Exp Clin Endocrinol Diabetes 2021; 129(11): 842-847
DOI: 10.1055/a-1149-9030
Article

Metformin Associated Lactic Acidosis in Clinical Practice – A Case Series

Philipp Schädle
1   Centre of Internal Medicine I, Marienhospital Stuttgart, Vinzenz von Paul Kliniken, Stuttgart, Germany
,
Otto Tschritter
1   Centre of Internal Medicine I, Marienhospital Stuttgart, Vinzenz von Paul Kliniken, Stuttgart, Germany
2   Emergency Department, Zollernalb Klinikum gGmbH, Balingen, Germany
,
Monika Kellerer
1   Centre of Internal Medicine I, Marienhospital Stuttgart, Vinzenz von Paul Kliniken, Stuttgart, Germany
› Author Affiliations

Abstract

Aims The aim of this case report is to specify the frequency and mortality of Metformin-Associated Lactic Acidosis (MALA) in emergency medicine, as the diagnosis seems to occur more often than estimated.

Methods To identify the subjects, we developed screening criteria for MALA. We measured the serum metformin concentration to confirm the diagnosis in all patients fulfilling these criteria. Retrospectively the patients were grouped according to individual risk (according to a defined risk score) and the application of renal replacement therapy.

Results From 2013 until 2018 we were able to identify 11 MALA patients revealing a frequency of 1:4,000 emergency patients. Six patients survived and five died in the follow-up. All three patients in the high-risk group died although all of them received renal replacement therapy. In the low-risk group (three patients, one with renal replacement therapy), all patients survived, while in the intermediate-risk group (five patients, one with renal replacement therapy) three patients survived and two died. Additional severe comorbidities also contributed to mortality.

Conclusions Every patient matching the screening criteria of acute renal failure, lactic acidosis and continued intake of metformin can be considered a potential MALA case. A risk score assessment which includes severe comorbidities may help to identify high-risk individuals and should be evaluated in larger studies.To prevent MALA, patients should be trained to immediately interrupt their own metformin use when showing signs of volume depletion. Physicians should be aware of the additional risk factors such as co-medication with diuretics, ACE (angiotensin converting enzyme) ACE inhibitors and NSAIDs (non steroidal anti inflammatory drugs).



