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Metformin-associated lactic acidosis in a patient with normal kidney function
diabetes research and clinical practice 96 (2012) e57–e58
Contents lists available at ScienceDirect
Diabetes Research and Clinical Practice journ al h omepage: www .elsevier.co m/lo cate/diabres
Brief report
Metformin-associated lactic acidosis in a patient with normal kidney function T.T. van Sloten, E. Pijpers, C.D.A. Stehouwer, M.C.G.J. Brouwers * Department of Internal Medicine, Divisions of General Internal Medicine and Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands
article info
abstract
Article history:
The existence of metformin-induced lactic acidosis has been questioned, in particular in the
Received 13 February 2011
absence of specific risk factors such as impaired renal function. This report describes the
Accepted 18 July 2011
presence of lactic acidosis in a patient with normal kidney function and normal doses of
Published on line 11 August 2011
metformin. Subsequent positive rechallenge with metformin confirms causality. # 2011 Elsevier Ireland Ltd. All rights reserved.
Keywords: Metformin Biguanides Treatment type 2 diabetes
1.
Presentation of case
An 84-year-old patient with type 2 diabetes mellitus (T2DM) was admitted to our hospital because of an acute prostatitis and delirium. His medical history revealed an anxiety disorder, hypertension and a transient ischaemic attack. There was no history of renal, hepatic, cardiac or pulmonary disease. His T2DM had been treated with metformin 500 mg twice daily (HbA1c: 6.5%, 48 mmol/mol). At presentation, his blood pressure was 130/76 mmHg, pulse 75 beats/min and respiratory rate 25 breaths/min with normal oxygen saturation while breathing ambient air. Physical examination demonstrated no abnormalities, besides a painful prostate during rectal examination. Laboratory measurements revealed a combined respiratory alkalosis and metabolic acidosis with increased lactate levels (Table 1). Liver and kidney function were normal (creatinine level on admission
101 mmol/L, creatinine clearance based on 24-h collection during admission 70 mL/min). Because there were no signs of tissue hypoperfusion, lactic acidosis due to metformin use was suspected. Metformin was discontinued and lactate levels reverted to normal after 48 h (Table 1). Because metformininduced lactic acidosis is uncommon in patients with normal kidney function, we rechallenged our patient with metformin. After a week, plasma lactate levels were again increased (4.4 mmol/L), and again normalized after subsequent withdrawal (Table 1).
2.
Discussion
The present case illustrates that metformin-associated lactic acidosis can occur in patients with normal kidney function. The positive rechallenge procedure implicates causality [1].
* Corresponding author at: Department of Internal Medicine, Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Tel.: +31 43 3882129; fax: +31 43 367 0916. E-mail address: [email protected] (M.C.G.J. Brouwers). 0168-8227/$ – see front matter # 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2011.07.021
e58
diabetes research and clinical practice 96 (2012) e57–e58
Table 1 – Clinical variables at baseline, withdrawal, rechallenge and subsequent withdrawal of metformin. Clinical parameters
Metformin
Withdrawal
Rechallenge
Withdrawal
Arterial pH Bicarbonate, mmol/L pCO2, kPa Lactate, mmol/L MAP, mmHg Creatinine, mmol/L Metformin, mg/La
7.50 15.0 2.6 5.9 94 101 2.1
7.55 24.2 3.8 1.1 86 101 0.6
7.42 18.4 3.9 4.4 95 65 1.3
7.47 23.7 4.5 1.4 108 76 <0.3
Abbreviations: MAP: mean arterial pressure, calculated as: (2 * diastolic blood pressure + systolic blood pressure)/3. Therapeutic levels of metformin generally do not exceed 4 mg/L.
