Metformin

Biguanides. Oral antihyperglycemic agents

ATC code: A10BA02 (Metformin)

Brand names

Glucophage, Glucophage XR, Fortamet, Glumetza, Riomet

Mechanism of action

Reduces hepatic glucose production, mainly by suppressing gluconeogenesis. Increases peripheral insulin sensitivity and improves muscle glucose uptake. Slows intestinal glucose absorption. Does not stimulate insulin secretion, so monotherapy does not cause hypoglycemia in non-diabetic individuals.

Indications

Type 2 diabetes mellitus

First line

First-line pharmacological treatment for type 2 diabetes in adults. Lowers HbA1c by 1.0–1.5% as monotherapy, supports weight reduction or weight neutrality, and does not cause hypoglycemia as monotherapy. ADA 2024, ADA/EASD 2022, and NICE NG28 list metformin as the baseline agent in the absence of contraindications. Combinations with SGLT2 inhibitors or GLP-1 receptor agonists are built around individual cardiovascular and renal risk.

Contraindicated at eGFR < 30 mL/min/1.73 m². At eGFR 30–44 mL/min/1.73 m² the dose is halved, and new patients do not start therapy at this level of kidney function.

Sources

Polycystic ovary syndrome

Adjunct

In polycystic ovary syndrome metformin is used as an adjunct to lifestyle change in patients with metabolic features (insulin resistance, impaired glucose tolerance, overweight). The 2023 international ESHRE guideline and NICE CKS support metformin for metabolic components of PCOS and for ovulation restoration in a subset of patients. The 2020 Cochrane review demonstrated a modest but clinically meaningful effect on ovulation and pregnancy rates when combined with clomiphene.

Does not replace lifestyle change as the baseline intervention. In patients without metabolic features the evidence base for prescribing is weak.

Sources

Prediabetes

Individual decision

Metformin is used in a subset of patients with prediabetes and high risk of progression to T2D: BMI ≥ 35 kg/m², age under 60, and women with a history of gestational diabetes. ADA 2024 recommends considering metformin for this subgroup in addition to mandatory lifestyle intervention. The Diabetes Prevention Program trial demonstrated a 31% reduction in T2D incidence over 2.8 years on metformin 850 mg twice daily.

The decision is individual and follows shared decision-making. Lifestyle modification remains a mandatory part of the intervention.

Sources

Anti-aging and longevity (marketed indication)

Not recommended

Metformin is not used for slowing aging or prolonging lifespan in healthy non-diabetic individuals in international recommendations. The TAME (Targeting Aging with Metformin) trial is ongoing and results are not yet published. International guidelines from ADA, EASD, NICE, and UpToDate do not recommend metformin for this purpose.

Prescribing to healthy individuals for anti-aging lacks an evidence base and carries potential adverse effects without offsetting benefit.

Sources

Weight loss in non-diabetics (marketed indication)

Not recommended

Metformin is not supported as a weight-loss agent in non-diabetic adults without obesity-related metabolic disorders by international guidelines. The expected weight effect in this group is 1–3 kg over 6 months and does not exceed the effect of lifestyle modification. For obesity treatment other drugs (GLP-1 receptor agonists, combination agents) approved for this indication are used.

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Practical notes

Timing and administration

Taken with meals or immediately after food. This reduces the severity of gastrointestinal side effects (nausea, diarrhea, abdominal discomfort). Extended-release forms (Glucophage XR) are taken once daily with the evening meal.

Dose titration

Starting dose 500 mg 1–2 times daily. Every 7–14 days the dose is increased by 500 mg up to the target 1500–2000 mg daily in 2–3 divided doses. Maximum daily dose 3000 mg in adults. Slow titration reduces the discontinuation rate due to gastrointestinal side effects from 20% to 5–7%.

Monitoring

Check HbA1c every 3 months until target is met, then every 6 months during stable control. Assess eGFR at least once a year, and every 3–6 months in patients with eGFR 45–60 mL/min/1.73 m². Check serum vitamin B12 yearly during long-term therapy (more than 4 years).

Special situations

Before elective surgery with general anesthesia or iodinated contrast administration, metformin is discontinued for 48 hours. It is resumed after kidney function normalizes and the patient is stable. During acute illness with vomiting, dehydration, or lactic acidosis risk, therapy is temporarily withheld.

Common myths

Myth: “metformin causes hypoglycemia”. Fact: not in monotherapy. Hypoglycemia only occurs when combined with insulin or sulfonylureas. Myth: “metformin damages the liver”. Fact: not hepatotoxic, does not raise transaminases. Contraindicated only in severe hepatic impairment due to lactic acidosis risk, not due to direct liver injury. Myth: “taken in courses”. Fact: metformin is taken continuously while clinically indicated. Intermittent courses are not effective.

Drug–nutrient interactions

Vitamin B12

Long-term metformin use (over 4 years) is associated with vitamin B12 deficiency in 10–30% of patients. Mechanism: metformin impairs calcium-dependent binding of the B12–intrinsic factor complex to ileal receptors. Check serum B12 annually; at levels below 200 pg/mL, prescribe oral or parenteral replacement.

Source: UpToDate: Metformin in the treatment of adults with type 2 diabetes mellitus (2024)

Safety

Boxed warning

FDA boxed warning: risk of lactic acidosis with metformin in patients with renal impairment, tissue hypoxia, acute illness, and those receiving iodinated contrast. Metformin is not prescribed in patients with eGFR < 30 mL/min/1.73 m².

Contraindications

eGFR < 30 mL/min/1.73 m²
Acute metabolic acidosis of any etiology, including diabetic ketoacidosis
Severe hepatic impairment
States with tissue hypoxia: acute heart failure, recent myocardial infarction, respiratory failure
Acute alcohol intoxication, chronic alcoholism
Periods 48 hours before and after intravenous iodinated contrast media

Serious adverse effects

Lactic acidosis (very rare but life-threatening — incidence estimated at 3 cases per 100 000 patient-years when contraindications are respected)

Common adverse effects

Dyspepsia, nausea, vomiting, diarrhea (usually transient, resolved by taking with meals)
Metallic taste
Reduced appetite
Mild weight loss

Uncommon adverse effects

Vitamin B12 deficiency with long-term therapy
Erythema, pruritus, urticaria

PregnancyFDA B

FDA category B. Metformin is used in gestational diabetes and in pregestational T2D when insulin is not suitable. Safety data come from large cohort studies. The decision is made jointly with the endocrinologist and obstetrician.

Breastfeeding

Passes into breast milk in minimal amounts. LactMed classifies metformin as compatible with breastfeeding. Monitor the infant for gastrointestinal symptoms.