Clinical Outcomes of Metformin Use in Populations With Chronic Kidney Disease, Congestive Heart Failure, or Chronic Liver Disease: A Systematic Review

Abstract

Background: Recent changes to the U.S. Food and Drug Administration boxed warning for metformin will increase its use in persons with historical contraindications or precautions. Prescribers must understand the clinical outcomes of metformin use in these populations.

Purpose: To synthesize data addressing outcomes of metformin use in populations with type 2 diabetes and moderate to severe chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease (CLD) with hepatic impairment.

Data sources: MEDLINE (via PubMed) from January 1994 to September 2016, and Cochrane Library, EMBASE, and International Pharmaceutical Abstracts from January 1994 to November 2015.

Study selection: English-language studies that: 1) examined adults with type 2 diabetes and CKD (with estimated glomerular filtration rate less than 60 mL/min/1.73 m2), CHF, or CLD with hepatic impairment; 2) compared diabetes regimens that included metformin with those that did not; and 3) reported all-cause mortality, major adverse cardiovascular events, and other outcomes of interest.

Data extraction: 2 reviewers abstracted data and independently rated study quality and strength of evidence.

Data synthesis: On the basis of quantitative and qualitative syntheses involving 17 observational studies, metformin use is associated with reduced all-cause mortality in patients with CKD, CHF, or CLD with hepatic impairment, and with fewer heart failure readmissions in patients with CKD or CHF.

Limitations: Strength of evidence was low, and data on multiple outcomes of interest were sparse. Available studies were observational and varied in follow-up duration.

Conclusion: Metformin use in patients with moderate CKD, CHF, or CLD with hepatic impairment is associated with improvements in key clinical outcomes. Our findings support the recent changes in metformin labeling.

Primary funding source: U.S. Department of Veterans Affairs. (PROSPERO: CRD42016027708).

Figure 1. Flow of articles through the literature search and screening process

Abbreviations: CHF=congestive heart failure; CKD=chronic kidney disease; CLD=chronic liver disease ^*Search results are from Embase (2512), PubMed (2312), Cochrane (17). ^†Three references were relevant to both CKD and CHF.

Figure 2. Meta-analysis of all-cause mortality among patients with moderate-to-severe CKD using treatment regimens including metformin versus regimens not including metformin^{* † ‡}

Abbreviations: CI=confidence interval; CKD=chronic kidney disease; eGFR=estimated glomerular filtration rate; HR=hazard ratio; ROB=risk of bias; SCr=serum creatinine ^*Studies on the forest plot are ordered by increasing CKD severity. ^†Eckstrom, 2012 (31) and Roussel, 2010 (34) stratified their respective populations by eGFR; these eGFR categories are presented separately for these studies. ^‡SCr (serum creatinine) > 132.6 μmol/L (1.5mg/dL)

Figure 3. Meta-analysis of all-cause mortality among patients with CHF using treatment regimens including metformin versus regimens not including metformin^*

Abbreviations: CI=confidence interval; CHF=congestive heart failure; HR=hazard ratio; ROB=risk of bias ^*Studies on the forest plot are ordered chronologically.