Skip to main content
Log in

Retrospective analysis of lactic acidosis-related parameters upon and after metformin discontinuation in patients with diabetes and chronic kidney disease

  • Nephrology - Original Paper
  • Published:
International Urology and Nephrology Aims and scope Submit manuscript

Abstract

Purpose

To investigate association between renal functions, lactic acid levels and acid–base balance in type 2 diabetes patients with chronic kidney disease under metformin treatment and after metformin discontinuation in a real-life setting.

Methods

A total of 65 patients with diabetes (mean age 68.5 ± 8.9 years, 56.9 % females) in whom metformin treatment was discontinued due to reduced glomerular filtration rate (GFR) were included in this retrospective study. Data on patient demographics, metformin treatment and laboratory findings on the last day of metformin treatment and 2–3 weeks after metformin discontinuation including blood lactate and creatinine, estimated glomerular filtration rate (eGFR) and acid–base balance measurements in blood [pH, bicarbonate, base excess] were collected from medical records. The correlation of lactate levels with eGFR, blood pH and creatinine levels and changes in laboratory findings after metformin discontinuation were evaluated.

Results

Before metformin discontinuation, hyperlactatemia was observed in 78.5 % of patients and metabolic acidosis in 36.9 % of patients, but none had lactic acidosis. Patients with normolactatemia and hyperlactatemia were similar in terms of metformin dosage and laboratory parameters. Lactate levels were not significantly correlated with serum creatinine (r = −0.14; p = 0.263) and eGFR (r = 0.11, p = 0.374). After metformin discontinuation, a significant decrease was observed in median lactate levels (from 2.20 to 1.85 mmol/L; p = 0.002).

Conclusion

In conclusion, our findings support the low risk of MALA among patients with mild-to-moderate renal impairment and the likelihood of metformin to be an innocent bystander without a pathogenic role in the lactic acidosis in most cases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M et al (2012) 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 35:1364–1379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865

    Article  Google Scholar 

  3. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R et al (2009) American Diabetes Association; European Association for the Study of Diabetes. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 52:17–30

    Article  CAS  PubMed  Google Scholar 

  4. Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R et al (2011) Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med 154:602–613

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kajbaf F, Arnouts P, de Broe M, Lalau JD (2013) Metformin therapy and kidney disease: a review of guidelines and proposals for metformin withdrawal around the world. Pharmacoepidemiol Drug Saf 10:1027–1035

    Google Scholar 

  6. Misbin RI, Green L, Stadel BV, Gueriguian JL, Gabbi A, Fleming GA (1998) Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med 338:265–266

    Article  CAS  PubMed  Google Scholar 

  7. Fall PJ, Szerlip HM (2005) Lactic acidosis: from sour milk to septic shock. J Intensive Care Med 20:255–271

    Article  PubMed  Google Scholar 

  8. DeFronzo R, Fleming AG, Chenc K, Bicsak TA (2016) Metformin-associated lactic acidosis: current perspectives on causes and risk. Metab. Clin Exp 65:20–29

    Article  CAS  PubMed  Google Scholar 

  9. Lalau JD (2010) Lactic acidosis induced by metformin: incidence, management and prevention. Drug Saf 33:727–740

    Article  CAS  PubMed  Google Scholar 

  10. Scheen AJ, Paquot N (2013) Metformin revisited: a critical review of the benefit-risk balance in at-risk patients with type 2 diabetes. Diabetes Metab 39:179–190 (Review)

    Article  CAS  PubMed  Google Scholar 

  11. Glucophage (metformin hydrochloride) and Glucophage XR (extended-release) prescribing information. Bristol-Myers Squibb, Bristol (2009). Available at: http://packageinserts.bms.com/pi/pi_glucophage_xr.pdf. Accessed 13 Dec 2015

  12. McCormack J, Johns K, Tildesley H (2005) Metformin’s contraindications should be contraindicated. CMAJ 173:502–504

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lemyze M, Mallat J, Thevenin D (2011) Metformin-associated lactic acidosis: Is it really just an association? Am J Emerg Med 29:349–350

    Article  PubMed  Google Scholar 

  14. Juurlink DN, Roberts DM (2014) The enigma of metformin-associated lactic acidosis. Clin Toxicol (Philadelphia, Pa) 52:85–87

    Article  CAS  Google Scholar 

  15. Adam WR, O’Brien RC (2014) A justification for less restrictive guidelines on the use of metformin in stable chronic renal failure. Diabet Med 31:1032–1038 (Review)

    Article  CAS  PubMed  Google Scholar 

  16. Cryer DR, Nicholas SP, Henry DH, Mills DJ, Stadel BV (2005) Comparative outcomes study of metformin intervention versus conventional approach the COSMIC approach study. Diabetes Care 28:539–543

    Article  CAS  PubMed  Google Scholar 

  17. 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 1:CD002967

    PubMed  Google Scholar 

  18. Bodmer M, Meier C, Krahenbuhl 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 

  19. Peters N, Jay N, Barraud D, Cravoisy A, Nace L, Bollaert PE et al (2008) Metformin-associated lactic acidosis in an intensive care unit. Crit Care 12:R149

    Article  PubMed  PubMed Central  Google Scholar 

  20. Almirall J, Briculle M, Gonzalez-Clemente JM (2008) Metformin associated lactic acidosis in type 2 diabetes mellitus: incidence and presentation in common clinical practice. Nephrol Dial Transpl 23:2436–2438

    Article  CAS  Google Scholar 

  21. Richy FF, Sabido-Espin M, Guedes S, Corvino FA, Gottwald-Hostalek U (2014) Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: a retrospective cohort study. Diabetes Care 37:2291–2295

