A patient with T2DM and an eGFR of 28 mL/min/1.73 m² is on metformin. The risk of lactic acidosis with metformin in renal impairment is due to:

• A Metformin directly inhibits mitochondrial complex I, impairing oxidative phosphorylation and increasing pyruvate to lactate conversion; accumulation in renal impairment amplifies this effect
• B Metformin reduces hepatic gluconeogenesis from lactate, and its accumulation due to reduced renal excretion further inhibits lactate clearance
• C Both A and B contribute: metformin inhibits complex I and accumulates renally, and its hepatic mechanism of AMPK activation reduces lactate consumption by gluconeogenesis ✓
• D Metformin activates AMPK which phosphorylates acetyl-CoA carboxylase, diverting pyruvate to lactate via enhanced pyruvate dehydrogenase kinase activity

Explanation

Metformin accumulates in renal impairment (it is renally excreted unchanged, not metabolized) and exerts two mechanistic contributions to lactic acidosis: (1) It inhibits mitochondrial respiratory chain complex I, increasing the cytoplasmic NADH/NAD+ ratio and shifting pyruvate toward lactate via lactate dehydrogenase; (2) By activating AMPK and inhibiting hepatic gluconeogenesis (its therapeutic mechanism), it reduces the liver's ability to consume lactate as a gluconeogenic substrate. Both effects combine when metformin accumulates. Current KDIGO guidance: continue metformin if eGFR ≥30, discontinue if eGFR <30 mL/min/1.73 m².

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

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