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Meta-Analysis
. 2024 Jun 4;6(6):CD013414.
doi: 10.1002/14651858.CD013414.pub2.

Metformin for preventing the progression of chronic kidney disease

Ragada El-Damanawi  1 , Isabelle Kitty Stanley  2 , Christine Staatz  3 , Elaine M Pascoe  4 , Jonathan C Craig  5   6 , David W Johnson  7   8   9 , Andrew J Mallett  8   10   11   12 , Carmel M Hawley  7   8   9 , Elasma Milanzi  13 , Thomas F Hiemstra  14 , Andrea K Viecelli  7   8
Affiliations
Meta-Analysis

Metformin for preventing the progression of chronic kidney disease

Ragada El-Damanawi et al. Cochrane Database Syst Rev. .

Abstract

Background: Metformin has been used in the management of diabetes for decades. It is an effective, low-cost intervention with a well-established safety profile. Emerging evidence suggests that metformin targets a number of pathways that lead to chronic kidney damage, and long-term use may, therefore, slow the rate of kidney function decline and chronic kidney disease (CKD) progression.

Objectives: To evaluate the effect of metformin therapy on kidney function decline in patients with CKD with or without diabetes mellitus and assess the safety and dose tolerability in this population.

Search methods: We searched the Cochrane Kidney and Transplant Register of Studies up to 19 July 2023 with assistance from an Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria: We included randomised controlled trials (RCTs) that reported kidney-related outcomes with a minimum duration of 12 months delivery of the metformin intervention and whose eligibility criteria included adult participants with either i) a diagnosis of CKD of any aetiology and/or ii) those with a diagnosis of diabetes mellitus. Comparisons included placebo, no intervention, non-pharmacological interventions, other antidiabetic medications or any other active control. Studies that included patients on any modality of kidney replacement therapy were excluded.

Data collection and analysis: Two authors independently carried out data extraction using a standard data extraction form. The methodological quality of the included studies was assessed using the Cochrane risk of bias tool. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Main results: This review included 11 studies reporting on 8449 randomised participants. Studies were conducted in patient populations with Autosomal Dominant Polycystic Kidney Disease (ADPKD) (four studies) or diabetes mellitus (seven studies). Six studies compared metformin with no active control, four studies compared metformin with active controls (rosiglitazone, glyburide, pioglitazone, or glipizide), and one study included treatment arms that randomised to either metformin, diet and lifestyle modifications, or other antidiabetic therapies. The risk of bias in included studies varied; two studies were abstract-only publications and were judged to have a high risk of bias in most domains. Other included publications were judged to have a low risk of bias in most domains. Across comparisons, GRADE evaluations for most outcomes were judged as low or very low certainty, except for those relating to side effects, tolerance, and withdrawals, which were judged as moderate certainty. The evidence suggests that compared to placebo, metformin may result in i) a slightly smaller decline in kidney function (3 studies, 505 participants: MD 1.92 mL/min, 95% CI 0.33 to 3.51; I2 = 0%; low certainty), ii) very uncertain effects on the incidence of kidney failure (1 study, 753 participants: RR 1.20, 95% CI 0.17 to 8.49), iii) little or no effect on death (3 studies, 865 participants: RR 1.00, 95% CI 0.76 to 1.32; I2 = 0%; moderate certainty), iv) little or no effect on the incidence of serious adverse events (3 studies, 576 participants: RR 1.15, 95% CI 0.76 to 1.72; I2 = 0%; moderate certainty), and v) likely higher incidence of intolerance leading to study withdrawal than placebo (4 studies, 646 participants: RR 2.19, 95% CI 1.46 to 3.27; I2 = 0%; moderate certainty). The certainty of the evidence for proteinuria was very uncertain. Compared to other active controls (rosiglitazone, glyburide, pioglitazone, or glipizide), metformin i) demonstrated very uncertain effects on kidney function decline, ii) may result in little or no difference in death (3 studies, 5608 participants: RR 0.95 95% CI 0.63 to 1.43; I2 = 0%; low certainty), iii) probably results in little or no difference in intolerance leading to study withdrawal (3 studies, 5593 participants: RR 0.92, 95% CI, 0.79 to 1.08; I2 = 0%; moderate certainty), iv) probably results in little or no difference in the incidence of serious adverse events (2 studies, 5545 participants: RR 1.16, 95% CI 0.79 to 1.71; I2 = 0%; moderate certainty), and v) may increase the urinary albumin-creatinine ratio (2 studies, 3836 participants: MD 14.61, 95% CI 8.17 to 21.05; I2 = 0%; low certainty). No studies reported the incidence of kidney failure.

