What type of lactic acidosis is associated with metformin in a patient with Chronic Kidney Disease (CKD) and diabetes?

Metformin-Associated Lactic Acidosis: Type B (Non-Hypoxic)

Metformin causes Type B lactic acidosis, characterized by elevated lactate (>5 mmol/L), anion gap acidosis without ketonuria, increased lactate:pyruvate ratio, and metformin plasma levels generally >5 mcg/mL. 1

Pathophysiologic Mechanism

Metformin-associated lactic acidosis (MALA) is fundamentally a Type B lactic acidosis, meaning it occurs without tissue hypoxia or hypoperfusion as the primary driver. 1 The mechanism differs from Type A lactic acidosis (seen in shock, sepsis, or severe hypoxemia) in several critical ways:

• Metformin decreases hepatic lactate uptake, preventing the liver from clearing lactate produced by peripheral tissues, leading to lactate accumulation in the bloodstream. 1
• Mitochondrial impairment at the cellular level causes ATP depletion, acceleration of glycolytic flux, increased glucose uptake, and generation of lactate that effluxes into circulation rather than being oxidized. 2
• The liver is the key organ for both metformin's antidiabetic effect and the development of lactic acidosis—liver failure combined with renal dysfunction creates the perfect storm for MALA. 2

Critical Context: When Type B Becomes Life-Threatening

In patients with CKD, metformin itself does not cause acute kidney injury—rather, AKI or severe CKD impairs metformin clearance, leading to drug accumulation and subsequent lactic acidosis. 3 This is a crucial distinction:

• Metformin is entirely renally excreted unchanged, making it completely dependent on kidney function for elimination. 3
• Most MALA episodes occur concurrent with acute illness where AKI contributes to reduced metformin clearance rather than metformin causing the kidney injury. 3
• Toxic metformin levels (>5 mcg/mL) accumulate when eGFR falls below 30 mL/min/1.73 m², creating the substrate for Type B lactic acidosis. 1

Clinical Presentation and Diagnostic Features

The presentation of MALA is often subtle initially but can rapidly progress:

• Early symptoms include malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence—these nonspecific symptoms can delay recognition. 1
• Severe acidosis manifests with hypotension and resistant bradyarrhythmias, along with Kussmaul's respiration. 1
• Laboratory hallmarks: pH often <7.0, lactate >5 mmol/L (often >10 mmol/L in severe cases), anion gap acidosis without ketonuria or ketonemia, and metformin levels >5 mcg/mL. 1, 4, 5

Risk Stratification by eGFR in CKD Patients

The risk of MALA increases exponentially as renal function declines:

• eGFR ≥60 mL/min/1.73 m²: Standard dosing safe, MALA risk negligible. 3
• eGFR 45-59 mL/min/1.73 m²: Continue current dose but increase monitoring frequency to every 3-6 months; MALA risk remains very low. 3
• eGFR 30-44 mL/min/1.73 m²: Reduce dose by 50% and monitor every 3-6 months; MALA risk begins to increase. 3, 1
• eGFR <30 mL/min/1.73 m²: Absolute contraindication—discontinue immediately; MALA risk becomes substantial and potentially fatal. 3, 1

Additional Risk Factors That Accelerate Type B Lactic Acidosis

Beyond renal impairment, several conditions can precipitate or worsen MALA:

• Liver disease, heart failure, or respiratory failure accelerate lactic acidosis development because they impair lactate clearance or increase lactate production. 6, 1
• Acute illnesses causing volume depletion (sepsis, severe diarrhea, vomiting) can trigger AKI and subsequent metformin accumulation. 3, 6
• Excessive alcohol intake potentiates metformin's effect on lactate metabolism. 1
• Age ≥65 years increases risk due to higher likelihood of hepatic, renal, or cardiac impairment. 1

Management of Suspected MALA

When MALA is suspected, immediate action is required:

• Discontinue metformin immediately and institute general supportive measures in a hospital setting. 1
• Prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable with clearance up to 170 mL/min under good hemodynamic conditions). 1
• Hemodialysis provides both symptomatic and etiological treatment by eliminating lactate and metformin, and has often resulted in reversal of symptoms and complete recovery. 1, 2
• Intravenous fluids and bicarbonate infusion may be used as temporizing measures while arranging hemodialysis. 5, 7

Critical Pitfall to Avoid

The mortality associated with MALA is not from metformin itself but from the underlying acute illness that precipitated the event. 2 Direct metformin-related mortality is close to zero when recognized and treated appropriately with hemodialysis. 2 However, delayed recognition or failure to initiate hemodialysis can result in death from severe metabolic acidosis and its cardiovascular consequences. 4, 7, 8