From the Guidelines
Lactic acidosis is a rare but serious side effect of metformin use, which can occur when toxic levels of metformin accumulate, particularly in patients with chronic kidney disease (CKD) 1.
Causes of Lactic Acidosis
The causes of lactic acidosis can be divided into two main categories: Type A (associated with tissue hypoxia) and Type B (occurring without tissue hypoxia). Type A causes include:
- Shock (cardiogenic, hypovolemic, septic)
- Severe hypoxemia
- Severe anemia
- Carbon monoxide poisoning
- Severe exercise Type B causes include:
- Medications such as metformin 1
- Liver disease
- Kidney failure
- Malignancies (especially lymphomas and leukemias)
- Thiamine deficiency
- Mitochondrial disorders
- Inborn errors of metabolism
- D-lactic acidosis from short bowel syndrome
Pathophysiology and Treatment
The pathophysiology of lactic acidosis involves either increased lactate production due to tissue hypoxia forcing anaerobic metabolism, or decreased lactate clearance due to liver or kidney dysfunction 1. Treatment should focus on addressing the underlying cause while supporting vital functions and, in severe cases, may include sodium bicarbonate administration to temporarily correct the acidosis.
Medication-Related Lactic Acidosis
Metformin is a common cause of medication-related lactic acidosis, particularly in patients with CKD 1. The risk of lactic acidosis with metformin use is increased in patients with a serum creatinine (SCr) level of 1.5 mg/dL or higher in men, or 1.4 mg/dL or higher in women. However, the exact glomerular filtration rate (GFR) cutoff for metformin use to avoid lactic acidosis is controversial 1. The use of metformin should be reevaluated when the GFR is 45 mL/min/1.73 m2 and stopped when the GFR is 30 mL/min/1.73 m2 1.
From the FDA Drug Label
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. Drug interactions —The concomitant use of metformin hydrochloride tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation Age 65 or greater —The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Radiologic studies with contrast —Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Surgery and other procedures —Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. Hypoxic states —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) Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. Excessive alcohol intake —Alcohol potentiates the effect of metformin on lactate metabolism Hepatic impairment —Patients with hepatic impairment have developed cases of metformin- associated lactic acidosis.
The causes of lactic acidosis include:
- Renal impairment: The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment.
- Drug interactions: The concomitant use of metformin with specific drugs may increase the risk of metformin-associated lactic acidosis.
- Age 65 or greater: The risk of metformin-associated lactic acidosis increases with the patient's age.
- Radiologic studies with contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients may lead to an acute decrease in renal function and the occurrence of lactic acidosis.
- Surgery and other procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment.
- Hypoxic states: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure.
- Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia: These conditions have been associated with lactic acidosis and may cause prerenal azotemia.
- Excessive alcohol intake: Alcohol potentiates the effect of metformin on lactate metabolism.
- Hepatic impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis 2, 2.
From the Research
Causes of Lactic Acidosis
- Metformin-associated lactic acidosis (MALA) 3, 4, 5, 6: a rare but serious complication of metformin use, particularly in patients with renal impairment or those taking other medications that interact with metformin.
- Acute renal failure 3: can lead to lactic acidosis due to the accumulation of lactate and other acidic substances in the blood.
- Gastrointestinal fluid loss 3: can cause lactic acidosis by leading to dehydration and electrolyte imbalances.
- Sepsis 6: can cause lactic acidosis by leading to tissue hypoxia and increased lactate production.
- Diabetic ketoacidosis 6: can cause lactic acidosis by leading to increased lactate production and decreased lactate clearance.
- Excessive alcohol consumption 6: can cause lactic acidosis by interfering with lactate metabolism and leading to increased lactate production.
- Histamine-2 receptor antagonists 6: can increase the risk of lactic acidosis by reducing renal elimination of metformin.
- Ribociclib 6: can increase the risk of lactic acidosis by reducing renal elimination of metformin.
- Renal impairment 6: can increase the risk of lactic acidosis by reducing renal elimination of metformin.
Other Factors Contributing to Lactic Acidosis
- Liver dysfunction 4: can lead to impaired lactate clearance and contribute to lactic acidosis.
- Mitochondrial dysfunction 4: can lead to impaired aerobic metabolism of lactate and contribute to lactic acidosis.
- Angiotensin-converting enzyme inhibitors 3: can increase the risk of lactic acidosis by leading to decreased renal function and increased lactate production.