The report is a product of the VA/HSR Evidence Synthesis Program.

Metformin Use in Patients with Historical Contraindications or Precautions

Metformin is an oral hypoglycemic medication used primarily for treating type 2 diabetes mellitus. Evidence suggests that in addition to improving glycemic control, metformin may be associated with improved all-cause and cardiovascular mortality and decreased risk of some cancers. However, clinicians have traditionally been advised by the U.S. Food and Drug Administration (FDA) to exercise caution in prescribing metformin to individuals with chronic kidney disease (CKD), unstable congestive heart failure (CHF), chronic liver disease (CLD), and older age due to perceived risk of side effects, including lactic acidosis (LA). Recent literature highlights the rarity of metformin-associated LA and supports the cautious expansion of metformin use. In addition, in April 2016 the FDA modified its position on CKD to extend use of metformin to some patients with moderate CKD. Yet there remain uncertainties regarding the risks and benefits of metformin use in populations with CKD, CHF, CLD, and older age.

To address these concerns, investigators with VA's Evidence-based Synthesis Program Center located in Durham, North Carolina conducted a systematic review and meta-analysis that targeted the following key questions:

• For patients with type 2 diabetes and a historical contraindication or precaution to metformin use (as mentioned above), what is the rate of LA in those taking metformin? And how does the rate of LA in patients taking metformin compare with the rate in those taking other hypoglycemic medications?
• For patients with type 2 diabetes and an historical contraindication or precaution to metformin use, what are the potential benefits and harms (other than lactic acidosis) of continued treatment with metformin?

To address these questions, investigators searched MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, and the International Pharmaceutical Abstracts. They also evaluated the reference lists of systematic or non-systematic reviews and queried Bristol-Myers Squibb – manufacturer of Glucophage (branded formulation of metformin) – for relevant studies. From nearly 5,000 abstracts and 523 full articles, 37 studies (29 observational studies and 8 randomized clinical trials) were selected to answer the key questions.

Summary of Review
Most studies evaluated metformin use in patients with type 2 diabetes and moderate chronic kidney disease or congestive heart failure. Based on limited evidence, the rate of LA associated with metformin use among patients with historical contraindications or precautions does not appear higher than that of other diabetes medications. Metformin appears to be associated with reduced all-cause mortality in patients with CKD and patients with CHF, and appears to be associated with reduced hospital readmission for CHF. Though data are otherwise limited, risks of metformin use do not appear higher than those associated with other diabetes medications among patients with historical contraindications or precautions. Despite this review's limitations, findings support recent FDA labeling changes, may inform clinical practice, and point toward important areas for future research. Specific findings include:

• Five studies comparing rates of LA with metformin use versus non-metformin diabetes treatment do not suggest a higher rate of LA with metformin use among individuals with CKD, CHF, or CLD. No study reported this outcome for older adults without one of these comorbid conditions.
• Among patients with type 2 diabetes and CKD, metformin use is associated with a significantly lower risk of all-cause mortality (n=5 studies); limited evidence was identified for major adverse cardiovascular events (n=2 studies).
• Among patients with type 2 diabetes and CHF, metformin use is associated with a significantly lower risk of all-cause mortality (n=11 studies) and heart failure readmission (n=4 studies); risk of cardiovascular mortality did not differ between metformin users and non-users (n=3 studies).
• Among patients with type 2 diabetes and CLD, limited evidence suggests a lower risk of all-cause mortality (n=3 studies) may be associated with metformin use.
• While limited evidence suggests that progressively lower estimated glomerular filtration rate (eGFR) may diminish the mortality benefit associated with metformin use, the impact of CHF severity, CLD severity, and increasing older age on the effects of metformin is unclear.
  • No evidence was identified regarding the effects of metformin on glycemic control, lipid control, weight, hypoglycemia, or vitamin B12 deficiency among patients with medically treated type 2 diabetes and CKD, CHF, or CLD.

Future Research
The primary gap in the current evidence regarding metformin use in populations with historical contraindications or precautions is the lack of randomized trials in this domain; large simple pragmatic trials could fill this gap. Even without randomized controlled trials, new observational studies will remain important to ensure that rates of metformin-associated LA and mortality do not increase as metformin prescribing increases among populations with traditional contraindications or precautions (especially CKD). Observational studies also will be useful in comparing metformin to newer diabetes agents in these populations. Additional studies focusing specifically on cohorts with an estimated glomerular filtration rate (eGFR) of 30-45 mL/min/1.73m2 or even <30 mL/min/1.73m2 would further inform prescribing of metformin in these groups, and refinement of clinical guidelines. Data regarding the impact of precaution severity in CHF, CLD, and older age are sparse, and further observational research could address these gaps. The possibility of tailoring prescribing recommendations based on the severity of historical contraindications or precautions also would benefit from further research. Finally, future research is warranted to explore outcomes of interest beyond mortality.

Reference
Crowley MJ, Diamantidis CJ, McDuffie JR, Cameron B, Stanifer J, Mock CK, Kosinski A, Wang X, Tang S, Williams, Jr, JW. Metformin Use in Patients with Historical Contraindications or Precautions. VA ESP Project #09-009; 2016.

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