China: Metformin and Cimetidine Interaction Study

Metformin combined with cimetidine may raise the risk of lactic acidosis (LA) in patients with mild-to-moderate renal failure (RF), a recent study published in Diabetes Care has revealed.

"Following the 2016 FDA approval of metformin for mild-to-moderate kidney disease, there was an increase in the percentage of patients with renal failure reporting lactic acidosis associated with metformin combined with cimetidine," the researchers reported.

Jiaping Zheng, Department of Rehabilitation Medicine, School of Health, Fujian Medical University, Fuzhou, China, and colleagues aimed to evaluate the risk of lactic acidosis when using metformin combined with histamine H2 receptor inhibitors (H2RI) in patients with renal failure.

For this purpose, the researchers analyzed FDA Adverse Event Reporting System data (2012Q4 to 2022Q4) to characterize reports of lactic acidosis linked with metformin alone or combined with histamine H2 receptor inhibitors. They assessed LA risk signals in the overall population and patients with renal failure, using a disproportionality approach.

A physiologically based pharmacokinetic (PBPK) model was developed for predicting pharmacokinetic changes in metformin and cimetidine following conventional doses of the combinations in patients with various degrees of RF. A peak plasma metformin concentration of 3 mg/L was considered the threshold to explore its correlation with LA risk.

Study Findings

• Following the 2016 U.S. Food and Drug Administration metformin approval for mild-to-moderate RF, there was an increase in the percentage of patients with RF reporting LA associated with metformin combined with H2RI.
• Disproportionality analysis showed reported LA risk signals associated with metformin and cimetidine in the overall population within the study timeframe only.
• With PBPK simulations, for metformin (1,000 mg b.i.d.) with cimetidine (300 mg q.i.d. or 400 mg b.i.d.) in stage 1 of chronic kidney disease, metformin (1,000 mg b.i.d.) with cimetidine (300 mg q.i.d. or 400 mg b.i.d. or 800 mg q.d.) in stage 2, and most combinations in stage 3, the peak plasma metformin concentrations exceeded the 3 mg/L threshold.

"Metformin paired with cimetidine at conventional doses may cause lactic acidosis in patients with reduced renal function," the researchers concluded.

Reference

Wenhuo Xie, Jianbin Li, Chenghua Kong, Wei Luo, Jiaping Zheng, Yu Zhou; Metformin-Cimetidine Drug Interaction and Risk of Lactic Acidosis in Renal Failure: A Pharmacovigilance-Pharmacokinetic Appraisal. Diabetes Care 20 December 2024; 47 (1): 144–150. https://doi.org/10.2337/dc23-1344