Skip to main content
Top
Published in: Acta Diabetologica 4/2016

01-08-2016 | Original Article

Dose-related effects of metformin on acid–base balance and renal function in patients with diabetes who develop acute renal failure: a cross-sectional study

Authors: David Cucchiari, Manuel Alfredo Podestà, Elisa Merizzoli, Albania Calvetta, Emanuela Morenghi, Claudio Angelini, Claudio Ponticelli, Salvatore Badalamenti

Published in: Acta Diabetologica | Issue 4/2016

Login to get access

Abstract

Aims

The role of metformin in the development of lactic acidosis (LA) in the setting of acute renal failure (ARF) is debated. Moreover, recent experiments suggested that metformin can also be nephrotoxic, but little clinical data exist about this topic. We sought to investigate these possible associations in a large cohort of patients with diabetes who developed ARF.

Methods

We analyzed data from patients with diabetes admitted to our emergency department between 2007 and 2011 with ARF and a previously normal renal function (n = 126). We compared acid–base balance and renal function of patients taking metformin (n = 74) with patients not taking it (n = 52).

Results

Patients taking metformin had decreased pH (7.31 ± 0.16 vs 7.39 ± 0.11, p = 0.008) and higher lactates (4.54 ± 4.30 vs 1.71 ± 1.14 mmol/L, p < 0.001). Both acidosis (pH < 7.35) and LA (lactates >5 mmol/L and pH < 7.35) were more frequently observed in this group (p = 0.0491 and p < 0.001, respectively). Multivariate analysis ruled out the role of some possible confounders, especially decreased renal function. The influence of metformin on pH and lactates grew significantly with higher doses of the drug (p = 0.259 and p = 0.092 for <1 g/day, p = 0.289 and p < 0.001 for 1–2 g/day, p = 0.009 and p < 0.001 for 2–3 g/day, for pH and lactates, respectively). Metformin influenced creatinine levels in a dose-related manner as well (p = 0.925 for <1 g/day, p = 0.033 for 1–2 g/day, p < 0.001 for 2–3 g/day).

