ABSTRACT
Potassium-competitive acid blockers (P-CABs) are a new class of acid-suppressing drugs; to date, only one of them (vonoprazan) has been approved for use in the United States. The authors of this article review how P-CABs (and vonoprazan in particular) differ from proton pump inhibitors (PPIs), evidence supporting their effectiveness, indications for vonoprazan, and ongoing and future studies.
Vonoprazan, unlike PPIs, does not need to be taken 30 to 60 minutes before meals to be maximally effective. Also, it has a faster onset of action, it maintains a more consistent gastric pH, especially at night, and it avoids cytochrome P450 2C19 (CYP2C19) metabolism.
Vonoprazan has been approved to treat gastroesophageal reflux disease with or without esophagitis and Helicobacter pylori infection.
PPIs remain the first-line acid-suppressing drugs, but vonoprazan should be considered in cases of severe esophagitis, clarithromycin-resistant H pylori infection, PPI intolerance, or PPI failure.
Higher costs and formulary restrictions often necessitate prior authorization or step-up therapy for P-CAB approval, restricting access.
For decades, proton pump inhibitors (PPIs) have been the cornerstone of therapy for acid-related disorders such as gastroesophageal reflux disease, peptic ulcers, and Helicobacter pylori infection. However, between 10% and 40% of patients with gastroesophageal reflux disease experience suboptimal symptom control with PPIs.1,2 Limitations of PPIs include the inconvenience of timing around mealtime (usually, 30 to 60 minutes before breakfast) and a relatively short plasma half-life.3
A new class of drugs, potassium-competitive acid blockers (P-CABs), has emerged as an effective alternative to PPIs. In this review, we explore the pharmacologic profile, efficacy, safety, and indications of P-CABs. We focus on vonoprazan, given that to date it is the only drug of this class approved by the US Food and Drug Administration (FDA).
HOW P-CABs DIFFER FROM PPIs
PPIs are prodrugs that require activation in an acidic environment. Once activated, they inhibit the enzyme hydrogen-potassium adenosine triphosphatase—the proton pump embedded in the cell membrane of gastric parietal cells that, as its name indicates, pulls potassium into the cell while driving hydrogen out, using adenosine triphosphatase as fuel. PPIs form irreversible covalent bonds with cysteine residues of the enzyme, blocking hydrogen and potassium exchange.4,5
Because the parietal cells are constantly making new proton pump molecules and cycling them to the cell membrane, PPIs must be taken several days in a row to achieve maximum acid suppression.6 As mentioned, they should be taken on an empty stomach, and food needs to be consumed 30 to 60 minutes afterward. Another disadvantage of PPIs is that they are metabolized in the liver by cytochrome P450 (CYP) 2C19, which has multiple polymorphisms, leading to wide differences among patients in speed of metabolism, plasma levels, efficacy, and dosage requirements.7
P-CABs, on the other hand, form reversible ionic bonds with hydrogen-potassium adenosine triphosphatase, though at a different site, one near the potassium binding site.8 They are already active (not prodrugs), are meal independent, and have a rapid onset of action, within hours.4,9 They are weakly basic and lipophilic, allowing them to accumulate in the secretory tubules of the parietal cells, which enhances the half-life and duration of acid suppression.7,10 P-CABs are not affected by CYP2C19 genetic polymorphisms, as they are metabolized through CYP3A4.10
Bottom line: P-CABs maintain target intragastric pH for a greater portion of the day than PPIs do, and they result in consistent and potent acid suppression.
The main differences between PPIs and P-CABs are listed in Table 1.7
Potassium-competitive acid blockers and proton pump inhibitors compared
FDA-APPROVED INDICATIONS FOR VONOPRAZAN
Erosive reflux disease
Erosive esophagitis occurs when excessive acid reflux results in esophageal ulcers.
In a phase 3 randomized controlled trial involving 1,024 patients with erosive esophagitis, vonoprazan was noninferior to lansoprazole for initial and maintained healing of erosive esophagitis: initial healing occurred in 92.9% vs 84.6% of patients (P < .0001).11 In the same trial, vonoprazan was noninferior to lansoprazole in controlling symptoms (mean 66.8 ± 34.6 vs 64.1 ± 35.3 heartburn-free days, P < .0001).11 A meta-analysis also found vonoprazan to be superior to lansoprazole for healing the more severe forms of erosive esophagitis.12
An important limitation is that the studies of the efficacy of vonoprazan in erosive esophagitis included patients with all grades of erosive esophagitis. Minimal erosive disease can be seen in up to 7.5% of healthy people and may not be clinically relevant.13 Regardless, this is a small subset of the study population, and the major benefits were seen in those with more severe forms of erosive esophagitis.11
The dosing for the initial phase is 20 mg daily, and for the maintenance phase it is 10 mg daily (Table 2 9,14).
Vonoprazan approved indications, comparative efficacy, and dosing
Nonerosive reflux disease
A substantial subset of patients with gastroesophageal reflux disease have nonerosive reflux disease—an abnormal acid burden but no visible esophageal mucosal erosions or breaks on endoscopy.15
Vonoprazan was found to be superior to placebo in improving heartburn symptoms in patients with nonerosive reflux disease in a randomized controlled trial.14 Unlike PPIs, which require daily sustained use, vonoprazan has been shown to be effective when used as-needed for symptom control; in another randomized trial, 60.6% of patients (n = 327) receiving vonoprazan 20 mg had symptom relief compared with 27.3% (n = 370) of those receiving placebo (P < .0001).16 There are no studies to our knowledge that compare intermittent use of vonoprazan with histamine-2 receptor antagonists.