a
At first sight, this observation appears in contrast with the recently reported meta-analysis by the Cochrane collaboration that pooled data from 347 studies with, in total, 70,490 patient years and concluded that there is no evidence for metformin-associated risk of life-threatening lactic acidemia. Plasma lactate levels – recorded in a subset of 220 patients with normal kidney function – revealed a trend towards increased levels after treatment compared to a nonmetformin group, albeit not clinically relevant (mean difference in plasma lactate: 0.12 mmol/L metformin versus nonmetformin, p = 0.07) [2]. The observed acidosis in our patient should therefore be regarded as an extreme response. Nevertheless, it is currently unclear how often such extreme responses occur. Given the extensive worldwide prescription of metformin, it is likely that a substantial proportion of metformin-treated patients display these unrecognized, high lactate levels. Furthermore, it is unknown if and how this metformin-associated lactic acidosis contributes to the development of life-threatening lactic acidemia in co-morbid conditions, such as systemic hypoperfusion (e.g. septic shock). Biological explanations for the extreme lactate response could be offered by genetic variants in proteins that play a principal role in the pharmacokinetics of metformin, such as organic anion transporter 1 (OCT1), which facilitates the hepatic uptake of metformin [3,4]. Single nucleotide polymorphisms in OCT1 have been associated with plasma glucose levels [3]. It can be anticipated that gain of function variants in OCT1 are associated with high intracellular metformin levels and, therefore, with an increased vulnerability to develop lactic acidosis at apparently therapeutic plasma metformin concentrations [5].
In conclusion, the present case report demonstrates that metformin-treated patients with normal kidney function can also present with increased lactate levels, possibly because of a genetic susceptibility. Since it is not known if and how lactate levels will change concomitant to other co-morbid conditions, we decided to permanently withdraw metformin in our patient.
Conflict of interest The authors declare that they have no conflict of interest.
references
[1] Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000;356:1255–9. [2] Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2010;4:CD002967. [3] Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 2007;117:1422–31. [4] Boyle JG, Salt IP, McKay GA. Metformin action on AMPactivated protein kinase: a translational research approach to understanding a potential new therapeutic target. Diabet Med 2010;27:1097–106. [5] Wang DS, Kusuhara H, Kato Y, Jonker JW, Schinkel AH, Sugiyama Y. Involvement of organic cation transporter 1 in the lactic acidosis caused by metformin. Mol Pharmacol 2003;63:844–8.
Contents lists available at ScienceDirect
Diabetes Research and Clinical Practice journ al h omepage: www .elsevier.co m/lo cate/diabres
Brief report
Metformin-associated lactic acidosis in a patient with normal kidney function T.T. van Sloten, E. Pijpers, C.D.A. Stehouwer, M.C.G.J. Brouwers * Department of Internal Medicine, Divisions of General Internal Medicine and Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands
article info
abstract
Article history:
The existence of metformin-induced lactic acidosis has been questioned, in particular in the
Received 13 February 2011
absence of specific risk factors such as impaired renal function. This report describes the
Accepted 18 July 2011
presence of lactic acidosis in a patient with normal kidney function and normal doses of
Published on line 11 August 2011
metformin. Subsequent positive rechallenge with metformin confirms causality. # 2011 Elsevier Ireland Ltd. All rights reserved.
Keywords: Metformin Biguanides Treatment type 2 diabetes
1.
Presentation of case
An 84-year-old patient with type 2 diabetes mellitus (T2DM) was admitted to our hospital because of an acute prostatitis and delirium. His medical history revealed an anxiety disorder, hypertension and a transient ischaemic attack. There was no history of renal, hepatic, cardiac or pulmonary disease. His T2DM had been treated with metformin 500 mg twice daily (HbA1c: 6.5%, 48 mmol/mol). At presentation, his blood pressure was 130/76 mmHg, pulse 75 beats/min and respiratory rate 25 breaths/min with normal oxygen saturation while breathing ambient air. Physical examination demonstrated no abnormalities, besides a painful prostate during rectal examination. Laboratory measurements revealed a combined respiratory alkalosis and metabolic acidosis with increased lactate levels (Table 1). Liver and kidney function were normal (creatinine level on admission
101 mmol/L, creatinine clearance based on 24-h collection during admission 70 mL/min). Because there were no signs of tissue hypoperfusion, lactic acidosis due to metformin use was suspected. Metformin was discontinued and lactate levels reverted to normal after 48 h (Table 1). Because metformininduced lactic acidosis is uncommon in patients with normal kidney function, we rechallenged our patient with metformin. After a week, plasma lactate levels were again increased (4.4 mmol/L), and again normalized after subsequent withdrawal (Table 1).
