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Continuous use of metformin in patients receiving contrast medium: what is the evidence? A systematic review and meta-analysis

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Abstract

Objectives

Substantial inconsistencies exist in current guidelines regarding recommendations of metformin usage with the administration of a contrast medium. We aimed to perform a meta-analysis to determine whether the risks of contrast-induced acute kidney injury (CI-AKI) and lactic acidosis increase with metformin use in diabetic patients receiving a contrast medium.

Methods

Studies were retrieved from databases from inception to May 15, 2021. Studies that compared the outcomes of using metformin with not using metformin during contrast medium administration were included. The primary outcomes were incidence of CI-AKI and lactic acidosis. The secondary outcomes were renal function changes from baseline. Data analysis was using risk ratio (RR) for dichotomous outcomes and mean differences (MD) with 95% confidence intervals (CI) for continuous outcomes.

Results

Analyses of two randomized controlled trials and four retrospective cohorts examining a total of 1459 patients revealed no significant differences in the incidence of CI-AKI (RR = 1.08; 95% CI, 0.72 to 1.63) and in changes in renal function measurements (serum creatinine: MD = 0.00 mg/dL, 95% CI, − 0.05 to 0.05; estimated glomerular filtration rate: MD = 0.22, 95% CI, − 2.47 to 2.91) after contrast medium administration between patients using and not using metformin.

Conclusions

There is no evidence that continuing metformin during contrast medium administration is associated with a higher risk of CI-AKI, lactic acidosis, or renal function deterioration compared to patients who discontinued metformin or who were not metformin users. The limited quality of the included studies may compromise the strength of evidence provided in this meta-analysis.

Key Points

  • There is no need to discontinue metformin either before or after intravenous contrast medium exposure in patients with eGFR > 30 mL/min/1.73 m2.

  • In patients receiving intra-arterial contrast medium with first-pass renal exposure, there is no need to withhold metformin if eGFR is above 60 mL/min/1.73 m2.

  • For patients who have an eGFR level between 30 and 60 mL/min/1.73 m 2 and are receiving intra-arterial contrast medium with first-pass renal exposure, no case of lactic acidosis was observed based on present data, but further evidence is needed to make a strong suggestion regarding its safety.

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Abbreviations

ACR:

American College of Radiology

CI:

Confidence interval

CI-AKI:

Contrast-induced acute kidney injury

DM:

Diabetes mellitus

eGFR:

Estimated glomerular filtration rate

FDA:

Food and Drug Administration

GRADE:

Grading of Recommendations, Assessment, Development and Evaluations

MD:

Mean difference

OHA:

Oral hypoglycemic agent

PCI:

Percutaneous coronary intervention

RCT:

Randomized controlled trial

RR:

Risk ratio

SCr:

Serum creatinine

SD:

Standard deviation

STEMI:

ST-segment elevation myocardial infarction

References

  1. Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F (2012) Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 122:253–270

    Article  CAS  Google Scholar 

  2. Pernicova I, Korbonits M (2014) Metformin–mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol 10:143–156

    Article  CAS  PubMed  Google Scholar 

  3. Zhou T, Xu X, Du M, Zhao T, Wang J (2018) A preclinical overview of metformin for the treatment of type 2 diabetes. Biomed Pharmacother 106:1227–1235

    Article  CAS  PubMed  Google Scholar 

  4. Graham GG, Punt J, Arora M et al (2011) Clinical pharmacokinetics of metformin. Clin Pharmacokinet 50:81–98

    Article  CAS  PubMed  Google Scholar 

  5. DeFronzo R, Fleming GA, Chen K, Bicsak TA (2016) Metformin-associated lactic acidosis: current perspectives on causes and risk. Metabolism 65:20–29

    Article  CAS  PubMed  Google Scholar 

  6. Mehran R, Nikolsky E (2006) Contrast-induced nephropathy: definition, epidemiology, and patients at risk. Kidney Int Suppl. https://doi.org/10.1038/sj.ki.5000368:S11-15

