What is the risk of lactic acidosis in Metformin (Glucophage) therapy?

From the Guidelines

The risk of lactic acidosis in Metformin (Glucophage) therapy is low, but it can be increased in patients with certain conditions, such as chronic kidney disease (CKD), acute kidney injury (AKI), or other acute illnesses that contribute to reduced metformin clearance 1.

Key Factors Influencing Lactic Acidosis Risk

• eGFR: Metformin is recommended for use in most patients with T2D and CKD who have eGFR ≥30 ml/min/1.73 m², although careful patient selection and downward dose adjustment based on eGFR is recommended 1.
• Dose Adjustment: The dose of metformin should be reduced to 1000 mg daily in patients with eGFR between 30 and 44 ml/min/1.73 m², and a reduction should also be considered in patients with eGFR of 45–59 ml/min/1.73 m² if they have a comorbidity that places them at increased risk of lactic acidosis due to hypoperfusion and hypoxemia 1.
• Monitoring: eGFR should be monitored at least annually in patients with CKD, with the recommended frequency of monitoring increased to every 3–6 months once eGFR falls <60 ml/min/1.73 m² 1.

Clinical Considerations

• Metformin should be discontinued in patients presenting with acute conditions associated with lactic acidosis, such as cardiogenic or distributive shock 1.
• Lactate concentrations should be measured in fragile patients and metformin should be withdrawn if increased lactate concentrations are apparent 1.
• Metformin should also be discontinued in patients at risk for lactic acidosis (ie, acute kidney injury, hypoxia, shock) or before an iodinated contrast imaging procedure in patients with reduced eGFR (<60 mL/min per 1.73 m²), a history of liver disease, alcoholism, acute heart failure, or in those receiving intra-arterial contrast 1.

From the Research

Risk of Lactic Acidosis in Metformin Therapy

The risk of lactic acidosis in metformin therapy is a significant concern, particularly in patients with underlying kidney disease or other risk factors 2, 3, 4, 5, 6.

• Metformin increases plasma lactate levels in a plasma concentration-dependent manner by inhibiting mitochondrial respiration predominantly in the liver 2.
• Elevated plasma metformin concentrations, as occur in individuals with renal impairment, and a secondary event or condition that further disrupts lactate production or clearance, are typically necessary to cause metformin-associated lactic acidosis (MALA) 2.
• The reported incidence of lactic acidosis in clinical practice has proved to be very low, with less than 10 cases per 100,000 patient-years 2.
• Several studies suggest that current renal function cutoffs for metformin are too conservative, thus depriving a substantial number of type 2 diabetes patients from the potential benefit of metformin therapy 2, 3.

Incidence and Management of Lactic Acidosis

• Lactic acidosis associated with metformin treatment is a rare but important adverse event, and unraveling the problem is critical 3.
• The relationship between metformin and lactic acidosis is complex, since use of the drug may be causal, co-responsible, or coincidental 3.
• Haemodialysis should systematically be performed in severe forms of lactic acidosis, since it provides both symptomatic and aetiological treatment (by eliminating lactate and metformin) 3.
• Almost all cases of metformin-associated lactic acidosis reviewed presented with independent risk factors for lactic acidosis, supporting the suggestion that metformin plays a contributory role 4.

Prevention and Awareness

• The prescribed metformin dose exceeded published guidelines in 60% of cases in patients with impaired kidney function 4.
• Metformin steady-state plasma concentrations prior to admission were predicted to be below the proposed upper limit of the therapeutic range of 5 mg/L 4.
• Awareness of metformin-associated lactic acidosis among patients and clinicians is insufficient, resulting in many patients continuing metformin in situations where there is an increased risk of developing MALA 6.
• Temporarily discontinuing metformin in situations where the risk of lactic acidosis is increased, such as severe infection, dehydration, and acute kidney insufficiency, is recommended 6.