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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2017  |  Volume : 28  |  Issue : 6  |  Page : 1356-1361
Lactate levels and risk of lactic acidosis with metformin in diabetic kidney disease patients


Department of Nephrology, Medical College, Thiruvananthapuram, Kerala, India

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Date of Web Publication18-Dec-2017
 

   Abstract 


Metformin as an oral antidiabetic drug (OAD) is not recommended in renal failure due to the presumed risk of lactic acidosis though it has advantages in cardiovascular protection with a low risk of hypoglycemia. Few studies have measured lactic acid blood levels in patients with diabetic kidney disease on metformin and demonstrated lactic acidosis. The aim of our study is to see if patients with diabetic kidney disease are at risk of elevated lactate blood levels and lactic acidosis. Lactate levels and blood pH were estimated in patients with type 2 diabetes mellitus receiving metformin in different stages of chronic kidney disease (CKD) and were compared with a similar group not receiving metformin. Patients with diabetic kidney disease, with estimated glomerular filtration rate <60 mL/min who were previously receiving metformin started in centers elsewhere and referred here were studied and compared with a similar group taking other OADs or insulin. Independent sample t-test or ANOVA were used to compare quantitative variables between groups. Pearson correlation was used to analyze association between quantitative variables and linear regression analysis and was employed to note the relationship between quantitative variables. Of 57 patients who received a mean dose of 1.134 grams of metformin, 33 (55.9%) were in stage 3, 16 (28.1%) in stage 4, and 8 (14%) in stage 5 CKD. Mean serum pH (P = 0.572), bicarbonate (P = 0.978), and plasma lactate (P = 0.449) levels in those taking and not taking metformin were comparable. There was no difference in the plasma lactate levels in different stages of CKD in the metformin group (P = 0.498) although there was significant correlation with metformin dose (P <0.05). Blood lactate levels were not elevated in patients with diabetic kidney disease at a daily dose of metformin <1 g.

How to cite this article:
Bipi P K, George J, Gomathy S, Gracious N, Kumar S, Mohandas M K. Lactate levels and risk of lactic acidosis with metformin in diabetic kidney disease patients. Saudi J Kidney Dis Transpl 2017;28:1356-61

How to cite this URL:
Bipi P K, George J, Gomathy S, Gracious N, Kumar S, Mohandas M K. Lactate levels and risk of lactic acidosis with metformin in diabetic kidney disease patients. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2019 Dec 5];28:1356-61. Available from: http://www.sjkdt.org/text.asp?2017/28/6/1356/220870



   Introduction Top


Of the oral antidiabetic (OAD) drugs, metformin has shown significant risk reduction for several diabetes-related end points, all-cause mortality, and death and has hence been recommended as the first drug to be used after diet, and exercise has failed to control blood sugars.[1] Unlike most OADs, there is a low risk of hypoglycemia with metformin when used in renal failure. Its low cost and being weight friendly are other advantages. However, there are concerns that its use in renal failure may cause increased metformin blood levels and lactic acidosis as the kidney is the main route of excretion of metformin.[2],[3] Although the U. S. Food and Drug Administration contraindicate metformin use in men and women with serum creatinine concentrations ≥1.5 and ≥1.4 mg/dL, respectively, restriction of metformin use based on creatinine cutoff alone has been questioned with suggestions that metformin could still be used with estimated glomerular filtration rate (eGFR) <45 mL/min and probably be stopped only when eGFR is <30 mL/min.[4],[5],[6]

As there is limited data on the lactate levels in patients with chronic kidney disease (CKD) receiving metformin, we estimated blood lactate levels in patients with an eGFR <60 mL/min receiving metformin.


   Subjects and Methods Top


All patients with diabetic kidney disease, with eGFR <60 mL/min (MDRD 4 variable equation) who were previously receiving metformin started at elsewhere centers and referred to our department for evaluation from January to December 2013 were studied (Group A). They were compared with a similar group taking other OADs or insulin (Group B). Those with recent worsening of renal function (serum creatinine rise of more than 0.3 mg/dL over a week), evidence of active infection, presence of peripheral vascular disease (evidenced by absent upper limb radial and ulnar pulsations and a positive Allens test which precluded upper limb arterial blood sampling), hepatic dysfunction, cardiac failure, and those receiving bicarbonate supplementation were excluded.

