Systematic Reviews
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Aug 15, 2022; 13(8): 654-664
Published online Aug 15, 2022. doi: 10.4239/wjd.v13.i8.654
Metformin toxicity: A meta-summary of case reports
Deven Juneja, Prashant Nasa, Ravi Jain
Deven Juneja, Institute of Critical Care Medicine, Max Super Speciality Hospital, Saket, New Delhi 110017, India
Prashant Nasa, Department of Critical Care Medicine, NMC Specialty Hospital, Dubai 7832, United Arab Emirates
Ravi Jain, Department of Critical Care Medicine, Mahatma Gandhi Medical College and Hospital, Jaipur 302022, India
Author contributions: Juneja D contributed to acquisition of data, analysis and interpretation of data, drafting the article, final approval; Nasa P contributed to acquisition of data, analysis and interpretation of data, drafting the article, final approval; Jain R contributed to interpretation of data, revising the article, final approval.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Deven Juneja, DNB, FCCP, MBBS, Director, Institute of Critical Care Medicine, Max Super Speciality Hospital, Saket, 1 Press Enclave Road, New Delhi 110017, India. devenjuneja@gmail.com
Received: March 22, 2022
Peer-review started: March 22, 2022
First decision: May 11, 2022
Revised: May 17, 2022
Accepted: July 25, 2022
Article in press: July 25, 2022
Published online: August 15, 2022
Processing time: 142 Days and 21.2 Hours
Abstract
BACKGROUND

Metformin is arguably the most commonly prescribed oral hypoglycemic agent for the management of diabetes. Due to the lack of randomized control trials, most of the data pertaining to the clinical course, therapeutic interventions and outcomes of patients with metformin induced toxicity has come from case reports or series.

AIM

To analyse the symptomology, clinical interventions and outcomes of patients presenting with severe metformin toxicity by reviewing the published case reports and series.

METHODS

We performed a systematic search from PubMed, Science Direct, Reference Citation Analysis (https://www.referencecitationanalysis.com/) and Google Scholar databases using the terms “metformin” AND “toxicity” OR “overdose” OR “lactic acidosis” OR “hyperlactatemia”. The inclusion criteria were: (1) Case reports or case series with individual patient details; and (2) Reported toxicity or overdose of metformin in adults, published in the English language. Data regarding baseline demographics, clinical presentation, therapeutic interventions, intensive care unit course and overall outcome were collected.

RESULTS

Two hundred forty-two individual cases were analysed, from 158 case reports and 26 case series, with a cumulative mortality of 19.8%. 214 (88.4%) patients were diabetics on metformin. 57 (23.6%) had acute ingestion, but a great majority (76.4%) were on metformin in therapeutic doses when they developed toxicity. Metformin associated lactic acidosis (MALA) was the most commonly reported adverse effect present in 224 (92.6%) patients. Most of the patients presented with gastrointestinal and neurological symptoms and a significant number of patients had severe metabolic acidosis and hyperlactatemia. The organ support used was renal replacement therapy (RRT) (68.6%), vaso-pressors (58.7%) and invasive mechanical ventilation (52.9%). A majority of patients (68.6%) received RRT for toxin removal, renal dysfunction and correction of MALA. Patients with lowest pH and highest serum lactate and metformin levels also had favourable outcomes with use of RRT.

CONCLUSION

Most of the reported cases were on therapeutic doses of metformin but developed toxicity after an acute deterioration in renal functions. These patients may develop severe lactic acidosis, leading to significant morbidity and need for organ support. Despite severe MALA and the need for multiple organ support, they may have good outcomes, especially when RRT is used. The dose of metformin, serum pH, lactate and metformin levels may indicate the severity of toxicity and the need for aggressive therapeutic measures but may not necessarily indicate poor outcomes.

Keywords: Extracorporeal toxin removal; Haemodialysis; Metformin associated lactic acidosis; Metformin overdose; Renal replacement therapy

Core Tip: Metformin may be associated with significant toxicity, even when used in therapeutic doses, of which metformin associated lactic acidosis is the most commonly reported toxicity. These patients may have favourable outcomes in spite of consumption of high doses, severe acidosis, and high serum lactate and metformin concentrations. Early aggressive supportive care, use of renal replacement therapy for toxin removal and organ support may help in improving outcomes.