Publication History

Received: 30 September 2019
Received: 08 March 2020

Accepted: 25 March 2020

Article published online:
13 May 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Johnson JA, Simpson SH, Toth EL. et al. Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with Type 2 diabetes. Diabet Med 2005; 22: 497-502
  • 2 Evans JM, Ogston SA, Emslie-Smith A. et al. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: A comparison of patients treated with sulfonylureas and metformin. Diabetologia 2006; 49: 930-936
  • 3 UKPDS, Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854-865
  • 4 Inzucchi SE, Bergenstal RM, Buse JB. et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012; 35: 1364-1379
  • 5 FDA. FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. 2016 [cited 2019 June 17]; Available from: https://www.fda.gov/media/96771/download
  • 6 EMA. Use of metformin to treat diabetes now expanded zp patients with moderately reduced kidney function. Recommendations for patients with kidney impairment updated in product information. 2016 [cited 2019 June 17]; Available from: https://www.ema.europa.eu/en/documents/referral/metformin-article-31-referral-use-metformin-treat-diabetes-now-expanded-patients-moderately-reduced_en.pdf
  • 7 BfArM. EU-Risikobewertungsverfahren gemäß Artikel 31 der Richtlinie 2001/83/EG für Humanarzneimittel mit dem Wirkstoff "Metformin" (EMEA/H/A-31/1432). 2017 [cited 2019 June 17]; Available from: https://www.bfarm.de/SharedDocs/Downloads/DE/Arzneimittel/Pharmakovigilanz/Risikoinformationen/RisikoBewVerf/m-r/metformin-durchfuehrungsbeschluss.pdf?__blob=publicationFile&v=1
  • 8 Lenssen R, Liekweg A. Strategies of age-adapted pharmacotherapy in renal failure. Z Gerontol Geriatr 2016; 49: 494-499
  • 9 Adam WR, O'Brien RC. A justification for less restrictive guidelines on the use of metformin in stable chronic renal failure. Diabet Med 2014; 31: 1032-1038
  • 10 Kim MJ, Han JY, Shin JY. et al. Metformin-associated lactic acidosis: Predisposing factors and outcome. Endocrinol Metab (Seoul) 2015; 30: 78-83
  • 11 Eppenga WL, Lalmohamed A, Geerts AF. et al. Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study. Diabetes Care 2014; 37: 2218-2224
  • 12 Salpeter SR, Greyber E, Pasternak GA. et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2010; 14: CD002967
  • 13 Richy FF, Sabidó-Espin M, Guedes S. et al. Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: A retrospective cohort study. Diabetes Care 2014; 37: 2291-2295
  • 14 Brown JB, Pedula K, Barzilay J. et al. Lactic acidosis rates in type 2 diabetes. Diabetes Care 1998; 21: 1659-1663
  • 15 Bailey CJ, Rurner RC. Metformin. N Engl J Med 1996; 334: 574–579
  • 16 Misbin RI, Green L, Stadel BV. et al. Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med 1998; 338: 265-266
  • 17 Bergman U, Boman G, Wiholm BE. Epidemiology of adverse drug reactions to phenformin and metformin. Br Med J 1978; 2: 464-466
  • 18 Ekström N, Schiöler L, Svensson AM. et al. Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: A cohort study from the Swedish National Diabetes Register. BMJ Open 2012; 2: e001076
  • 19 Inzucchi SE, Lipska KJ, Mayo H. et al. Metformin in patients with type 2 diabetes and kidney disease: A systematic review. JAMA 2014; 312: 2668-2675
  • 20 Stang M, Wysowski DK, Butler-Jones D. Incidence of lactic acidoses in metformin users. Diabetes Care 1999; 22: 925-927
  • 21 Bodmer M, Meier C, Krähenbühl S. et al. Metformin, sulfonylureas, or other antidiabetic drugs and the risk of lactic acidosis or hypoglycemia: A nested case-control analysis. Diabetes Care 2008; 31: 2086-2091
  • 22 van Berlo-van de Laar IR, Vermeij CG, Doorenbos CJ. Metformin associated lactic acidosis: Incidence and clinical correlation with metformin serum concentration measurements. J Clin Pharm Ther 2011; 36: 376-382
  • 23 Aharaz A, Pottegard A, Henriksen DP. et al. Risk of lactic acidosis in type 2 diabetes patients using metformin: A case control study. PLoS One 2018; 13: e0196122
  • 24 Schulz M, Iwersen-Bergmann S, Andresen H. et al. Therapeutic and toxic blood concentrations of nearly 1000 drugs and other xenobiotics. Crit Care 2012; 16: R136
  • 25 Patel D, Kumar P, Sharma S. et al. Analytical Methods for Metformin Estimation. Crit Rev Anal Chem 2017; 47: 405-417
  • 26 Greco P, Regolisti G, Maggiore U. et al. Sustained low-eficiency dialysis for metformin-associated lactic acidosis in patients with acute kidney injury. J Nephrol 2019; 32: 297-306
  • 27 Stammschulte T, Spranger J, Daul A. et al. A case-series of metformin-associated lactic acidosis in the German spontaneous reporting system - time to remember this serious adverse drug reaction!. In: 13th Annual Meeting of the International Society of Pharmacovigilance. 2013
  • 28 Prabhu RA, Mareddy AS, Nagaraju SP. et al. Lactic acidosis due to metformin in type 2 diabetes mellitus and chronic kidney disease stage 3-5: is it significant?. Int Urol Nephrol. 2019 (Epub ahead of print 2019 Apr 8)
  • 29 Angioi A, Cabiddu G, Conti M. et al. Metformin associated lactic acidosis: a case series of 28 patients treated with sustained low-efficiency dialysis (SLED) and long-term follow-up. BMC Nephrol 2018; 19: 77