Abstract: The management of acid-based disorders was transformed in the 1980s with the advent of proton pump inhibitors (PPIs), which target the hydrogen-potassium adenosine triphosphatase (proton pump) of the parietal cell. Potassium-competitive acid blockers (P-CABs), a newer class of medications, act at the same proton pump through a novel mechanism resulting in profound and sustained acid suppression. Although trials in Asian populations over the past decades have highlighted the potential benefit of P-CABs, clinical trials in Western populations have been initiated more recently. These trials evaluated vonoprazan in patients with Helicobacter pylori infection, erosive esophagitis, and heartburn with nonerosive reflux disease and have demonstrated promising results, culminating in US Food and Drug Administration approval for these indications. Adverse event profiles between PPIs and P-CABs appear comparable thus far, although additional long-term data on P-CABs are needed. While navigating the evolving landscape of acid suppression, it is crucial to identify which patients and diseases are poised to derive the most benefit from this emerging therapeutic option. This article seeks to highlight important pharmacologic properties of PPIs and P-CABs, understand the current literature with a focus on clinical trials Ia/Ib or IIa/IIb peptic ulcers.33 Results showed noninferiority of oral vonoprazan in preventing 30-day rebleeding compared with the PPI regimen, which encompassed both intravenous and oral PPI administration. These findings suggest a possible future role for oral management via vonoprazan in management of bleeding ulcers, with further studies in the Western population needed to help generalize the results.
Other Diseases
Ongoing studies worldwide are exploring how P-CABs compare with PPIs in various esophageal and acid-related conditions. Likely research directions include the evaluation of P-CABs in diseases where PPIs are the standard first-line treatments, such as BE. Another intriguing avenue is the potential for P-CABs in other esophageal disorders such as eosinophilic esophagitis (EoE); a small Japanese study indicated that vonoprazan is comparable to PPIs in inducing remission in EoE.34 However, further data are necessary in patients with BE, EoE, and other acid-related disorders to understand the prospect of P-CABs as a potential therapeutic option.
Adverse Events and Safety
Because PPIs have a well-established safety profile,35 understanding any adverse events unique to P-CABs will be
crucially important. A systematic review with meta-analysis by Cheng and colleagues noted that the most common TEAEs associated with P-CABs include nasopharyngitis, headache, upper respiratory infection, and gastroenteritis, with a risk ratio for TEAEs of 1.08 (95% CI, 0.96-1.22; P=.20).36 Other reported adverse reactions to P-CABs include abdominal pain, nausea, and urinary tract infection.8,37 Additionally, acute tubulointerstitial nephritis has been associated with vonoprazan use.38 In general, current data show comparable rates of TEAEs with P-CABs in clinical trials when compared with PPIs.39
Given the potent acid suppression of vonoprazan, not surprisingly serum gastrin has been found elevated in patients receiving vonoprazan, with a dose-dependent relationship noted in short-term studies.19 Regarding long-term evaluation of adverse effects, the VISION study was designed to evaluate nearly 200 patients receiving vonoprazan 10 mg daily or lansoprazole 15 mg daily for 260 weeks at 33 centers in Japan.40 An interim analysis at 3 years found that the cumulative incidence of parietal cell, gastrin-producing cell, and enterochromaffin-like cell hyperplasia was similar between the vonoprazan and lansoprazole groups after 3 years of maintenance therapy. Gastric polyp rates were also similar between the groups (81% in the lansoprazole group vs 72% in the vonoprazan group).41 No neoplastic changes were noted in either group. Contrastingly, a single retrospective cohort analysis suggested a possible association with gastric cancer.42 Ultimately, more long-term data on the use of P-CABs will be essential for establishing their true adverse event profile and determining how it compares with that of PPI agents.
Conclusion
The introduction of PPIs several decades ago marked a significant advancement in the treatment of acid-based disorders. The potent and prolonged acid suppression offered by P-CABs necessitates consideration of their role in managing these conditions. Recent data have shown their efficacy in healing and maintenance in erosive esophagitis, particularly in severe, LA grade C and D populations. There is growing momentum for the use of P-CABs in H pylori treatment with the emergence of vonoprazan-based regimens, especially for clarithromycin-resistant strains. The real-world effects of the recent FDA approval for the use of vonoprazan in patients with heartburn without erosive esophagitis remain to be seen. The potential role of P-CABs in patients with NERD and positive pH testing, EoE, BE, and other upper gastrointestinal conditions warrants continued investigation. Numerous clinical trials are underway across various disease states to clarify the comparative positioning of P-CABs vs PPIs in this rapidly evolving landscape of acid-suppression therapy.
Disclosures
Dr Ketchem has no relevant conflicts of interest to disclose. Dr Lynch has served as a consultant to Medtronic and Sanofi and on the medical advisory board of Phathom.
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