Risk of Fatal and Nonfatal Lactic Acidosis With Metformin Use in Type 2 Diabetes Mellitus: Systematic Review and Meta-analysis
Abstract
Background Metformin therapy for type 2 diabetes mellitus has been shown to reduce total mortality rates compared with other antihyperglycemic treatments but is thought to increase the risk of lactic acidosis. The true incidence of fatal and nonfatal lactic acidosis associated with metformin use is not known. Methods A comprehensive search was performed to identify all comparative trials or observational cohort studies published between January 1, 1959, and March 31, 2002, that evaluated metformin therapy, alone or in combination with other treatments, for at least 1 month. The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years for metformin treatment and for placebo or other treatments. In a second analysis, lactate levels were measured as a net change from baseline or as mean treatment values for metformin and comparison groups. Results Pooled data from 194 studies revealed no cases of fatal or nonfatal lactic acidosis in 36 893 patient-years in the metformin group or in 30 109 patients-years in the nonmetformin group. Using Poisson statistics with 95% confidence intervals, the probable upper limit for the true incidence of lactic acidosis in the metformin and nonmetformin groups was 8.1 and 9.9 cases per 100 000 patient-years, respectively. There was no difference in lactate levels for metformin compared with placebo or other nonbiguanide therapies. Conclusion There is no evidence to date that metformin therapy is associated with an inc…
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Very high circulating metformin levels, such as from overdose or acute kidney injury, have been associated with lactic acidosis.
“Very high circulating levels (e.g., as a result of overdose or acute kidney injury) have been associated with lactic acidosis (99).”
From 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025 (2025) · cites this paper as [99]
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- Authors
- Salpeter, S. R., Greyber, E., Pasternak, G. A., & Salpeter, E. E.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Salpeter, Shelley R.
- Venue
- Archives of Internal Medicine
- Publisher
- American Medical Association (AMA)
- Published
- 2003-11-24
- Volume
- 163
- Issue
- 21
- Pages
- 2594
- ISSN
- 0003-9926 (ISSN-L)
- OpenAlex
- W2170760052
- Cited by
- 312
- References
- 6
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 3 · 2023: 6 · 2022: 7 · 2021: 7 · 2020: 6 · 2019: 10 · 2018: 10 · 2017: 13 · 2016: 14 · 2015: 13 · 2014: 11 · 2013: 21 · 2012: 16
- FWCI
- 12.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Internal Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- metformin, lactic acidosis, type 2 diabetes, drug safety, lactate levels, antidiabetic drugs, biguanides, adverse drug reactions
- MeSH terms
- Acidosis, Lactic, Diabetes Mellitus, Type 2, Humans, Hypoglycemic Agents, Metformin, Phenformin, Risk Assessment
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