Metformin in Patients With Type 2 Diabetes and Kidney Disease: A Systematic Review

Inzucchi, Silvio E.; Lipska, Kasia J.; Mayo, Helen; Bailey, Clifford J.; McGuire, Darren K.

doi:10.1001/jama.2014.15298

Cited by 601Diabetes Treatment and ManagementChronic Kidney Disease and DiabetesDiabetes Management and Research

Metformin in Patients With Type 2 Diabetes and Kidney Disease: A Systematic Review

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Inzucchi, Silvio E., Lipska, Kasia J., Mayo, Helen, Bailey, Clifford J., McGuire, Darren K.·2014·JAMA

DOI 10.1001/jama.2014.15298PMC PMC4427053

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Abstract

IMPORTANCE: Metformin is widely viewed as the best initial pharmacological option to lower glucose concentrations in patients with type 2 diabetes mellitus. However, the drug is contraindicated in many individuals with impaired kidney function because of concerns of lactic acidosis. OBJECTIVE: To assess the risk of lactic acidosis associated with metformin use in individuals with impaired kidney function. EVIDENCE ACQUISITION: In July 2014, we searched the MEDLINE and Cochrane databases for English-language articles pertaining to metformin, kidney disease, and lactic acidosis in humans between 1950 and June 2014. We excluded reviews, letters, editorials, case reports, small case series, and manuscripts that did not directly pertain to the topic area or that met other exclusion criteria. Of an original 818 articles, 65 were included in this review, including pharmacokinetic/metabolic studies, large case series, retrospective studies, meta-analyses, and a clinical trial. RESULTS: Although metformin is renally cleared, drug levels generally remain within the therapeutic range and lactate concentrations are not substantially increased when used in patients with mild to moderate chronic kidney disease (estimated glomerular filtration rates, 30-60 mL/min per 1.73 m2). The overall incidence of lactic acidosis in metformin users varies across studies from approximately 3 per 100,000 person-years to 10 per 100,000 person-years and is generally indistinguishable from the background rate in the overall population with diabetes. Data suggesting an increased risk of lactic acidosis in metformin-treated patients with chronic kidney disease are limited, and no randomized controlled trials have been conducted to test the safety of metformin in patients with significantly impaired kidney function. Population-based studies demonstrate that metformin may be prescribed counter to prevailing guidelines suggesting a renal risk in up to 1 in 4 patients with type 2 diabetes mellitus--use which, in most reports, has not been associated with increased rates of lactic acidosis. Observational studies suggest a potential benefit from metformin on macrovascular outcomes, even in patients with prevalent renal contraindications for its use. CONCLUSIONS AND RELEVANCE: Available evidence supports cautious expansion of metformin use in patients with mild to moderate chronic kidney disease, as defined by estimated glomerular filtration rate, with appropriate dosage reductions and careful follow-up of kidney function.

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Metformin may be used safely in individuals with estimated glomerular filtration rate $30 mL/min/1.73m2.
“Recent studies have indicated that it may be used safely in individuals with estimated glomerular filtration rate $30 mL/min/1.73m 2 (104).”
From 13. Older Adults: Standards of Care in Diabetes—2024 (2024) · cites this paper as [104]
The Discussion’s Summary of Key Findings supports metformin use at eGFR 30–60 mL/min/1.73 m², but only when kidney function is stable and the patient is closely observed. The Recommendations also call for dose reductions and careful follow-up. The citing sentence omits these safety conditions. (LLM, conf=0.86)
Experimental — accuracy not yet measured
The overall risk for metformin-associated lactic acidosis is low.
“Evidence, however, suggests the overall risk for metformin-associated lactic acidosis is low (53), and the U.S. Food and Drug Administration has revised the U.S. label to reflect its safety in most patients with eGFR ≥30 mL/min/1.73 m2 (52).”
From Diabetes management in chronic kidney disease: a consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) (2022) · cites this paper as [53]
Data from two retrospective cohort studies including 111,971 patients with diabetes suggest an adverse safety profile of sulphonylureas, with approximately 20-60% higher death rate and approximately 20-30% higher risk of heart failure compared with metformin.
“Data from two retrospective cohort studies, including 111 971 patients with diabetes, suggest an adverse safety profile showing ∼20-60% higher death rate and ∼20-30% higher risk of HF compared with metformin.560,561”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [561]

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[28]Lalau JD Lacroix C De Cagny B Fournier A Metformin-associated lactic acidosis in diabetic patients with acute renal failure: a critical analysis of its pathogenesis and prognosis Nephrol Dial Transplant 1994 9 suppl 4 126 129 7800245

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Authors: Inzucchi, S. E., Lipska, K. J., Mayo, H., Bailey, C. J., & McGuire, D. K.
Affiliations: Yale University (US)
The University of Texas Southwestern Medical Center (US)
Aston University (GB)
ORCID: Inzucchi, Silvio E.
Lipska, Kasia J.
Mayo, Helen
Bailey, Clifford J.
McGuire, Darren K.
Venue: JAMA
Publisher: American Medical Association (AMA)
Published: 2014-12-24
Volume: 312
Issue: 24
Pages: 2668
ISSN: 0002-9955 (ISSN-L)
0098-7484
DOI: 10.1001/jama.2014.15298
PMC: PMC4427053
OpenAlex: W1986628483
Cited by: 601
References: 86
Citations by year: 2026: 20 · 2025: 32 · 2024: 57 · 2023: 32 · 2022: 49 · 2021: 46 · 2020: 50 · 2019: 54 · 2018: 61 · 2017: 77 · 2016: 75 · 2015: 47
FWCI: 53.35
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: JAMA (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute on Aging (L30 AG045923, K23AG048359, R03AG045086, P30AG021342)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords: metformin, type 2 diabetes, chronic kidney disease, lactic acidosis, drug safety, estimated glomerular filtration rate, macrovascular outcomes
MeSH terms: Contraindications, Acidosis, Lactic, Diabetes Mellitus, Type 2, Glomerular Filtration Rate, Humans, Hypoglycemic Agents, Metformin, Risk, Renal Insufficiency, Chronic

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Metformin in Patients With Type 2 Diabetes and Kidney Disease: A Systematic Review

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