Metformin: Meta-Analysis of Benefits in Comorbid Patients

Broadening access: Meta-analysis suggests benefits of metformin therapy in patients with comorbid kidney or heart disease.

By Martina M. McGrath, MD
February 9, 2017

Metformin is a safe, effective and well-tolerated agent, which is recommended as the first line oral hypoglycemic in treatment of newly diagnosed Type II diabetes. Its central role is underpinned by research showing reductions in long-term cardiovascular mortality in patients treated with metformin, as compared to sulphonylureas or placebo.

Metformin-induced lactic acidosis is a rare but life-threatening complication, with a fatality rate estimated at around 50 percent. The risk is elevated in patients with liver and renal dysfunction and as a result, it was previously advised that metformin be discontinued in those with impaired liver function and a serum creatinine <1.5mg/dL in men or 1.4mg/dL in women. However, on review of more recent data regarding risk, last year the FDA relaxed its recommendations to a contraindication to metformin use in patients with eGFR <30mls/min and advised against initiating therapy in patients with eGFR <45mls/min1. Dose reduction for declining eGFR is required and patients should be counseled to stop the drug in clinical situations where they are at risk of lactic acidosis (hypotension, sepsis, radiocontrast dye exposure etc).

Given the expected increase in prescription of metformin to patients with comorbidities associated with increased risk of lactic acidosis, namely heart failure, chronic liver disease and chronic kidney disease, a group from Duke University has published a meta-analysis of 17 studies examining the use of metformin in these populations2. As most studies were observational and showed statistical heterogeneity, the strength of evidence was graded as low overall.

Outcomes Associated with Metformin Use (adapted from ref 2):

Outcome Studies No. of patients Findings
Chronic Kidney Disease (eGFR 30-60mls/min)
All cause mortality 5 observational 33,442 HR 0.77 (95% CI 0.61-0.97)
Congestive Heart Failure
All cause mortality 11 observational 35,410 HR 0.78 (95% CI 0.71-0.87)
Cardiovascular mortality 3 observational 6,468 HR 0.77 (95% CI 0.53-1.12)
CHF readmissions 4 observational 26,510 HR 0.87 (95% CI 0.78-0.97)
 

This meta-analysis does not address the incidence of lactic acidosis in these patient populations, but does suggest that the FDA’s revised prescribing guidelines are appropriate, and indicates that treatment with metformin may bring benefit to selected patients for whom it was previously not recommended.

References:

1.http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm494829.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery. (Accessed 02/06/17)

2. 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. Annals of Internal Medicine 2017;166:191-200.


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Headshot of Dr. McGrathDr. Martina McGrath is an Instructor in Medicine at Harvard Medical School, and a member of the Renal Division, Department of Medicine, at Brigham and Women’s Hospital, both in Boston. Dr. McGrath is the Medical Editor for the Trends in Medicine blog.

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