title: The Role of Metformin in Metformin-Associated Lactic Acidosis (MALA): Case Series and Formulation of a Model of Pathogenesis.
abstract: BACKGROUND
  Lactic acidosis is an adverse event associated with metformin usage. Patients with metformin-associated lactic acidosis (MALA), however, often have other conditions contributing to the event. The relative contribution of metformin is often unclear. MALA is usually diagnosed without measuring the plasma concentrations of metformin.
  
  
  OBJECTIVE
  The objectives of this study were, first, to examine the plasma concentrations of metformin, lactate and creatinine and the arterial pH of patients with suspected MALA and, second, to review critically the mechanisms of MALA.
  
  
  METHODS
  Patients who were suspected of having MALA were identified during the period October 2008-September 2011. Repeated blood samples were collected to determine the plasma concentrations of lactate, metformin and creatinine. The pH of arterial blood was also measured on several occasions in each patient.
  
  
  RESULTS
  Patients (n = 15; 9 female, 6 male) were 70 ± 12 years of age. There was one acute metformin overdose (estimated dose 5 g). Metformin was undetectable in one patient and one patient had therapeutic concentrations of metformin on admission (<5 mg/L). There were ten patients with chronic kidney disease, whereby the estimated glomerular filtration rate (eGFR) was less than 60 mL/min/1.73 m(2) before the acidotic event. Metformin doses ranged from 1 to 3 g daily (excluding the deliberate overdose). On admission, the mean plasma concentration of metformin on admission was 29.8 ± 19.1 mg/L (mean ± SD), the mean lactate concentration was 12.9 ± 6.1 mmol/L and the mean pH was 7 ± 0.2. The mean creatinine concentration on admission was 481 ± 225 μmol/L. The main pre-admission symptoms were vomiting and diarrhoea (n = 12). There were linear relationships between venous lactate, venous creatinine and arterial pH, with the venous plasma concentrations of metformin in most patients. Three patients died but metformin was unlikely to have been a significant factor.
  Most patients with MALA presented to the hospital with high metformin concentrations. The following factors appear to have been involved in the development of MALA in these patients: vomiting and diarrhoea, acute kidney injury, high doses or excessive accumulation of metformin, and acute disease states leading to tissue hypoxia. The extent of metformin accumulation in patients with MALA can be determined by investigating the concentrations of metformin. We suggest that the development of MALA is due to a positive feedback system involving one or more of these factors. While nausea is a common adverse effect of metformin, vomiting and diarrhoea out of the ordinary is a clear first sign of MALA. In this condition, dosage with metformin should be stopped and patients should receive urgent medical attention.
authors.affiliation: School of Medical Sciences, University of New South Wales, Kensington, NSW, Australia.|Department of Clinical Pharmacology and Toxicology, Level 2 Xavier Building, St Vincent's Hospital, 390 Victoria Street, Darlinghurst, NSW, 2010, Australia.
authors.forename: Janna K
authors.initials: JK
authors.lastname: Duong
authors.affiliation: Department of Nephrology, St. Vincent's Hospital, Darlinghurst, NSW, Australia.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Furlong
authors.affiliation: Department of Clinical Pharmacology and Toxicology, Level 2 Xavier Building, St Vincent's Hospital, 390 Victoria Street, Darlinghurst, NSW, 2010, Australia.|Department of Nephrology, St. Vincent's Hospital, Darlinghurst, NSW, Australia.|Department of Renal Medicine, Concord Repatriation General Hospital, Concord, NSW, Australia.
authors.forename: Darren M
authors.initials: DM
authors.lastname: Roberts
authors.affiliation: School of Medical Sciences, University of New South Wales, Kensington, NSW, Australia.|Department of Clinical Pharmacology and Toxicology, Level 2 Xavier Building, St Vincent's Hospital, 390 Victoria Street, Darlinghurst, NSW, 2010, Australia.
authors.forename: Garry G
authors.initials: GG
authors.lastname: Graham
authors.affiliation: Department of Endocrinology, St Vincent's Hospital, Darlinghurst, NSW, Australia.|Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Greenfield
authors.affiliation: School of Medical Sciences, University of New South Wales, Kensington, NSW, Australia.|Department of Clinical Pharmacology and Toxicology, Level 2 Xavier Building, St Vincent's Hospital, 390 Victoria Street, Darlinghurst, NSW, 2010, Australia.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Williams
authors.affiliation: School of Medical Sciences, University of New South Wales, Kensington, NSW, Australia. r.day@unsw.edu.au.|Department of Clinical Pharmacology and Toxicology, Level 2 Xavier Building, St Vincent's Hospital, 390 Victoria Street, Darlinghurst, NSW, 2010, Australia. r.day@unsw.edu.au.|St Vincent's Hospital Clinical School, Medicine, University of New South Wales, Darlinghurst, NSW, Australia. r.day@unsw.edu.au.
authors.forename: Richard O
authors.initials: RO
authors.lastname: Day
mesh_terms: D000140:Acidosis, Lactic / Q000097:blood* / Q000139:chemically induced / Q000473:pathology; D000368:Aged; D003404:Creatinine / Q000097:blood; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000097:blood; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000097:blood*
chemical_list: D019344:Lactic Acid; D008687:Metformin; D003404:Creatinine
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