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Abstract

Background:

Proton pump inhibitors (PPIs) are the standard treatment for erosive esophagitis (EE), yet 20%–40% of patients show inadequate response. Vonoprazan, a potassium-competitive acid blocker (P-CAB), provides faster and more sustained acid suppression than PPIs.

Objectives:

To evaluate the efficacy and safety of vonoprazan compared with lansoprazole in the treatment and maintenance of EE, and to explore dose–response and duration effects using meta-regression analysis.

Design:

Systematic review and meta-analysis of randomized controlled trials (RCTs).

Data sources and methods:

Electronic databases (PubMed, Embase, Cochrane CENTRAL, ClinicalKey, ProQuest, ScienceDirect, Web of Science, and ClinicalTrials.gov) were searched through March 31, 2025. Eligible RCTs compared vonoprazan with lansoprazole for EE treatment. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random-effects models. Meta-regression assessed dose- and duration-dependent effects.

Results:

Seven RCTs involving 3754 participants (mean age 54.6 ± 3.2 years; 68.5% male) were included. Vonoprazan significantly improved healing rates versus lansoprazole (OR = 1.855; 95% CI: 1.386–2.482; p < 0.001; I² = 8.38%) and recurrence-free rates (OR = 2.920; 95% CI: 1.636–5.211; p < 0.001; I² = 70.99%). Serum gastrin levels were higher with vonoprazan (OR = 2.707; 95% CI: 1.430–5.123; p = 0.002). Meta-regression showed that longer treatment duration (β = 0.0163 per day; p < 0.0001) and higher dosage (β = 0.0293 per mg; p < 0.0001) were associated with improved healing. Adverse event rates did not differ significantly between groups (OR = 1.104; 95% CI: 0.922–1.321; p = 0.331; I² = 12.99%).

Conclusion:

Vonoprazan provides superior healing and maintenance efficacy compared with lansoprazole without increasing adverse events. Its benefits are dose- and duration-dependent, supporting vonoprazan as a first-line option for EE, particularly in severe or PPI-refractory cases.

Trial registration:

This study was registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY; INPLASY202590075; DOI: 10.37766/inplasy2025.9.0075).

Plain language summary

Longer and higher-dose vonoprazan works best for healing erosive esophagitis

What is this study about?

Erosive esophagitis (EE) is a serious type of acid reflux that damages the esophagus. Doctors usually treat EE with acid-reducing medicines called proton pump inhibitors (PPIs), such as lansoprazole. However, many patients do not respond well to these drugs. Vonoprazan is a newer medicine that works in a different way and may control acid more effectively.

What did we do?

We looked at all available clinical trials comparing vonoprazan with lansoprazole in adults with EE. We used a statistical method called meta-regression to see whether longer treatment or higher doses of vonoprazan led to better results.

What did we find?

Better healing: Patients taking vonoprazan were more likely to have complete healing of their esophagus compared to those taking lansoprazole.

Fewer recurrences: Vonoprazan also reduced the chance of EE coming back after treatment.

Dose and time effects: Longer treatment duration and higher doses of vonoprazan were linked to even better healing outcomes.

Safety: Side effects were similar between vonoprazan and lansoprazole, even at higher doses.

Why is this important?

Our findings suggest that vonoprazan may be a better option than lansoprazole for people with EE, especially for those with severe disease or frequent recurrences. Doctors may consider longer treatment or higher doses of vonoprazan to achieve the best results without added safety risks.

Keywords

EE gastroesophageal reflux disease meta-analysis potassium-competitive acid blocker proton pump inhibitor vonoprazan

Introduction

Gastroesophageal reflux disease (GERD) affects approximately 13.3% of the global population, with erosive esophagitis (EE) representing its most severe endoscopic manifestation in 10% of cases.¹ While proton pump inhibitors (PPIs) remain the first-line therapy, 20%–40% of patients exhibit an inadequate response to standard treatment, particularly those with Los Angeles grade C/D esophagitis.² This therapeutic gap has driven interest in vonoprazan, a potassium-competitive acid blocker (P-CAB) that achieves faster and more sustained acid suppression through distinct pharmacological mechanisms compared to PPIs.³

Vonoprazan, a first-in-class P-CAB, has emerged as a potent therapeutic agent for acid-related disorders. By inhibiting the H+, K+-ATPase enzyme system in gastric parietal cells, vonoprazan effectively suppresses both basal and stimulated gastric acid secretion, leading to a rapid and sustained increase in intragastric pH.⁴ Unlike PPIs, which form covalent bonds with the enzyme, vonoprazan acts in a reversible, potassium-competitive manner, potentially offering advantages in efficacy and onset of action.⁵