    Article  CAS  PubMed  Google Scholar 

  22. 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 4:CD002967

    PubMed  Google Scholar 

  23. Seidowsky A, Nseir S, Houdret N, Fourrier F (2009) Metformin-associated lactic acidosis: a prognostic and therapeutic study. Crit Care Med 37:2191–2196

    Article  CAS  PubMed  Google Scholar 

  24. Arroyo D, Melero R, Panizo N, Goicoechea M, Rodríguez-Benítez P, Vinuesa SG et al (2011) Metformin-associated acute kidney injury and lactic acidosis. Int J Nephrol 2011:749653

    Article  PubMed  PubMed Central  Google Scholar 

  25. Jones GC, Macklin JP, Alexander WD (2003) Contraindications to the use of metformin. BMJ 326:4–5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cases of lactic acidosis in patients undergoing treatment with metformin for the treatment of type 2 diabetes. Danish Health and Medicines Authority Pharmacovigilance Update #9 (2012). Available at: https://laegemiddelstyrelsen.dk/~/media/93E960D87BC74E9FA6FF7D2299684E59.ashx. Accessed 7 Oct 2015

  27. Hanatani T, Sai K, Tohkin M, Segawa K, Saito Y (2015) Impact of Japanese regulatory action on metformin-associated lactic acidosis in type II diabetes patients. Int J Clin Pharm 37:537–545

    Article  CAS  PubMed  Google Scholar 

  28. Goldberg T, Kroehl ME, Suddarth KH, Trinkley KE (2015) Variations in Metformin prescribing for type 2 Diabetes. J Am Board Fam Med 28:777–784

    Article  PubMed  Google Scholar 

  29. Philbrick AM, Ernst ME, McDanel DL, Ross MB, Moores KG (2009) Metformin use in renal dysfunction: is a serum creatinine threshold appropriate? Am J Health Syst Pharm 66:2017–2023

    Article  CAS  PubMed  Google Scholar 

  30. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group. Ann Intern Med. 130:461–470

    Article  CAS  PubMed  Google Scholar 

  31. Pongwecharak J, Tengmeesri N, Malanusorn N, Panthong M, Pawangkapin N (2009) Prescribing metformin in type 2 diabetes with a contraindication: prevalence and outcome. Pharm World Sci 31:481–486

    Article  PubMed  Google Scholar 

  32. Huang W, Castelino RL, Peterson GMJ (2015) Adverse event notifications implicating metformin with lactic acidosis in Australia. Diabetes Complicat. 29:1261–1265

    Article  Google Scholar 

  33. Kajbaf F, Lalau JD (2013) The criteria for metformin-associated lactic acidosis: the quality of reporting in a large pharmacovigilance database. Diabet Med 30:345–348

    Article  CAS  PubMed  Google Scholar 

  34. Luft D, Deichsel G, Schmulling R, Stein N, Eggstein M (1983) Definition of clinically relevant lactic acidosis in patients with internal diseases. Am J Clin Pathol 80:484–489

    Article  CAS  PubMed  Google Scholar 

  35. Salpeter S, Greyber E, Pasternak G, Salpeter E (2003) Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2:CD002967

    PubMed  Google Scholar 

  36. Lalau J, Lacroix C (2003) Measurement of metformin concentration in erythro-cytes: clinical implications. Diabetes Obes Metab 5:92–98

    Article  Google Scholar 

  37. Davis TM, Jackson D, Davis WA, Bruce DG, Chubb P (2001) The relationship between metformin therapy and the fasting plasma lactate in type 2 diabetes: the Fremantle Diabetes Study. Br J Clin Pharmacol 52:137–144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Emslie-Smith AM, Boyle DI, Evans JM, Sullivan F, Morris AD (2001) DARTS/MEMO collaboration. Contraindications to metformin therapy in patients with type 2 diabetes- a population-based study of adherence to prescribing guidelines. Diabet Med 18:483–488

    Article  CAS  PubMed  Google Scholar 

  39. Mathieu C (2015) Metformin-associated lactic acidosis: time to let it go? J Diabetes Complicat. 29:974–975

    Article  PubMed  Google Scholar 

  40. Rachmani R, Slavacheski I, Levi Z, Zadok B, Kedar Y, Ravid M (2002) Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications. Eur J Intern Med 13:428–433

    Article  CAS  PubMed  Google Scholar 

  41. Stades AME, 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 

  42. Scale T, Harvey JN (2011) Diabetes, metformin and lactic acidosis. Clin Endocrinol (Oxf) 74:191–196

    Article  CAS  Google Scholar 

  43. van Berlo-van de Laar IR, Vermeij CG, Doorenbos CJ (2011) Metformin associated lactic acidosis: incidence and clinical correlation with metformin serum concentration measurements. J Clin Pharm Ther 36:376–382

    Article  CAS  PubMed  Google Scholar 

  44. Duong JK, Kumar SS, Kirkpatrick CM, Greenup LC, Arora M, Lee TC et al (2013) Population pharmacokinetics of metformin in healthy subjects and patients with type 2 diabetes mellitus: simulation of doses according to renal function. Clin Pharmacokinet 52:373–384

    Article  CAS  PubMed  Google Scholar 

  45. 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  Google Scholar 

  46. Lalau JD, Race JM (2001) Lactic acidosis in metformin therapy: searching for a link with metformin in reports of ‘metformin-associated lactic acidosis’. Diabetes Obes Metab 3:195–201

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Savas Sipahi.

Ethics declarations

Conflict of interest

Authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sipahi, S., Solak, Y., Acikgoz, S.B. et al. Retrospective analysis of lactic acidosis-related parameters upon and after metformin discontinuation in patients with diabetes and chronic kidney disease. Int Urol Nephrol 48, 1305–1312 (2016). https://doi.org/10.1007/s11255-016-1288-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11255-016-1288-x

Keywords

Navigation