    Article  PubMed  Google Scholar 

  7. Mamoulakis C, Tsarouhas K, Fragkiadoulaki I et al (2017) Contrast-induced nephropathy: basic concepts, pathophysiological implications and prevention strategies. Pharmacol Ther 180:99–112

    Article  CAS  PubMed  Google Scholar 

  8. Hossain MA, Costanzo E, Cosentino J et al (2018) Contrast-induced nephropathy: pathophysiology, risk factors, and prevention. Saudi J Kidney Dis Transpl 29:1–9

    Article  PubMed  Google Scholar 

  9. FORTAMET® (metformin hydrochloride) [package insert]. Fort Lauderdale: Actavis Laboratories FL, Inc; April 2017. Retrieved June 4, 2021, from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021574s020lbl.pdf.

  10. GLUCOPHAGE® (metformin hydrochloride) Tablets [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; April 2017. Retrieved June 4, 2021, from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020357s037s039,021202s021s023lbl.pdf

  11. Lalau JD, Race JM (1999) Lactic acidosis in metformin-treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations. Drug Saf 20:377–384

    Article  CAS  PubMed  Google Scholar 

  12. Radiology ESoU (March 2018) ESUR guidelines on contrast agents (Version10.0). Retrieved June 4, 2021, from https://www.esur.org/fileadmin/content/2019/ESUR_Guidelines_10.0_Final_Version.pdf

  13. Media ACoDaC (2021) American College of Radiology manual on contrast media. Retrieved June 4, 2021, from https://www.acr.org/-/media/ACR/files/clinical-resources/contrast_media.pdf

  14. Radiologists TRAaNZCo (2018) Iodinated contrast media guideline, V2.3. RANZCR, Sydney. Retrieved June 4, 2021, from https://www.ranzcr.com

  15. Owen RJ, Hiremath S, Myers A, Fraser-Hill M, Barrett BJ (2014) Canadian Association of Radiologists consensus guidelines for the prevention of contrast-induced nephropathy: update 2012. Can Assoc Radiol J 65:96–105

    Article  PubMed  Google Scholar 

  16. Liew A, Bavanandan S, Prasad N et al (2020) Asian Pacific Society of Nephrology clinical practice guideline on diabetic kidney disease - an executive summary. Nephrology (Carlton) 25:809–817

    Article  Google Scholar 

  17. Hur KY, Kim MK, Ko SH, Han M, Lee DW, Kwon HS (2020) Metformin treatment for patients with diabetes and chronic kidney disease: a Korean Diabetes Association and Korean Society of Nephrology consensus statement. Diabetes Metab J 44:3–10

    Article  PubMed  PubMed Central  Google Scholar 

  18. Isaka Y, Hayashi H, Aonuma K et al (2020) Guideline on the use of iodinated contrast media in patients with kidney disease 2018. Clin Exp Nephrol 24:1–44

    Article  PubMed  Google Scholar 

  19. radiologists Trco (2014) Standards for intravascular contrast administration to adult patients, third edition. UK. Retrieved June 4, 2021, from https://www.rcr.ac.uk/sites/default/files/Intravasc_contrast_web.pdf

  20. Page MJ, McKenzie JE, Bossuyt PM et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj 372:n71

  21. van der Molen AJ, Reimer P, Dekkers IA et al (2018) Post-contrast acute kidney injury - Part 1: definition, clinical features, incidence, role of contrast medium and risk factors: recommendations for updated ESUR Contrast Medium Safety Committee guidelines. Eur Radiol 28:2845–2855

    Article  PubMed  PubMed Central  Google Scholar 

  22. Mehta RL, Kellum JA, Shah SV et al (2007) Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 11:R31

    Article  PubMed  PubMed Central  Google Scholar 

  23. Kraut JA, Madias NE (2014) Lactic acidosis. N Engl J Med 371:2309–2319

    Article  PubMed  CAS  Google Scholar 

  24. Cumpston M, Li T, Page MJ et al (2019) Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev 10:Ed000142

  25. Higgins JP, Altman DG, Gøtzsche PC et al (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. Bmj 343:d5928

  26. Sterne JA, Hernán MA, Reeves BC et al (2016) ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. Bmj 355:i4919

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wan X, Wang W, Liu J, Tong T (2014) Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 14:135

