title: Metformin associated lactic acidosis: incidence and clinical correlation with metformin serum concentration measurements.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Pharmacy, Deventer Hospital, Deventer, The Netherlands. laarvdi@dz.nl
authors.forename: I R F
authors.initials: IR
authors.lastname: van Berlo-van de Laar
authors.forename: C G
authors.initials: CG
authors.lastname: Vermeij
authors.forename: C J
authors.initials: CJ
authors.lastname: Doorenbos
mesh_terms: D000140:Acidosis, Lactic / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality / Q000628:therapy; D000368:Aged; D000369:Aged, 80 and over; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000453:epidemiology; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use; D015994:Incidence; D019344:Lactic Acid / Q000097:blood; D008297:Male; D008499:Medical Records; D008687:Metformin / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D051437:Renal Insufficiency / Q000453:epidemiology; D012307:Risk Factors; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D007004:Hypoglycemic Agents; D019344:Lactic Acid; D008687:Metformin