Why does metformin cause lactic acidosis in patients with congestive heart failure (CHF)?

From the Guidelines

Metformin causes lactic acidosis in patients with congestive heart failure (CHF) primarily due to impaired drug clearance and altered tissue perfusion, and its use should be avoided in those with advanced renal insufficiency or hypoperfusion, hypoxemia, impaired hepatic function, or heart failure 1. The mechanisms underlying this association include decreased cardiac output leading to reduced renal perfusion, which impairs metformin elimination since the drug is primarily cleared by the kidneys. Additionally, the poor tissue perfusion characteristic of CHF results in increased anaerobic metabolism and lactate production. Metformin further contributes to lactate accumulation by inhibiting mitochondrial complex I in the electron transport chain, which decreases cellular respiration and promotes anaerobic glycolysis. The drug also reduces hepatic gluconeogenesis from lactate, impairing the liver's ability to clear lactate from the bloodstream. These mechanisms create a dangerous cycle where lactate accumulates while clearance mechanisms are compromised. According to the most recent guidelines, metformin may be used safely in individuals with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m², while lower doses may be used in those with an eGFR 30–45 mL/min/1.73 m² 1. However, it is crucial to monitor eGFR every 3 to 6 months in those at risk for decline in kidney function and to temporarily discontinue metformin before procedures that may compromise renal or liver function 1. Key considerations for the use of metformin in patients with CHF include:

• Careful monitoring of renal function and adjustment of the metformin dose accordingly
• Avoidance of metformin in patients with advanced renal insufficiency or those at risk for lactic acidosis
• Temporary discontinuation of metformin during hospitalizations or acute illnesses that may compromise renal or liver function
• Regular assessment of the risk-benefit ratio of metformin use in patients with CHF, taking into account the potential benefits of improved glycemic control and the risks of lactic acidosis 1.

From the FDA Drug Label

Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia)

Metformin can cause lactic acidosis in patients with congestive heart failure (CHF) due to the potential for hypoperfusion and hypoxemia in this setting, which may increase the risk of metformin accumulation and lactic acidosis.

• Key factors that contribute to this risk include:
  • Impaired renal function
  • Hemodynamic changes
  • Interference with acid-base balance
  • Increased metformin accumulation When such an event occurs, discontinuation of metformin is recommended 2.

From the Research

Metformin and Lactic Acidosis in Congestive Heart Failure

• Metformin is a commonly prescribed medication for type 2 diabetes, but it can cause lactic acidosis, a serious metabolic complication, especially in patients with congestive heart failure (CHF) 3, 4.
• The risk of lactic acidosis is increased in patients with CHF due to reduced renal function, which can lead to elevated plasma metformin concentrations 5, 6.
• Metformin-associated lactic acidosis (MALA) is a rare but potentially lethal complication, with a mortality rate approaching 50% 5, 7.
• The pathogenesis of MALA involves the inhibition of mitochondrial respiration, leading to increased lactate production and decreased lactate clearance 5, 7.

Risk Factors for Metformin-Associated Lactic Acidosis

• Renal impairment is a significant risk factor for MALA, as it reduces the elimination of metformin and increases the risk of toxic metformin levels 5, 6.
• Other risk factors include hepatic failure, cardiac failure, and excessive alcohol consumption, which can further disrupt lactate production or clearance 4, 6, 7.
• The use of certain medications, such as histamine-2 receptor antagonists and ribociclib, can also increase the risk of MALA by reducing renal elimination of metformin 7.

Diagnosis and Management of Metformin-Associated Lactic Acidosis

• MALA should be suspected in patients with high anion gap metabolic acidosis and lactate levels exceeding 5 mmol/L, especially in those with a history of metformin use 7.
• Treatment involves immediate cessation of metformin, supportive management, and addressing any underlying causes of lactic acidosis, such as sepsis or diabetic ketoacidosis 6, 7.
• Severe MALA may require extracorporeal removal of metformin using hemodialysis or continuous kidney replacement therapy 4, 7.