    Article  PubMed  PubMed Central  Google Scholar 

  28. Follmann D, Elliott P, Suh I, Cutler J (1992) Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol 45:769–773

    Article  CAS  PubMed  Google Scholar 

  29. Abrams KR, Gillies CL, Lambert PC (2005) Meta-analysis of heterogeneously reported trials assessing change from baseline. Stat Med 24:3823–3844

    Article  PubMed  Google Scholar 

  30. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748

    CAS  PubMed  Google Scholar 

  31. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. Bmj 327:557–560

    Article  PubMed  PubMed Central  Google Scholar 

  32. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Guyatt G, Oxman AD, Akl EA et al (2011) GRADE guidelines: 1. Introduction—GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 64:383–394

    Article  PubMed  Google Scholar 

  34. Yu Q, Zhu JJ, Liu WX (2020) Effect of continuous use of metformin on kidney function in diabetes patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. BMC Cardiovasc Disord 20:187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Oktay V, Calpar Çıralı İ, Sinan ÜY, Yıldız A, Ersanlı MK (2017) Impact of continuation of metformin prior to elective coronary angiography on acute contrast nephropathy in patients with normal or mildly impaired renal functions. Anatol J Cardiol 18:334–339

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kim SK, Jung J, Jung JH, Kim KY, Baek JH, Hahm JR (2016) The association between use of metformin and change in serum CO2 level after administration of contrast medium. Clin Radiol 71:532–536

    Article  CAS  PubMed  Google Scholar 

  37. Namazi MH, AlipourParsa S, Roohigilani K et al (2018) Is it necessary to discontinue metformin in diabetic patients with GFR > 60 ml/min per 1.73 m2 undergoing coronary angiography: a controversy still exists? Acta Biomed 89:227–232

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Jung J, Cho YY, Jung JH et al (2019) Are patients with mild to moderate renal impairment on metformin or other oral anti-hyperglycaemic agents at increased risk of contrast-induced nephropathy and metabolic acidosis after radiocontrast exposure? Clin Radiol 74:651.e651-651.e656

    Article  Google Scholar 

  39. Lal A, Kaur N, Trivedi N (2019) Metformin, arterial contrast and acute kidney injury. Acta Biomed 90:355–356

    CAS  PubMed  Google Scholar 

  40. Zeller M, Labalette-Bart M, Juliard JM et al (2016) Metformin and contrast-induced acute kidney injury in diabetic patients treated with primary percutaneous coronary intervention for ST segment elevation myocardial infarction: a multicenter study. Int J Cardiol 220:137–142

    Article  PubMed  Google Scholar 

  41. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE (2010) Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2010:Cd002967

  42. Goergen SK, Rumbold G, Compton G, Harris C (2010) Systematic review of current guidelines, and their evidence base, on risk of lactic acidosis after administration of contrast medium for patients receiving metformin. Radiology 254:261–269

    Article  PubMed  Google Scholar 

  43. Prabhu RA, Mareddy AS, Nagaraju SP, Rangaswamy D, Guddattu V (2019) Lactic acidosis due to metformin in type 2 diabetes mellitus and chronic kidney disease stage 3–5: is it significant? Int Urol Nephrol 51:1229–1230

    Article  PubMed  Google Scholar 

  44. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK (2014) Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA 312:2668–2675

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Lee EY, Hwang S, Lee YH et al (2017) Association between metformin use and risk of lactic acidosis or elevated lactate concentration in type 2 diabetes. Yonsei Med J 58:312–318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kamber N, Davis WA, Bruce DG, Davis TM (2008) Metformin and lactic acidosis in an Australian community setting: the Fremantle Diabetes Study. Med J Aust 188:446–449

    Article  PubMed  Google Scholar 

  47. Brown JB, Pedula K, Barzilay J, Herson MK, Latare P (1998) Lactic acidosis rates in type 2 diabetes. Diabetes Care 21:1659–1663

