Safety and Effectiveness of Metformin for Patients with Reduced Renal Function

The primary safety concern for metformin in patients with impaired renal function is its ability to cause lactic acidosis. 

Metformin, the most commonly prescribed medication for the treatment of diabetes type 2, has many benefits that make it a first-line therapy option. Those benefits include cardiovascular protection, low risk of hypoglycemia, effectiveness in lowering glucose, and low cost. However, metformin’s primary safety concern is its ability to cause lactic acidosis, which was why other drugs in this class were withdrawn from the market. While metformin can cause lactic acidosis, the risk is very low and it was allowed to be reintroduced to the market in 1995. Although the overall risk for causing lactic acidosis is low, the risk potential still poses a significant problem for patients with chronic kidney disease. Studies that have evaluated this potential risk in CKD patients are “The long-term effects of Metformin on patients with type 2 diabetes 2020” and “Metformin doses to ensure efficacy and safety in patients with reduced kidney function.”  

When metformin was reintroduced into the US market in 1995, it came with a warning of its contraindication in patients with impaired renal function for the potential to cause the risk of lactic acidosis. In 2016 the warnings were revised, and metformin was permitted based on categorized eGFR measurements.  Before 2014 no meta-analysis was done to provide the information needed on the safety and efficacy of metformin in patients with impaired renal function. Therefore, this study was performed for a systematic review of metformin’s safety and effectiveness in impaired kidney function using multiple studies done since the change in FDA labeling in 2016. This study searched PubMed and Embase databases from the inception of metformin to August 2020. Any study that reported original data on metformin with patient-centered outcomes in those patients with eGFR of less than 60 ml/min/1.73m2, what they defined as impaired renal function, was included. Post Hoc meta-analysis was performed for mortality, cardiovascular, and acidosis outcomes, the most studied and analyzed outcomes in the data. Secondary outcomes discussed in this meta-analysis were acute kidney injury, renal disease progression, acute dialysis, and hypoglycemia.  

The retrospective studies only examined overall mortality and cardiovascular events as the prospective studies weren’t powered to investigate this outcome. Metformin was associated with lower overall mortality with no evidence of mortality reduction with eGFR less than 30mL/min and no effect on patients with higher eGFR values. This finding suggests a mortality benefit in patients without advanced renal disease but no impact on patients with higher functioning renal. Lactic acidosis results were consistent with former research in that there was no evidence of increased risk with metformin use at eGFR 30mL/min and greater. Prospective studies showed possible safe use of metformin in patients with eGFR’s less than 30mL/min but showed high rates of subclinical elevation in lactic acid rates in patients. Retrospective studies showed no peak in acidosis rates in patients with normal eGFR levels but with higher rates of lactic acidosis in patients with lower eGFR levels. This study meta-analysis suggests a two-times increase in the risk in patients with lower eGFR levels.  

Data supports the safety and efficacy in patients with eGFR’s higher than 30mL/min and especially an eGFR 45mL/min and higher. The benefit and safety are questioned in an eGFR less than 30mL/min and should be avoided in patients that meet this criterion or approaching this cutoff. This would conclude that metformin should be avoided in patients with advanced renal dysfunction. These conclusions would support data consistent with current FDA guidelines on metformin use. More prospective studies should be done to evaluate the use of metformin in patients with more advanced renal disease, and also more studies evaluating its mortality benefit in patients with normal eGFR above 60mL/min. 

Practice Pearls: 

• Metformin is the commonly most prescribed first-line treatment in patients with type 2 diabetes. 
• Metformin’s use can be associated with increased safety and efficacy in patients without advanced renal disease, with benefits ranging for glucose-lowering and cardiovascular protection. 
• More studies should be done to continue to assess the harm and potential to cause lactic acidosis in patients with impaired renal function. 

Orloff, J,  Min, JY,  Mushlin, A,  Flory, J.  Safety and effectiveness of metformin in patients with reduced renal function: A systematic review. Diabetes Obes Metab.  2021; 23( 9): 2035– 2047. Safety and effectiveness of metformin in patients with reduced renal function: A systematic review. Diabetes-2020. Diabetes Care. 2020; 43(Suppl 1): S98- S110. 

Erica Hicks, PharmD Candidate 2022, South College School of Pharmacy