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Letters to the Editor |
Department of Emergency Medicine, Kaiser Permanente Medical Center, 7300 North Fresno Street, Fresno, CA 93720, e-mail: rajesh.gupta@kp.org
Editor:
In daily practice of prescribing oral agents in medical treatment of type 2 diabetes mellitus (1), a practical issue of whether to use intravenous contrast agents in patients with diabetes who receive metformin, which should be considered in emergency medicine practice, is typically not considered. In almost every hospital in this country—including small community hospitals—radiologists refuse to use intravenous contrast agents in such patients, even in emergency situations.
The following points should be considered in the patients receiving metformin.
1. The rate of lactic acidosis in patients with diabetes who did not receive metformin was equivalent to that in patients with diabetes who received metformin (2). Although this finding suggests both that metformin may not be a cause of increased lactic acidosis and that other conditions may cause lactic acidosis in patients with diabetes, the retrospective study (2) merits further investigation. Nonetheless, according to the U.S. Food and Drug Administration (FDA), lactic acidosis in patients using metformin is rare: The condition occurs at an annual rate of five cases per 100,000 persons (2).
2. In nonurgent situations and when serum creatinine level is within normal range (<1.5 mg/dL [<132.6 µmol/L]), intravenous contrast agents are not contraindicated. The generally recommended step of withholding administration of metformin for 48 hours before and after administration of an intravenous contrast agent in patients with type 2 diabetes may not be necessary.
The same strategy applies in emergency situations in which serum creatinine level is normal. In such situations, patients should be well hydrated before receiving the intravenous contrast agent (3–5).
3. In nonurgent cases in which the patient is receiving metformin and has a creatinine level greater than 1.5 mg/dL (>132.6 µmol/L), metformin administration should be replaced with an alternative diabetes control medication (eg, insulin) for a few days before the intravenous contrast agent–enhanced study is performed (3–5).
4. In urgent cases in which the patient has a creatinine level greater than 1.5 mg/dL (>132.6 µmol/L), metformin administration should be stopped and steps (eg, intravenous hydration) should be taken to improve renal function. The intravenous contrast agent study should then be performed but must be accompanied by both close postprocedure monitoring and alternative diabetic control (3–5).
I hope these points are helpful to general practitioners, as well as to emergency practitioners.
ACKNOWLEDGMENTS
The Medical Editing Department of Kaiser Foundation Research Institute provided editorial assistance.
REFERENCES
Department of Radiology, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, e-mail: michael.a.bettmann@hitchcock.org
Dr Gupta raises several points that I believe warrant clarification. Radiologists clearly have concerns regarding concurrent use of metformin and iodinated contrast agents. The concerns are particularly compelling because of the wide use of metformin on the one hand and the fear of lactic acidosis on the other.
Lactic acidosis associated with metformin, although relatively rare, is reported to be associated with a high incidence of fatality (1). Metformin is eliminated unchanged by the kidneys by means of glomerular filtration, as well as by means of tubular excretion. The incidence of lactic acidosis is increased in patients with increased lactate production, as in cardiac dysfunction, decreased ability to metabolize lactic acid (eg, patients with acute liver disease), and renal disease. In fact, renal dysfunction is a contradiction to the use of metformin, according to the FDA package insert (2).
This is true for both Glucophage, which is metformin alone, and Glucovance (both from Bristol-Myers Squibb, Princeton, NJ), which is a combination of glyburide and metformin. There are two reasons for concern about concomitant administration of metformin and an iodinated contrast agent: First, since the contrast agent is also excreted unchanged by the kidney, albeit solely by means of glomerular filtration, it has been believed that the deleterious effects of the two drugs may be additive. Second, in evaluating patients taking metformin who had developed fatal lactic acidosis, it was determined that several had simultaneously received iodinated contrast agents (1,3). With careful examination of the available data, however, it is not at all clear that there is a true causal relationship between the use of metformin, the administration of iodinated contrast agent, and the development of lactic acidosis. In discussing this issue with representatives of the U.S. manufacturer of metformin and the FDA, it seemed that the caution suggesting that metformin be stopped 48 hours prior to contrast agent administration was included in the package insert for theoretical rather than experimental or observational reasons. As a result, the FDA-approved package insert was changed in 1998 to state that metformin should be stopped at the time of contrast agent administration and not be restarted for 48 hours (2).
The caution to stop metformin at the time a contrast agent is administered should not cause substantial problems in general. Patients can take a morning dose immediately before a study. Fortunately, most patients taking metformin, unlike patients with type 1 diabetes, can safely refrain from taking such medication for 48 hours. A more pressing clinical problem is how to establish that it is safe to restart metformin at 48 hours. The FDA-approved package insert is deliberately vague on this point. In patients who are known to have clearly normal renal function prior to contrast agent administration, are well hydrated (either orally or parenterally), and do not have intervening potentially nephrotoxic events (eg, surgery, gentamycin administration, dehydration due to diarrhea or vomiting), it is probably not necessary to recheck serum creatinine levels before restarting administration of metformin. In others, such as patients with high-normal creatinine levels, it is appropriate to recheck serum values.
In summary, there are two key points: First, metformin is contraindicated in patients with renal dysfunction. Surprisingly, it is relatively common for the radiologist to discover this prior to a study in which an iodinated contrast agent is required, and it is then imperative that this be communicated, preferably to both the patient and the referring physician. Second, although it may in fact not be necessary to stop metformin at all, it is currently recommended that it be stopped at the time a contrast agent is to be administered. There is, then, no need to delay emergency studies.
Finally, these recommendations apply only to metformin (Glucophage) and the metformin-glyburide combination (Glucovance) and to adult nonpregnant individuals who are going to be receiving intravascular iodinated contrast agents.
REFERENCES
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  For questions on Emerg. Med. J., October 1, 2008; 25(10): 705 - 705. [Full Text] [PDF]
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