Metformin associated lactic acidosis: incidence and clinical correlation with metformin serum concentration measurements

J Clin Pharm Ther. 2011 Jun;36(3):376-82. doi: 10.1111/j.1365-2710.2010.01192.x. Epub 2010 Aug 25.


What is known and objective: The reported incidence of metformin associated lactic acidosis (MALA) in type 2 diabetes mellitus (DM) is 3-9 cases per 100,000 patient-years. In clinical practice, 22-94% of patients using metformin have contraindications to metformin, so the incidence of MALA may be higher than reported.

Aim of the study: To estimate the incidence of MALA in type 2 DM patients by means of metformin serum concentration measurements and investigate the correlation of metformin serum concentration with the clinical outcome of MALA.

Methods: MALA cases were identified by reviewing the medical records of patients with metformin serum concentrations measured between January 2000 and October 2008. MALA was defined as arterial pH <7·35 and lactate concentration >5·0 mmol/L in patients using metformin. The incidence of MALA was calculated from the number of cases and the at risk population. The correlation coefficient between the metformin and lactate concentration was calculated by linear regression. The relationship between metformin serum concentration, lactate concentration and outcome was examined by calculating the mean metformin and lactate concentration in patients who survived and those who died. The Student's t-test was used to compare groups.

Results and discussion: In 29 patients metformin serum concentration was measured, 16 had MALA. Eleven of the 16 MALA cases (69%) had risk factors for lactic acidosis in their medical history, 13 cases (81%) had renal failure on admission. The incidence of MALA was estimated at 47 per 100,000 patient-years, this is 5-16 times higher than previously reported. This may be explained by the use of metformin in the presence of risk factors for lactic acidosis. Survivors had a higher metformin serum concentration (18·9 mg/L) than non-survivors (2·9 mg/L, P = 0·006) which can be explained by less severe underlying disease in patients who survived MALA, rather than an effect of metformin itself.

What is new and conclusion: The incidence of MALA estimated from metformin serum concentration measurements in type 2 DM patients is 5-16 times higher than reported in literature. MALA is probably caused by the frequent use of metformin in the presence of risk factors for lactic acidosis. Metformin serum concentration measurements may aid in the timely diagnosis and therapy of MALA. The outcome of MALA is determined by the severity of the underlying disease, rather than by metformin itself.

MeSH terms

  • Acidosis, Lactic / diagnosis
  • Acidosis, Lactic / epidemiology*
  • Acidosis, Lactic / mortality
  • Acidosis, Lactic / therapy
  • Aged
  • Aged, 80 and over
  • Diabetes Mellitus, Type 2 / blood*
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetic Nephropathies / epidemiology
  • Early Diagnosis
  • Female
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / blood*
  • Hypoglycemic Agents / therapeutic use
  • Incidence
  • Lactic Acid / blood
  • Male
  • Medical Records
  • Metformin / adverse effects
  • Metformin / blood*
  • Metformin / therapeutic use
  • Middle Aged
  • Netherlands / epidemiology
  • Renal Insufficiency / epidemiology
  • Risk Factors
  • Severity of Illness Index
  • Treatment Outcome


  • Hypoglycemic Agents
  • Lactic Acid
  • Metformin