Metformin

Metformin belongs to the biguanide family. It enters mainly the liver cells through a transporter called OCT1, organic cation transporter 1, which concentrates its action on that organ. Inside the cells, it inhibits complex I of the respiratory chain of the mitochondria, the cell’s power plants. This inhibition reduces the production of ATP, the molecule that stores energy, raises the AMP:ATP ratio and activates AMPK, an enzyme that senses the cell’s energy state.

Its central effect is to slow hepatic gluconeogenesis, the production of glucose by the liver. By producing less sugar, the liver releases less into the blood and blood glucose falls. According to studies on its mechanism, metformin may also inhibit mitochondrial glycerophosphate dehydrogenase, mGPD, an enzyme of the glycerophosphate shuttle, which would limit the production of glucose from glycerol and lactate. The importance of this pathway at therapeutic doses remains debated. These levers act on the liver rather than on the pancreas.

Metformin is prescribed in type 2 diabetes to lower blood glucose. Its action rests on the pharmacology described above: by slowing the production of glucose by the liver, it reduces the amount of sugar released into the blood between and during meals. It is not metabolised by the liver and is eliminated unchanged by the kidney, with a half-life of about 6.2 hours. This renal elimination explains why kidney function governs its use.

In daily use, it is taken during or after a meal, spread over two to three doses a day, which follows its relatively short half-life. The dose is increased gradually at the start of treatment to improve digestive tolerance. Taking the doses regularly supports blood glucose control throughout the day. It should not be stopped on one’s own initiative: any adjustment is decided with the doctor who oversees the treatment.

Digestive disturbances are the most common effects: nausea, vomiting, diarrhoea, abdominal pain and loss of appetite. They are very common, with a frequency of at least 1 person in 10, occur mainly at the start of treatment and most often resolve on their own. Taking the medicine with a meal and increasing the dose gradually are aimed precisely at limiting them. A taste disturbance, often a metallic taste, is common, with a frequency of at least 1 in 100 and less than 1 in 10.

Lactic acidosis is a very rare effect, fewer than 1 case in 10,000, but serious. Its risk rises above all in cases of renal failure, heart failure and alcohol consumption. A Cochrane review found no case of lactic acidosis over 70,490 patient-years of exposure to metformin, the upper limit of the estimated incidence being 4.3 cases per 100,000 patient-years, a figure comparable to that of untreated patients. Medical follow-up targets precisely the situations where this risk rises.

Metformin reduces the absorption of vitamin B12. The documented mechanism is a calcium-dependent interference with the binding between intrinsic factor and vitamin B12 in the terminal ileum, the last part of the small intestine where this vitamin is taken up. Disrupted at this point, dietary B12 passes less well into the body. The effect sets in mainly over time.

Since June 2022, the British medicines agency, the MHRA, has classified the fall in vitamin B12 as a common effect of metformin, affecting up to 1 person in 10, especially at high doses or during prolonged treatment. It recommends measuring B12 in patients at risk or showing symptoms. This measurement is among the markers that follow-up can check. It points towards supplementation when the fall is confirmed.

Vitamin B12 is the point where the plate meets what the treatment shifts. It is found only in foods of animal origin: fish, meats, poultry, eggs, milk and dairy products. Plant foods do not contain it naturally, except when they are fortified. A plate that regularly makes room for salmon, eggs, cheese or meat therefore supports the starting intake.

This dietary intake keeps all its value, but it meets a limit specific to metformin. When the medicine hinders the uptake of B12 in the ileum, increasing the share of these foods does not always close the gap, since it is the absorption step that is at issue. This is where a targeted intake makes sense, in addition to your treatment, never in its place. The choice of dose is then read together with the biological follow-up.

Kidney function governs the use of metformin, since the kidney eliminates it. It is contraindicated when the estimated glomerular filtration rate, the eGFR, is below 30 mL/min/1.73 m². Between 30 and 44, the dose is reduced to a maximum of 1,000 mg per day. Kidney function is assessed before starting and then at least once a year.

Certain situations require stopping the treatment: an examination with iodinated contrast medium in patients with reduced kidney function, between 30 and 60 eGFR, liver damage, alcoholism, heart failure or an intra-arterial injection. Kidney function is then reassessed 48 hours later before resuming. Alcohol increases the risk of lactic acidosis: its metabolism shifts the NAD+/NADH ratio towards NADH, which reduces the liver’s ability to eliminate lactate. These points frame the dialogue with the care team.