2.
Discussion
The present case illustrates that metformin-associated lactic acidosis can occur in patients with normal kidney function. The positive rechallenge procedure implicates causality [1].
* Corresponding author at: Department of Internal Medicine, Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Tel.: +31 43 3882129; fax: +31 43 367 0916. E-mail address: [email protected] (M.C.G.J. Brouwers). 0168-8227/$ – see front matter # 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2011.07.021
e58
diabetes research and clinical practice 96 (2012) e57–e58
Table 1 – Clinical variables at baseline, withdrawal, rechallenge and subsequent withdrawal of metformin. Clinical parameters
Metformin
Withdrawal
Rechallenge
Withdrawal
Arterial pH Bicarbonate, mmol/L pCO2, kPa Lactate, mmol/L MAP, mmHg Creatinine, mmol/L Metformin, mg/La
7.50 15.0 2.6 5.9 94 101 2.1
7.55 24.2 3.8 1.1 86 101 0.6
7.42 18.4 3.9 4.4 95 65 1.3
7.47 23.7 4.5 1.4 108 76 <0.3
Abbreviations: MAP: mean arterial pressure, calculated as: (2 * diastolic blood pressure + systolic blood pressure)/3. Therapeutic levels of metformin generally do not exceed 4 mg/L.
a
At first sight, this observation appears in contrast with the recently reported meta-analysis by the Cochrane collaboration that pooled data from 347 studies with, in total, 70,490 patient years and concluded that there is no evidence for metformin-associated risk of life-threatening lactic acidemia. Plasma lactate levels – recorded in a subset of 220 patients with normal kidney function – revealed a trend towards increased levels after treatment compared to a nonmetformin group, albeit not clinically relevant (mean difference in plasma lactate: 0.12 mmol/L metformin versus nonmetformin, p = 0.07) [2]. The observed acidosis in our patient should therefore be regarded as an extreme response. Nevertheless, it is currently unclear how often such extreme responses occur. Given the extensive worldwide prescription of metformin, it is likely that a substantial proportion of metformin-treated patients display these unrecognized, high lactate levels. Furthermore, it is unknown if and how this metformin-associated lactic acidosis contributes to the development of life-threatening lactic acidemia in co-morbid conditions, such as systemic hypoperfusion (e.g. septic shock). Biological explanations for the extreme lactate response could be offered by genetic variants in proteins that play a principal role in the pharmacokinetics of metformin, such as organic anion transporter 1 (OCT1), which facilitates the hepatic uptake of metformin [3,4]. Single nucleotide polymorphisms in OCT1 have been associated with plasma glucose levels [3]. It can be anticipated that gain of function variants in OCT1 are associated with high intracellular metformin levels and, therefore, with an increased vulnerability to develop lactic acidosis at apparently therapeutic plasma metformin concentrations [5].
In conclusion, the present case report demonstrates that metformin-treated patients with normal kidney function can also present with increased lactate levels, possibly because of a genetic susceptibility. Since it is not known if and how lactate levels will change concomitant to other co-morbid conditions, we decided to permanently withdraw metformin in our patient.
Conflict of interest The authors declare that they have no conflict of interest.
references
[1] Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000;356:1255–9. [2] Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2010;4:CD002967. [3] Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 2007;117:1422–31. [4] Boyle JG, Salt IP, McKay GA. Metformin action on AMPactivated protein kinase: a translational research approach to understanding a potential new therapeutic target. Diabet Med 2010;27:1097–106. [5] Wang DS, Kusuhara H, Kato Y, Jonker JW, Schinkel AH, Sugiyama Y. Involvement of organic cation transporter 1 in the lactic acidosis caused by metformin. Mol Pharmacol 2003;63:844–8.