    Article  CAS  PubMed  Google Scholar 

  48. Orloff J, Min JY, Mushlin A, Flory J (2021) Safety and effectiveness of metformin in patients with reduced renal function: a systematic review. Diabetes Obes Metab. https://doi.org/10.1111/dom.14440

    Article  PubMed  Google Scholar 

  49. Lazarus B, Wu A, Shin JI et al (2018) Association of metformin use with risk of lactic acidosis across the range of kidney function: a community-based cohort study. JAMA Intern Med 178:903–910

    Article  PubMed  PubMed Central  Google Scholar 

  50. Posma RA, Lexis CP, Lipsic E et al (2015) Effect of metformin on renal function after primary percutaneous coronary intervention in patients without diabetes presenting with ST-elevation myocardial infarction: data from the GIPS-III Trial. Cardiovasc Drugs Ther 29:451–459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Misbin RI (2004) The phantom of lactic acidosis due to metformin in patients with diabetes. Diabetes Care 27:1791–1793

    Article  PubMed  Google Scholar 

  52. Lalau JD, Kajbaf F, Protti A, Christensen MM, De Broe ME, Wiernsperger N (2017) Metformin-associated lactic acidosis (MALA): moving towards a new paradigm. Diabetes Obes Metab 19:1502–1512

    Article  PubMed  Google Scholar 

  53. Chan NN, Brain HP, Feher MD (1999) Metformin-associated lactic acidosis: a rare or very rare clinical entity? Diabet Med 16:273–281

    Article  CAS  PubMed  Google Scholar 

  54. Bodmer M, Meier C, Krähenbühl S, Jick SS, Meier CR (2008) Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis. Diabetes Care 31:2086–2091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Stades AM, Heikens JT, Erkelens DW, Holleman F, Hoekstra JB (2004) Metformin and lactic acidosis: cause or coincidence? A review of case reports. J Intern Med 255:179–187

    Article  CAS  PubMed  Google Scholar 

  56. Lazzeri C, Valente S, Chiostri M, Attanà P, Picariello C, Gensini GF (2012) The prognostic role of in-hospital peak glycemia in stemi patients with and without diabetes. Acta Diabetol 49:379–386

    Article  CAS  PubMed  Google Scholar 

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Funding

The authors state that this work has not received any funding.

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Authors and Affiliations

  1. School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Ting-Wan Kao

  2. Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Kuo-Hua Lee

  3. Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Kuo-Hua Lee

  4. Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

    Kuo-Hua Lee

  5. Department of Radiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    Wing P. Chan

  6. Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Wing P. Chan

  7. Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan

    Kang-Chih Fan

  8. Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

    Kang-Chih Fan

  9. Department of Orthopedics, Cathay General Hospital, Taipei, Taiwan

    Che-Wei Liu

  10. Research Center of Big Data and Meta-Analysis, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    Che-Wei Liu & Yu-Chen Huang

  11. Department of Dermatology, Wan Fang Hospital, Taipei Medical University, No. 111, Sec. 3, Xinglong Rd., Wenshan Dist., Taipei City, Taiwan

    Yu-Chen Huang

  12. Department of Dermatology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Yu-Chen Huang

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  1. Ting-Wan Kao
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Correspondence to Yu-Chen Huang.

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Guarantor

The scientific guarantor of this publication is Huang Yu-Chen.

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The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article.

Statistics and Biometry

No complex statistical methods were necessary for this paper.

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Written informed consent was not required for this study because this is a meta-analysis.

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This is a meta-analysis and Institutional Review Board approval was not required in our institution.

Study subjects or cohorts overlap

This is a meta-analysis including randomized controlled studies and retrospective cohort studies.

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Kao, TW., Lee, KH., Chan, W.P. et al. Continuous use of metformin in patients receiving contrast medium: what is the evidence? A systematic review and meta-analysis. Eur Radiol 32, 3045–3055 (2022). https://doi.org/10.1007/s00330-021-08395-7

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