Metformin-associated lactic acidosis


  • Acute and chronic use of metformin can lead to rare complication of Metformin-associate lactic acidosis (MALA)
  • Excreted (unmetabolized) in proximal tubules
  • Stimulates anaerobic glucose metabolism in splanchnic bed → increased lactate production
  • Inhibits mitochondrial respiratory chain → decreased gluconeogenesis from lactate → lactate accumulation
  • Associated with overdose, renal failure, liver disease, and septicemia[1]
  • Acidosis onset several hours after acute ingestion
  • Mortality rate 45%[2]
    • Lactate only predictive of mortality in overdose patients, not in incidental metformin accumulation
    • Elevated PT associated with increased mortality
    • pH >6.9, lactate >25 portends a poor prognosis[3]

Clinical Features

Differential Diagnosis

Lactic acidosis

By Type

  • Type A (tissue hypoperfusion)
  • Type B (decreased utilization)
    • Alcoholism
      • ↓ Lactate utilization secondary to hepatic dysfunction
      • ↓ NAD+/NADH ratio leads to ↑ conversion of pyruvate to lactate
    • Metformin
    • DKA
      • Mainly due to D-lactate production, though hypovolemia contributes
    • Liver disease (decreased clearance)
    • Adrenergic receptor agonism; viz., albuterol, epinephrine, etc
    • Malignancy
    • Carbon Monoxide poisoning
    • Cyanide poisoning
  • Type D
    • episodes of encephalopathy and metabolic acidosis typically following high carbohydrate meals in patients with short bowel syndrome
    • metabolic acidosis and high serum anion gap, normal lactate level, short bowel syn or other forms of malabsorption, and characteristic neurologic findings
      • Type D lactate is not detected with standard lactate levels

Complete List

  • Any shock state
  • SIRS; lactate may be 2-5 mEq/L
  • Thiamine deficiency; more often seen in ICU settings; Thiamine is a co-factor for pyruvate dehydrogenase
  • Seizure
  • Dead gut
  • Hepatic failure
  • Malignancy
  • Exercise
  • Albuterol and other beta agonists[4]
  • Toxicologic Causes:
    • Cyanide
    • Carbon Monoxide
    • Metformin
    • Didanosine
    • Stavudine
    • Zidovudine
    • Linezolid
    • Strychnine
    • Emtriva
    • Rotenone (Fish Poison
    • NaAzide (Lab Workers)
    • APAP (if Liver Fx)
    • Phospine (rodenticide)
    • NaMonofluoroacetate (Coyote Poison‐ give Etoh as antidote)
    • INH (if patient seizes)
    • Hemlock
    • Valproate
    • Hydrogen Sulfide
    • Nitroprusside (if cyanide toxic)
    • Ricin & Castor Beans
    • Propofol
    • Sympathomimetics (cocaine, methamphetamine)
    • Jequirty peas (Abrus precatorius)
    • Prunus Amygdalus plants
    • Crab tree apple seeds & cassava (yucca)
    • HAART-induced lactic acidosis


  • FS
  • [ASA]
  • [APAP]
  • ECG
  • bHCG
  • ABG
  • Chem
  • Lactate


  • If intubated, maintain minute ventilation so as to not remove respiratory compensation for acidosis
  • Activated charcoal if peri-ingestion/mental status appropriate
  • Metformin should not cause hypoglycemia and, if present, should lead to work up of cause
  • Sodium Bicarbonate
    • No evidence to support its use in MALA patients[5]
  • Hemodialysis
    • Metformin can be cleared with hemodialysis and CVVH (continuous venovenous hemofiltration)[6]
      • Former preferred
      • CVVH should be used in unstable patient
    • Reduction in metformin levels following acute ingestion reported to require prolonged HD[7]
    • Consider if:
      • pH <7.1
      • Renal insufficiency
    • Mortality benefits mainly from improving acidosis than from removing Metformin

See Also


  1. Goldfrank, Lewis R. Goldfrank's Toxicologic Emergencies. 9th Ed. New York: McGraw-Hill, 2011
  2. Seidowsky, A., Nseir, S., Houdret, N., & Fourrier, F. (2009). Metformin-associated lactic acidosis: a prognostic and therapeutic study. Critical care medicine, 7, 2191–2196.
  3. Dell'Aglio, D. M., Perino, L. J., Kazzi, Z., Abramson, J., Schwartz, M. D., & Morgan, B. W. (2009). Acute metformin overdose: examining serum pH, lactate level, and metformin concentrations in survivors versus nonsurvivors: a systematic review of the literature. Annals of emergency medicine, 6, 818–823.
  4. Dodda V and Spiro P. Albuterol, an Uncommonly Recognized Culprit in Lactic Acidosis. Chest. 2011;140.
  5. Kruse, J. A. (2001). Metformin-associated lactic acidosis. The Journal of emergency medicine, 3, 267–272.
  6. Barrueto, F., Meggs, W. J., & Barchman, M. J. (2002). Clearance of metformin by hemofiltration in overdose. Journal of toxicology. Clinical toxicology, 2, 177–180.
  7. Rifkin, S. I., McFarren, C., Juvvadi, R., & Weinstein, S. S. (2011). Prolonged hemodialysis for severe metformin intoxication. Renal failure, 4, 459–461.
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