Authors' conclusions: This review highlights the lack of RCTs reporting on the effects of metformin on kidney function, particularly in patients with CKD. Future research in this field requires adequately powered RCTs comparing metformin to placebo or standard care in those with CKD. Seven ongoing studies were identified in this review, and future updates, including their findings, may further inform the results of this review.

Trial registration: ClinicalTrials.gov NCT00279045 NCT02903511 NCT01483560 NCT02656017 NCT01794143 NCT01245166 NCT01289119 NCT02252081 NCT03222765 NCT03764605 NCT03831464 NCT04939935 NCT05373680 NCT05469659 NCT03982381.

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Conflict of interest statement

  1. Ragada El‐Damanawi: No relevant interests were disclosed

  2. Isabelle Kitty Stanley: No relevant interests were disclosed

  3. Christine Staatz: No relevant interests were disclosed

  4. Elaine M Pascoe: No relevant interests were disclosed

  5. Jonathan C Craig: No relevant interests were disclosed

  6. David W Johnson has received consultancy fees, research grants, speaker's honoraria and travel sponsorships from Baxter Healthcare and Fresenius Medical Care. He has received consultancy fees from AstraZeneca and travel sponsorships from Amgen. All funding was unrelated to this review

  7. Andrew J Mallett is a Principle Investigator for a proposed investigator‐initiated clinical trial applying metformin to slow progression of kidney dysfunction in autosomal dominant polycystic kidney disease. In this role, he has received competitive peer‐reviewed research grant funding from PKD Australia for this clinical trial

  8. Carmel M Hawley has received fees from Amgen, Shire, Roche, Abbott, Bayer, Fresenius, Baxter, Gambro, Janssen‐Cilag and Genzyme in relation to consultancy, speakers' fees, education, and grants for activities unrelated to this review

  9. Elasma Milanzi: No relevant interests were disclosed

  10. Thomas F Hiemstra: No relevant interests were disclosed

  11. Andrea K Viecelli: No relevant interests were disclosed

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Metformin versus placebo, Outcome 1: eGFR: change
1.2
1.2. Analysis
Comparison 1: Metformin versus placebo, Outcome 2: eGFR: final measure
1.4
1.4. Analysis
Comparison 1: Metformin versus placebo, Outcome 4: All‐cause death
1.5
1.5. Analysis
Comparison 1: Metformin versus placebo, Outcome 5: Kidney failure
1.6
1.6. Analysis
Comparison 1: Metformin versus placebo, Outcome 6: Adverse events
1.8
1.8. Analysis
Comparison 1: Metformin versus placebo, Outcome 8: Withdrawal due to intolerance
1.10
1.10. Analysis
Comparison 1: Metformin versus placebo, Outcome 10: Quality of life
1.12
1.12. Analysis
Comparison 1: Metformin versus placebo, Outcome 12: Vitamin B12 deficiency
2.1
2.1. Analysis
Comparison 2: Metformin versus active control, Outcome 1: eGFR: change
2.2
2.2. Analysis
Comparison 2: Metformin versus active control, Outcome 2: eGFR: final measure
2.3
2.3. Analysis
Comparison 2: Metformin versus active control, Outcome 3: All‐cause death
2.4
2.4. Analysis
Comparison 2: Metformin versus active control, Outcome 4: Adverse events
2.5
2.5. Analysis
Comparison 2: Metformin versus active control, Outcome 5: Withdrawal due to adverse events
2.7
2.7. Analysis
Comparison 2: Metformin versus active control, Outcome 7: UACR: % change
2.8
2.8. Analysis
Comparison 2: Metformin versus active control, Outcome 8: Progression to UACR > 30 mg/g
3.1
3.1. Analysis
Comparison 3: Subgroup analysis: metformin versus placebo, Outcome 1: Death: ADPKD subgroup analysis
3.2
3.2. Analysis
Comparison 3: Subgroup analysis: metformin versus placebo, Outcome 2: eGFR change: ADPKD subgroup analysis
3.3
3.3. Analysis
Comparison 3: Subgroup analysis: metformin versus placebo, Outcome 3: Death: age subgroup analysis
3.4
3.4. Analysis
Comparison 3: Subgroup analysis: metformin versus placebo, Outcome 4: eGFR change: duration of study subgroup analysis
3.5
3.5. Analysis
Comparison 3: Subgroup analysis: metformin versus placebo, Outcome 5: Death: duration of study subgroup analysis
4.1
4.1. Analysis
Comparison 4: Subgroup analysis: metformin versus active control, Outcome 1: Death: age subgroup analysis
4.2
4.2. Analysis
Comparison 4: Subgroup analysis: metformin versus active control, Outcome 2: Change in UACR (%): age subgroup analysis
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References to other published versions of this review

El‐Damanawi 2019
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