By Jeff Unger, MD
Medical Director, Unger Primary Care Medicine Group, Rancho Cucamonga, CA
Dr. Unger reports no financial relationships relevant to this field of study.
SYNOPSIS: Expansion of the metformin label to include patients with mild-to-moderate kidney disease is appropriate.
SOURCE: Inzucchi SE, et al. Metformin in patients with type 2 diabetes and kidney disease. A systematic review. JAMA 2014;312:
2668-2675.
There were 818 manuscripts published between 1950 and June 2014 that were reviewed from MEDLINE and Cochrane database pertaining to metformin, kidney disease, and lactic acidosis. Although metformin is renally cleared, drug levels generally remain within therapeutic range and lactate concentrations are not substantially increased in patients with estimated glomerular filtration rates of 30-60 mL/min per 1.73 m2. The overall incidence of lactic acidosis in metformin users varies across studies from 3 per 100,000 patient years to 10 per 100,000 patient years, which is indistinguishable from the non-diabetic population. No randomized, controlled trials have been conducted to test the safety and efficacy of metformin in patients with severely impaired renal function (eGFR < 30 mL/min per 1.73 m2). Expansion of the metformin label to include patients with mild-to-moderate kidney disease is appropriate. (See Table 2.)
COMMENTARY
Metformin was initially approved by the FDA for use in type 2 diabetes in 1994. The drug is widely accepted as the foundation of care for patients with type 2 diabetes based on its low cost, safety profile, potential cardiovascular benefits, and likelihood of reducing cancer risk in some patients. Another biguanide, phenformin, was withdrawn in 1977 due to a risk of lactic acidosis. Metformin is renally cleared. Thus, patients with chronic kidney disease may be exposed to lactate accumulation when using metformin. The risk of lactic acidosis is very small, yet the FDA has stipulated stringent prescribing criteria for the use of metformin, as noted in Table 1.
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Table 1. Current FDA Prescribing Guidelines for Metformin as Related to Kidney Function
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Metformin is contraindicated in renal disease or renal dysfunction (e.g., As suggested by serum creatinine levels > 1.5 mg/dL in males, > 1.4 mg/dL in females, or abnormal creatinine clearance).
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Metformin should not be initiated in patients > 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.
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Source: Metformin final printed labeling. Glucophage (metformin hydrochloride) [final printed labeling]. US Food and Drug Administration website. http://www.accessdata.fda.gov/drugsatfda.docs/nda/2000/203575019.Glucophage_prntlbl.pdf. Accessed 12/28/14.
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The original label was intended to provide a safety margin to minimize the risk of treatment-emergent lactic acidosis. Diabetologists have petitioned the FDA to expand the label, which would allow greater access to metformin from a medical-legal standpoint.
This review demonstrates that the risk of treatment-emergent lactic acidosis in patients with mild-to-moderate chronic kidney disease is similar to individuals who are not exposed to metformin. In fact, current guidelines regarding use of metformin in patients with chronic kidney disease are commonly disregarded. Yet, when the drug is prescribed to “high-risk patients,” the incidence of treatment-emergent lactic acidosis is nil. Although not confirmed by appropriate randomized, controlled clinical trials, metformin is unlikely to increase the risk of lactic acidosis in patients with mild-to-moderate chronic kidney disease (i.e., eGFR 30-60 mL/min per 1.73 m2).
The authors suggest a possible approach to metformin prescribing, as noted in Table 2. Note, that this strategy has not been evaluated or validated in a clinical trial and there are no data to support this approach.
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Table 2. Possible Approach To Metformin Prescribing In The Setting Of Chronic Kidney Disease
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Chronic Kidney
Disease State
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eGFR
mL/Min per 1.73 m2
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Maximal Total Daily Dose of Metformin
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Other Recommendations
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1
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> 90
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2550
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2
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60- < 90
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2550
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3a
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45- < 60
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2000
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Avoid if kidney function is, or is expected to become, unstable. Consider more cautious follow-up of renal function.
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3b
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30- < 45
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1000
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Do not initiate therapy at this stage, but drug may be continued. Avoid if kidney function is, or is expected to become, unstable. Consider more cautious follow-up of renal function
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4
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15-30
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Do not use
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5
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<15
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Do not use
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REFERENCES
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Bodmer M, et al. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: A nested case-controlled analysis. Diabetes Care 2008;31:2086-2091.
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Frid A, et al. Novel assay of metformin levels in patients with type 2 diabetes and varying levels of renal function: Clinical recommendations. Diabetes Care 2010;33:1291-1293.
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Lalau JD, Race JM. Lactic acidosis in metformin therapy: Searching for a link with metformin in reports of “metformin-associated lactic acidosis.” Diabetes Obes Metab 2001;3:195-201.
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Richy FF, et al. Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: A retrospective cohort study. Diabetes Care 2014;37: 2291-2295.