Arterial samples for blood gas analysis and venous samples for lactate and other biochemical parameters were sent at the first visit. Thereafter, patients on metformin were shifted to other OADs/insulin as recommended. Lactate levels were estimated by chemiluminescence method, and arterial blood gas was analyzed by COBAS B 121 machine.

At the first visit, biochemical parameters, arterial blood gas, and venous lactate levels were sent. Patients on metformin were thereafter shifted to other OADs/insulin as recommended. Chemiluminescence methods were used to estimate lactate levels while arterial blood gas samples were analyzed using a blood gas machine (COBAS B121).

Lactic acidosis was considered to be present if arterial lactate was more than 5 mmol/L with arterial blood pH <7.35. This study was approved by the institutional ethics committee.


   Statistical Analysis Top


Mean and standard deviation was used to describe quantitative variables and percentage distribution for qualitative variables. Independent sample t-test or ANOVA was used to compare quantitative variables between groups. Pearson correlation was used to analyze association between quantitative variables and linear regression analysis and was employed to note the relationship between quantitative variables. P <0.05 was considered significant.


   Results Top


Fifty-seven patients were included in the metformin group (Group A) and 54 in the non-metformin group (Group B). Both groups were comparable with regard to age, duration of diabetes mellitus, body mass index (BMI), and degree of renal failure [Table 1].
Table 1: Details of patients in each group.

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In Group A, eight patients received metformin at a dose of 500 mg daily, 38 patients 1 g/day, three patients 2 g/day, and two patients 3 g/day. The mean dose of metformin was 1.134 ± 0.37 g/day.

There was no significant difference in the arterial pH, serum bicarbonate, and serum lactate levels in both groups [Table 2]. Lactate levels in different stages of CKD in the metformin group were comparable [Table 3]. Correlation analysis did not reveal any significant correlation between lactate levels, duration of diabetes mellitus and eGFR. A significant correlation between the lactate levels and the metformin dose was seen with a dose of 500 mg of metformin per day being associated with a lactate level of 1 mmol/L while a lactate level of 1.5 mmol/L was seen with dose of 3 g/day [Table 4].
Table 2: Comparison of pH, bicarbonate, and lactate levels in metformin and non-metformin groups.

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Table 3: Comparison of lactate levels in metformin groups with different stages of CKD.

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Table 4: Correlation between lactate levels with metformin dose, duration of diabetes, and eGFR.

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   Discussion Top


Phenformin was the first biguanide to be introduced and was soon documented to be associated with lactic acidosis.[7] Metformin was subsequently introduced and was found to significantly control diabetes with notable benefits in cardiovascular survival.[1] Other notable advantages included low risk of hypoglycemia and cost. Metformin was associated with lower risk of mortality in patients with atherosclerosis with benefit seen even in patients with CKD with GFR of 30–60 mL/min/1.73 m2.[8] Despite these advantages, its use in renal failure was not advocated due to the presumed risk of lactic acidosis documented in a few case reports. Mechanisms attributed to metformin-induced lactic acidosis were shifting of redox potential from aerobic to anaerobic metabolism by inhibiting pyruvate dehydrogenase and inhibiting hepatic gluconeogenesis from lactate.[9],[10]

A review of these case reports however raised doubts regarding the conclusion of metformin being responsible for development of lactic acidosis and suggested that other causes, especially sepsis, cardiovascular causes, and hepatic events could have accounted for the lactic acidosis with the use of metformin being coincidental rather than causal.[11] Subsequent reviews also found no evidence that metformin was associated with an increased risk of lactic acidosis or increased levels of lactate compared to other OADs.[12] No significant difference in the incidence of lactic acidosis was seen when comparing metformin to sulfonylureas.[13]

Due to predominant renal excretion, the risk of metformin-induced lactic acidosis was considered to be higher in patients with CKD.[14] However, metformin was not associated with increased risk of acidosis, infection, and all-cause mortality when used with eGFR of 45–60 mL/min.[15]

We noted that the mean lactate levels in patients with CKD with and without metformin were higher compared to normal population. The higher lactate levels in non-metformin group could be attributed to the fact that kidneys play significant role in lactate metabolism and the decreased clearance being the main reason for the higher lactate levels.[16] Nevertheless, the levels were significantly lower than the lactic acidosis defining level of 5 mmol/L.

