Metformin is contraindicated in patients with estimated GFR < 30 mL/min/1.73 m². The primary reason is:

• A Accumulation of metformin causes hypoglycaemia due to enhanced insulin sensitivity
• B Metformin causes nephrotoxic tubular injury at high plasma concentrations
• C Renal accumulation of metformin increases risk of lactic acidosis by inhibiting hepatic mitochondrial complex I and gluconeogenesis ✓
• D Metformin inhibits renal ammonia excretion, causing metabolic acidosis

Explanation

Metformin is entirely renally excreted unchanged; impaired renal function causes drug accumulation. At high concentrations, metformin inhibits mitochondrial complex I in hepatocytes, impairing oxidative phosphorylation and promoting anaerobic lactate production, while also suppressing gluconeogenesis (which consumes lactate). The net result is type-B lactic acidosis—a rare but potentially fatal complication. It is not nephrotoxic and does not cause hypoglycaemia as monotherapy. Guidelines allow cautious use down to GFR 30–45 with dose reduction.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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