Metformin Warnings: Important Safety Information

Kidney function is the single most important safety consideration when prescribing metformin. The drug is not metabolised by the liver; instead, it is excreted unchanged by the kidneys.

When renal clearance is reduced, metformin accumulates in the body, increasing the risk of the rare but potentially fatal complication of lactic acidosis.

The BNF provides clear thresholds based on the estimated glomerular filtration rate (eGFR):

• eGFR 60 mL/min or above: metformin can be used at full dose without restriction
• eGFR 45 to 59 mL/min: metformin can continue, but renal function should be monitored every 3 to 6 months and the dose reviewed
• eGFR 30 to 44 mL/min: the maximum daily dose should be reduced to 1,000 mg. Review renal function every 3 months. Consider stopping if eGFR is declining
• eGFR below 30 mL/min: metformin must be stopped. The risk of accumulation and lactic acidosis is too high

Your GP or diabetes nurse should check your eGFR before starting metformin and at least annually thereafter.

More frequent monitoring is needed if your kidney function is borderline or if you have conditions that can affect the kidneys, such as hypertension, heart failure or recurrent urinary tract infections.

Acute kidney injury (AKI) can occur during any serious illness, particularly with dehydration, sepsis or nephrotoxic drugs.

This is why the sick-day rules for metformin are so important: temporarily stopping the drug during illness prevents accumulation during a period when kidney function may be transiently impaired.

The sick-day rules are a set of guidelines that tell you when to temporarily stop metformin to prevent dangerous accumulation during acute illness.

They are endorsed by NHS England, Diabetes UK and NICE.

When to stop metformin temporarily:

• Vomiting or severe diarrhoea that persists for more than a few hours
• High fever (above 38.5 degrees C) with signs of dehydration
• Severe infection requiring antibiotics and bed rest
• Any illness that prevents you from eating or drinking normally
• Acute heart failure or significant breathlessness at rest

What to do:

1. Stop taking metformin tablets
2. Continue to monitor your blood glucose if you have testing equipment
3. Drink small, frequent sips of water or clear fluids to maintain hydration
4. Contact your GP, diabetes nurse or NHS 111 for advice within 24 hours
5. Resume metformin only when you are eating and drinking normally and feeling significantly better, typically 24 to 48 hours after symptoms resolve

Why this matters

During acute illness, kidney function can drop rapidly due to dehydration and reduced blood pressure.

If metformin continues to be taken during this period, it can accumulate to levels that overwhelm the body's ability to clear lactate, triggering lactic acidosis.

This is a medical emergency with a mortality rate of approximately 30 to 50% when it occurs.

Practical tip

Keep a written reminder of the sick-day rules with your medicines or on your fridge door. Some diabetes teams provide wallet cards or fridge magnets with this information.

Ensure family members also know the rules in case you are too unwell to manage your own medications.

Two common clinical scenarios require temporary discontinuation of metformin: surgical procedures and radiological investigations involving iodinated contrast media.

Before surgery

Metformin should be stopped on the day of surgery (or the evening before, if the procedure is in the morning).

The reason is twofold: general anaesthesia and surgical stress can reduce kidney perfusion, and patients are typically fasting and may become dehydrated, both of which increase the risk of metformin accumulation.

The BNF advises restarting metformin only when the patient is eating and drinking normally and renal function has been confirmed as stable, which is usually 48 hours after surgery.

For minor procedures under local anaesthesia where the patient can eat and drink immediately afterwards, interruption may not be necessary, but this should be discussed with the surgical team.

Before contrast-enhanced imaging

Iodinated contrast media (used in CT scans, angiograms and some other imaging studies) can cause contrast-induced nephropathy, a temporary decline in kidney function.

If metformin is present during this period, it may accumulate.

Current UK guidelines recommend:

• For patients with eGFR 30 to 44: stop metformin 48 hours before the procedure and do not restart until renal function has been rechecked 48 hours after contrast administration
• For patients with eGFR 45 or above: metformin can be continued, but some departments prefer to stop it on the day of the procedure as a precaution
• For emergency imaging: the procedure should not be delayed for metformin. Stop metformin as soon as possible and monitor renal function afterwards

Always inform the radiology department that you take metformin when booking or attending for contrast-enhanced imaging.

Alcohol use alongside metformin requires careful consideration because both substances interact with the same metabolic pathways and amplify each other's risks.

