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Metformin Reduces Mortality in CKD, CHF, and CLD

FDA label update will increase drug use in persons with historical contraindications or precautions.

From 1950 to 1995, we only had 1 class of drugs for type 2 diabetes. Then in 1994, metformin was approved. And it has become the cornerstone therapy for patients with type 2 diabetes.

There was and still is a warning of possible lactic acidosis. However, because phenformin was withdrawn due to lactic acidosis in 1977, the FDA put a boxed warning on metformin stating that it should not be used in patients with chronic kidney disease (CKD), to avoid accumulation of the drug, which could possibly lead to lactic acidosis.  There was also a warning concerning individuals who may accumulate lactate such as patients with congestive heart failure (CHF) and chronic liver disease (CLD).

However, over the years, individuals who had CKD, CHF, or CLD were on metformin. This present study looked at these patients to see if metformin conferred any benefit relative to their chronic diseases.

The researchers reviewed five observational studies with a total of 33,442 patients with moderate to severe CKD. In the metformin-treated groups, all-cause mortality was reduced by 33% (HR, 0.77).

They looked at 11 observational studies with 35,410 patients with CHF. All-cause mortality was reduced by 22% (HR, 0.78) in the metformin-treated groups.  In the three studies on CLD, there was a trend toward benefit with metformin; however, the numbers were small they did not reach statistical significance.

This article nicely shows that there was no increased harm in using metformin in patients with CKD, CHF, or CLD; in fact, there was a significant reduction in death in CKD and CHF patients.  Therefore, the new FDA label for metformin that was just updated in April 2016 seems to be a step in the right direction.

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.  The new FDA label for metformin as of April 2016 says:

  • Start metformin if eGFR >45 mL/min/1.73 m2.
  • Stop metformin if eGFR <30 mL/min/1.73 m2.
  • Stop metformin before contrast imaging for patients with eGFR 30–60 or CKD, CHF, or CLD. Can restart after 48 hours if the renal function is stable.

The purpose of the study was to obtain 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 was obtained from January 1994 to September 2016, and Cochrane Library, EMBASE, and International Pharmaceutical Abstracts from January 1994 to November 2015.

They took the information from 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.

From the results of reviewing the studies, and 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.

So from the results, it was decided to support the current changes in the recent metformin labeling, and was decided that metformin use in patients with moderate CKD, CHF, or CLD with hepatic impairment is associated with improvements in key clinical outcomes.

Practice Pearls:

  • The relative risk for readmission for CHF during follow-up “was 13% lower for patients receiving metformin than for those not receiving it.
  • Moreover, in a study of 1,644 patients with eGFR lower than 60 mL/minute per 1.73 m2, both glyburide and insulin were associated with more hypoglycemia than metformin, and those results persisted in patients with lower eGFR levels.
  • A meta-analysis of five studies that examined all-cause mortality in 33,442 subjects showed a 22% reduction in relative risk of dying with metformin than without.


Metformin label update http://www.fda.gov/Drugs/DrugSafety/ucm493244.htm”  Ann Intern Med. Published online January 3, 2017. Abstract, Editorial