Evaluation of dipeptidyl peptidase-4 inhibitor-associated gastrointestinal symptoms using the prescription claims database

Dipeptidyl peptidase-4 inhibitors (DPP-4is) are widely used in Japan; however, their incretin activity raise concerns about gastrointestinal adverse events (GAEs). Therefore, we aimed to investigate GAEs symptoms commonly associated with DPP-4is and associated symptomatic treatment, to enable community pharmacists in charge of pharmaceutical management of outpatient prescriptions in Japan to strengthen patient intervention strategies. Therefore, we conducted a prescription sequence symmetry analysis (PSSA) using a prescription claims database (2018-2022) of a domestic chain pharmacy to evaluate the association between DPP-4is and GAEs. Adjusted sequence ratios (ASRs), a safety index, were calculated based on three treatment groups: prokinetic agents (dopamine D2 receptor blockers and serotonin 5-HT4 receptor agonists), gastric acid suppressants (histamine H2 receptor blockers and proton pump inhibitors), and laxatives, and the order in which DPP-4is were prescribed. The ASR was calculated for 90, 180, and 360 days, and subgroup analyses were performed for prokinetic agents and gastric acid suppressants groups based on their mechanism of action. ASR values > 1 indicated significant association with DPP-4is. PSSA results showed DPP-4is association across all observation periods for prokinetic agents and laxatives, but not for gastric acid suppressants. Subgroup analyses indicated a similar trend, suggesting that DPP-4is are associated with nausea and constipation owing to functional impairment rather than gastric acid secretion. Additionally, prescription data confirmed the possibility of adding gastrointestinal medications, which could cause a potential prescribing cascade, after prescribing DPP-4is. These findings highlight the importance of strengthening follow-up between patient visits to facilitate the early detection of GAEs caused by DPP-4is, and carefully considering the risks and benefits of symptomatic treatment.