American College of Radiology and Metformin: A Guide to Contrast Media Safety
Contrast media (CM) are essential tools in modern radiology, enhancing the diagnostic accuracy of various imaging examinations. However, their use is not without potential risks, particularly for patients with pre-existing conditions or those taking certain medications. The American College of Radiology (ACR) plays a crucial role in providing guidance and recommendations for the safe and effective use of contrast media in both adults and children. This article delves into the ACR's recommendations regarding metformin, a common medication for type 2 diabetes, and its interaction with contrast media, particularly in the context of contrast-induced acute kidney injury (CI-AKI).
The Role of Contrast Media in Radiological Examinations
Gadolinium-based contrast agents are administered to approximately 30 million patients every year to improve the diagnostic accuracy of MR examinations. The ACR Committee on Drugs and Contrast Media has created a guide for radiologists to promote safe and effective use of contrast media in both adults and children. The ACR guidelines also include a comprehensive list of currently employed contrast agents and their specifications.
Understanding Contrast-Induced Acute Kidney Injury (CI-AKI)
Contrast-induced acute kidney injury (CI-AKI) has been identified to be a major healthcare problem. With the widespread use of contrast media (CM) in diagnostic and interventional procedures, CI-AKI ranks third in hospital-acquired AKI. In the general population, the incidence of CI-AKI ranged from 12% to 27%, but escalated to 50% or more in patients with multiple risk factors. The potential for CI-AKI is considered to be the link between metformin, CM administration, and the risk of lactic acidosis.
Metformin and its Implications
Metformin is indicated as the first-line medical treatment for type 2 diabetes mellitus (T2DM) unless there are contraindications. Its anti-inflammatory and cardioprotective effects, in addition to its glucose-lowering properties, can reduce all-cause mortality. Metformin has no direct nephrotoxic effect, but it is cleared via renal filtration, and very high circulating levels from an overdose or acute renal failure have been associated with lactic acidosis (LA). However, due to the extremely rare complication of LA, metformin can be safely used in patients with renal impairment.
Historical Concerns and Evolving Guidelines
Early guidelines based on expert consensus have strictly recommended discontinuing metformin before using CM. However, guidelines for the use of metformin and CM have become less stringent following the recent FDA recommendation update. The CMSC amended their recommendations so that patients with eGFR >30 mL/min/1.73 m2 and no evidence of AKI can continue to take metformin normally while using CM, as the American College of Radiology (ACR) did for patients with eGFR of 30 mL/min/1.73 m2 or greater. Nonetheless, these guidelines lacked direct evidence-based support.
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Current ACR Recommendations on Metformin and Contrast Media
More specifically, if AKI were to be caused by CM, an accumulation of metformin could occur, with ensuing risk of lactic acidosis. 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. The eGFR should be re-evaluated 48 hours after the imaging procedure, and metformin restarted if renal function is stable.
Intravenous vs. Intra-arterial CM Administration
There are also inconsistences in recommendations regarding IA CM. Intraarterial CM administration is categorized into procedures with first-pass and second-pass renal exposure. 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.
Meta-Analyses and Emerging Evidence
Two recent MAs assessed the relationship between metformin and CI-AKI to provide direct evidence of metformin use in patients exposed to CM. 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. However, both MAs were limited by the small number of included studies, which were either unblinded randomized controlled trials (RCTs) or observational studies (majority). 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.
Meta-Analysis Findings on Metformin and CI-AKI
This systematic review and meta-analysis of 7 studies, comprising 2,325 individuals and 279 new cases of CI-AKI, have revealed no significant association between metformin use and CI-AKI incidence. Continuous metformin therapy had no deleterious effects on renal function, regardless of whether CM was administered via coronary or venous routes. The MA by Qiao et al found no significant association between metformin use and CI-AKI incidence. Continuous metformin therapy did not have any harmful effects on kidney function, regardless of whether CM was administered via coronary or venous routes.
Lactic Acidosis: Separating Fact from Fiction
Historically, the development of LA was a nightmare that hampered the use of metformin and the prejudice originated from phenformin, a metformin precursor. Phenformin, which was first launched in the 1950s, has been widely used before it was banned in 1977 due to the frequency of LA (40-64 cases per 100,000 people/year) and the associated mortality. Unlike phenformin, the causal relationship between metformin and LA is controversial, and metformin-associated LA is reported in only 3-9 cases per 100,000 patients/year, with a mortality rate of about 50%. In a nested case-control study on 50,048 patients with T2DM, 6 cases of LA were identified, yielding a crude incidence rate of 3.3 cases per 100,000 people/year with metformin therapy and 4.8 cases per 100,000 people/year with sulfonylureas. The development of LA may be related to poor clinical conditions rather than specific types of oral antidiabetic medications. Meanwhile, several studies suggest that metformin has no effect on LA incidence in patients with T2DM and normal, mild, moderate, or severe renal insufficiency.
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Risk Factors for AKI in Patients Exposed to CM
Although nephrotoxicity is evident in all iodine CM, the association between CM use and the development of AKI remains controversial. Pre-existing renal insufficiency, acute hyperglycemia, nephrotoxic drugs, and other variables were also found to be important risk factors for AKI in patients exposed to CM.
Implications for Clinical Practice
This present study indicates that metformin can be safely used in patients with moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m2) during CM exposure. All of the results and analyses were derived from previously published studies. Afterward, the potential negative effects of metformin should not be considered in diabetic patients exposed to intravenous or arterial CM except for first-pass renal exposure and eGFR of 30 mL/min/1.73 m2 or higher, as approved by the FDA.
Other Contrast Media Considerations
Gadolinium-based contrast agents are administered to approximately 30 million patients every year to improve the diagnostic accuracy of MR examinations. Researchers have found that gadolinium-based contrast agents may leave deposits in the brain, bone and other organs.
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