What it is
Metformin is the first-line oral antidiabetic in type 2 diabetes in all the international guidelines. It has been in clinical use for more than 60 years and remains irreplaceable because of a unique combination: efficacy, safety, low cost and a proven cardiovascular benefit in some groups.
Unlike other antidiabetics, it does not cause hypoglycaemia on its own and does not increase weight. It needs adequate kidney function to be used safely.
Reduced glucose production by the liver
Metformin's exact mechanism is not fully understood, but its main effects are:
- It inhibits complex I of the mitochondrial respiratory chain → it activates hepatic AMPK.
- It reduces hepatic gluconeogenesis (glucose production by the liver): the main mechanism.
- It improves peripheral insulin sensitivity in muscle and fat tissue.
- It reduces intestinal glucose absorption.
- It does not stimulate insulin secretion from the pancreas → it does NOT cause hypoglycaemia on its own.
- A neutral or slightly favourable effect on body weight.
At the counter
When to recommend it
- Supply on a valid prescription
- Remind the patient to take it with meals: it reduces nausea and gastrointestinal discomfort
- Start with low doses and increase gradually: it improves digestive tolerance
- Explain that it may need to be stopped around procedures with iodinated contrast
- Reinforce adherence: it is a long-term treatment with no benefit the patient can feel
- Remind them that with long-term use vitamin B12 should be checked: a supplement is for the doctor to prescribe if there is a deficiency
When not to
- eGFR below 30 mL/min (absolute contraindication) or 30–45 mL/min (use with caution, reduced dose)
- Severe liver failure
- Situations with a risk of severe dehydration (vomiting, heavy diarrhoea, high fever)
- Major surgery: stop the day before or on the day
- Iodinated contrast: depending on kidney function, stop at the time of the test and do not restart until 48 h later with the kidney checked
- Alcoholism: it increases the risk of lactic acidosis
Warnings
- Important LACTIC ACIDOSIS: the most serious side effect, although very rare. It happens mainly when the drug is used in conditions of tissue hypoxia (severe kidney, liver or heart failure, sepsis). It can be fatal. That is why the contraindications are strict.
- Important IODINATED CONTRAST: contrast can cause transient acute kidney injury, and with accumulated metformin this can trigger lactic acidosis. Stop it according to the protocol around contrast procedures.
- Caution VITAMIN B12: metformin interferes with ileal absorption of B12 (mediated by intrinsic factor and calcium). With long-term use, a significant share of patients develop B12 deficiency. Review blood tests periodically.
- Caution GASTROINTESTINAL EFFECTS: nausea, diarrhoea and abdominal pain are common at the start. They usually improve in 2–4 weeks. Taking it with meals and increasing the dose gradually reduces them significantly.
- Worth knowing SURGERY: stop metformin the day before or on the day of any major surgery and do not restart it until kidney function is confirmed (usually 48 h later).
Pharmacokinetics
- Absorption
- Oral: absorbed in the small intestine. Bioavailability of 50–60%, not affected by food (although taking it with food reduces gastrointestinal effects). Peak plasma level at 2–3 hours.
- Distribution
- It does not bind to plasma proteins. It distributes into tissues, especially the gut, liver and kidney. It does not cross the blood–brain barrier.
- Metabolism
- It is not metabolised in the liver. It is eliminated unchanged. That is why it accumulates in kidney failure.
- Elimination
- Exclusively renal, by active tubular secretion. Half-life: 4–8 hours. CONTRAINDICATED with eGFR below 30 mL/min. Caution between 30 and 45 mL/min.
Metformin vs sulphonylureas (glibenclamide)
| Aspect | Metformin | Sulphonylureas (glibenclamide) |
|---|---|---|
| Mechanism | Reduces hepatic gluconeogenesis | Stimulates insulin secretion |
| Hypoglycaemia | Does not cause it on its own | A real risk of hypoglycaemia |
| Weight | Neutral or a slight loss | Weight gain |
| Cardiovascular risk | Proven benefit (UKPDS) | Neutral or slightly negative |
| Kidney failure | Contraindicated with eGFR below 30 | Also limited; hypoglycaemia is dangerous |
| Cost | Very low (generic) | Low |
Metformin is first line precisely because it does not cause hypoglycaemia, does not cause weight gain, has a proven cardiovascular benefit and is very cheap. Sulphonylureas have moved to second line because of the risk of hypoglycaemia.
Self-assessment
Three questions. When you check your answers you will see the explanation for each one.
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Iodinated contrast can cause transient acute kidney injury. If metformin accumulates because the kidney deteriorates, the risk of lactic acidosis rises. Depending on kidney function, the product information says to stop it at the time of the test and not restart until 48 hours later, with the kidney checked.
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Hypoglycaemia happens when there is more insulin than needed (from pancreatic stimulation or injected insulin). Metformin does not stimulate insulin secretion: it reduces glucose production in the liver and improves sensitivity to the insulin already circulating. So on its own it does not take glucose below normal.
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Metformin interferes with the ileal absorption of vitamin B12 by disrupting uptake that depends on intrinsic factor and calcium. With long-term use, a significant share of patients develop B12 deficiency, which can cause megaloblastic anaemia and peripheral neuropathy. Periodic checks are recommended, with supplements if levels fall.
Training content. It does not replace the summary of product characteristics or clinical judgement.