In reply: Why is metformin contraindicated in chronic kidney disease?

In Reply: We appreciate Dr. Imam’s comments regarding using metformin in those with chronic kidney disease.

The US Food and Drug Administration currently lists metformin as contraindicated in those with mild to moderate renal insufficiency, with serum creatinine levels greater than or equal to 1.5 mg/dL in males and greater than or equal to 1.4 mg/dL in females. This contraindication is based on the pharmacokinetics of the medication and, likely, the association of a similar medication, phenformin, with lactic acidosis, which eventually led to its withdrawal from the market. However, lactic acidosis is much less frequent with metformin than with phenformin.¹

We agree that metformin is an invaluable medication for diabetes mellitus not requiring insulin. We also agree that lactic acidosis is rare, especially in those with mild renal insufficiency. However, lactic acidosis does occur in patients with chronic kidney disease while on metformin and, however rare, when it does occur it is a life-threatening event.²

The clearance of metformin is strongly dependent on kidney function,³ and therefore guidelines still recommend reducing the dose in those with moderate renal insufficiency and recommend considering stopping the medication in those with severe renal insufficiency—the population we were talking about in our article.⁴ We are aware of changes to the guidelines that have been made by various groups, and in many circumstances we ourselves take an individualized approach, weighing the risks and benefits of continued therapy with the patient and his or her primary care provider. That being said, we did not believe that such nuanced recommendations were appropriate for our article, especially since they are contrary to marketing restrictions for the drug.

In Reply: We appreciate Dr. Imam’s comments regarding using metformin in those with chronic kidney disease.

The US Food and Drug Administration currently lists metformin as contraindicated in those with mild to moderate renal insufficiency, with serum creatinine levels greater than or equal to 1.5 mg/dL in males and greater than or equal to 1.4 mg/dL in females. This contraindication is based on the pharmacokinetics of the medication and, likely, the association of a similar medication, phenformin, with lactic acidosis, which eventually led to its withdrawal from the market. However, lactic acidosis is much less frequent with metformin than with phenformin.¹

We agree that metformin is an invaluable medication for diabetes mellitus not requiring insulin. We also agree that lactic acidosis is rare, especially in those with mild renal insufficiency. However, lactic acidosis does occur in patients with chronic kidney disease while on metformin and, however rare, when it does occur it is a life-threatening event.²

The clearance of metformin is strongly dependent on kidney function,³ and therefore guidelines still recommend reducing the dose in those with moderate renal insufficiency and recommend considering stopping the medication in those with severe renal insufficiency—the population we were talking about in our article.⁴ We are aware of changes to the guidelines that have been made by various groups, and in many circumstances we ourselves take an individualized approach, weighing the risks and benefits of continued therapy with the patient and his or her primary care provider. That being said, we did not believe that such nuanced recommendations were appropriate for our article, especially since they are contrary to marketing restrictions for the drug.

In Reply: We appreciate Dr. Imam’s comments regarding using metformin in those with chronic kidney disease.

The US Food and Drug Administration currently lists metformin as contraindicated in those with mild to moderate renal insufficiency, with serum creatinine levels greater than or equal to 1.5 mg/dL in males and greater than or equal to 1.4 mg/dL in females. This contraindication is based on the pharmacokinetics of the medication and, likely, the association of a similar medication, phenformin, with lactic acidosis, which eventually led to its withdrawal from the market. However, lactic acidosis is much less frequent with metformin than with phenformin.¹

We agree that metformin is an invaluable medication for diabetes mellitus not requiring insulin. We also agree that lactic acidosis is rare, especially in those with mild renal insufficiency. However, lactic acidosis does occur in patients with chronic kidney disease while on metformin and, however rare, when it does occur it is a life-threatening event.²

The clearance of metformin is strongly dependent on kidney function,³ and therefore guidelines still recommend reducing the dose in those with moderate renal insufficiency and recommend considering stopping the medication in those with severe renal insufficiency—the population we were talking about in our article.⁴ We are aware of changes to the guidelines that have been made by various groups, and in many circumstances we ourselves take an individualized approach, weighing the risks and benefits of continued therapy with the patient and his or her primary care provider. That being said, we did not believe that such nuanced recommendations were appropriate for our article, especially since they are contrary to marketing restrictions for the drug.