What causes lactic acidosis?

From the Guidelines

Lactic acidosis is primarily caused by metformin use in patients with risk factors such as significant renal impairment, liver failure, or conditions leading to anaerobic metabolism, as evidenced by a recent study showing an adjusted hazard ratio of 4.46 for lactic acidosis in patients with type 2 diabetes and COVID-19 taking metformin 1.

Causes of Lactic Acidosis

The causes of lactic acidosis can be broadly categorized into two types: type A, which occurs due to tissue hypoxia, and type B, which happens without tissue hypoxia. Key factors that contribute to lactic acidosis include:

• Tissue hypoxia, as seen in shock, severe heart failure, sepsis, and respiratory failure
• Metformin use, especially in patients with significant renal impairment (eGFR < 30 mL/min per 1.73 m²) or liver disease 1
• Liver disease, which reduces lactate clearance
• Medications other than metformin, such as nucleoside reverse transcriptase inhibitors and propofol
• Alcohol abuse
• Diabetes mellitus
• Malignancies
• Certain inborn errors of metabolism
• Seizures
• Excessive exercise
• Thiamine deficiency

Mechanism and Treatment

The underlying mechanism of lactic acidosis involves cells switching to anaerobic glycolysis when oxygen is insufficient, producing lactic acid as a byproduct. Treatment should focus on addressing the underlying cause while supporting vital functions. In the case of metformin-induced lactic acidosis, discontinuation of metformin is recommended, especially in patients at risk for lactic acidosis or with increased lactate concentrations 1. Additionally, dose reduction is advised if the eGFR is 30–45 mL/min per 1.73 m². Lactate concentrations should be measured in fragile patients, and metformin should be withdrawn if increased lactate concentrations are apparent.

From the FDA Drug Label

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal impairment — The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment 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.

Lactic acidosis causes include:

• Renal impairment: Significant renal impairment can increase the risk of metformin accumulation and lactic acidosis.
• Drug interactions: Certain drugs can increase the risk of lactic acidosis, such as those that impair renal function or interfere with acid-base balance.
• Age 65 or greater: Elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment, which can increase the risk of lactic acidosis.
• Radiologic studies with contrast: Administration of intravascular iodinated contrast agents can 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 can increase the risk for volume depletion, hypotension, and renal impairment.
• Hypoxic states: Conditions such as acute congestive heart failure, cardiovascular collapse, acute myocardial infarction, sepsis, and other conditions associated with hypoxemia can increase the risk of lactic acidosis.
• Excessive alcohol intake: Alcohol can potentiate the effect of metformin on lactate metabolism, increasing the risk of lactic acidosis.
• Hepatic impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. 2

From the Research

Causes of Lactic Acidosis

• Lactic acidosis can be caused by biguanide-associated therapy in diabetic patients with renal insufficiency 3
• Metformin, a common diabetes drug, may reduce lactate clearance by inhibiting mitochondrial oxidative phosphorylation, leading to metformin-associated lactic acidosis (MALA) 4
• Risk factors for MALA include renal impairment, excessive alcohol consumption, and certain medications such as histamine-2 receptor antagonists and ribociclib 4

Pathophysiology of Lactic Acidosis

• Metformin acts by enhancing the sensitivity to insulin by decreasing hepatic glucose production and increasing peripheral glucose use, but can lead to lactic acidosis in certain situations 5
• The relationship between metformin and lactic acidosis remains largely controversial, but can be distinguished into three situations with different prognoses: metformin-induced lactic acidosis, coincidental lactic acidosis, and lactic acidosis worsened by a precipitating factor leading to metformin accumulation 5

Risk Factors and Prevention

• The incidence of metformin-associated lactic acidosis is very low when contraindications and appropriate rules for prescribing this drug are respected 5
• Certain conditions, such as renal impairment, cirrhosis, sepsis, or hypoperfusion, can increase the risk of MALA 6
• Prevention of lactic acidosis requires respect of metformin contraindications and better education of physicians and patients for safe prescription 5
• The reported incidence of lactic acidosis in clinical practice has proved to be very low, but mortality rate for MALA approaches 50% 6