Guidelines for Metformin Hydrochloride and Intravascular Contrast Media

Recommended Guidelines

Individual radiology practices in consultation with their referring clinicians may vary these guidelines to achieve best practice taking into account the available evidence as outlined and as may become apparent in the future.

A summary of the evidence is appended following these recommendations.

A. For patients who are on Metformin and especially those who have borderline or abnormal renal function, consider an alternative examination that does not require the administration of intravascular contrast media.

B. If is it necessary to use intravascular contrast then:

(i) Patients with pre-existing abnormal renal function:
If it is an elective examination, the best practice would be for the clinician to change Metformin to another treatment regime prior to administration of intravascular contrast.

If it is an urgent examination, stop Metformin on the day of the procedure and continue with the contrast examination.

As Metformin therapy is contraindicated in renal failure, this should be changed to another treatment regime following the contrast examination. At the very least Metformin should not be re-instituted unless renal function test at 48 hours is normal which would be very unlikely in a patient with prior abnormal renal function.

(ii) Patients with pre-existing borderline renal function:

Stop Metformin at the time of intravascular contrast media administration and cease for 48 hours. Recommence Metformin if renal function at 48 hours has not deteriorated and still within normal limits.

(iii) Patients with pre-existing unknown renal function:

Stop Metformin at the time of intravascular contrast media administration and cease for 48 hours. Recommence Metformin if renal function at 48 hours is normal.

(iv) Patients with pre-existing normal renal function:

There are 2 options that should be considered:

1) Provided the referring clinician has informed the patient that the risk of MALA (Metformin Associated Lactic Acidosis) is either negligible or very low in patients with normal renal function, then a logical and reasonable case can be made on available evidence that there is no need to stop Metformin at the time of contrast media administration. There should be no requirement to re-evaluate renal function provided the volume of contrast material used is not large and there is no significant risk for contrast induced renal failure.

If a large volume of contrast media is expected to be used and other factors suggest that there is an increased risk of inducing renal failure in a particular patient, then the second option below should be adopted.

OR

2) Stop Metformin at the time of contrast media administration and cease for 48 hours. Recommence Metformin if renal function at 48 hours is normal.

C. If Metformin therapy has to be ceased for the 48 hours, other means of managing the blood sugar level need to be considered.

Adopted by Council: August 2003
Updated & adopted by Council: February 2005
Prepared by: Interventional Radiology Reference Group
Date for Review: August 2006

Appended Evidence on which RANZCR guidelines are based.

1. Nature of problem

Metformin is not nephrotoxic.

There is no known reaction between Metformin and iodinated contrast media.

The basis of concern: If acute renal failure occurs, as a result of the administration of intravascular contrast media, then the potential exists for accumulation of high serum levels of Metformin, and which can lead to increased serum lactate which can then result in lactic acidosis (LA).

Acute and chronic renal failure are particular risk factors in Metformin associated lactic acidosis (MALA). Therefore renal failure is a contraindication for use of Metformin (1,2).

2. Scope of problem

1. The incidence of lactic acidosis associated with Metformin is 0.03cases/1000 patient years (or 3 cases per 100,000 patients per year) with 50 % mortality (3).
   
   
2. A recent Cochrane Database Systematic Review calculated the upper limit for true incidence of MALA in patients not given concomitant intravascular contrast to be 8 cases per 100,000 patient years (4).
   
   
3. There have been over 100 published cases of MALA:
   
   In the above publications, 17 patients had intravascular contrast media. All these patients either had renal dysfunction prior to IV/IA contrast or had acute renal failure following the procedure. Also large volume of contrast used (not sure whether ionic or non ionic). In at least 14 of these patients, Metformin was continued or restarted despite renal failure.
   6 patients died (5-13).
   
   
4. In a systemic review of the literature for MALA following the concomitant use on intravascular contrast, in 17 of 18 cases, renal failure was present. There was only one reported case of MALA following the use of intravascular contrast media in a patient with normal renal function (14).
   
   
5. In another paper, Pond et al estimated that the incidence of lactic acidosis in patients who have received Metformin and intravascular contrast is 2 per 1,000,000 (15).
   
   
6. The risk factors for lactic acidosis include renal impairment, old age and high doses of Metformin above 2 gm per day (2).
   
   
7. 48 cases of MALA were reported in Australia to date. 15 cases fatal. In 35 cases, risk factors were known (16).
   
   
8. Nawaz reviewed 33 patients on Metormin and who had angiography. All 29 patients with normal renal function had no rise in serum creatinine. 4 patients had abnormal renal function prior and all had deterioration in renal function and 2 died from MALA (13).
   
   
9. The problem of MALA only concerns intravascular contrast. There is no problem with oral or non-iodinated contrast (1).

3. Pharmacokinetics of Metformin Hydrochloride

The half-life is short, about 6 hours. 90 % is eliminated within 24 hours.

Contrast induced renal failure typically peaks at 24 to 48 hours and therefore 48 hours is the suggested time that Metformin be withheld subsequent to contrast administration if withholding is indicated.

