What are current best practices on holding metformin prior to and post contrast administration?

Background

Contrast-induced acute kidney injury (CI-AKI) is a serious complication of iodinated contrast medium (CM) administration.1 In recent years, there has been a marked rise in the use of CM in diagnostic and interventional procedures.2 Contrast-induced AKI is consequently the third most common cause of hospital-acquired AKI, accounting for increases in morbidity, mortality, hospital length of stay, and treatment costs.1,2 The incidence of CI-AKI ranges from 12% to 27% in the general population, but escalates to ≥50% in individuals with multiple risk factors.2 Some risk factors include acute hyperglycemia, pre-existing renal insufficiency, and use of nephrotoxic drugs.

Metformin was approved by the U.S. Food and Drug Administration (FDA) in 1994, and has since been widely accepted as first-line therapy for type 2 diabetes mellitus.2-4 Metformin has no direct nephrotoxic effect.2,5 However, it is cleared via renal filtration, and very high circulating drug levels, acute renal failure (resulting in decreased drug clearance), or conditions such as tissue hypoxia (resulting in increased production of lactic acid) have been associated with lactic acidosis.2,6 This is believed to occur since metformin inhibits hepatic glucose production from lactate, resulting in lactate accumulation.5,6

The potential for CI-AKI is considered to be the link between metformin, CM administration, and the risk of lactic acidosis.5,6 More specifically, if AKI were to be caused by CM, an accumulation of metformin could occur, with ensuing risk of lactic acidosis. Due to this risk, the metformin label initially recommended that the drug be temporarily discontinued prior to or at the time of any radiological procedure using intravascular CM, withheld for 48 hours following the procedure, and reinitiated only after renal function was reevaluated and found to be normal.4,7 However, this warning did not distinguish between patients with varying degrees of renal impairment.4 Newer evidence indicated that metformin may be safely used in certain situations, especially since metformin-induced lactic acidosis is very rare, with an incidence of less than 10 events per 100,000 patient-years of exposure.2,8

Therefore, the label was amended in 2016 and now recommends discontinuing metformin prior to or at the time of CM administration in patients with an estimated glomerular filtration rate (eGFR, in mL/min/1.73 m2) between 30 and 60; in patients with a history of hepatic impairment, alcoholism or heart failure; or in patients who will be administered intraarterial (IA) iodinated contrast.4,7 The eGFR should be re-evaluated 48 hours after the imaging procedure, and metformin restarted if renal function is stable. These recommendations are based on the minimal risk of metformin-associated lactic acidosis in patients without chronic kidney disease undergoing procedures using intravenous (IV) iodinated CM.4 Notably, the FDA now makes a distinction between IV and IA administration of CM, recommending that metformin be withheld, irrespective of eGFR, when the latter route is used (for example, during cardiac catheterization).4,7

Guideline recommendations

Table 1 summarizes guidelines from U.S. and international societies that have provided recommendations regarding the use of CM in patients receiving metformin.9-16 Since the metformin label update, newer studies have emerged suggesting that the role of the drug in lactic acidosis may be exaggerated and that coexisting conditions associated with diabetes may instead be the root cause in most cases.6 Some guideline recommendations were thus revised in recent years to be less stringent compared to the FDA label.2,6 Most guidelines agree with discontinuing metformin in patients with eGFR 60 receiving IV CM. 9-16 However, inconsistencies exist in guidance for patients with eGFR ranging from 30 to 60.

There are also inconsistences in recommendations regarding IA CM. Intraarterial CM administration is categorized into procedures with first-pass and second-pass renal exposure.6,13 In procedures with first-pass renal exposure (i.e., injection into the left heart, thoracic and suprarenal abdominal aorta, or the renal arteries), the CM reaches the kidney in a relatively undiluted form and poses a higher risk of CI-AKI. Conversely, in procedures with second-pass renal exposure (i.e., injection into the right heart, pulmonary artery, etc.), the CM reaches the kidney after dilution in either the pulmonary or peripheral circulation, and the risk of CI-AKI is comparable to that of IV injections. Some guidelines suggest cessation of metformin with IA CM administration in patients with normal or only mildly impaired renal function, similar to the FDA.7,12,13 In other guidelines, however, discontinuation of metformin is only implicated in patients with poor renal function even for IA procedures with first-pass renal exposure.9,14 A few guidelines do not specifically distinguish between IA and IV CM in their statements.10,15,16

