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The Association between Metformin Therapy and Lactic Acidosis

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Abstract

Introduction and Objectives

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.

Methods

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.

Results

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.

Conclusions

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.

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Data Availability

A database of metformin-associated lactic acidosis case reports (including cases where metformin was taken therapeutically and in overdose) has been generated from this work. The database of case reports is available in the figshare repository, https://figshare.com/s/4a1129faa048322cfa0c.

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Acknowledgements

Isabelle Kuan was funded by the University of Otago Special Health Research Scholarship. We thank Michelle Hsieh, Alexis Yang, Joselyn Sim, Bernice Leong, Nathan Ong and Stephanie Powzun for an initial exploration of this topic as part of an undergraduate elective project.

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  1. School of Pharmacy, University of Otago, PO Box 56, Dunedin, New Zealand

    Isabelle H. S. Kuan, Stephen B. Duffull & Daniel F. B. Wright

  2. New Zealand Pharmacovigilance Centre, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

    Ruth L. Savage

  3. Department of General Practice, University of Otago, Christchurch, New Zealand

    Ruth L. Savage

  4. Department of Medicine, University of Otago, Dunedin, New Zealand

    Robert J. Walker

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  1. Isabelle H. S. Kuan
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Correspondence to Daniel F. B. Wright.

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Isabelle Kuan, Ruth Savage, Stephen Duffull, Robert Walker and Daniel Wright have no conflicts of interest that are directly relevant to the content of this study.

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Kuan, I.H.S., Savage, R.L., Duffull, S.B. et al. The Association between Metformin Therapy and Lactic Acidosis. Drug Saf 42, 1449–1469 (2019). https://doi.org/10.1007/s40264-019-00854-x

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