Association of CYP2C19 Polymorphism With Proton Pump Inhibitors Effectiveness and With Fractures in Real‐Life: Retrospective Cohort Study

Abstract

Symptom refractoriness of patients treated with proton pump inhibitors (PPIs) might be explained by polymorphism in CYP2C19. This is a retrospective cohort study in which we used the computerized database of Clalit Health Services to compose a cohort from cancer case‐control studies’ participants that had been genotyped, and that have been dispensed PPI (January 1, 2002 to November 10, 2020). We retrieved demographic and clinical variables on date of PPI initiation (cohort entry), and studies’ questionnaires‐reported consumption of foods/beverages known to increase peptic‐related symptoms. Primary outcome was an abdominal pain diagnosis; secondary outcome was a composite of abdominal pain, visit to a gastroenterology clinic, change to another PPI, PPI dose increase, or metoclopramide prescription, reflecting symptoms persistence/recurrence; in a 2‐year follow‐up. We also evaluated the association between genetic groups and hip/wrist/spine fractures, in a long‐term follow‐up. Of 3,326 PPI initiators, there were 66 (2.0%), 739 (22.2%), 1394 (41.9%), 947 (28.5%), and 180 (5.4%) CYP2C19 poor, intermediate, normal, rapid, and ultra‐rapid metabolizers, respectively. Being a poor metabolizer was associated with lower risk for the primary outcome, hazard ratio (HR) = 0.50 (95% confidence interval (CI) 0.27–0.91), HR = 0.52 (95% CI 0.28–0.94); and for the secondary outcome, HR = 0.57 (95% CI 0.38–0.86), HR = 0.58 (95% CI 0.39–0.87), in univariate and multivariable cox regression analyses, respectively. In long‐term follow‐up with 20,142 person‐years of follow‐up: 7.6% (5 cases) within the poor metabolizers group, and 11.6%, 12.9%, 12.8%, and 11.1% in the normal, intermediate, rapid, and ultra‐rapid metabolizers groups, respectively, had a new fracture (nonsignificant). We conclude that CYP2C19 poor metabolizer status is associated with higher effectiveness of PPIs, and is not associated with higher risk for fractures.

CYP2C19 genotypes and osteoporotic fractures in long‐term users of proton pump inhibitors: A hospital‐based study

“…However, no definitive evidence suggested there was a correlation between CYP2C19 polymorphism and the risk of fractures in individuals who had been on PPI therapy for over a year. Similar findings were reported by Naomi et al 26 in their study involving an Israeli population. While the author of the previous study recruited patients who had received a minimum of one PPI prescription, 26 our investigation included individuals who underwent a minimum of 336 days of PPI use.…”

“…Similar findings were reported by Naomi et al 26 in their study involving an Israeli population. While the author of the previous study recruited patients who had received a minimum of one PPI prescription, 26 our investigation included individuals who underwent a minimum of 336 days of PPI use. However, despite the extension of PPI exposure to 336 days, CYP2C19 polymorphism did not demonstrate any apparent association with an increased risk of fractures.…”

“…Nonetheless, the exact correlation between genetic variation and the potential for fracture risk remains indeterminate, with relatively few studies having investigated this phenomenon. 2,26 In our study, the incidence of fractures following a 1-year course of PPI use was observed to be approximately 2.3% to 3.5%. However, no definitive evidence suggested there was a correlation between CYP2C19 polymorphism and the risk of fractures in individuals who had been on PPI therapy for over a year.…”

“…Lima et al 25 found an association between CYP2C19 genotype and respiratory adverse events which showed a higher frequency of upper respiratory infections in IMs/PMs than those seen in normal metabolizers. Nonetheless, the exact correlation between genetic variation and the potential for fracture risk remains indeterminate, with relatively few studies having investigated this phenomenon 2,26 . In our study, the incidence of fractures following a 1‐year course of PPI use was observed to be approximately 2.3% to 3.5%.…”

Association Between ABCG2, ABCB1, ABCC2 Efflux Transporter Single‐Nucleotide Variants and Irinotecan Adverse Effects in Patients With Colorectal Cancer: A Real‐Life Study

“…In the current retrospective cohort study we chose, from the source population described above that underwent GWAS, 21 only CRC cases that have also been prescribed systemic therapy. The main study cohort was composed of all patients with CRC who have been dispensed irinotecan (at least one dose).…”