Table 1. Summary of guideline recommendations for CM administration in patients taking metformin9-16
Issuing Society (Year)
Recommendations
ACR9 (2023)
Patients with eGFR ≥30 and no evidence of AKI:  no need to discontinue metformin either prior to or following IV iodinated CM administration; no need to reassess the renal function following the test/procedure
 
Patients with severe CKD (stage IV or V [eGFR <30]) or AKI, or who are undergoing arterial catheter studies that might result in emboli (atheromatous or other) to the renal arteriesa: temporarily discontinue metformin prior to or at the time of the procedure, withhold for 48 hours subsequent to the procedure, and reinstitute only after renal function reevaluated and found to be normal
CAR10 (2022)b
Patients with eGFR >30: do not recommend stopping metformin
 
Patients with eGFR ≤30 or AKI: hold metformin prior to or at the time of iodinated CM administration, and do not restart for ≥48 hours and only then if kidney function remains stable (<25% increase compared with baseline creatinine) and the ongoing use of metformin has been reassessed
APSN11 (2020)
Patients with eGFR 30 to 60 who are undergoing imaging with IV contrast: temporarily discontinue metformin
KDA + KSN12
(2020)
IV administration of iodinated CM: Discontinue metformin starting the day of procedure and up to 48 hours after the procedure if eGFR is <60
 
IA administration of iodinated CM: Discontinue metformin starting the day of procedure and up to 48 hours after the procedure
 
Reevaluate renal function after procedure and restart metformin if renal function has not declined after the procedure
ESUR13 (2018)
Patients with eGFR >30 and no evidence of AKI, receiving either IV CM or IA CM with second-pass renal exposure: continue metformin
 
Patients with eGFR <30 receiving IV CM or IA CM with second-pass renal exposure, or those receiving IA CM with first-pass renal exposure (regardless of eGFR), or those with AKI: stop taking metformin from the time of CM administration, measure eGFR within 48 hours, and restart metformin if renal function has not changed significantly
RANZCR14 (2018)
IV administration of iodinated CM:
Patients with eGFR >30: continue metformin
 
Patients with an unknown recent eGFR or eGFR <30, or who are unwell or have deteriorating renal function: cease metformin for ≥48 hours from the time of the examination, and check eGFR prior to restarting metformin
 
IA administration of iodinated CM:
Patients with eGFR >45: continue metformin
 
Patients undergoing an IA procedure involving larger volumes of CM and/or a procedure involving a risk of renal embolisation with an unknown recent eGFR or an eGFR <45, or who are unwell or have deteriorating renal function: cease metformin for ≥48 hours following CM administration, and check eGFR prior to restarting metformin
JSN + JRS + JCS15
(2018)b
All patients: discontinue metformin prior to use of iodinated CM, except for cases requiring emergency contrast radiography; do not resume during the 48 hours after the use of iodinated CM
RCR16 (2014)b
Patients with serum creatinine in normal reference range and/or eGFR >60: no need to stop metformin after CM administration
 
Patients with serum creatinine above normal reference range or eGFR <60: any decision to stop metformin for 48 hours following CM administration should be made in consultation with the referring clinic
aWhile the ACR does not specifically use the term ‘IA’ in its recommendations, IA CM is administered during cardiac catheterization. The ACR recommends temporarily discontinuing metformin before/at the time of this procedure since it confers a higher risk for CM-induced nephropathy due to atheroembolic sequelae, and, perhaps, a more abrupt and concentrated CM dose delivered to the kidneys.4
bGuideline recommendations do not specify IV versus IA CM administration.
Abbreviations: ACR=American College of Radiology, AKI=acute kidney injury, APSN=Asian-Pacific Society for Nephrology, CAR=Canadian Association of Radiologists, CKD=chronic kidney disease, CM=contrast media, eGFR= estimated glomerular filtration rate (in mL/min/1.73m2), ESUR=European Society of Urogenital Radiology, KDA=Korean Diabetes Association, KSN=Korean Society of Nephrology, IA=intraarterial, IV=intravenous, JCS=Japanese Circulation Society, JRS=Japanese Radiology Society, JSN=Japanese Society of Nephrology, RANZCR=Royal Australian and New Zealand College of Radiologists, RCR=Royal College of Radiologists.