Conclusions

In patients with diabetes who were admitted to our emergency department with ARF, the use of metformin was associated in a dose-related fashion with both LA and worse renal function.
Literature
1.
go back to reference Renda F, Mura P, Finco G, Ferrazin F, Pani L, Landoni G (2013) Metformin-associated lactic acidosis requiring hospitalization. A national 10 year survey and a systematic literature review. Eur Rev Med Pharmacol Sci 17(Suppl 1):45–49PubMed Renda F, Mura P, Finco G, Ferrazin F, Pani L, Landoni G (2013) Metformin-associated lactic acidosis requiring hospitalization. A national 10 year survey and a systematic literature review. Eur Rev Med Pharmacol Sci 17(Suppl 1):45–49PubMed
2.
go back to reference Spiller HA, Quadrani DA (2004) Toxic effects from metformin exposure. Ann Pharmacother 38:776–780CrossRefPubMed Spiller HA, Quadrani DA (2004) Toxic effects from metformin exposure. Ann Pharmacother 38:776–780CrossRefPubMed
3.
go back to reference Li Cavoli G, Tortorici C, Bono L, Giammarresi C, Ferrantelli A, Zagarrigo C et al (2011) Acute kidney injury associated with metformin. Am J Emerg Med 29:568–569CrossRefPubMed Li Cavoli G, Tortorici C, Bono L, Giammarresi C, Ferrantelli A, Zagarrigo C et al (2011) Acute kidney injury associated with metformin. Am J Emerg Med 29:568–569CrossRefPubMed
4.
go back to reference Runge S, Mayerle J, Warnke C, Robinson D, Roser M, Felix SB et al (2008) Metformin-associated lactic acidosis in patients with renal impairment solely due to drug accumulation? Diabetes Obes Metab 10:91–93PubMed Runge S, Mayerle J, Warnke C, Robinson D, Roser M, Felix SB et al (2008) Metformin-associated lactic acidosis in patients with renal impairment solely due to drug accumulation? Diabetes Obes Metab 10:91–93PubMed
5.
go back to reference 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 CD002967. doi:10.1002/14651858.CD002967.pub4 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 CD002967. doi:10.​1002/​14651858.​CD002967.​pub4
6.
go back to reference Frid A, Sterner GN, Löndahl M, Wiklander C, Cato A, Vinge E et al (2010) Novel assay of metformin levels in patients with type 2 diabetes and varying levels of renal function: clinical recommendations. Diabetes Care 33:1291–1293CrossRefPubMedPubMedCentral Frid A, Sterner GN, Löndahl M, Wiklander C, Cato A, Vinge E et al (2010) Novel assay of metformin levels in patients with type 2 diabetes and varying levels of renal function: clinical recommendations. Diabetes Care 33:1291–1293CrossRefPubMedPubMedCentral
7.
go back to reference Dell’Aglio DM, Perino LJ, Kazzi Z, Abramson J, Schwartz MD, Morgan BW (2009) Acute metformin overdose: examining serum pH, lactate level, and metformin concentrations in survivors versus nonsurvivors: a systematic review of the literature. Ann Emerg Med 54:818–823CrossRefPubMed Dell’Aglio DM, Perino LJ, Kazzi Z, Abramson J, Schwartz MD, Morgan BW (2009) Acute metformin overdose: examining serum pH, lactate level, and metformin concentrations in survivors versus nonsurvivors: a systematic review of the literature. Ann Emerg Med 54:818–823CrossRefPubMed
8.
go back to reference Wills BK, Bryant SM, Buckley P, Seo B (2010) Can acute overdose of metformin lead to lactic acidosis? Am J Emerg Med 28:857–861CrossRefPubMed Wills BK, Bryant SM, Buckley P, Seo B (2010) Can acute overdose of metformin lead to lactic acidosis? Am J Emerg Med 28:857–861CrossRefPubMed
9.
go back to reference Guo PYF, Storsley LJ, Finkle SN (2006) Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin. Semin Dial 19:80–83CrossRefPubMed Guo PYF, Storsley LJ, Finkle SN (2006) Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin. Semin Dial 19:80–83CrossRefPubMed
10.
go back to reference Bruijstens LA, van Luin M, Buscher-Jungerhans PMM, Bosch FH (2008) Reality of severe metformin-induced lactic acidosis in the absence of chronic renal impairment. Neth J Med 66:185–190PubMed Bruijstens LA, van Luin M, Buscher-Jungerhans PMM, Bosch FH (2008) Reality of severe metformin-induced lactic acidosis in the absence of chronic renal impairment. Neth J Med 66:185–190PubMed
11.
go back to reference Rifkin SI, McFarren C, Juvvadi R, Weinstein SS (2011) Prolonged hemodialysis for severe metformin intoxication. Ren Fail 33:459–461CrossRefPubMed Rifkin SI, McFarren C, Juvvadi R, Weinstein SS (2011) Prolonged hemodialysis for severe metformin intoxication. Ren Fail 33:459–461CrossRefPubMed
12.
