What medications can cause lactic acidosis in a patient with diabetes and chronic kidney disease (Impaired renal function)?

Medications That Cause Lactic Acidosis in Patients with Diabetes and Chronic Kidney Disease

Metformin is the primary medication that causes lactic acidosis in patients with diabetes and impaired renal function, and it must be discontinued when eGFR falls below 30 mL/min/1.73 m² 1, 2.

Primary Culprit: Metformin

Metformin is contraindicated when eGFR is less than 30 mL/min/1.73 m² due to the risk of metformin-associated lactic acidosis (MALA) 2. The drug is renally cleared, and accumulation occurs when kidney function is impaired, leading to toxic levels that can trigger fatal lactic acidosis 2, 3.

Mechanism of Metformin-Associated Lactic Acidosis

• Metformin decreases hepatic uptake of lactate, increasing blood lactate levels 2
• The drug is substantially excreted by the kidneys unchanged, making it entirely dependent on renal function for elimination 4, 2
• When eGFR declines, metformin accumulates to levels generally >5 mcg/mL, characterized by elevated blood lactate (>5 mmol/L) and anion gap acidosis 2
• Decreased kidney function significantly accelerates metformin accumulation and hastens lactic acidosis development 5

eGFR-Based Prescribing Thresholds

The FDA established clear thresholds in 2016 that supersede older creatinine-based restrictions 4:

• eGFR ≥60 mL/min/1.73 m²: Standard dosing permitted 4
• eGFR 45-59 mL/min/1.73 m²: Continue current dose but reassess benefit-risk; do not initiate new therapy 4
• eGFR 30-44 mL/min/1.73 m²: Reduce dose by 50%; do not initiate new therapy 4
• eGFR <30 mL/min/1.73 m²: Absolute contraindication—discontinue immediately 4, 2

High-Risk Clinical Scenarios Requiring Metformin Discontinuation

Beyond chronic kidney disease, several acute conditions dramatically increase lactic acidosis risk and mandate temporary or permanent metformin discontinuation 1, 2:

• Radiocontrast procedures: Stop metformin 48 hours before procedures when eGFR is 30-60 mL/min/1.73 m², or in patients with liver disease, alcoholism, or heart failure 1, 4
• Acute kidney injury risk: Temporarily discontinue during sepsis, fever, severe diarrhea, vomiting, dehydration, or any hospitalization where AKI risk is elevated 4, 6
• Hypoxic states: Discontinue in acute congestive heart failure, cardiovascular collapse, acute myocardial infarction, or sepsis 2
• Hepatic impairment: Avoid use in patients with clinical or laboratory evidence of hepatic disease due to impaired lactate clearance 2
• Surgical procedures: Temporarily discontinue when food and fluids are restricted due to volume depletion and hypotension risk 2

Other Medications That Increase Lactic Acidosis Risk

NSAIDs and Nephrotoxic Agents

Stop nonsteroidal anti-inflammatory agents, aminoglycosides, and amphotericin B 48 hours before radiocontrast procedures 1. These drugs increase the risk of acute kidney injury, which impairs metformin clearance and precipitates lactic acidosis 3.

Drugs That Impair Metformin Clearance

Several medications interfere with renal tubular transport systems (OCT2/MATE inhibitors) and increase systemic metformin exposure 2:

• Ranolazine, vandetanib, dolutegravir, and cimetidine: Consider more frequent monitoring when used concomitantly with metformin 2
• These drugs can increase metformin plasma levels and elevate lactic acidosis risk even when eGFR appears adequate 2

Carbonic Anhydrase Inhibitors

Topiramate, zonisamide, acetazolamide, and dichlorphenamide frequently cause metabolic acidosis and may increase lactic acidosis risk when combined with metformin 2. Consider more frequent monitoring of acid-base status in patients taking these medications 2.

Alcohol

Alcohol potentiates metformin's effect on lactate metabolism 2. Patients should be warned against excessive alcohol intake while receiving metformin, as alcohol is known to increase lactic acidosis risk 2.

Clinical Recognition and Management

Presenting Symptoms of MALA

Initial symptoms are often nonspecific and include 2, 7:

• Malaise, myalgias, abdominal pain
• Respiratory distress or increased somnolence
• Nausea, vomiting, disorientation
• Hypotension and resistant bradyarrhythmias in severe cases

Diagnostic Criteria

MALA is characterized by 2, 3:

• Elevated blood lactate >5 mmol/L
• Anion gap acidosis (without ketonuria or ketonemia)
• Increased lactate:pyruvate ratio
• Metformin plasma levels generally >5 mcg/mL

Emergency Management

Prompt hemodialysis is recommended to correct acidosis and remove accumulated metformin 2. Metformin is dialyzable with clearance up to 170 mL/min under good hemodynamic conditions 2. Continuous venovenous hemodiafiltration (CVVHDF) has advantages over intermittent hemodialysis by correcting acidosis without risk of hypernatremia or fluid overload 3.

Critical Pitfalls to Avoid

• Using serum creatinine alone rather than eGFR: This leads to inappropriate continuation of metformin, especially in elderly or small-statured patients 4
• Failing to temporarily discontinue during acute illness: The "sick day rule" requires stopping metformin during any acute illness affecting kidney function 6, 5
• Continuing metformin during contrast procedures: Always hold metformin before iodinated contrast in at-risk patients and re-evaluate eGFR 48 hours post-procedure 4, 2
• Ignoring drug interactions: OCT2/MATE inhibitors and carbonic anhydrase inhibitors significantly increase MALA risk 2

Evidence Quality Note

The absolute incidence of lactic acidosis with metformin is extremely low (3-10 cases per 100,000 patient-years), similar to background rates in the diabetes population 8, 9. However, when MALA occurs in the setting of severe renal impairment, mortality is substantial 5, 7. The FDA label warnings and KDOQI guidelines represent the highest quality evidence and should guide prescribing decisions 1, 2.