There is increasing evidence to suggest that therapeutic doses of metformin are unlikely to cause lactic acidosis. The aims of this research were (1) to formally evaluate the association between metformin therapy and lactic acidosis in published case reports using two causality scoring systems, (2) to determine the frequency of pre-existing independent risk factors in published metformin-associated lactic acidosis cases, (3) to investigate the association between risk factors and mortality in metformin-associated lactic acidosis cases, and (4) to explore the relationship between prescribed metformin doses, elevated metformin plasma concentrations and the development of lactic acidosis in cases with chronic renal impairment. A systematic review was conducted to identify metformin-associated lactic acidosis cases. Causality was assessed using the World Health Organisation-Uppsala Monitoring Centre system and the Naranjo adverse drug reaction probability scale. Compliance to dosing guidelines was investigated for cases with chronic renal impairment as well as the association between steady-state plasma metformin concentrations prior to admission. We identified 559 metformin-associated lactic acidosis cases. Almost all cases reviewed (97%) presented with independent risk factors for lactic acidosis. The prescribed metformin dose exceeded published guidelines in 60% of cases in patients with impaired kidney function. Metformin steady-state plasma concentrations prior to admission were predicted to be below the proposed upper limit of the therapeutic range of 5 mg/L. Almost all cases of metformin-associated lactic acidosis reviewed presented with independent risk factors for lactic acidosis, supporting the suggestion that metformin plays a contributory role. The prescribed metformin dose, on average, exceeded the dosing recommendations by 1000 mg/day in patients with varying degrees of renal impairment but the predicted pre-admission plasma concentrations did not exceed the therapeutic range.

The Association between Metformin Therapy and Lactic Acidosis.

A 33-year-old, 34-week gestation patient with metformin treated gestational diabetes presented with lactic acidosis Subsequent examination and ultrasound confirmed foetal death Examination of the blood and urine provided evidence of ethanol and cocaine use on the day prior to admission

Lactic acidosis has been reported after the use of metformin, but it is exceptionally rare Precipitants such as ethanol and cocaine create a biochemically favourable environment in which lactic acidosis can occur Therefore, in patients receiving metformin who have ingested such agents, lactic acidosis should be considered Copyright © 2008 John Wiley & Sons

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/pdi.1232

D McLellan

Papers

Foetal death following lactic acidosis induced by ethanol, cocaine and metformin