What is the toxic dose of metformin (biguanide oral hypoglycemic)

Metformin Toxic Dose

Metformin overdoses involving ingestion of greater than 50 grams are considered toxic, though severe toxicity and lactic acidosis can occur at lower doses depending on renal function and clinical context. 1

Defining Toxic Exposure

• The FDA label documents that overdoses involving amounts greater than 50 grams have been reported, with lactic acidosis occurring in approximately 32% of metformin overdose cases 1
• The highest reported survival involved ingestion of 75-100 grams of metformin, resulting in a serum metformin concentration of 160 mcg/mL (therapeutic range is 1-2 mcg/mL), with a serum pH nadir of 6.59 and peak lactate of 40.0 mmol/L 2
• A meta-analysis of 242 cases found that only 23.6% involved acute ingestion, while 76.4% developed toxicity while on therapeutic doses due to accumulation from renal dysfunction 3

Serum Metformin Levels and Toxicity

• Therapeutic serum metformin concentration: 1-2 mcg/mL 2
• Toxic levels: >5 mcg/mL are generally associated with toxicity, though severe toxicity typically occurs at much higher levels 2
• Serum metformin levels of 160 mcg/mL have been survived with aggressive supportive care including hemodialysis 2

Clinical Context: Therapeutic Dose Toxicity

• The maximum recommended daily dose is 2,550 mg/day divided into multiple doses with meals 4
• Metformin must be discontinued when eGFR falls below 30 mL/min/1.73 m² because accumulation leads to toxic levels even at therapeutic dosing 5
• Dose reduction to 1,000 mg daily is required when eGFR is 30-44 mL/min/1.73 m² 5, 4
• Metformin use should be reviewed when eGFR is 30-44 mL/min/1.73 m² (GFR category G3b) 5

Metformin-Associated Lactic Acidosis (MALA)

• MALA carries a mortality rate of 30-50% if not promptly treated, representing the most severe form of metformin toxicity 4, 6
• The incidence of MALA is approximately 2-9 cases per 100,000 patient-years 4
• MALA was present in 92.6% of reported toxicity cases in a comprehensive meta-analysis 3

Risk Factors for Toxicity at Any Dose

• Severe renal impairment (eGFR <30 mL/min/1.73 m²) is the primary risk factor 4
• Severe heart failure with left ventricular ejection fraction <30% 4
• Dehydration or acute illness compromising renal function 4
• Administration of iodinated contrast agents 4
• Liver dysfunction or hypoxemic conditions 4

Clinical Presentation of Toxicity

• Nonspecific gastrointestinal symptoms (nausea, vomiting, abdominal pain) 6
• Neurological symptoms including altered mental status and obtundation 3
• Severe metabolic acidosis with high anion gap 6, 3
• Hyperlactatemia (lactate levels can exceed 40 mmol/L in severe cases) 2
• Hypotension, hypothermia, and cardiovascular collapse in severe cases 2

Management of Suspected Toxicity

• Hemodialysis is the definitive treatment for metformin removal, with clearance up to 170 mL/min under good hemodynamic conditions 1
• In the meta-analysis, 68.6% of patients received renal replacement therapy for toxin removal and correction of MALA 3
• Aggressive supportive care including mechanical ventilation (52.9% of cases), vasopressors (58.7% of cases), and sodium bicarbonate 3
• Early nephrology and toxicology consultation is critical 6
• Despite severe metabolic derangements (pH as low as 6.59), patients can survive with aggressive intervention 2

Critical Pitfall to Avoid

The most important clinical pitfall is failing to recognize that most metformin toxicity (76.4% of cases) occurs in patients on therapeutic doses who develop acute renal dysfunction, not from acute overdose. 3 Any patient on metformin presenting with elevated lactate and metabolic acidosis should be considered at risk for MALA and requires immediate aggressive management including early consideration of hemodialysis. 6