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Renal Disease Impact On Long-Term Metformin Use

Apr 18, 2020
Editor: Steve Freed, R.PH., CDE

Author: Deonna Andrews, PharmD Candidate 2020 of Florida Agricultural & Mechanical University College of Pharmacy and Pharmaceutical Sciences 

As we are all familiar with how metformin can impact patients with existing renal disease, researchers aimed to study how far the limitations can be pushed.  

Chronic kidney disease is well known to be caused by diabetes. As scientists have studied the disease for years and novel treatments can assist in the management of it, metformin is still considered a first-line treatment for type 2 diabetes. Metformin is not expensive, has excellent efficacy, is weight neutral, and has benefits regarding cardiovascular outcomes. However, if a patient has chronic kidney disease, metformin is not recommended as a first-line treatment due to the risk of lactic acidosis. Historically, the risk of this fatal adverse effect has resulted in the withdrawal of biguanide, phenformin, and buformin off the market. The purpose of this study was to assess the efficacy and safety of metformin in patients with type 2 diabetic kidney disease.  


Previous studies such as the Cochrane review reported a lack of evidence that metformin treatment increases the incidence of incidence of lactic acidosis compared with other antidiabetic drugs. Additionally, numerous recent studies found no difference between the number of lactic acidosis events between patients with chronic kidney disease who were using metformin and those using other antidiabetic drugs. Furthermore, there are not many studies that have estimated the long-term advantages of metformin use, and the results are controversial. Researchers of this study hypothesized that metformin administration to advanced chronic kidney disease patients can be beneficial in terms of all-cause mortality and incident end-stage renal disease and cannot increase the incidence of lactic acidosis.  

The study was a retrospective observational cohort study comprised of 10,682 patients with type 2 diabetes that were followed at the nephrology clinics of two tertiary hospitals in South Korea. Using de-identified patient data, researchers retrieved medical records inclusive of the patient’s date of birth, sex, body mass index, diagnostic codes, drug prescriptions, and laboratory results. Patients were excluded from the study if they had missing data such as serum creatinine levels, short follow-up periods, and who received renal replacement before or within 30 days of the first visit. Primary outcomes were determined by all-cause mortality and progression to end-stage renal disease. Drug-induced acidosis events identified secondary issues. A lactic acidosis event was defined as a serum lactate concentration >5.9 mmol/L and serum pH <7.36 simultaneously. As for statistical analysis, an X2 test was used for categorical variables, and an unpaired student t-test for continuous variables to compare the baseline characteristics. Categorical variables were reported as percentages and continuous variables as the mean standard deviations. To compare adverse events due to overdispersion, a negative binomial regression analysis was conducted. Also, multiple Cox proportional hazard models were used to calculate the hazard ratios, and 95% confidence intervals were used for all-cause mortality and renal outcomes.  

While analyzing the results, researchers found that all-cause mortality and incident end-stage renal disease were lower in the metformin group when referring to the multivariate Cox analysis. The two groups reported a significant differed baseline characteristic, which called for patient-specific mortality to be performed. Even with this, metformin usage was still associated with lower all-cause mortality with an adjusted hazard ratio of 0.65, 95% confidence interval 0.57 to 0.73, and a p-value <0.001. End-stage renal disease progression was reported with a hazard ratio of 0.67, 95% confidence interval 0.58 to 0.77, and p-value <0.001. There was only one event of metformin-associated lactic acidosis that was recorded. Finally, in both the original and patient-specific mortality groups, metformin usage did not increase the risk of lactic acidosis events from all causes.  

In conclusion, this retrospective study found metformin use decreased the risk of all-cause mortality and incident end-stage renal disease in patients with advanced chronic kidney disease, especially those with chronic kidney disease 3B. Also, metformin use did not increase the risk of lactic acidosis. Although these findings are promising, there are remaining biases after patient-specific mortality that warrant the need for further randomized controlled trials to change real-world practice.  

Practice Pearls: 

  • Metformin administration in patients with end-stage renal disease may not be as fatal as we thought. 
  • Metformin was found to have a significantly low risk of all-cause mortality and end-stage renal disease in patients with chronic kidney disease.  
  • More studies and further research need to be conducted to implement this into current guideline treatment.  


Kwon, Soie, et al. “The Long-Term Effects of Metformin on Patients With Type 2 Diabetic Kidney Disease.” Diabetes Care, Apr. 2020, p. dc190936., doi:10.2337/dc19-0936. 


Deonna Andrews, PharmD Candidate 2020 of Florida Agricultural & Mechanical University College of Pharmacy and Pharmaceutical Sciences 


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