Metformin and tiredness: does metformin make you tired, and what other causes should you look for?

Tiredness is not among the recognised side effects of metformin in Europe, but the US prescribing information reports asthenia slightly more often than with placebo. Tiredness can also appear during treatment for indirect reasons.

The summary of product characteristics for Glucophage, the reference metformin, in its UK version revised in 2025, does not list tiredness among its side effects. It lists as very common digestive problems (nausea, vomiting, diarrhoea, abdominal pain, loss of appetite) and as common lower vitamin B12 levels and taste disturbance¹. The US prescribing information, drafted earlier, reports the results of a placebo-controlled monotherapy trial: asthenia was reported by 9.2% of the 145 patients on metformin, against 5.5% of the 141 patients on placebo².

The gap between the two groups in the US trial is modest, and asthenia ranks far behind diarrhoea (53.2% against 11.7%). The prescribing information does not say whether this asthenia accompanied the digestive problems at the start of treatment or arose from another mechanism.

Tiredness is one of the most common symptoms of type 2 diabetes itself: a meta-analysis of 32 studies puts it at 50% in these patients. It therefore exists before any question of treatment.

This meta-analysis, covering nearly 35,000 people with type 2 diabetes, finds two factors consistently linked to tiredness: depression and lack of physical activity³. An older review describes diabetes-related tiredness as a multi-layered phenomenon. It combines physiological causes (blood sugar too high or too low, inflammation, complications), psychological causes (distress related to the disease, depression) and lifestyle causes (sleep, inactivity, weight)⁴.

Swings in blood sugar, upwards as well as downwards, are associated with tiredness. In a study cited by this review, patients on insulin felt tired during hyperglycaemia, even before becoming thirsty or passing urine more often⁴. When a person starts metformin at the time their diabetes is diagnosed, the tiredness they attribute to the medicine may just as well come from the disease itself.

Other causes, not directly linked to diabetes, also deserve to be ruled out. A review by the American Academy of Family Physicians lists among the causes of tiredness to look for anaemia or iron deficiency, an underactive thyroid, sleep apnoea and the side effects of other medicines⁵. Sleep apnoea is very common in type 2 diabetes with obesity: in the Sleep AHEAD study, more than 86% of the 306 participants had at least a mild form on sleep recording⁶. It often goes unnoticed because it happens at night. Loud snoring, pauses in breathing noticed by others or daytime sleepiness should prompt consideration of this possibility.

Taken alone, metformin does not cause hypoglycaemia under normal conditions of use. The risk arises when it is combined with insulin or other diabetes medicines.

The European summary of product characteristics states that metformin as monotherapy does not cause hypoglycaemia and therefore has no effect on driving, but that caution is needed in combination with insulin, sulphonylureas or glinides¹. The US prescribing information adds that hypoglycaemia can occur with insufficient calorie intake, strenuous uncompensated exercise or alcohol consumption².

Sudden tiredness with sweating, trembling, hunger or palpitations, especially in someone who also takes a sulphonylurea or insulin, suggests hypoglycaemia. It is confirmed by measuring blood sugar at the time of the symptoms.

It is a serious possibility when treatment has lasted several years: metformin is associated with lower vitamin B12, and tiredness is one of the signs of deficiency.

A meta-analysis of 31 studies reports a 2.09-fold higher risk of B12 deficiency in people taking metformin, with an effect that increases with dose and duration of treatment⁷. In the US DPPOS cohort, the proportion of low or borderline levels reached 20.3% against 15.6% on placebo after 13 years⁸. B12 deficiency causes anaemia, with tiredness, breathlessness and pallor, and nerve problems such as tingling or numbness in the feet⁹.

Since 2022, the metformin product information has advised checking B12 levels when deficiency is suspected and considering periodic monitoring in people at risk¹⁰. Vitamin B12 contributes to the reduction of tiredness and fatigue and to normal energy-yielding metabolism, but this property says nothing about tiredness that has another cause. A blood test shows whether this possibility applies, and any supplementation is decided with your doctor or pharmacist.

They can cause tiredness indirectly. The nausea, diarrhoea and loss of appetite at the start of treatment reduce intake and disrupt daily life, which can show up as tiredness.

Digestive problems are the most common side effect of metformin. A review by Bonnet and Scheen points out that they affect a large share of patients, especially when treatment starts, and that some of them cannot tolerate adequate doses¹¹. The mechanisms are still poorly understood: build-up of the medicine in the gut, changes in the microbiota, an effect on bile acids.

These problems most often resolve on their own¹. The product information recommends splitting the dose into two or three intakes during or after meals and increasing the dose gradually. A prolonged-release form also exists and may improve tolerance¹¹. These adjustments are a matter for the doctor, who can also check that prolonged diarrhoea has not led to dehydration.

A slight effect on peak exercise capacity has been measured in healthy volunteers, with no change in perceived exertion. Its relevance in everyday life has not been established.

Metformin moderately slows one step of energy production in the mitochondria. In a double-blind crossover trial in 17 healthy adults, 7 to 9 days of metformin (2,000 mg a day by the end of the period) reduced peak oxygen uptake by 2.7% and exercise duration by 4.1%. The perception of effort, however, did not change¹².

These differences are statistically significant but small, and the trial involved neither people with diabetes nor tiredness felt in daily life. It does not allow chronic tiredness to be attributed to metformin. In the meta-analysis cited above, physical activity is in fact one of only two factors consistently linked to tiredness in people with diabetes³.

Tiredness that persists, worsens or comes with other signs deserves to be reported to your doctor, without stopping or changing metformin on your own.

Certain signs point to a specific cause and warrant prompt advice:

• severe weakness with muscle pain, abdominal pain, unusual breathlessness and feeling cold, which may suggest lactic acidosis, a very rare but serious complication: it requires urgent medical attention;
• sweating, trembling and sudden hunger, especially in combination with insulin or a sulphonylurea, which suggest hypoglycaemia;
• tingling, numbness in the feet or hands, pallor or breathlessness on exertion, which suggest vitamin B12 deficiency or anaemia;
• intense thirst, passing large amounts of urine and weight loss, which indicate blood sugar that is too high;
• persistent sadness, loss of interest or sleep problems, which may signal depression.

The doctor has simple tests to narrow things down: blood glucose and HbA1c, full blood count, vitamin B12 level, kidney and thyroid function. The summary of product characteristics points out that lactic acidosis presents as asthenia with cramps, abdominal pain and breathing difficulties, and that these symptoms require immediate medical attention¹. Other causes of tiredness can be investigated without urgency, through these simple tests.