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Metformin use in kidney disease
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When metformin was approved by the FDA in 1994, it initially had rather stringent renal function monitoring requirements because of its structural relationship with phenformin, which was removed from the market in 1977 because of an increased risk for lactic acidosis.
Fortunately, the risk for lactic acidosis with metformin has been very low since its introduction. The reported incidence per the manufacturer is about 0.03 cases per 1,000 patient-years.
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There are several pharmacologic differences between metformin and phenformin. One example is that metformin does not affect plasma lactate concentrations, lactate turnover or oxidation of lactate. In contrast, phenformin stimulates glucose conversion to lactate and decreases lactate oxidation.
Metformin is contraindicated in men who have a serum creatinine of at least 1.4 mg/dL and in women who have a level of at least 1.5 mg/dL, as well as those with an abnormal creatinine clearance because of the potential for an increase in metformin concentrations and lactic acidosis.
Available data
A recent study by Vasisht and colleagues reported a retrospective analysis of 234 patients to identify metformin use in patients with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2 and to determine the incidence of lactic acidosis in this population. Researchers hypothesized that metformin was used in patients with undetected advanced chronic kidney disease (serum creatinine of at least 1.5 mg/dL). Results showed that 15.3% of the patients with an eGFR of less than 60 mL/min/1.73 m2 received metformin. The researchers concluded that metformin is used more often than predicted in patients with CKD if simply relying on serum creatinine. None of the 234 patients developed lactic acidosis.
When the researchers reviewed patient data from the National Health and Nutrition Examination Survey, they found similar results. The researchers further recommended that eGFR be used as the primary determinant of renal function and the appropriate use of metformin because serum creatinine may not accurately reflect renal function, especially in the young and old. Furthermore, in this small population, metformin use appeared to be safe despite the initially undetected CKD.
Of course, other things may cause lactic acidosis, including type 2 diabetes. The estimated incidence of lactic acidosis from studies of patients who received metformin ranges from less than one to nine events per 100,000 patient-years. More notably, it has been estimated that among all patients with type 2 diabetes, there are 9.7 to 16.9 lactic acidosis events per 100,000 patient-years.
Another study by Salpeter and colleagues examined pooled results from 206 studies involving 47,846 patient-years of metformin use and 38,221 patient-years of non-metformin use. Overall, there were 6.3 cases of lactic acidosis per 100,000 patient-years in those receiving metformin and 7.8 cases per 100,000 patient-years in those not receiving metformin.
Rachmani and colleagues followed 393 patients receiving metformin who developed a contraindication to therapy (serum creatinine 1.49 mg/dL to 2.49 mg/dL) and randomly assigned patients to continue the metformin or discontinue therapy. In those who discontinued, metformin was restarted in 26 patients within the next 12 months. Average serum creatinine at baseline was 1.84 mg/dL in the group assigned to continue metformin and 1.81 mg/dL in those who discontinued it. Plasma lactate levels increased in both groups and were comparable between the two groups. No cases of lactic acidosis were reported in either group. Although it involved a relatively small number of patients, this study lends support to the use of metformin in patients with elevated serum creatinine.
In a retrospective, case-control study of more than 50,000 patients, by Bodmer and colleagues evaluated the safety of metformin and sulfonylureas. Seven patients developed lactic acidosis. Five of the patients were using metformin at the time of diagnosis; one was a past user; and one had never used metformin but was taking a sulfonylurea. Five patients who developed lactic acidosis also had other risk factors for lactic acidosis, such as heart failure, urosepsis, hypovolemia, seizure or acute renal failure. In analyzing the crude data, lactic acidosis developed in 3.3 per 100,000 patient-years in those receiving metformin vs. 4.8 cases per 100,000 patient-years in those receiving a sulfonylurea.
Potential guides for metformin use
Other available research, such as a study by Herrington and colleagues, provides recommendations for specific eGFR cutoffs and metformin use. Researchers have proposed allowing metformin use if eGFR was less than 60 mL/min. For patients with an eGFR of 30 mL/min to 60 mL/min, the researchers recommended reducing metformin dose by 50%. If eGFR fell below 30 mL/min, they recommended that continued use be weighed against potential risks, even though there is little evidence to say that these patients are at increased risk for lactic acidosis. Other authors, like Nisbet and colleagues, have suggested using creatinine clearance as a guide to metformin use.
Although eGFR and creatinine clearance offer some advantages to serum creatinine, they are not without their own limitations. For example, they may not be accurate in underweight or overweight patients. Based on the paucity of data indicating that those with renal impairment are at increased risk for lactic acidosis from metformin, perhaps it is more appropriate to look at the entire patient and other risk factors they may have for lactic acidosis rather than some arbitrary lab cutoff value. Either way, some clinicians, whether they know it or not, are using metformin in patients with CKD, and there has not been any indication that lactic acidosis rates are increasing.
James R. Taylor, PharmD, CDE, is a clinical associate professor in the department of pharmacy practice at the University of Florida in Gainesville.
For more information:
- Bodmer M. Diabetes Care. 2008;31:2086-2091.
- Brown JB. Diabetes Care. 1998;21:1659-1663.
- Herrington WG. Int Urol Nephrol. 2008;50:411-417.
- Howlett HC. Drug Saf. 1999;20:489-503.
- Nisbet JC. Med J Aust. 2004;180-53.
- Philbrick AM. Am J Health Syst Pharm. 2009;66:2017-2023.
- Rachmani R. Eur J Intern Med. 2002;13:428-33.
- Salpeter SR. Cochrane Database Sys Rev. 2006;1:CD002967.
- Vasisht KP. Diabetes Obes Metab. 2010;12:1079-1083.
Disclosure: Dr. Taylor reports no relevant financial disclosures.