What are the risks and precautions associated with Metformin (Metformin) use, particularly in patients with impaired renal function?

From the Guidelines

Metformin should be used with caution in patients with impaired renal function, and the risk of lactic acidosis increases with conditions like liver disease, excessive alcohol intake, and heart failure. The use of metformin in patients with impaired renal function requires careful monitoring due to the increased risk of lactic acidosis, a rare but potentially fatal complication 1.

Key Considerations

• Metformin is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73m².
• Dose adjustments are necessary for those with eGFR between 30-45 mL/min/1.73m².
• For patients with moderate renal impairment (eGFR 45-59 mL/min/1.73m²), the maximum daily dose should be reduced to 1,000-1,500 mg, while those with eGFR 30-44 mL/min/1.73m² should not exceed 1,000 mg daily.
• Regular kidney function monitoring is essential, with assessments recommended at least annually for stable patients and more frequently for those at risk of worsening renal function.
• Metformin should be temporarily discontinued before procedures involving iodinated contrast media and in situations that may compromise renal function, such as dehydration, severe infection, or shock.

Patient Education

• Patients should be educated about the symptoms of lactic acidosis, including unusual muscle pain, difficulty breathing, unusual sleepiness, and stomach discomfort.
• Patients should be instructed to seek immediate medical attention if these symptoms occur.

Comorbidities

• The risk of lactic acidosis increases with other conditions like liver disease, excessive alcohol intake, and heart failure, so these comorbidities require additional caution when prescribing metformin 1. According to the most recent and highest quality study, metformin can be used safely in patients with estimated glomerular filtration rate ≥30 mL/min/1.73 m², but it is contraindicated in patients with advanced renal insufficiency 1.

From the FDA Drug Label

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis Metformin associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

Metoformin can induce lactic acidosis, especially in patients with impaired renal function. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney.

• Key risk factors for metformin-associated lactic acidosis include:
  • Renal impairment
  • Age 65 or greater
  • Radiologic studies with contrast
  • Surgery and other procedures
  • Hypoxic states
  • Excessive alcohol intake
  • Hepatic impairment 2

From the Research

Risks and Precautions of Metformin Use

• Metformin is associated with a rare but potentially life-threatening complication known as metformin-associated lactic acidosis (MALA) 3, 4, 5, 6, 7.
• The risk of lactic acidosis is increased in patients with impaired renal function, as metformin is primarily cleared by the kidneys 4, 5.
• Other risk factors for MALA include liver disease, heart failure, and other metabolic disturbances 5, 6.
• The incidence of lactic acidosis in clinical practice has been reported to be very low, with less than 10 cases per 100,000 patient-years 5.

Management and Prevention of Lactic Acidosis

• Management of MALA is primarily supportive, with aggressive interventions including decontamination and extracorporeal treatments such as continuous renal replacement therapy (CRRT) to reverse acidosis and clear metformin metabolites 4, 6.
• Prevention is a key factor, and patients should be aware that discontinuation of metformin for a limited time does not affect their health, but it may avoid a serious, potentially fatal adverse event 4.
• Early identification and initiation of extracorporeal treatment are crucial in managing severe metabolic acidosis and improving patient outcomes 6.

Contraintications and Warnings

• Metformin has been contraindicated in moderate and severe renal impairment since its FDA approval, to minimize the potential for toxic metformin levels and MALA 5.
• However, some studies suggest that current renal function cutoffs for metformin may be too conservative, and that metformin may be safe for use in patients with mild to moderate renal impairment 5.
• Patients with diabetes, particularly those with renal impairment or undergoing procedures that may exacerbate kidney injury, should be carefully monitored and managed to minimize the risk of MALA 6, 7.