What medications can cause lactic acidosis (elevated lactate levels)?

From the Guidelines

Metformin is the most common medication associated with lactic acidosis, and its use should be avoided in patients at risk for lactic acidosis, such as those with anaerobic metabolism, impaired metformin clearance, or impaired lactic acid clearance. Other medications that can cause lactic acidosis include nucleoside reverse transcriptase inhibitors (NRTIs) like zidovine and stavudine used in HIV treatment, linezolid (an antibiotic), propofol (an anesthetic), and certain cancer drugs like sorafenib 1. Metformin-associated lactic acidosis typically occurs in patients with impaired kidney function, liver disease, or during acute illness, as these conditions reduce the body's ability to clear lactate. The mechanism involves inhibition of mitochondrial respiration, shifting metabolism toward anaerobic glycolysis which produces excess lactic acid. Alcohols like ethanol and methanol can also cause lactic acidosis through similar metabolic disruption.

Key Points to Consider

• Metformin should be discontinued if the estimated glomerular filtration rate (eGFR) is less than 30 mL/min per 1.73 m² 1.
• Lactate concentrations should be measured in fragile patients and metformin should be withdrawn if increased lactate concentrations are apparent 1.
• Other risk factors for experiencing lactic acidosis include obesity, being female, and prolonged use of NRTIs, although cases have been reported with risk factors being unknown 1.
• Symptoms of medication-induced lactic acidosis include nausea, vomiting, abdominal pain, rapid breathing, and confusion.
• Management involves discontinuing the offending medication, supporting vital functions, and sometimes using bicarbonate therapy for severe cases.

Prevention and Management

• Patients with kidney disease should have metformin doses adjusted or consider alternative medications to prevent this potentially life-threatening complication 1.
• Clinicians must first rely on other laboratory abnormalities plus symptoms when lactic acidosis is suspected, as routine monitoring of lactate level is not usually recommended 1.
• Measurement of lactate requires a standardized mode of sample handling, including prechilled fluoride-oxalate tubes, which should be transported immediately on ice to the laboratory and processed within 4 hours after collection 1.

From the FDA Drug Label

5 WARNINGS AND PRECAUTIONS

1. 1 Lactic Acidosis 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.

Medications that may cause Lactic Acidosis:

• Metformin: The primary medication associated with lactic acidosis, as described in the warning and precautions section of the drug label 2, 2. Key Risk Factors:
• Renal impairment
• Drug interactions (e.g., carbonic anhydrase inhibitors, drugs that reduce metformin clearance)
• Age 65 or greater
• Radiologic studies with contrast
• Alcohol consumption

Management:

• Discontinue metformin if lactic acidosis is suspected
• Prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin 2, 2.

From the Research

Medication Causing Lactic Acidosis

• Metformin is a medication that can cause lactic acidosis, particularly in patients with renal impairment 3, 4, 5, 6, 7.
• The risk of metformin-associated lactic acidosis (MALA) is increased in patients with chronic kidney disease, elderly patients, and those with other predisposing factors such as cirrhosis, sepsis, or hypoperfusion 4, 6.
• The incidence of MALA is rare, but the mortality rate is high, approaching 50% 4, 7.
• Symptoms of metformin-associated lactic acidosis are non-specific, and physicians should be aware of the potential risk of fatal lactic acidosis due to drug accumulation in patients with renal impairment 3.
• Guidelines for reducing or deprescribing metformin can be considered in older adults with chronic kidney disease to prevent morbidity, mortality, and adverse outcomes 6.

Patient Populations at Risk

• Elderly patients are at higher risk of developing MALA due to aging kidneys and decreased clearance of drugs 6.
• Patients with chronic kidney disease are at increased risk of developing MALA, particularly if they have acute kidney injury or other predisposing factors 4, 6.
• Patients with other medical conditions, such as cirrhosis, sepsis, or hypoperfusion, are also at increased risk of developing MALA 4.

Treatment and Prevention

• Aggressive treatment strategies, such as hemodialysis, peritoneal dialysis, continuous bicarbonate infusion, and tight glucose control, may be necessary to manage MALA 7.
• Physicians should be aware of the potential risk of MALA and take steps to prevent it, such as monitoring renal function and adjusting metformin doses accordingly 3, 4, 6.