go back to reference Lacher M, Hermanns-Clausen M, Haeffner K, Brandis M, Pohl M (2005) Severe metformin intoxication with lactic acidosis in an adolescent. Eur J Pediatr 164:362–365CrossRefPubMed Lacher M, Hermanns-Clausen M, Haeffner K, Brandis M, Pohl M (2005) Severe metformin intoxication with lactic acidosis in an adolescent. Eur J Pediatr 164:362–365CrossRefPubMed
13.
go back to reference Nguyen H-L, Concepcion L (2011) Metformin intoxication requiring dialysis. Hemodial Int 15(Suppl 1):S68–S71CrossRefPubMed Nguyen H-L, Concepcion L (2011) Metformin intoxication requiring dialysis. Hemodial Int 15(Suppl 1):S68–S71CrossRefPubMed
14.
go back to reference Protti A, Fortunato F, Monti M, Vecchio S, Gatti S, Comi GP et al (2012) Metformin overdose, but not lactic acidosis per se, inhibits oxygen consumption in pigs. Crit Care 16:R75CrossRefPubMedPubMedCentral Protti A, Fortunato F, Monti M, Vecchio S, Gatti S, Comi GP et al (2012) Metformin overdose, but not lactic acidosis per se, inhibits oxygen consumption in pigs. Crit Care 16:R75CrossRefPubMedPubMedCentral
15.
go back to reference Luft D, Deichsel G, Schmülling RM, Stein W, Eggstein M (1983) Definition of clinically relevant lactic acidosis in patients with internal diseases. Am J Clin Pathol 80:484–489CrossRefPubMed Luft D, Deichsel G, Schmülling RM, Stein W, Eggstein M (1983) Definition of clinically relevant lactic acidosis in patients with internal diseases. Am J Clin Pathol 80:484–489CrossRefPubMed
16.
go back to reference Nye HJ, Herrington WG (2011) Metformin: The safest hypoglycaemic agent in chronic kidney disease? Nephron Clin Pract 118:c380–c383CrossRefPubMed Nye HJ, Herrington WG (2011) Metformin: The safest hypoglycaemic agent in chronic kidney disease? Nephron Clin Pract 118:c380–c383CrossRefPubMed
17.
go back to reference 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 352:854–865CrossRef 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 352:854–865CrossRef
18.
go back to reference Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F (2012) Cellular and molecular mechanisms of metformin: an overview. Clin Sci 122:253–270CrossRefPubMedPubMedCentral Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F (2012) Cellular and molecular mechanisms of metformin: an overview. Clin Sci 122:253–270CrossRefPubMedPubMedCentral
19.
go back to reference Protti A, Russo R, Tagliabue P, Vecchio S, Singer M, Rudiger A et al (2010) Oxygen consumption is depressed in patients with lactic acidosis due to biguanide intoxication. Crit Care 14:R22CrossRefPubMedPubMedCentral Protti A, Russo R, Tagliabue P, Vecchio S, Singer M, Rudiger A et al (2010) Oxygen consumption is depressed in patients with lactic acidosis due to biguanide intoxication. Crit Care 14:R22CrossRefPubMedPubMedCentral
21.
go back to reference Eppenga WL, Lalmohamed A, Geerts AF, Derijks HJ, Wensing M, Egberts A et al (2014) Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study. Diabetes Care 37:2218–2224CrossRefPubMed Eppenga WL, Lalmohamed A, Geerts AF, Derijks HJ, Wensing M, Egberts A et al (2014) Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study. Diabetes Care 37:2218–2224CrossRefPubMed
22.
go back to reference Vecchio S, Giampreti A, Petrolini VM, Lonati D, Protti A, Papa P et al (2014) Metformin accumulation: lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy. Clin Toxicol 52:129–135CrossRef Vecchio S, Giampreti A, Petrolini VM, Lonati D, Protti A, Papa P et al (2014) Metformin accumulation: lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy. Clin Toxicol 52:129–135CrossRef
23.
go back to reference Waikar SS, Wald R, Chertow GM, Curhan GC, Winkelmayer WC, Liangos O et al (2006) Validity of international classification of diseases, ninth revision, clinical modification codes for acute renal failure. J Am Soc Nephrol 17:1688–1694CrossRefPubMed Waikar SS, Wald R, Chertow GM, Curhan GC, Winkelmayer WC, Liangos O et al (2006) Validity of international classification of diseases, ninth revision, clinical modification codes for acute renal failure. J Am Soc Nephrol 17:1688–1694CrossRefPubMed
Metadata
Title
Dose-related effects of metformin on acid–base balance and renal function in patients with diabetes who develop acute renal failure: a cross-sectional study
Authors
David Cucchiari
Manuel Alfredo Podestà
Elisa Merizzoli
Albania Calvetta
Emanuela Morenghi
Claudio Angelini
Claudio Ponticelli
Salvatore Badalamenti
Publication date
01-08-2016
Publisher
Springer Milan
Published in
Acta Diabetologica / Issue 4/2016
Print ISSN: 0940-5429
Electronic ISSN: 1432-5233
DOI
https://doi.org/10.1007/s00592-016-0836-2

Other articles of this Issue 4/2016

Acta Diabetologica 4/2016 Go to the issue