UMEM Educational Pearls

Metformin is the first line medication for the treatment of type II diabetes. A rare complication of chronic metformin use is MALA.

  • Incidence: 2-9 cases per 100,000 patients
  • Mortality: 30-50%

The association between metformin accumulation and development of lactic acidosis is controversial as patients with suspected MALA experience concurrent illnesses such as sepsis/septic shock, tissue hypoxia, and/or organ dysfunction (especially renal failure).

  • Greater than 90% of metformin (unchanged) is eliminated by the kidney.
  • Metformin accumulation (from renal failure) leads to inhibition of complex I of the electron transport chain.1,2
  • A case series of 66 patients MALA experienced severe lactic acidosis (pH: 6.91+ 0.18; lactate 14.36+ 4.9 mmol/L) and renal failure (Cr 7.24 + 3.29 mg/dL)3
  • Prodromal GI symptoms in 77%
  • Clinical findings at time of admission/presentation:
  • AMS/coma: 57%
  • Dyspnea/hyperventilation: 42%
  • Hemodynamic shock: 39%
  • Hypotension (SBP < 100 mmHg): 23%
  • No correlation between lactate and metformin level.
  • Risk factors
    • Renal failure (metformin accumulation)
    • Elderly population (higher mortality)
    • Cardiac or respiratory insufficiency causing central hypoxia
    • Sepsis/septic shock
    • Liver disease
    • IV contrast use (resulting in renal insufficiency)
  • Treatment: emergent hemodialysis


  1. Owens MR et al. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain.   Biochem J. 2000;348;607-614.
  2. Protti A et al.  Metformin overdose, but not lactic acidosis per se, inhibits oxygen consumptions in pigs. Crit Care 2012;16:R75.
  3. Vecchio S et al. Metformin accumulation: lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy. Clin Toxicol 2014;52:129-135.