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.
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
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.
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
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
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
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.
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
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.
- Rachmani R. Eur J Intern Med. 2002;13:428-33.
- Salpeter SR. Cochrane Database Sys Rev.
- Vasisht KP. Diabetes Obes Metab.
Disclosure: Dr. Taylor reports no relevant financial disclosures.