title: Metformin and lactic acidosis: cause or coincidence? A review of case reports.
abstract: OBJECTIVE
  Metformin has been associated with the serious side-effect lactic acidosis. However, it remains unclear whether the use of metformin was a cause or a coincidence in lactic acidosis.
  
  
  METHODS
  A literature search of the Index Medicus (1959-66) and of the databases Embase, Medline, Medline Express (1966-99) was performed using the keywords metformin, biguanides and lactic acidosis. All articles of cases with metformin-induced lactic acidosis (MILA) were cross-referenced.
  
  
  METHODS
  Cases were included for analysis if they met the following criteria: serum pH < or =7.35, lactate concentration > or =5 mmol L(-1).
  
  
  METHODS
  A forum of six experts in intensive care medicine independently categorized the cases in MILA unlikely (score 0), possible MILA (score 1) or probable MILA (score 2).
  
  
  METHODS
  Statistical analysis included the paired interobserver agreement (kappa) and multivariate regression analysis.
  
  
  RESULTS
  Of 80 reported cases, 33 were excluded because of insufficient quality. The forum scores of the remaining 47 cases were distributed normally with a mean score of 7 (range 2-10). The kappa-value was 0.041 (SD = 0.24, range -0.514, 0.427). Neither lactate concentration nor mortality correlated with serum metformin concentrations.
  
  
  CONCLUSIONS
  Given the low interobserver agreement and the lack of any relationship between metformin levels and outcome parameters, the concept that there is a simple, causal relationship between metformin use and lactic acidosis in diabetic patients has to be reconsidered.
authors.affiliation: Department of Internal Medicine, Diakonessenhuis, Utrecht, The Netherlands. amestades@yahoo.com
authors.forename: A M E
authors.initials: AM
authors.lastname: Stades
authors.forename: J T
authors.initials: JT
authors.lastname: Heikens
authors.forename: D W
authors.initials: DW
authors.lastname: Erkelens
authors.forename: F
authors.initials: F
authors.lastname: Holleman
authors.forename: J B L
authors.initials: JB
authors.lastname: Hoekstra
mesh_terms: D000140:Acidosis, Lactic / Q000139:chemically induced*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D008297:Male; D008499:Medical Records; D008687:Metformin / Q000009:adverse effects*; D008875:Middle Aged; D012044:Regression Analysis; D012307:Risk Factors
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin