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Metabolic Effects of Metformin in Patients with Acute Renal Failure

Metformin use has been associated with significant disturbances in acid-base balance.

Metformin remains the first-line therapy for majority of patients with type 2 diabetes mellitus. Its metabolic effects have provided great support for its use in diabetes management. However, risks of renal impairment and lactic acidosis have always warranted close monitoring in patients with predisposing factors to these events. In fact, lactic acidosis has been associated with renal impairment. Metformin is not metabolized in the liver and is excreted by active tubular secretion.

The risk of developing lactic acidosis greatly depends on the magnitude of each patient’s renal impairment and their age. Nonetheless, these studies fail to take into consideration those patients with renal failure. The majority of trials out there exclude patients with renal defects due to its nephrotoxic potential. The nephrotoxicity of increased levels of metformin relies on its effect on renal mitochondrial activity. Previous studies have demonstrated that therapeutic doses of metformin are not associated with risk of lactic acidosis. Renal mitochondrial dysfunction can lead to tubular cell ischemia and increased lactic acid production. Hence, those patients with renal impairment will warrant closer monitoring and dose optimization strategies to prevent these complications while obtaining optimal glucose control. Recently, renal dose adjustments changed. Now patients are to be monitored based on glomerular filtration rate and not serum creatinine for metformin therapy.

A recent study conducted by David Cucchiari and colleagues evaluated the dose-related effects of metformin on acid-base balance in patients with diabetes who develop acute renal failure. In this cross-sectional study, 126 patients were included, of which 74 were taking metformin and 52 were taking insulin, other oral antidiabetic drugs, or both. All patients had type 2 diabetes and presented to the emergency department with acute kidney failure. Those patients who had type 1 diabetes and chronic kidney disease were excluded. The study aimed to understand the occurrence of acidosis and lactic acidosis, to asses if metformin use and various doses of the drug influenced pH and lactate levels despite renal function. In addition, it sought to understand the influence of metformin on renal function despite other causes, and the influence of metformin on the need for hemodialysis and hospital-survival.

Results from the analysis showed that acidosis and lactic acidosis occurred more frequently in those patients taking metformin with a median dose of 1500 mg (p=0.0491 for acidosis and p<0.001 for lactic acidosis). Doses of greater than 1000 mg per day tended to increase lactate levels (p<0.001). However, the effect on pH became significant only in those patients taking more than 2000 mg per day (p= 0.009).  Multivariate analysis showed an independent effect of metformin on pH and lactate levels when taking into consideration other variables for these effects. Furthermore, it was also seen that renal function was worse in those patients who presented to the emergency department and were on a metformin regimen with higher doses showing elevated serum creatinine levels (p=0.003; 1000 mg-2000mg per day vs. p<0.001 for 2000-3000 mg per day). The need for hemodialysis and hospital-survival did not show any statistical difference.

In conclusion, there is a strong association between metformin use and pH and lactate levels.  Acid-base balance appears to be affected greatly by the use of metformin (pH 7.31 + 0.16) when compared to the global population (pH 7.35 + 0.15) (p=0.008). These findings highlight the need for close monitoring of renal function especially in those who may have precipitating factors for acute renal failure. Those patients with renal hypoperfusion can be at great risk for kidney damage secondary to tissue hypoxia. The findings of this trial can help further understand the nature of this relationship, but from a prospective point of view in future research efforts. The retrospective nature of this cross-sectional study did not take into consideration metformin plasma levels and the pharmacokinetics properties in the event of acute renal failure. Even though, multiple variables for worsening kidney function were taken into consideration, further evaluation should be done to understand how these multiple variables can potentially contribute to the metabolic effects observed.

Practice Pearls:

  • The nephrotoxic nature of metformin is hypothesized to be through renal mitochondrial dysfunction.
  • The risk of lactic acidosis increases with higher doses of metformin (>2000 mg/day), independent of baseline renal function.
  • In the setting of acute renal function, metformin should be stopped until normal function is restored.

Researched and prepared by Pablo A. Marrero-Núñez – USF College of Pharmacy Student Delegate –  Doctor of Pharmacy Candidate 2017 – University of South Florida – College of Pharmacy

References:

Cucchiari, David, Manuel Alfredo Podestà, Elisa Merizzoli, Albania Calvetta, Emanuela Morenghi, Claudio Angelini, Claudio Ponticelli, and Salvatore Badalamenti. “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.” Acta Diabetol Acta Diabetologica 53.4 (2016): 551-58. Web.

Carlson, Nicholas, Kristine Hommel, Jonas Bjerring Olesen, Thomas Alexander Gerds, Anne-Merete Soja, Tina Vilsbøll, Anne-Lise Kamper, Christian Torp-Pedersen, and Gunnar Gislason. “Metformin-associated Risk of Acute Dialysis in Patients with Type 2 Diabetes: A Nationwide Cohort Study.” Diabetes Obes Metab Diabetes, Obesity and Metabolism (2016): n. pag. Web.