Lactic acidosis risk

Alcohol inhibits gluconeogenesis in the liver, which is also metformin's primary mechanism of action. When both are present, the liver's ability to clear lactate is significantly compromised.

Heavy or binge drinking while on metformin markedly increases the risk of lactic acidosis, particularly if the patient is also dehydrated or has impaired kidney function.

Hypoglycaemia risk

Alcohol suppresses hepatic glucose production for up to 12 hours after consumption.

In patients taking metformin (especially if also on a sulphonylurea or insulin), this can cause delayed hypoglycaemia, often occurring during the night or the following morning.

Symptoms include sweating, tremor, confusion and in severe cases, loss of consciousness.

Vitamin B12 interaction

Chronic alcohol use independently increases the risk of B12 and folate deficiency.

Combined with metformin's known effect on B12 absorption, heavy drinking patients face a substantially higher risk of developing macrocytic anaemia and peripheral neuropathy.

Practical guidance

The BNF advises patients taking metformin to avoid excessive alcohol intake. In practical terms:

• Moderate, occasional drinking (within the UK Chief Medical Officers' guideline of 14 units per week, spread across several days) is generally acceptable for patients with good kidney and liver function
• Binge drinking (more than 6 units in a single session) should be avoided entirely
• Patients with liver disease, even fatty liver, should discuss alcohol limits with their diabetes team
• Never drink alcohol on an empty stomach while taking metformin

Metformin has relatively few pharmacokinetic drug interactions compared with many other medicines, but several combinations require awareness.

ACE inhibitors and ARBs

These blood-pressure-lowering drugs can reduce renal blood flow, potentially causing a rise in metformin levels.

The combination is very common in diabetes care and is generally safe, but eGFR should be monitored regularly, particularly after dose changes.

Diuretics

Loop diuretics (furosemide) and thiazides can cause dehydration, which impairs renal clearance of metformin. Adequate fluid intake is essential, especially in hot weather or during illness.

Iodinated contrast agents

As discussed above, these can trigger acute kidney injury. Metformin should be managed according to local radiology protocols before any contrast-enhanced procedure.

Alcohol

Addresses above, alcohol potentiates the risk of both lactic acidosis and hypoglycaemia.

Corticosteroids

Systemic steroids (prednisolone, dexamethasone) raise blood glucose levels, potentially undermining metformin's effect.

Patients starting a steroid course may need their metformin dose increased or an additional diabetes medication added temporarily.

Cimetidine

This H2-receptor antagonist competes with metformin for renal tubular secretion, raising metformin levels by up to 50%.

The interaction is rarely clinically significant at standard cimetidine doses, but alternative acid-suppressing drugs (ranitidine, PPIs) are preferred where possible.

Dolutegravir

This antiretroviral drug increases metformin plasma concentrations.

The BNF recommends a maximum metformin dose of 1,000 mg daily in patients taking dolutegravir, with close monitoring of glycaemic control and renal function.

Always carry an up-to-date medication list and show it to every prescriber involved in your care.

Metformin use during pregnancy and breastfeeding is an evolving area of practice with an increasingly positive evidence base.

Pregnancy

Metformin crosses the placenta, but it has not been associated with an increased risk of major congenital malformations in large observational studies.

NICE guideline NG3 (diabetes in pregnancy) states that metformin may be used during pregnancy as an adjunct to or alternative to insulin in gestational diabetes, particularly when insulin is declined or impractical.

In type 2 diabetes, metformin may be continued in pregnancy if it was providing good glycaemic control pre-conception, but many diabetes teams prefer to switch to insulin for tighter glucose management.

The decision should be individualised and made jointly between the patient and her diabetes-obstetric team.

For women with PCOS, metformin is sometimes used in early pregnancy to reduce the risk of miscarriage and gestational diabetes, although the evidence for this is not conclusive.

Breastfeeding

Metformin is excreted in breast milk at very low levels (typically less than 1% of the maternal dose). The BNF states that it is compatible with breastfeeding.

The amount the infant ingests is far below any therapeutic dose and no adverse effects on breastfed infants have been reported in published studies.

Key points

• Do not stop metformin abruptly if you discover you are pregnant. Contact your diabetes team for advice on whether to continue, switch or adjust your treatment
• Blood glucose targets are tighter during pregnancy (fasting below 5.3 mmol/L, 1-hour postprandial below 7.8 mmol/L)
• Ensure adequate folic acid supplementation (5 mg daily) before conception and during the first trimester if you have diabetes