Literature on metformin and contrast

There are differences in the nature and quality of the scientific evidence upon which guideline recommendations are based, which may explain the inconsistencies previously described.5,6 While guidelines generally lack direct evidence-based support, two recent systematic reviews with meta-analysis (MA) provide direct evidence of metformin use in patients exposed to CM.2,6 Table 2 summarizes key characteristics and findings of these MAs.

The MA by Qiao et al found no significant association between metformin use and CI-AKI incidence.2 Continuous metformin therapy did not have any harmful effects on kidney function, regardless of whether CM was administered via coronary or venous routes. A major limitation of the MA was significant heterogeneity among the included studies, and possible causes for this included metformin dosage, baseline renal function, and population differences. The MA by Kao et al had similar findings.6 No significant differences in the incidence of CI-AKI and changes in renal function measurements were observed between patients who used metformin and patients who did not. Based on the results, authors concluded that there is no need to withhold metformin either before or after the procedure in patients with eGFR >30 who are receiving IV CM and in patients with eGFR >60 who are receiving IA CM with first-pass renal exposure. However, further evidence is needed to assess the safety of continuing metformin in patients with eGFR 30 to 60 receiving IA CM with first-pass renal exposure. Limitations of the MA included suboptimal design of included studies and large heterogeneity in outcomes that involved measurements of renal function. Notably, there is significant overlap in the studies included in both MAs.2,6 However, a major discrepancy is that Qiao et al stated that all included studies were of high quality while Kao et al noted that most included studies were not of high quality which limited the strength of the MA.

Table 2: Meta-analyses on CM administration in patients taking metformin.2,6
Study
 
Population 
Results
Conclusions
Qiao et al
(2022)2
 
 
7 studies (1 unblinded RCT, 2 cohort studies, 2 case-control) on associations between metformin use and CI-AKI incidence were included
 
N=2325 individuals, with 279 new cases of CI-AKI
Association between metformin and CI-AKI:
No statistically significant
increase in risk of CI-AKI development in patients who used metformin continuously (random-effects OR, 1.15; 95% CI, 0.70 to 1.90, p=NS)
 
Incidence of metformin-associated lactic acidosis:
No cases reported during CM exposure
Metformin can be safely used in patients with moderate renal impairment (eGFR ≥30) during CM exposure.
Kao et al
(2022)6
 
6 studies (2 unblinded RCTs, 4 retrospective cohort studies) that compared the outcomes of using metformin versus not using metformin during CM administration were included
 
N=1459 individuals
Incidence of CI-AKI after CM administration:
No significant difference in the metformin versus control group (RR, 1.08; 95% CI, 0.72 to 1.63)

Net change in serum creatinine after CM administration:
No significant difference in the metformin versus control group: MD=0.00 mg/dL; 95% CI, -0.05 to 0.05
 
Change in eGFR from baseline after CM administration:
MD=0.22; 95% CI, -2.47 to 2.91
 
Incidence of metformin-associated lactic acidosis:
No cases reported in both groups
Continuation of metformin during CM administration is not associated with a higher risk of CI-AKI, lactic acidosis,
or renal function deterioration compared to patients who
discontinue metformin or who are not metformin users.
 
 
Abbreviations: CI=confidence interval, CI-AKI=contrast-induced acute kidney injury; CM=contrast media, eGFR=estimated glomerular filtration rate (in mL/min/1.73m2), MD=mean difference, NS=not significant, OR=odds ratio, RCT=randomized controlled trial, RR=risk ratio.

Conclusion

While CI-AKI is common in clinical practice, evidence has accumulated that the overall risk of metformin-induced lactic acidosis precipitated by metformin accumulation due to CI-AKI is very low in the absence of other concurrent acute medical conditions (e.g., sepsis).1,10 Therefore, the FDA guidance on CM and metformin has progressively been superseded by less restrictive recommendations by the American College of Radiology, the Canadian Association of Radiologists, and various other organizations.6,9,10 Guidelines generally lack direct evidence-based support since few studies have been published on CM use in patients receiving metformin.2

Two recent MAs assessed the relationship between metformin and CI-AKI to provide direct evidence of metformin use in patients exposed to CM.2,6 Findings largely support the newer, less conservative guideline recommendations. Both MAs concluded that metformin can be safely used in patients with moderate renal impairment (eGFR >30) exposed to IV CM. Kao et al additionally concluded that metformin may be safely continued in patients with eGFR >60 receiving IA CM with first-pass renal exposure.6 However, both MAs were limited by the small number of included studies, which were either unblinded randomized controlled trials (RCTs) or observational studies (majority).2,6 Additional large-scale RCTs are necessary to reinforce findings from the MAs. Evidence remains limited especially in individuals with moderately impaired kidney function (eGFR 30 to 60) and/or receiving IA CM. If future studies continue to support safe use of metformin in patients with various degrees of renal impairment exposed to CM, another FDA update of the metformin label may eventually be warranted.

