Metformin treatment in patients with type 2 diabetes and chronic kidney disease stages 3A, 3B, or 4
Open accessAbstract
OBJECTIVE This study was conducted to define a safe, effective dose regimen for metformin in moderate and severe chronic kidney disease (CKD; stages 3A/3B and 4, respectively), after the lifting of restrictions on metformin use in patients with diabetes with moderate-to-severe CKD in the absence of prospective safety and efficacy studies. RESEARCH DESIGN AND METHODS Three complementary studies were performed: 1) a dose-finding study in CKD stages 1–5, in which blood metformin concentrations were evaluated during a 1-week period after each dose increase; 2) a 4-month metformin treatment study for validating the optimal metformin dose as a function of the CKD stage (3A, 3B, and 4), with blood metformin, lactate, and HbA1c concentrations monitored monthly; and 3) an assessment of pharmacokinetic parameters after the administration of a single dose of metformin in steady-state CKD stages 3A, 3B, and 4. RESULTS First, in the dose-finding study, the appropriate daily dosing schedules were 1,500 mg (0.5 g in the morning [qam] +1 g in the evening [qpm]) in CKD stage 3A, 1,000 mg (0.5 g qam + 0.5 g qpm) in CKD stage 3B, and 500 mg (qam) in CKD stage 4. Second, after 4 months on these regimens, patients displayed stable metformin concentrations that never exceeded the generally accepted safe upper limit of 5.0 mg/L. Hyperlactatemia (>5 mmol/L) was absent (except in a patient with myocardial infarction), and HbA1c levels did not change. Third, there were no significant differences in pharmacokinetic parameters among the CKD stage groups. CONCLUSIONS Provided that the dose is adjusted for renal function, metformin treatment appears to be safe and still pharmacologically efficacious in moderate-to-severe CKD.
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Metformin is contraindicated in individuals with an eGFR <30 mL/min/1.73m2.
“1) metformin is contraindicated in individuals with an eGFR <30 mL/min/1.73m 2”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [104]
The paper’s Conclusions recommend considering metformin initiation in severe CKD when the dose is adjusted to eGFR. Its figure defines CKD stage 4 as an eGFR of 15–29 mL/min/1.73 m², directly at odds with an unqualified claim that metformin is contraindicated below 30. The paper does not establish what a particular regulator’s labeling says for that range. (LLM, conf=0.84)
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Experimental — accuracy not yet measuredMetformin should not be initiated for individuals with an eGFR <45 mL/min/1.73m2.
“4) metformin should not be initiated for individuals with an eGFR <45 mL/min/1.73m 2”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [104]
The Conclusions (page not available in our copy) say the results “open the way for the initiation of metformin treatment in severe CKD,” provided the dose is adjusted to eGFR. The paper identifies CKD stages 3B and 4 as below 45 mL/min/1.73 m², so its conclusion runs counter to a blanket recommendation not to initiate treatment below that threshold. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredeGFR should be monitored while taking metformin.
“2) eGFR should be monitored while taking metformin”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [104]
The ‘Concerning the metformin dose’ section recommends assessing eGFR every six months in patients with CKD stage 3 taking metformin. The citing sentence omits that population limit and presents monitoring as a recommendation for everyone taking metformin. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe benefits and risks of continuing metformin treatment should be reassessed when eGFR falls to <45 mL/min/1.73m2.
“3) the benefits and risks of continuing treatment should be reassessed when eGFR falls to <45 mL/min/1.73m 2 (104,105)”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [104]
The Conclusions define CKD stage 3B as eGFR 44–30 mL/min/1.73 m² and recommend a lower metformin dose than for stage 3A. The paper thus supports reviewing treatment when eGFR falls below 45, but it does not specifically say to reassess the benefits and risks of continuing it. (LLM, conf=0.83)
Experimental — accuracy not yet measuredMetformin should be temporarily discontinued at the time of or before iodinated contrast imaging procedures in individuals with eGFR 30-60 mL/min/1.73m2.
“5) metformin should be temporarily discontinued at the time of or before iodinated contrast imaging procedures in individuals with eGFR 30-60 mL/min/1.73m 2 .”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [104]
The Conclusions discuss continuing metformin at eGFR-adjusted doses, and the dosing recommendations advise withdrawal when acute kidney injury is likely. Searches for iodinated contrast, imaging procedures, and withdrawal before imaging found no passage addressing the claimed temporary discontinuation rule for eGFR 30–60 mL/min/1.73 m². (LLM, conf=0.74)
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References 25 · Cited by 162
Research works printed but not linked: 2
- Lalau JD, Kajbaf F, Protti A, Christensen MM, De Broe ME, Wiernsperger N. Metformin-associated lactic acidosis (MALA): moving towards a new par- adigm. Diabetes Obes Metab 2017;19:1502-1512
- Lalau JD, Lacroix C. Measurement of metfor- min concentration in erythrocytes: clinical impli- cations. Diabetes Obes Metab 2003;5:93-98
- Authors
- Lalau, J.-D., Kajbaf, F., Bennis, Y., Hurtel-Lemaire, A.-S., Belpaire, F., & De Broe, M. E.
- Affiliations
- Inserm (FR)
- Centre Hospitalier Universitaire Amiens-Picardie (FR)
- Laboratoire de Pharmacologie Clinique, Amiens University Medical Center, Amiens, France
- Ghent University (BE)
- Laboratory of Pathophysiology, University of Antwerp, Wilrijk, Belgium
- Corresponding author
- Lalau, Jean-Daniel
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2018-01-05
- Volume
- 41
- Issue
- 3
- Pages
- 547-553
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- OpenAlex
- W2782341309
- Cited by
- 162
- References
- 25
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 22 · 2023: 13 · 2022: 23 · 2021: 24 · 2020: 28 · 2019: 15 · 2018: 19
- FWCI
- 17.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes Care (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- 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, hyperlactatemia, HbA1c, drug safety in kidney disease
- MeSH terms
- Creatinine, Diabetes Mellitus, Type 2, Dose-Response Relationship, Drug, Female, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Male, Metformin, Lactic Acid, Renal Insufficiency, Chronic
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