What medications can increase lactate levels?

Medications That Can Increase Lactate Levels

Metformin is the most well-documented medication that can increase lactate levels, particularly in patients with renal impairment, hypoxic states, or other conditions that impair lactate clearance. 1, 2

Primary Medications That Increase Lactate

1. Metformin

• Mechanism: Inhibits mitochondrial respiration predominantly in the liver, leading to increased plasma lactate levels in a concentration-dependent manner 3
• Risk factors for lactic acidosis with metformin use:
  • Renal impairment (eGFR <45 mL/min/1.73 m²) 1
  • Hypoxic states (sepsis, heart failure, respiratory failure) 2
  • Hepatic impairment (impaired lactate clearance) 2
  • Excessive alcohol intake 2
  • Dehydration or volume depletion 1
  • Advanced age (>65 years) 2
  • Higher metformin doses (>2g daily) 4

2. Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

• Particularly older agents like stavudine, didanosine, and zidovudine
• Mechanism: Mitochondrial toxicity leading to impaired oxidative phosphorylation 5

Other Medications That May Increase Lactate

3. SGLT2 Inhibitors

• May indirectly increase lactate through euglycemic diabetic ketoacidosis, particularly in patients with poor food intake 1
• Examples: empagliflozin, canagliflozin, dapagliflozin

4. Beta-adrenergic agonists

• Increase glycolysis and lactate production
• Examples: epinephrine, albuterol, terbutaline

5. Propofol

• Can cause propofol infusion syndrome with lactic acidosis in high doses or prolonged use

6. Linezolid

• Inhibits mitochondrial protein synthesis, potentially leading to lactic acidosis with prolonged use

7. Alcohols and glycols

• Ethanol, methanol, ethylene glycol
• Metabolized to compounds that increase the anion gap and lactate

Clinical Management Considerations

Metformin Use Based on Renal Function

• eGFR ≥45 mL/min/1.73 m²: Safe to continue metformin 1
• eGFR 30-44 mL/min/1.73 m²: Dose reduction recommended; use with caution 1
• eGFR <30 mL/min/1.73 m²: Metformin is contraindicated 1, 2

Temporary Discontinuation of Metformin

Metformin should be temporarily discontinued in:

• Patients undergoing procedures with iodinated contrast 2
• Situations with risk of acute kidney injury 1
• Acute illness, surgery, or other conditions causing hypoxemia 1
• Severe infection or sepsis 1

Monitoring Recommendations

• Regular monitoring of renal function in all patients on metformin 2
• Consider lactate level monitoring in high-risk patients (elderly, multiple comorbidities) 1
• More frequent monitoring in patients with eGFR 30-45 mL/min/1.73 m² 1

Important Clinical Pitfalls

1. Overestimation of risk: Despite concerns, the actual incidence of metformin-associated lactic acidosis is very low (<10 cases per 100,000 patient-years) 3

2. Misattribution: Many cases of lactic acidosis in metformin users are due to underlying conditions rather than metformin itself 6

3. Inappropriate discontinuation: Discontinuing metformin unnecessarily may deprive patients of its cardiovascular and mortality benefits 1

4. Failure to recognize early signs: Symptoms of lactic acidosis (malaise, myalgias, respiratory distress, abdominal pain, somnolence) can be subtle and nonspecific 2

5. Inadequate dose adjustment: Failure to adjust metformin dose in patients with declining renal function increases risk 4