H pylori eradication
Vonoprazan is approved for H pylori eradication in 2 regimens: a dual regimen with amoxicillin and a triple regimen with amoxicillin and clarithromycin.
A meta-analysis found vonoprazan triple therapy to be superior to PPI triple therapy in eradicating H pylori (risk ratio 1.17, 95% confidence interval 1.11–1.22, P < .0001).17 Also, there are some data showing that vonoprazan dual therapy is superior to PPI triple and quadruple therapy, with a particular benefit in patients with clarithromycin-resistant strains.18,19
Gastrointestinal society guidelines overall recommend bismuth quadruple therapy as preferred empiric first-line treatment for H pylori, but other options can be considered based on prior antibiotic exposure and availability of susceptibility testing.20–22 Vonoprazan-based regimens could be considered in areas of clarithromycin resistance.
VONOPRAZAN DOSAGE RECOMMENDATIONS
For initial healing of erosive esophagitis: 20 mg once daily, typically for 4 to 8 weeks9,12
For maintenance of healing of erosive esophagitis: 10 mg once daily, long-term or indefinitely
For H pylori eradication triple therapy: vonoprazan 20 mg, amoxicillin 1,000 mg, and clarithromycin 500 mg, all taken twice daily for 14 days9,17,23
For H pylori eradication dual therapy: vonoprazan 20 mg twice daily and amoxicillin 1,000 mg 3 times daily for 14 days
For nonerosive reflux disease: 10 mg once daily for 4 weeks (Table 2).
ADMINISTRATION AND DOSING CONSIDERATIONS
Unlike PPIs, vonoprazan can be taken independently of mealtime. The half-life of vonoprazan is 6 to 9 hours, supporting once- or twice-daily dosing.20 Although renal and hepatic impairment may affect drug exposure, clinically relevant dose adjustments are uncommon and are largely confined to patients with severe organ dysfunction. Overall, vonoprazan has a predictable pharmacokinetic profile, which simplifies administration compared with PPIs.
SAFETY PROFILE OF P-CABs
The safety profile of P-CABs, including vonoprazan, is generally comparable to that of PPIs in both short- and medium-term use. Randomized controlled trials and meta-analyses consistently show that the overall risk of treatment-emergent adverse events with P-CABs compared with PPIs is low (pooled risk ratio 1.08, 95% confidence interval 0.89–1.31),12 and there is no significant difference in overall safety between PPIs and P-CABs.12,24
The most common adverse events with P-CABs include mild symptoms of nausea, diarrhea, and headaches.20 P-CABs can cause elevated serum gastrin.25 However, the clinical relevance remains unclear, and fortunately there is no known increased risk of neoplasia.20,26 Based on observational data, it is possible that P-CABs, like PPIs, may increase the risk of enteric infections, but larger long-term studies are needed.27,28
There are limited data regarding P-CAB use in pregnant and lactating patients; however, there was no maternal or developmental fetal toxicity in an animal study.29
An area of study will be the risks of osteopenia, osteoporosis, dementia, and renal disease. While a randomized controlled trial showed no increased risk after 3 years of PPI therapy,28 we currently lack such long-term data for P-CABs.30,31
Overall, P-CABs are well tolerated, with a safety profile similar to that of PPIs.
BARRIERS TO ACCESS
Several barriers to P-CAB access exist for many patients.20 Some insurance companies charge higher copayments for P-CABs than for PPIs and require prior authorizations for them. Most insurance companies require that PPIs have failed or that the patient be unable to tolerate one or more of them before approving vonoprazan. Also, P-CABs are not available over the counter, unlike many PPIs. Currently, vonoprazan is not on the Veterans Affairs national formulary, requiring a nonformulary request.32
THE FUTURE
Several clinical trials are evaluating P-CABs for additional indications, such as gastrointestinal bleeding and eosinophilic esophagitis (Table 3).33–36 Newer P-CABs such as linaprazan glurate and zastaprazan are in advanced stages of development, aiming to provide tailored dosing, extended-release formulations, and reduced adverse events.3
Potassium-competitive acid blockers in clinical development
WHEN TO CONSIDER VONOPRAZAN
P-CABs represent an important pharmacotherapeutic advancement by providing rapid, potent, and predictable acid suppression without the need for timing around meals. In general, PPIs remain first-line treatment for many acid-based disorders, and the current role of P-CABs is focused and limited. For internists and general gastroenterologists, P-CABs should be considered in certain scenarios.
First, vonoprazan is an FDA-approved, guideline-supported option for healing and maintaining healing of erosive esophagitis. Patients with more severe erosive esophagitis may benefit the most. Although PPIs remain first-line treatment, vonoprazan should be considered in cases of incomplete mucosal healing or intolerance to PPIs.20
Second, vonoprazan is FDA-approved for nonerosive reflux disease and is generally used when there are refractory symptoms on PPIs or an intolerance to PPIs.20
Third, vonoprazan has a defined role in H pylori eradication, particularly when there is concern for clarithromycin-resistant infections.21,22
DISCLOSURES
Dr. Beveridge has disclosed teaching and speaking for Asofarma, GastroGirl, and Vindico, and consulting for Sanofi, Takeda Pharmaceutical Ltd., and Christopher Place Healthcare. Dr. Wehbe reported no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.
- Copyright © 2026 The Cleveland Clinic Foundation. All Rights Reserved.
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