BLACK BOX WARNING
- lactic acidosis — fatal cases have occurred; risk increased in renal impairment, hepatic disease, heart failure with reduced cardiac output, excessive alcohol intake, and radiographic procedures with iodinated contrast
metformin
Brand: Glucophage, Glumetza, Fortamet, Riomet
⚠ BBW Prototype Drug
Drug Class: antidiabetic
Drug Family: antidiabetic
Subclass: biguanide
Organ Systems: endocrine
Mechanism of Action
Inhibits hepatic gluconeogenesis (primary effect, via mitochondrial complex I inhibition and AMPK activation); reduces intestinal glucose absorption; modestly increases peripheral insulin sensitivity; does not stimulate insulin secretion — no hypoglycemia risk as monotherapy.
AMP-activated protein kinase (AMPK)Complex I of mitochondrial respiratory chain
Indications
- type 2 diabetes mellitus (first-line)
- polycystic ovary syndrome (off-label)
- prevention of type 2 diabetes in high-risk patients (prediabetes)
Contraindications
- eGFR <30 mL/min/1.73m² (hold for eGFR 30–45 when initiating; reassess at 45)
- iodinated contrast media (hold 48 hours peri-procedure in patients with renal risk)
- decompensated heart failure
- hepatic failure
- alcohol dependence (lactic acidosis risk)
Adverse Effects
Common
- GI side effects (nausea, diarrhea, abdominal discomfort — in ~30% at initiation; reduced by titration and extended-release formulation)
- metallic taste
- vitamin B12 deficiency (chronic use)
Serious
- lactic acidosis (rare, ~3/100,000 patient-years; risk increases with renal/hepatic failure, tissue hypoxia, contrast media, alcohol)
Pharmacokinetics (ADME)
| Absorption | Oral bioavailability ~50–60%; not affected by food (extended-release improves GI tolerability) |
| Distribution | Not protein-bound; Vd ~654 L; accumulates in gut wall, liver, kidney |
| Metabolism | Not metabolized — excreted unchanged |
| Excretion | Entirely renal via active tubular secretion (OCT2); dose adjustment for CrCl/eGFR <45 mL/min |
| Half-life | 4–9 hours (plasma); 17.6 hours (blood) |
| Onset | ~1 week for glucose lowering; HbA1c effect at 6–8 weeks |
| Peak | 2.5 hours (IR) |
| Duration | 12 hours (IR); 24 hours (ER) |
| Protein Binding | 0% |
| Vd | ~654 L |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| iodinated contrast media | contrast-induced nephropathy increases metformin accumulation and lactic acidosis risk; hold before and 48 hours after contrast in patients with eGFR <60 | major |
| dolutegravir (antiretroviral) | OCT2 inhibition increases metformin levels by up to 79% | major |
| cimetidine / trimethoprim | renal OCT2 inhibition reduces metformin excretion, increasing levels | moderate |
Nursing Considerations
- Start low (500 mg BID or 850 mg QD with meals) and titrate over 4–8 weeks to minimize GI side effects; most GI effects resolve within 4 weeks of initiation
- Hold metformin before procedures using iodinated contrast in patients with eGFR <60 or high contrast volume; restart 48 hours after procedure if renal function is stable
- Monitor vitamin B12 levels every 2–3 years on long-term therapy; deficiency occurs in ~10% and can cause neuropathy, anemia, and cognitive dysfunction
- Metformin is associated with cardiovascular benefit beyond glucose lowering (UKPDS evidence) — it is preferred first-line even in patients with established CVD, provided renal function is adequate
Clinical Pearls
- Lactic acidosis from metformin is a medical emergency but is extremely rare in patients with normal renal function — the risk is concentrated in those with eGFR <30 and/or tissue hypoperfusion (sepsis, cardiac shock)
- Metformin does not cause hypoglycemia as monotherapy — it works by reducing hepatic glucose production and does not stimulate insulin secretion, making it safe for patients who drive or operate machinery
Safety Profile
Pregnancy safe
Lactation use-with-caution
Renal Adjustment Required
Hepatic Adjustment Required
TDM Not required
Concordance Terms
Cross-referenced clinical concepts — click any term to see all content where it appears.