A review of medical therapy for proton pump inhibitor nonresponsive gastroesophageal reflux disease

L. Hillman, Rena Yadlapati*, A. J. Thuluvath, M. A. Berendsen, J. E. Pandolfino

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

39 Scopus citations


Up to 40% of patients report persistent gastroesophageal reflux disease (GERD) symptoms despite proton pump inhibitor (PPI) therapy. This review outlines the evidence for medical therapy for PPI nonresponsive GERD. A literature search for GERD therapies from 2005 to 2015 in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews identified 2928 unique citations. Of those, 40 unique articles specific to the impact of PPI metabolizer genotype on PPI response and the use adjunctive medical therapies were identified. Thirteen articles reported impacts on CYP genotypes on PPI metabolism demonstrating lower endoscopic healing rates in extensive metabolizers; however, outcomes across genotypes were more uniform with more CYP independent PPIs rabeprazole and esomeprazole. Twenty-seven publications on 11 adjunctive medications showed mixed results for adjunctive therapies including nocturnal histamine-2 receptor antagonists, promotility agents, transient lower esophageal sphincter relaxation inhibitors, and mucosal protective agents. Utilizing PPI metabolizer genotype or switching to a CYP2C19 independent PPI is a simple and conservative measure that may be useful in the setting of incomplete acid suppression. The use of adjunctive medications can be considered particularly when the physiologic mechanism for PPI nonresponse is suspected. Future studies using adjunctive medications with improved study design and patient enrollment are needed to better delineate medical management options before proceeding to antireflux interventions.

Original languageEnglish (US)
Pages (from-to)1-15
Number of pages15
JournalDiseases of the Esophagus
Issue number9
StatePublished - Sep 1 2017


  • Adjunctive medication
  • Rapid metabolizer
  • Refractory gastroesophageal reflux disease

ASJC Scopus subject areas

  • Gastroenterology


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