We did not note increased lactate levels even with GFR <15 mL/min though the numbers were few to make a definite conclusion. Our observations are in accordance with others who noted that lactate levels in Asian patients with type 2 diabetes on metformin with GFR <60, 60–90 and >90 mL/min were comparable.[17]

Blood metformin levels with standard dose of metformin may not be markedly elevated. The erythrocyte metformin levels were comparable in patients with stage 1 CKD and lower GFR (stages 2–5 CKD).[18] However, the dose of metformin used was lower in the higher stages of CKD. Studies have also revealed that although the metformin levels rise in patients with CKD, their absolute values are just 3% the levels found in patients with lactic acidosis. This would suggest that lactic acidosis due to standard doses of metformin is unlikely.[3] We, however, did not analyze blood or erythrocyte metformin levels. It has also been suggested that elevated plasma metformin levels alone may not cause lactic acidosis and often a secondary event like sepsis, hypoperfusion, or underlying cirrhosis of liver is needed.[19],[20]

Although we noted a significant correlation between lactate levels and metformin dose, none of our patients had lactate levels sufficient to diagnose lactic acidosis. Although patients included in our study did receive higher doses of metformin, the numbers were too small to draw significant conclusions on whether higher doses of metformin could be associated with lactic acidosis. Although a relation between metformin dose and lactic acidosis has not been proved,[21] it may be inferred from our observations that up to 1 g of metformin per day can be safely administered to patients with CKD, as it caused a lactate level of only 1.2 mmol/L which is significantly lower than the lactic acidosis defining level of 5 mmol/L. Whether a reduction in metformin dose can reduce the risk of lactic acidosis needs to be confirmed.[22]

Another limitation of the study is that patients included in the study were outpatients and were relatively stable. It is known that lactic acidosis can be precipitated by sepsis, acute worsening of renal function, cardiac or respiratory failure.[23] It would therefore appear prudent to avoid or discontinue the drug in such situations and both the treating doctor and the patient be sensitized to this fact to avoid the risk of lactic acidosis.

Recent studies have revealed many therapeutic benefits of metformin therapy. By its action on respiratory chain, metformin is associated with inhibitory effect on production of reactive oxygen species[24] and thus protect from ischemia-reperfusion injury and cell death.[25] Interestingly, alongside the various pleotropic effects of metformin such as prevention of hepatic steatosis and treatment of polycystic ovarian disease, the latest addition is its protective effect on diabetic nephropathy.[26]

Most of the OADs are associated with significant risk of hypoglycemia which becomes even more pronounced in patients with CKD and are hence not recommended in renal failure. Metformin has a low risk of hypoglycemia and it has to be considered whether this advantage outweighs the rare risk of lactic acidosis. Although dipeptidyl peptidase 4 inhibitors can be still used in renal failure, their cost remains a major limitation. Metformin could be an alternative OAD at least in the early stages of renal failure with significant cardiovascular and economic benefits.

Long-term prospective studies, with enrollment of patients from emergency department as well, may be required to categorically state whether the drug can be safely administered in CKD patients. Measurement of plasma and erythrocyte metformin levels and frequent monitoring of lactate levels could provide safety limits for use of metformin in CKD.[27] It has also been suggested that metformin is in fact the safest OAD in CKD[28] and there may be a need to liberalize dose reduction of metformin in CKD.[29] Given the presumed cardiovascular benefits of metformin, low propensity to cause hypoglycemia, and low cost, further studies on the use of metformin in different stages of diabetic nephropathy appear to be desirable. Our observation of lack of elevated lactic acid levels in patients with stable CKD along with provisions for frequent monitoring of pH, blood lactate and metformin levels should clear the ethical concerns for such studies undertaken in the future.


   Acknowledgment Top


We thank the residents of our center who participated in this study.

Conflict of interest: None declared.



 
   References Top

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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.  Back to cited text no. 12
    
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Bodmer M, Meier C, Krähenbühl S, Jick SS, Meier CR. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: A nested casecontrol analysis. Diabetes Care 2008;31:2086-91.  Back to cited text no. 13
    
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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: pii: e001076.  Back to cited text no. 15
    
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Briet C, Saraval-Gross M, Kajbaf F, et al. Erythrocyte metformin levels in patients with type 2 diabetes and varying severity of chronic kidney disease. Clin Kidney J 2012; 5:65-7.  Back to cited text no. 18
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Correspondence Address:
Jacob George
Professor and Head of Nephrology, Medical College, Thiruvananthapuram, Kerala
India
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DOI: 10.4103/1319-2442.220870

PMID: 29265047

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    Abstract
   Introduction
   Subjects and Methods
   Statistical Analysis
   Results
   Discussion
   Acknowledgment
    References
    Article Tables
 

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