Crowley MJ, Diamantidis CJ, McDuffie JR, et al.   Clinical Outcomes of Metformin Use in Populations With Chronic Kidney Disease, Congestive Heart Failure, or Chronic Liver Disease: A Systematic Review.
Ann Intern Med. 2017 Feb 7;166(3):191-200. doi: 10.7326/M16-1901. Epub 2017 Jan 3.   (Systematic Review)   PMID: 28055049
Read Abstract Read┬áComments Read Free Full Text
Clinical Evidence Topic:
Diabetes: glycaemic control in type 2
Physician Disciplines Relevance to practice Is this news?
Endocrine
General Internal Medicine-Primary Care(US)
General Practice(GP)/Family Practice(FP)
Nephrology
Hospital Doctor/Hospitalists
Internal Medicine
Gastroenterology

Print     Share on Facebook   Follow me on Tweeter   Share on Del.icio.us   Share on Reddit   Share on Digg   Share on CiteULike

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).

Comments from Clinical Raters
Gastroenterology
This systematic review suggestd reduced all-cause mortlity in patients with histologic cirrhosis treated with metformin for type 2 diabetes mellitus. Analysis is limited to three studies but supports changes in FDA labeling for the oral hypoglycemic drug.
General Internal Medicine-Primary Care(US)
This is a helpful review, as many primary care providers may not be aware of updated FDA guidelines that have liberalized prescribing of metformin. Unfortunately, the data to support the broader guidelines are actually quite limited and more research is needed in this area to prove the effectiveness and safety of metformin for these additional populations.
General Internal Medicine-Primary Care(US)
Administrative data are not ideal for this question, but are better than nothing since it is a harm question and unlikely to be answered with an RCT. This information allows us to continue metformin for a while longer in patients with CHF, CKD or hepatic disease rather than switch to the very expensive (but effective) newer drugs.
General Practice(GP)/Family Practice(FP)
The quality of evidence is low. So contrary to popular opinion, metformin is not "Vitamin F" (pre-diabetes PCOS etc), at least not yet.
Hospital Doctor/Hospitalists
As a hospitalist, I expected these results, but I am glad this is being investigated further to back the trend toward prescribing metformin to a wider population. I know, I have been wary and this will cause me to worry less about giving metformin to someone with a GFR between 30 and 60.
Internal Medicine
A well-designed study evaluating the strength of the research showing benefit.
Internal Medicine
This is directly in the line-of-sight for the decision-making that primary care practitioners make every day. This supports the expanded use of metformin into populations for which is has been withheld heretofore.
Nephrology
The systematic review confirms what many practitioners suspect: metformin use probably does not require the degree of prescribing caution demanded by the FDA. Synthesising the available data in one paper is useful for clinicians.
Nephrology
This study is based on studies that purposely excluded advanced CKD, so any conclusions cannot comment on the high risk of using metformin in CKD4 and CKD5. Other publications like case reports still occasionally show the risk for severe lactic acidosis, so severe that it becomes intractable even with haemodialysis. So, there is good evidence of the beneficial effect of metformin in survival of persons with diabetes with normal or mildly impaired renal function; however, because the progression of kidney disease is likely in most diabetics, there is only a window of opportunity to use metformin safely. Current guidelines acknowledge this. There is also a need for widespread use of warning information for patients about stopping metformin who are vomiting or have diarrhoea or sepsis (ie "Medicine Sick Day Rules" NHS Scotland) to prevent acidosis associated with AKI. This paper provides information but not necessarily changes for clinical practice.
Nephrology
For CKD, the level of GFR is important and the controversy and area of uncertainty lies below 30 ml/min.