What Is Lactic Acidosis?
Acidosis is a condition in which there is an excess of acid in the body fluids. It is often classified as either respiratory or metabolic. Lactic acidosis, a type of metabolic acidosis, is a buildup of lactic acid in the bloodstream. Lactic acid is normally produced by muscle cells and red blood cells during anaerobic metabolism (when the body breaks down carbohydrates for energy without enough oxygen). The liver and kidneys typically clear this lactate from the body. When these organs are impaired or lactate production is excessive, levels can rise dangerously.
The Connection Between Metformin and Acidosis
The connection between metformin and acidosis lies in the drug's mechanism of action, particularly at high concentrations. Metformin works by decreasing glucose production in the liver and increasing the body's sensitivity to insulin. At therapeutic doses in healthy individuals, this process is well-managed. However, at toxic, elevated levels, metformin can inhibit mitochondrial respiration in liver cells. This interference shifts the body's metabolic processes towards anaerobic pathways, leading to an increase in lactate production and a decrease in lactate clearance, causing a toxic accumulation. This chain of events is known as Metformin-Associated Lactic Acidosis, or MALA.
It is crucial to differentiate MALA from the severe lactic acidosis associated with the drug's predecessor, phenformin, which was withdrawn from the market due to a much higher incidence of the complication. MALA is significantly rarer and typically occurs only when there are underlying predisposing conditions that prevent the body from clearing the metformin properly.
Risk Factors for Metformin-Associated Lactic Acidosis (MALA)
While the general risk of MALA is extremely low, certain factors can increase a patient's vulnerability. Identifying these factors is key to safe metformin use and management. The primary risk factors involve any condition that compromises the body's ability to clear metformin or increases lactate production.
Key Health Conditions
- Kidney Impairment: This is the most significant risk factor. Metformin is excreted by the kidneys, so impaired kidney function allows the drug to accumulate to toxic levels. For this reason, doctors assess renal function (via eGFR) before and during treatment. Metformin is contraindicated in patients with severe renal impairment (eGFR below 30 mL/min/1.73 m2) and not recommended for initiation with an eGFR between 30 and 45 mL/min/1.73 m2.
- Liver Disease: A damaged liver cannot efficiently clear lactate from the body, leading to its accumulation. Excessive alcohol intake or underlying liver dysfunction, such as cirrhosis, significantly raises the risk of MALA.
- Heart Failure: Severe, acute congestive heart failure can lead to states of hypoxia (low oxygen) and poor tissue perfusion, both of which increase lactate production and can trigger acidosis.
- Hypoxic States: Any condition causing systemic hypoxia, such as severe respiratory failure, sepsis, or shock, increases the risk of lactic acidosis.
Other Contributing Factors
- Excessive Alcohol Intake: Consuming excessive alcohol potentiates the effect of metformin on lactate metabolism and increases the risk of both lactic acidosis and hypoglycemia.
- Advanced Age: Elderly patients are more likely to have age-related decline in kidney function, requiring more frequent renal function monitoring and potentially lower doses.
- Medical Procedures: Procedures like radiological studies using iodinated contrast or surgery can temporarily impair kidney function or cause hypoxic states. Metformin is often temporarily discontinued around the time of these procedures.
- Other Medications: Certain medications, including carbonic anhydrase inhibitors and some drugs that reduce metformin clearance, can increase MALA risk.
Recognizing the Symptoms of Lactic Acidosis
Early recognition of lactic acidosis is critical. The symptoms can be subtle and non-specific, often mimicking other illnesses. If you are taking metformin and experience any of the following, seek immediate medical attention:
- Gastrointestinal Distress: Nausea, vomiting, abdominal pain, or diarrhea.
- General Malaise: Feeling unusually weak, tired, or having a general feeling of discomfort.
- Muscle Symptoms: Unusual muscle pain or cramping.
- Respiratory Distress: Deep and rapid breathing (hyperpnea), or shortness of breath.
- Neurological Changes: Unusual sleepiness, confusion, or dizziness.
- Circulatory Changes: Feeling cold, especially in the arms and legs, or a slow and irregular heartbeat.
How Healthcare Providers Manage the Risk
To mitigate the risk of MALA, healthcare providers follow several protocols. First, a thorough assessment of a patient's medical history and kidney function (eGFR) is performed before prescribing metformin and monitored periodically throughout treatment. For those with reduced kidney function, a lower dose or alternative medication may be chosen.
Patients are counseled on risk-increasing behaviors, such as excessive alcohol consumption, and advised to stop metformin temporarily if they develop an acute illness involving dehydration or potential hypoxia. If MALA is suspected, the drug is immediately discontinued, and supportive measures, including hemodialysis, are often initiated to remove metformin and correct the acidosis. Hemodialysis is particularly effective for MALA and can lead to a good prognosis if implemented promptly.
Comparison of Metformin-Associated Lactic Acidosis (MALA) vs. Other Acidosis Types
| Feature | MALA | Diabetic Ketoacidosis (DKA) | Type A Lactic Acidosis |
|---|---|---|---|
| Primary Cause | Metformin accumulation, often in the setting of impaired organ function or hypoxia. | Uncontrolled Type 1 or Type 2 diabetes, leading to insulin deficiency and ketone buildup. | Inadequate tissue oxygenation (hypoxia) due to conditions like shock, sepsis, or heart failure. |
| Metabolic Profile | High anion gap metabolic acidosis with elevated lactate levels and elevated metformin levels. | High anion gap metabolic acidosis with high levels of blood glucose and ketones. | High anion gap metabolic acidosis with elevated lactate levels, often without metformin accumulation. |
| Key Laboratory Finding | Lactate levels > 5 mmol/L and typically elevated metformin plasma concentration (>5 mcg/mL). | Hyperglycemia (high blood sugar), ketonemia, and high anion gap. | Signs of circulatory or respiratory failure, and lactate elevation in line with hypoxia. |
| Treatment | Immediately discontinue metformin, institute supportive care, and perform hemodialysis if severe. | Insulin therapy, intravenous fluids, and electrolyte replacement. | Address underlying cause (e.g., sepsis), oxygen support, and supportive care. |
| Associated Condition | Severe kidney disease, liver disease, excessive alcohol intake. | Undiagnosed or uncontrolled diabetes. | Sepsis, shock, severe heart or lung failure. |
Conclusion: The Overall Safety of Metformin
Ultimately, for the vast majority of patients without significant predisposing conditions, metformin is a safe and effective medication for managing Type 2 diabetes. The incidence of metformin-associated lactic acidosis (MALA) is exceedingly rare, with studies showing rates significantly lower than those associated with its predecessor drug. When MALA does occur, it is almost always in the presence of severe underlying health problems, especially compromised kidney function, that lead to a toxic accumulation of the drug.
By ensuring regular kidney function monitoring, adhering to the prescribed dosage, and avoiding excessive alcohol, patients can use metformin with a high degree of safety. For those with established risk factors, such as severe renal or liver disease, alternative medications are often used. Awareness of the non-specific symptoms of acidosis is the most powerful tool for early detection and favorable outcomes. While the potential risk of acidosis warrants serious consideration, for most, the benefits of metformin in managing diabetes far outweigh this rare complication.
For more information on the guidelines and safety surrounding metformin use, consult with a healthcare professional or refer to authoritative resources like the FDA's prescribing information.