References

  1. Zhao F, Lei R, Yang SK, et al. Comparative effect of iso-osmolar versus low-osmolar contrast media on the incidence of contrast-induced acute kidney injury in diabetic patients: a systematic review and meta-analysis. Cancer Imaging. 2019;19(1):38. doi:10.1186/s40644-019-0224-6
  2. Qiao H, Li Y, Xu B, Lu Z, Zhang J, Meng D, He S, Huang J. Metformin can be safely used in patients exposed to contrast media: a systematic review and meta-analysis. Cardiology. 2022;147(5-6):469-478. doi:10.1159/000527384.
  3. Corcoran C, Jacobs TF. Metformin. In: StatPearls. Treasure Island (FL): StatPearls Publishing; May 2, 2022.
  4. Lipska KJ, Flory JH, Hennessy S, Inzucchi SE. Citizen petition to the US Food and Drug Administration to change prescribing guidelines: the metformin experience. Circulation. 2016;134(18):1405-1408. doi:10.1161/CIRCULATIONAHA.116.023041
  5. Goergen SK, Rumbold G, Compton G, Harris C. Systematic review of current guidelines, and their evidence base, on risk of lactic acidosis after administration of contrast medium for patients receiving metformin. Radiology. 2010;254(1):261-269. doi:10.1148/radiol.09090690
  6. Kao TW, Lee KH, Chan WP, Fan KC, Liu CW, Huang YC. Continuous use of metformin in patients receiving contrast medium: what is the evidence? A systematic review and meta-analysis. Eur Radiol. 2022;32(5):3045-3055. doi:10.1007/s00330-021-08395-7
  7. Drugs@FDA. Rockville (MD): Food and Drug Administration (US), Center for Drug Evaluation and Research; 2023. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed August 4, 2023.
  8. Asif S, Bennett J, Marakkath B. Metformin-associated lactic acidosis: an unexpected scenario. Cureus. 2019;11(4):e4397. doi:10.7759/cureus.4397
  9. ACR Manual on Contrast Media. American College of Radiology. 2023. Accessed August 4, 2023. https://www.acr.org/-/media/acr/files/clinical-resources/contrast_media.pdf
  10. Macdonald DB, Hurrell C, Costa AF, et al. Canadian Association of Radiologists Guidance on Contrast Associated Acute Kidney Injury. Can Assoc Radiol J. 2022;73(3):499-514. doi:10.1177/08465371221083970
  11. Liew A, Bavanandan S, Prasad N, et al. Asian Pacific Society of Nephrology clinical practice guideline on diabetic kidney disease – an executive summary. Nephrology (Carlton). 2020;25(11):809-817. doi:10.1111/nep.13804
  12. Hur KY, Kim MK, Ko SH, et al. Metformin treatment for patients with diabetes and chronic kidney disease: A Korean Diabetes Association and Korean Society of Nephrology consensus statement. Diabetes Metab J. 2020;44(1):3-10. doi:10.4093/dmj.2020.0004
  13. ESUR Guidelines on Contrast Agents, version 10. European Society of Urogenital Radiology. March 2018. Accessed August 4, 2023. https://www.esur.org/wp-content/uploads/2022/03/ESUR-Guidelines-10_0-Final-Version.pdf
  14. Iodinated Contrast Media Guideline, V2.3. The Royal Australian and New Zealand College of Radiologists. 2018. Accessed August 4, 2023. https://www.ranzcr.com/college/document-library/ranzcr-iodinated-contrast-guidelines
  15. Isaka Y, Hayashi H, Aonuma K, et al. Guideline on the use of iodinated contrast media in patients with kidney disease 2018. Clin Exp Nephrol. 2020;24(1):1-44. doi:10.1007/s10157-019-01750-5
  16. Standards for intravascular contrast administration to adult patients, third edition. The Royal College of Radiologists. 2014. Accessed August 4, 2023. https://www.rcr.ac.uk/sites/default/files/Intravasc_contrast_web.pdf

 

Prepared by:
Honey Joseph, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

September 2023

The information presented is current as of August 5, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.