A retrospective study of patients with gastroesophageal reflux disease (GERD) found that nearly half of those who underwent CYP2C19 genotyping were rapid or ultrarapid metabolizers, a finding the authors said supports the use of genetic testing to guide proton pump inhibitor (PPI) therapy in selected patients.
The study, published in Clinical Gastroenterology and Hepatology, included 421 patients with GERD seen in an outpatient gastroenterology clinic between 2019 and 2024 who underwent CYP2C19 testing while receiving PPI therapy. According to the authors, 44% of patients were identified as rapid or ultrarapid metabolizers.
“Nearly one-half of patients presenting to GI clinic for GERD who underwent CYP2C19 genotyping were found to be RMs or URMs,” the authors wrote.
Most PPIs are metabolized by CYP2C19. The study was undertaken because “a large proportion of patients have an inadequate response to [PPIs], despite the optimization of dosing and timing,” the authors wrote, hypothesizing that CYP2C19 polymorphisms contribute to treatment failure in some patients.
The investigators reviewed genotype results, medication use before and after testing, endoscopic findings, pH testing results, and documentation of symptom improvement. Rapid and ultrarapid metabolizers were analyzed together as rapid metabolizers, while normal and intermediate metabolizers were grouped as normal metabolizers.
The authors reported that ultrarapid metabolizers were more likely than normal metabolizers to have Barrett’s esophagus or erosive esophagitis. On multivariable analysis controlling for age, ultrarapid metabolizer status remained associated with a higher prevalence of Barrett’s esophagus and/or erosive esophagitis.
The study also examined outcomes after changes in PPI therapy based on CYP2C19 results. Among rapid metabolizers who underwent repeat endoscopy after medication adjustment, most patients with baseline erosive esophagitis demonstrated resolution or improvement. The authors also reported a “nonstatistically significant trend towards higher odds of erosive esophagitis resolution when PPI was adjusted based on CYP results.”
Management changed after genetic testing in most rapid metabolizers. According to the study, many patients were switched to rabeprazole, which the authors noted undergoes minimal CYP2C19 metabolism. Rapid metabolizers who switched to rabeprazole were more likely to report symptom improvement at follow-up.
“These findings provide compelling evidence that standard PPI dosing in RMs is insufficient and that testing for CYP status is essential to personalize PPI therapy and optimize patient care,” the authors wrote.
Study author Bashar J. Qumseya, MD, University of Florida, Gainesville, said the findings suggest that genetic testing could help identify patients whose response to therapy is affected by PPI metabolism.
“In our study, we found that nearly half of patients with GERD who underwent genetic testing carried CYP2C19 variants that caused them to metabolize PPIs more rapidly, potentially reducing the effectiveness of these commonly prescribed medications,” Dr. Qumseya said.
He added that their findings suggest personalizing PPI therapy based on CYP2C19 genetic testing could improve treatment outcomes.
“Patients whose PPI therapy was adjusted according to their genetic test results showed a trend toward higher rates of esophagitis healing,” he said.
The authors noted that their findings are consistent with recent recommendations supporting CYP2C19 testing in the management of GERD. They said gastroenterologists should be aware of these findings and consider CYP2C19 testing as a tool in the evaluation of patients who don’t respond to standard PPI therapy.
Several limitations were acknowledged. The study was conducted at a single tertiary referral center and included a selected population of patients with GERD who underwent CYP2C19 testing at the discretion of their providers. Symptom improvement was assessed through chart review rather than standardized symptom instruments, and some subgroup analyses were limited by small sample sizes and wide confidence intervals.
Despite those limitations, the authors concluded that “our data adds to the evidence that support the use of CYP testing to guide pharmacotherapy in patients with GERD.”
Dr. King and Dr. Qumseya reported food and beverage compensation from industry sources, including EndoGastric Solutions, Medtronic, Fujifilm Healthcare Americas and Boston Scientific; the remaining authors reported no conflicts.