The impact of drug-drug interactions between proton pump inhibitors and metformin: A systematic review of clinical evidence

Abstract

Metformin, a substrate of the organic cation transporters, is commonly co-prescribed with proton pump inhibitors, which inhibits these transporters. However, the clinical significance of this potential drug-drug interaction remains unclear. This systematic review aimed to assess the potential and clinical relevance of the interaction between proton pump inhibitors and metformin based on published clinical evidence. PubMed and Embase were searched for studies reporting the effects of this interaction in adults (≥18 years old), published up to January 2024. Data on pharmacokinetic and pharmacodynamic effects were collected and analyzed. The study protocol is registered in PROSPERO (CRD42023456957). A total of 14 studies were included, comprising five experimental and nine observational studies. Experimental pharmacokinetic studies indicated minimal changes in metformin AUC when combined with proton pump inhibitors, with reported changes ranging from a slight decrease (-5.46%) to a moderate increase (up to +17%). Pharmacodynamic data from both experimental and observational studies supported these findings, showing minimal clinically relevant changes in HbA1c levels. However, some studies reported decreased vitamin B12 levels in patients with type 2 diabetes mellitus using both proton pump inhibitors and metformin. Based on the current clinical evidence, the impact of drug-drug interaction between proton pump inhibitors and metformin is minimal. However, regular monitoring of glucose and vitamin B12 levels is advised for high-risk populations and those on long-term metformin and proton pump inhibitor therapy.