How does metformin work? Understanding the first-line diabetes treatment

Metformin belongs to the biguanide class of medicines and has been used for type 2 diabetes since the 1950s.

Despite decades of use, its precise molecular mechanism is still being refined by researchers.

Primary actions:

• Reduces hepatic glucose output: metformin decreases the amount of glucose produced by the liver, which is abnormally high in type 2 diabetes. This is achieved by activating AMP-activated protein kinase (AMPK), a key enzyme in energy metabolism. AMPK activation suppresses gluconeogenesis (the process of making new glucose) and glycogenolysis (the breakdown of stored glycogen)
• Improves insulin sensitivity: metformin enhances the action of insulin in peripheral tissues, particularly skeletal muscle. This means the body's existing insulin works more effectively at moving glucose from the blood into cells
• Reduces intestinal glucose absorption: there is evidence that metformin decreases the amount of glucose absorbed from food in the small intestine, though this contributes less to its overall effect

What metformin does not do:

• It does not stimulate the pancreas to produce more insulin (unlike sulphonylureas)
• It does not cause hypoglycaemia when used as monotherapy, because it works by improving the body's response to existing insulin rather than increasing insulin levels
• It is not associated with weight gain and may even promote modest weight loss

The BNF lists metformin as the recommended first-line pharmacological treatment for type 2 diabetes in virtually all patients.

Metformin's place as the cornerstone of type 2 diabetes treatment is supported by decades of clinical evidence.

Blood sugar control:

• Metformin typically reduces HbA1c by approximately 1.0 to 1.5 percentage points when used as monotherapy
• In the landmark UKPDS (UK Prospective Diabetes Study), metformin was the only glucose-lowering medicine that reduced all-cause mortality and diabetes-related death in overweight patients with newly diagnosed type 2 diabetes

Cardiovascular benefits:

• The UKPDS showed a 36% reduction in all-cause mortality in the metformin group compared with conventional diet treatment alone
• Metformin reduced the risk of myocardial infarction by 39% in this study
• While more recent trials have not replicated these exact findings, metformin remains associated with a favourable cardiovascular profile

Weight neutrality:

• Unlike insulin, sulphonylureas and thiazolidinediones, metformin does not cause weight gain
• Patients may experience modest weight loss of 1 to 2 kg, possibly related to reduced appetite and gastrointestinal effects

Cost-effectiveness:

• Metformin is one of the most affordable diabetes treatments available, costing approximately 1 to 2 pounds per month on the NHS
• Its proven track record and low cost make it a highly cost-effective intervention

NICE guidelines (NG28) recommend metformin as the first-line medicine for all adults with type 2 diabetes, alongside lifestyle measures, unless there is a specific contraindication.

Metformin is suitable for the vast majority of adults with type 2 diabetes, but there are some important exceptions.

Recommended for:

• All adults with newly diagnosed type 2 diabetes as first-line treatment (NICE NG28)
• Patients who are overweight or obese, where metformin's weight-neutral profile is particularly advantageous
• Patients at cardiovascular risk, given the favourable outcomes data
• Women with polycystic ovary syndrome (PCOS), where metformin is used to improve insulin resistance and regulate menstrual cycles (off-label but endorsed by NICE)

Contraindications and cautions:

• Severe renal impairment: metformin should not be started if eGFR is below 30 mL/min/1.73m2. It should be used with caution and at reduced doses when eGFR is 30 to 45
• Acute conditions risking lactic acidosis: dehydration, severe infection, shock, major surgery or acute heart failure. Metformin should be temporarily withheld in these situations
• Hepatic impairment: severe liver disease increases the risk of lactic acidosis
• Excessive alcohol intake: chronic heavy drinking impairs lactate metabolism and increases the risk of lactic acidosis

Monitoring:

• Renal function (eGFR) should be checked at least annually, and more frequently if borderline
• Vitamin B12 levels should be monitored periodically, as metformin can reduce B12 absorption over time
• HbA1c should be checked every 3 to 6 months to assess treatment response

Gastrointestinal side effects are the main drawback of metformin, but they can usually be managed with practical strategies.

Common side effects (affecting 1 in 10 to 1 in 100 people):

• Nausea: particularly when first starting treatment
• Diarrhoea: the most frequently cited reason for discontinuation
• Abdominal discomfort and bloating
• Metallic taste: an unpleasant taste that some patients notice
• Reduced appetite: this may contribute to mild weight loss

Strategies to reduce gastrointestinal effects:

• Start at a low dose: the BNF recommends starting at 500 mg once or twice daily and increasing gradually over several weeks
• Take with meals: always take metformin with or immediately after food to reduce stomach upset
• Switch to modified-release: metformin MR (modified-release) tablets release the medicine more slowly and are significantly better tolerated. NICE recommends switching to MR if standard metformin causes persistent gastrointestinal symptoms
• Allow time: many patients find that side effects improve after the first 2 to 4 weeks

Rare but serious: lactic acidosis:

Metformin-associated lactic acidosis is very rare (estimated at 3 to 10 cases per 100,000 patient-years) but can be life-threatening.

It is almost always associated with renal impairment, severe illness or other risk factors. Symptoms include rapid breathing, abdominal pain, muscle cramps and feeling generally unwell.

Seek immediate medical attention if these develop.

Metformin is often the foundation upon which additional treatments are added if blood sugar targets are not met.

NICE type 2 diabetes treatment pathway:

• Step 1: lifestyle measures plus metformin
• Step 2: if HbA1c remains above target after 3 to 6 months, add a second agent. Options include an SGLT2 inhibitor (e.g. dapagliflozin, empagliflozin), a GLP-1 receptor agonist, a sulphonylurea or a DPP-4 inhibitor
• Step 3: triple therapy or insulin may be needed if dual therapy is insufficient

Common combinations:

• Metformin plus an SGLT2 inhibitor: particularly favoured for patients with heart failure or chronic kidney disease, given the cardiovascular and renal benefits of SGLT2 inhibitors
• Metformin plus a GLP-1 agonist: recommended for patients who would benefit from significant weight loss, or who have established cardiovascular disease
• Metformin plus a sulphonylurea: a long-established combination, though it carries a higher risk of hypoglycaemia and weight gain
• Metformin plus insulin: when other combinations are insufficient, metformin is usually continued alongside insulin to reduce the insulin dose required

Why metformin is almost always continued:

Even when additional medicines are prescribed, metformin is usually maintained because it improves insulin sensitivity without adding to the risk of hypoglycaemia or weight gain.

It also has an excellent safety record spanning over 60 years.