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American Journal of Health-System Pharmacy, Vol. 66, Issue 22, 2017-2022

Purpose. The relationship among metformin use, plasma lactate levels, and lactic acidosis in patients with type 2 diabetes mellitus and the appropriateness of metformin use in patients with renal dysfunction are discussed.

Summary. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes recommends metformin therapy as first-line therapy along with lifestyle modification to treat type 2 diabetes mellitus. Despite this recommendation, metformin may be underutilized due to the fear of metformin-associated lactic acidosis and because its use is contraindicated in patients with renal dysfunction. Several studies have attempted to characterize the relationship among plasma metformin levels, plasma lactate levels, and lactic acidosis. However, a causal relationship between metformin and lactic acidosis has not been definitively established. In the United States, the estimated rate of lactic acidosis among diabetic patients treated with metformin is similar to that of diabetic patients not taking metformin. Despite specific guidelines advising against prescribing metformin in renal dysfunction, published reports indicate that metformin is continued in 25% of patients after the contraindication is discovered. Individual studies point to a possible correlation between metformin levels and plasma lactate levels, but mortality does not appear to correlate with plasma metformin levels. These results indicate that there may not be a direct relationship between plasma lactate and metformin levels.

Conclusion. Current studies point to a weak causal relationship between metformin and lactic acidosis. In patients without comorbid conditions that would predispose them to lactic acidosis, elevated serum creatinine levels should be considered a risk factor for the development of lactic acidosis but not an absolute contraindication.

Index terms: Acidosis; Antidiabetic agents; Blood levels; Contraindications; Creatinine; Diabetes mellitus; Kidney diseases; Metformin; Pharmacokinetics; Protocols; Rational therapy; Toxicity

Recommendations for clinical application

Some authors have suggested more lenient guidelines for metformin use, such as discontinuing metformin once SCr concentrations increase above 1.7 mg/dL⁶; however, this recommendation was not supported with literature. Conversely, Nisbet et al.²⁸ examined creatinine clearance (calculated using the Cockcroft-Gault equation) and recommended discontinuation of metformin in patients with a creatinine clearance of <30 mL/min and recommended caution when prescribing metformin in patients with a creatinine clearance of 30–50 mL/min. In contrast, Herrington and Levy²⁹ suggested that metformin use be based on the estimated glomerular filtration rate (GFR) as calculated by the Modification of Diet in Renal Disease (MDRD) formula. Their proposal includes allowing metformin use at a GFR of >60 mL/min. For patients with a GFR of 30–60 mL/ min, they recommended decreasing the metformin dosage by half. Once the GFR falls below 30 mL/min, risks should be weighed against benefits to determine if metformin should be continued, though they acknowledged that the evidence indicating that these patients are at a higher risk for lactic acidosis is weak. Rachmani et al.¹⁸ found that metformin can be safely used in patients with an SCr of 1.8 mg/dL.

As there is as much opinion as evidence available on this controversy, it is difficult to establish a definitive recommendation. There are inherent flaws with strictly accepting SCr as a threshold cutoff. Creatinine is a byproduct of muscle breakdown; therefore, a very muscular patient could have an elevated SCr level but not necessarily renal dysfunction. Both the Cockcroft-Gault and MDRD equations are mere estimations of renal function and add bias, especially with underweight and overweight patients,³⁰ thus misrepresenting renal function. Increasing the SCr value for discontinuing metformin therapy would seem as arbitrary as the initial FDA-approved prescribing information and would continue to promote the dichotomization of metformin use as either appropriate or inappropriate. Rather, we suggest that FDA review the data regarding renal dysfunction as a contraindication to metformin use and move it to the Precautions section of the labeling. In addition, we recommend that rather than use a strict cutoff value (i.e., SCr concentrations of 1.5 mg/dL in men and 1.4 mg/dL in women), elevated SCr levels should be considered a risk factor for the development of lactic acidosis, and the patient’s complete clinical picture should be considered when deciding whether to initiate or continue met-formin therapy. Prescribers should be educated to approach each case on an individual basis and perform a risk–benefit analysis. If a patient has more than one comorbidity that predisposes him or her to lactic acidosis (e.g., chronic liver failure, chronic kidney disease, acute coronary syndrome, metabolic acidosis), an option other than metformin may be more appropriate. Patients with renal impairment who are treated with metformin should be educated about the signs and symptoms of lactic acidosis, such as malaise, somnolence, and abdominal pain.² However, these may be subtle and nonspecific and therefore difficult for a patient to recognize. It is also paramount to discontinue metformin therapy during acute situations that could increase a patient’s risk for lactic acidosis over his or her baseline risk (e.g., acute illness, administration of contrast media, acute liver disease) and to reassess the clinical picture when the acute situation has been resolved.