanib.
• Iodinated contrast: risk of acute kidney injury and accumulation (withhold around contrast studies).
• Topiramate, zonisamide and acetazolamide add metabolic acidosis risk.
• Alcohol excess raises lactic acidosis risk. Corticosteroids, thiazides and atypical antipsychotics raise glucose.

Special groups.

• Pregnancy: crosses the placenta; no increase in malformations. Used in gestational and pre-existing type 2 diabetes, often with insulin. Offspring exposed in utero may have slightly higher childhood weight; discuss this with the woman.
• Breastfeeding: small amounts in milk; compatible. Observe preterm or unwell infants.
• Children: licensed from 10 years for type 2 diabetes.
• Older adults: dose by eGFR; check B12; stop during intercurrent illness.
• Kidney impairment: maximum 2 g daily when eGFR is 45 to 59, 1 g daily when 30 to 44, stop when under 30.
• Liver impairment: usable in steatotic liver disease and compensated cirrhosis with normal renal function; avoid in decompensated cirrhosis and active alcohol misuse.
• Heart failure: usable in stable heart failure with eGFR 30 or more; withhold during acute decompensation.
• East Africa: dolutegravir-based first-line HIV therapy makes the metformin dose cap a frequent practical issue. Young lean adults presenting with diabetes may be insulin deficient (ketosis-prone or autoimmune diabetes); check for ketones and weight loss before relying on metformin alone.

Formulation and food. Take IR with or just after meals; take XR once daily with the evening meal and swallow whole. Ghost tablet shells of some XR products may appear in stool.

Sick day rules. Withhold during vomiting, diarrhoea, fever, sepsis or poor oral intake. Restart 24 to 48 hours after eating and drinking normally.

Iodinated contrast. With eGFR 30 to 59, intra-arterial contrast, acute kidney injury or unstable heart failure, withhold at the time of the study and for 48 hours afterwards; restart once eGFR is stable. With eGFR 60 or more and intravenous contrast, continuing is usual practice.

Surgery. Omit on the day of surgery when more than one meal will be missed; restart once eating normally and renal function is stable.

Baseline. HbA1c, eGFR, liver enzymes, B12 if anaemia, neuropathy or long prior use.

Monitoring.

• HbA1c every 3 months until stable, then every 6 months.
• eGFR at least annually; every 3 to 6 months when eGFR is 45 to 59; every 3 months when 30 to 44.
• B12 periodically in long-term use and whenever anaemia or neuropathy appears.
• No therapeutic drug monitoring.

Stopping thresholds. Stop when eGFR falls under 30, with suspected lactic acidosis, or during acute hypoxic or septic illness. Reduce to 1 g daily when eGFR falls to 30 to 44.

Referral and escalation. Admit and involve critical care for suspected metformin-associated lactic acidosis, especially with lactate over 10 mmol/L, pH under 7.1 or shock; arrange urgent haemodialysis. Refer to diabetes services when HbA1c stays over target on maximum tolerated dose.