What is Metformin and How Does It Work?
Metformin is a first-line oral antihyperglycemic agent prescribed to manage type 2 diabetes [1.2.7]. Its primary function is to decrease glucose production in the liver (hepatic gluconeogenesis) and improve the body's sensitivity to insulin, allowing cells to utilize glucose more effectively [1.2.3]. It is favored for its efficacy, safety profile, and its ability to reduce mortality rates compared to other diabetes treatments [1.2.1]. A common side effect is gastrointestinal upset, while its most serious, though rare, potential side effect is lactic acidosis [1.2.7, 1.4.8].
Understanding Lactic Acidosis
Lactic acidosis is a form of metabolic acidosis characterized by the buildup of lactate in the bloodstream [1.6.3]. Lactate is a natural byproduct of anaerobic metabolism, the process cells use to generate energy without oxygen. Normally, the liver and kidneys clear excess lactate from the blood. However, if lactate production overwhelms the body's ability to clear it, or if clearance is impaired, blood pH can drop to dangerous levels [1.4.14]. This condition is not exclusive to metformin; it can be caused by various conditions like sepsis, shock, heart failure, and excessive alcohol use [1.4.2].
Symptoms are often nonspecific and can include malaise, muscle pain (myalgias), respiratory distress, unusual sleepiness, and abdominal pain [1.4.7]. If suspected, it is considered a medical emergency requiring immediate hospitalization [1.6.5].
The Link: How Metformin Can Contribute to Lactic Acidosis
Metformin-associated lactic acidosis (MALA) is a real but uncommon event [1.2.2]. The drug works in part by inhibiting mitochondrial respiratory chain complex 1. This can lead to a decrease in the liver's ability to clear lactate, causing it to accumulate [1.6.7]. Metformin itself is not metabolized and is excreted unchanged by the kidneys [1.4.4, 1.4.8].
Crucially, in patients with normal kidney function, this effect is clinically insignificant [1.2.1]. The risk becomes substantial only when metformin accumulates in the body, which primarily happens in the setting of significant renal impairment [1.4.7]. Therefore, MALA is almost always precipitated by an underlying condition that impairs drug clearance or independently causes lactate production [1.4.1, 1.2.2].
The True Incidence: A Rare Complication
Multiple large-scale studies and meta-analyses have concluded that when prescribed appropriately, metformin does not increase the risk of lactic acidosis compared to other diabetes treatments [1.2.1]. The estimated incidence is very low, ranging from approximately 3 to 10 cases per 100,000 patient-years [1.2.5]. The risk is comparable to the background rate of lactic acidosis in the diabetic population not taking metformin [1.2.2]. The danger arises when contraindications are ignored [1.2.5].
Major Risk Factors for MALA
The development of MALA is nearly always linked to one or more underlying conditions that compromise the body's ability to clear metformin or lactate. The FDA has issued a boxed warning highlighting these risks [1.4.7].
- Renal Impairment: This is the most critical risk factor [1.4.2]. Since metformin is cleared by the kidneys, reduced function leads to drug accumulation. The risk significantly increases when the estimated glomerular filtration rate (eGFR) falls below 30 mL/min/1.73 m², a level at which metformin is contraindicated [1.4.7].
- Acute Conditions: Situations like sepsis, acute heart failure, shock, dehydration, and major surgery can cause tissue hypoxia (lack of oxygen) and/or acute kidney injury, drastically increasing the risk of lactic acidosis [1.4.2, 1.4.7].
- Hepatic Impairment: Since the liver is a primary site for lactate clearance, severe liver disease can contribute to lactate buildup [1.4.14, 1.4.7].
- Age: Patients over 65 are more likely to have decreased renal function and other comorbidities, increasing their risk profile. More frequent monitoring of kidney function is recommended for this group [1.4.7].
- Radiological Studies with Contrast: Iodinated contrast agents used in procedures like CT scans can cause a temporary decrease in kidney function. It is recommended to temporarily stop metformin before such procedures in at-risk patients [1.4.7, 1.6.12].
- Excessive Alcohol Intake: Alcohol can potentiate metformin's effect on lactate metabolism and should be avoided in excess [1.4.7, 1.6.2].
Comparison of Patient Risk Profiles
| Risk Profile | Characteristics | Risk of MALA | Recommended Action |
|---|---|---|---|
| Low Risk | Normal kidney function (eGFR > 45), no other major risk factors. | Very Low | Continue metformin with routine monitoring [1.4.7]. |
| Moderate Risk | Mild to moderate kidney impairment (eGFR 30-45), elderly, or stable heart failure. | Increased | Assess benefit vs. risk; consider dose reduction; more frequent renal monitoring [1.4.7]. |
| High Risk | Severe renal impairment (eGFR < 30), acute illness (sepsis, shock), severe liver disease, excessive alcohol use. | Significant | Metformin is contraindicated or should be immediately discontinued [1.4.7, 1.6.11]. |
Prevention and Management
Prevention is the cornerstone of avoiding MALA. This involves careful patient selection and ongoing monitoring.
Key Prevention Strategies:
- Regular Kidney Function Monitoring: Obtain an eGFR before starting metformin and at least annually thereafter, or more frequently in those at risk for renal impairment [1.4.7].
- Patient Education: Patients should be educated on the symptoms of lactic acidosis and instructed to stop the drug and seek medical help if they occur [1.6.7].
- Temporary Discontinuation: Metformin should be temporarily stopped before surgery, iodinated contrast studies, or during acute illnesses that cause dehydration or hypoperfusion [1.6.12].
- Avoid Excessive Alcohol: Patients should be warned against heavy alcohol consumption [1.4.7].
If MALA is suspected, it is a medical emergency. Treatment involves stopping metformin immediately, providing supportive care in a hospital, and often requires prompt hemodialysis to correct the acidosis and remove the accumulated drug from the body [1.4.7, 1.6.5].
Conclusion
So, does metformin cause lactic acidosis? While it can contribute to the condition, the event is exceptionally rare in patients who are appropriately prescribed the medication. MALA is not typically caused by the drug in isolation but rather by its accumulation due to underlying risk factors, most notably renal impairment. For the vast majority of patients with type 2 diabetes, metformin remains a safe and effective medication when used according to clinical guidelines that account for kidney function and other health conditions.
Authoritative Link: FDA Metformin Prescribing Information