Hence if Metformin has not been given in the interim, most of it will be excreted when the renal failure becomes maximal, and provided no additional Metformin is given, the plasma level will slowly decline.

4. Other colleges Guidelines

American College of Radiology

That Metformin be stopped at or before IV contrast and cease for 48 hours. Recommence only if renal function found to be normal afterwards. There is no requirement to stop for 48 hours prior to use of IV contrast

Royal College of Radiologists

That Metformin be stopped at, and for 48 hours after, the administration of intravascular contrast.

5. Pharmaceutical Companies Recommendations

1. Squibb (Glucophage, Metformin BC)

Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving Metformin. Therefore, in patients in whom any such studies are planned, Metformin should be discontinued at the time of, or prior to, the procedure and withheld for 48 hours subsequent to the procedure and re-instituted only after renal function has been re-evaluated and found to be normal.

2. Novartis (Metforal)

Treatment should be stopped 48 hours before intravenous urography or angiography and resumed 48 hours following the examination.

3. Bracco (contrast media)

Patients with non-insulin-dependent diabetes mellitus who are taking Metformin should therefore be instructed not to take any doses of this agent (Metformin) for 48 hours before, and 48 hours after the X-ray examination.

4. Arrow Pharmaceuticals (Glucophage)

Radiological studies involving the use of intravascular iodinated contrast materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving Metformin. Therefore, in patients in whom any such studies are planned, Metformin should be discontinued at the time of, or prior to, the procedure and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.

6. Clinical

Estimates of risk of MALA are low:

• MALA without use of contrast media: 3 to 8 per 100,000 patient years
  
  
• MALA in association with contrast media: 2 per 1,000,000 cases.

Intravascular use of contrast media maybe associated with deterioration in renal function.

Hence, there is a risk that if renal function deteriorates and the patient is on Metformin, then there is a potential for MALA.

The risk of inducing renal failure with the administration intra-vascular contrast media cannot be generalised for the whole population having contrast media as it is multifactorial including pre-existing renal function, co-existing morbidities, hydration status and volume of contrast media used. This will need to be assessed on a case-by-case basis.

Oral iodinated and non-iodinated contrast is safe to use with Metformin (1).

7. Potential for bias/weakness

Although a comprehensive review has been undertaken, the Accreditation Guidelines and Quality Committee acknowledge that searching for reported rare adverse drug reactions has its limitations. There may be situations where adverse cases may not have been reported. Also, the association of the use of intravascular contrast medium in the evaluation of MALA may not have been recognised or highlighted in the key word search.

8. Bibliography

1. Bristol-Myers Squibb Pharmaceuticals Product Information
   
2. Arrow Pharmaceuticals Product Information
   
3. Sirtori CR, Pasik C. Re-evaluation of a biguanide, Metformin: mechanism of action and tolerability. Pharmacological Research 1994;30:187-228.
   
4. Salpeter S et al. Cochrane Database Systematic Review. 2002, page 8
   
5. Hayat JC. The treatment of lactic acidosis in the diabetic patient by peritoneal dialysis in the presence of acute renal failure using sodium acetate. A report of two cases. Diabetologia 1977; 10:485-487.
   
6. Assan R, Hevclin CH, Ganeval D, et al. Metformin-induced lactic acidosis in the presence of acute renal failure. Diabetologia 1977;13:211-217.
   
7. Prinseau J, Jardin E, Sanchez A, et al. Insuffisance renale aigue après U.I.V. chez le diabetique. Frequence de l'acidose lactique sous traitement par la metformine. Ann Med Interne 1977;128:173-177.
   
8. Lalau JD, Westeel PF, Debussche X, et al. Bicarbonate haemodialysis: an adequate treatment for lactic acidosis in diabetics treated by metformin. Intensive Care Medicine 1987;13:383-387.
   
9. Lalau JD, Andrejak M, Muriniere PH, et al. Hemodialysis in the treatment of lactic acidosis in diabetics treated by metformin: a study of metformin elimination. Int J Clin Pharmacol Ther Toxicol 1989;27:285-288.
   
10. Westburg G. [Withdraw metformin prior to contrast radiography. A warning in the Fass was forgotten, two patients died.] Lakartidningen 1995;92:2520.
    
11. Safadi R, Dranitzki-Elhalal M, Popovtzer M, et al. Metformin-induced lactic acidosis associated with acute renal failure. Am I Nephrol 1996;16:520-522.
    
12. Zandijk, Demey HE, Bossaert LL. Metformin-induced lactic acidosis. Tijdschr. voor Geneeskunde 1997;53:543-546.
    
13. Nawaz S, Cleveland T, Gaines PA, et al. Clinical risk associated with contrast angiography in metformin treated patients: a clinical review. Clin Radiol 1998;53:342-344.
    
14. McCartney, MM et al Clinical Radiology 54(1): 29-33 Jan 1999
    
15. Pond SG, Smyth SH. Metformin and contrast media: genuine risk or witch hunt. Radioloy 1996;201:879-880.
    
16. ADRAC (Adverse Drug Reactions Advisory Committee) report Vol 20 No 1 Feb 2001.

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