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[Pharmacology](https://durgical.com/en/pharmacology/) · [Biguanides](https://durgical.com/en/pharmacology/classes/biguanides/)

# Metformin

First-line oral medicine for type 2 diabetes: it mainly lowers the glucose the liver makes, and alone it rarely causes hypoglycemia.

Updated 2026-11-01

- Class: [Biguanides](https://durgical.com/en/pharmacology/classes/biguanides/)
- Target: Mitochondrial respiratory chain, complex I
- ATC code: A10BA02
- WHO Model List of Essential Medicines

◆**Mitochondrial respiratory chain, complex I**Metformin

ⓘ The figure shows a pig respirasome (complexes I, III and IV) with metformin bound, cropped to complex I. Where metformin acts in patients, and how much this site explains its effect, is still under study.

**Target in 3D:** Mitochondrial respiratory chain, complex I. PDB structure 8ZSQ (RCSB PDB, public domain). [View the structure at RCSB PDB](https://www.rcsb.org/structure/8ZSQ) · Drag to rotate · pinch to zoom

## Mechanism of action

Metformin lowers blood glucose mainly by reducing hepatic gluconeogenesis. Its best-known action is mild inhibition of mitochondrial complex I in liver cells, which lowers ATP and raises AMP; this activates AMPK and shifts the cell's energy and redox state. How much each effect matters (AMPK-dependent and independent routes, glycerol-3-phosphate dehydrogenase, actions in the gut) is still debated. It does not stimulate insulin release, so on its own it rarely causes hypoglycemia.

- Accumulates in liver cells and mildly inhibits complex I
- Less ATP, more AMP: AMPK switches on and the energy state shifts
- The liver makes less new glucose (gluconeogenesis falls)
- Fasting glucose and HbA1c fall without hypoglycemia

## Pharmacokinetics

**Absorption**
Oral, from the small intestine; bioavailability is about 50 to 60%.

**Distribution**
Barely binds plasma proteins.

**Metabolism**
Not metabolized in the liver.

**Elimination**
Excreted unchanged in urine, mainly by tubular secretion, so kidney function sets its levels.

**Half-life**
About 6 hours in plasma.

## Indications

- Type 2 diabetes, as first-line drug together with diet and exercise [Type 2 diabetes mellitus →](https://durgical.com/en/conditions/type-2-diabetes-mellitus/)
- Prediabetes and insulin resistance in metabolic syndrome, to delay type 2 diabetes [Metabolic syndrome →](https://durgical.com/en/conditions/metabolic-syndrome/)
- Polycystic ovary syndrome with insulin resistance (off-label in many countries) [Polycystic ovary syndrome →](https://durgical.com/en/conditions/polycystic-ovary-syndrome/)

## Adverse effects

### Common

- Gastrointestinal: diarrhea, nausea, bloating, abdominal discomfort (the most common reason to stop)
- Metallic taste
- Vitamin B12 deficiency with long-term use

### Serious (rare, important)

- Lactic acidosis: rare but life-threatening; risk rises with kidney failure, shock, sepsis, acute myocardial infarction and other hypoxic states, liver disease or heavy alcohol use. Metformin is stopped when one of these events occurs.

## Contraindications

- Severe kidney impairment (eGFR below 30)
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis
- Hypersensitivity to metformin
- Its use is also avoided in liver disease

## Key interactions

**Iodinated contrast media**
Contrast can cause acute kidney injury and let metformin accumulate; in patients at risk it is stopped at the time of the study and kidney function is rechecked about two days later.

**Alcohol**
Strengthens metformin's effect on lactate metabolism and raises the risk of lactic acidosis.

**Drugs that reduce its renal clearance (ranolazine, vandetanib, dolutegravir, cimetidine)**
Raise metformin levels.

**Carbonic anhydrase inhibitors (topiramate, zonisamide, acetazolamide)**
Add a tendency to metabolic acidosis.

**Insulin or insulin secretagogues (sulfonylureas)**
These cause hypoglycemia, and adding metformin can raise that risk.

## What is monitored

- Kidney function (eGFR) at the start and periodically
- HbA1c
- Blood count yearly and vitamin B12 every few years during long-term treatment

## Memory aid

Metformin turns down the liver's sugar factory by dimming its power plant (complex I). With the power low, cells lean on glycolysis and make lactate, so a patient short of oxygen or kidney function is where trouble starts.

## Test yourself

Think of the answer, then tap the question to see it.

## Why does metformin alone rarely cause hypoglycemia?

It does not increase insulin secretion. It lowers hepatic glucose output and improves insulin action, so glucose falls toward normal but is not pushed below it.

## Which vitamin deficiency appears with long-term metformin, and why does it matter?

Vitamin B12. It can cause megaloblastic anemia and worsen or mimic diabetic neuropathy, so levels are checked during long treatment.

## A patient on metformin is scheduled for a CT with iodinated contrast. What is the concern?

Contrast can injure the kidney; metformin is cleared unchanged by the kidney, so it may accumulate and raise the risk of lactic acidosis. It is often paused and kidney function rechecked.

## How does complex I inhibition help explain the lactic acidosis risk?

Less mitochondrial oxidation pushes cells toward anaerobic glycolysis, so more pyruvate becomes lactate, while the liver, with gluconeogenesis slowed, clears less lactate. Hypoxia or kidney failure tips the balance.

[Add to my cards (4)](https://durgical.app/estudiar/?add=/en/pharmacology/metformin/)

## Related drugs

- [Regular human insulin](https://durgical.com/en/pharmacology/regular-human-insulin/)

## Related conditions

- [Type 2 diabetes mellitus](https://durgical.com/en/conditions/type-2-diabetes-mellitus/)
- [Metabolic syndrome](https://durgical.com/en/conditions/metabolic-syndrome/)
- [Polycystic ovary syndrome](https://durgical.com/en/conditions/polycystic-ovary-syndrome/)

[← Back to the class: Biguanides](https://durgical.com/en/pharmacology/classes/biguanides/)

Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: [Metformin: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a696005.html) (MedlinePlus (U.S. National Library of Medicine), 2026); [DailyMed - METFORMIN HYDROCHLORIDE- metformin hydrochloride tablet tablet](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8cd5555c-f6b2-28d8-e053-2a95a90a5f1e) (DailyMed (U.S. National Library of Medicine), 2026); [Respirasome closed state 1 bound by metformin (SC-MetC1)](https://www.rcsb.org/structure/8ZSQ) (RCSB Protein Data Bank, 2025); [eEML - Electronic Essential Medicines List](https://list.essentialmeds.org/) (World Health Organization, 2025).

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Representative model, for educational purposes only.

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