Beyond GERD management, vonoprazan has demonstrated efficacy in other acid-related conditions. It plays a crucial role in Helicobacter pylori eradication as part of first-line triple therapy (vonoprazan + amoxicillin + clarithromycin) and as a rescue therapy in cases of treatment failure.⁶ In addition, it is used for the treatment and prevention of peptic ulcer disease, particularly in patients on long-term NSAIDs or aspirin therapy.⁷ Furthermore, vonoprazan shows promise in stress ulcer prophylaxis, emerging as a potential option for critically ill patients and those at high risk of gastrointestinal bleeding due to prolonged NSAID use.⁸

This meta-analysis aims to synthesize current evidence from randomized controlled trials (RCTs) and observational studies to define vonoprazan’s role in EE management, with a focus on dose–response relationships and optimal treatment duration. By systematically evaluating healing rates and safety outcomes, this study seeks to provide a comprehensive assessment to guide clinical decision-making for this challenging patient population.

Materials and methods

Protocol and registration

This meta-analysis was conducted in accordance with the PRISMA 2020 guidelines (see Table S1).⁹ Since no human participants were involved, ethics review board approval and participant informed consent were not required. This study was registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY; registration number INPLASY202590075; DOI: 10.37766/inplasy2025.9.0075).

Search strategy and data collection

Two authors (P.-F.H. and H.-W.C.) made independent electronic searches in the PubMed, Embase, ClinicalKey, Cochrane CENTRAL, ProQuest, ScienceDirect, and Web of Science with keyword of (“Vonoprazan” OR “PCAB”) AND (“Lansoprazole” OR “PPI”) AND (“EE” OR “Erosive oesophagitis”) AND (“Healing rate” OR “Maintenance therapy” OR “Recurrence rate”) through the earliest record up to March 31, 2025. In addition, including gray literature and unpublished data, we also performed an electronic search on the ClinicalTrials.gov platform. A detailed search strategy is provided in the Supplemental Material (Table S2).

In the initial stage, these two authors screened the titles and abstracts for eligibility through consensus. To expand the pool of potential studies, we scrutinized the reference lists of review articles^10–16 and performed further manual searches. Later, a third reviewer (Y.-J.L.) was consulted in situations in which the two authors could not achieve consensus. No language restrictions were imposed.

Eligibility criteria and outcomes

This meta-analysis followed the PICO framework (Population, Intervention, Comparison, Outcome) as outlined: P: Adults with endoscopically confirmed EE; I: vonoprazan; C: Lansoprazole; O: healing rate, maintenance of healing, and adverse events.

Inclusion criteria included the following: (1) RCTs involving human participants; (2) trials comparing vonoprazan with lansoprazole in healing rate, maintenance of healing, and adverse events; and (3) studies providing data on healing rate, maintenance of healing, and adverse events. Exclusion criteria were as follows: (1) non-RCT studies, (2) studies lacking data on healing rate, maintenance of healing, and adverse events; and (3) studies with participant overlap from previously published trials.

Risk of bias and evidence quality

To investigate the methodological quality of the recruited studies, we used a version of the Cochrane risk-of-bias tool for randomized trials (RoB 2), which consists of six main items: randomization process, intervention adherence, missing outcome data, outcome measurement, selective reporting, and overall risk of bias.¹⁷

In RoB 2’s intervention adherence section, one of the two options should be selected for literature assessment: intention-to-treat (intervention assignment) or per-protocol (intervention adherence). In this meta-analysis, we chose a per-protocol evaluation. Any discrepancy in the opinions of assessments between the two evaluators (P.-F.H. and H.-W.C.) was solved by the judgment of the third evaluator (Y.-J.L.).

Primary outcome (healing rate andrecurrence-free rate)

The primary outcomes of this meta-analysis were the endoscopic healing rate and the maintenance of mucosal healing (recurrence-free rate) in patients receiving vonoprazan or lansoprazole for EE.^10–16 The healing rate was defined as the proportion of patients achieving complete endoscopic resolution of erosive lesions following induction therapy, whereas the recurrence-free rate represented the proportion of patients who maintained mucosal healing without relapse during maintenance therapy.

Pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated using a random-effects model to compare the efficacy of vonoprazan versus lansoprazole. Higher ORs indicated a greater likelihood of achieving or maintaining mucosal healing with vonoprazan relative to lansoprazole.

Exploratory random-effects meta-regression analyses were additionally performed to examine potential dose– and duration–response relationships across studies. Subgroup analyses were further performed according to vonoprazan dosage, treatment duration, and baseline disease severity, with the latter categorized using a median-split of the study-level proportion of patients with LA grade C/D esophagitis (low = predominantly LA A/B; high = predominantly LA C/D).

Secondary outcome (adverse events)

As a secondary outcome, this study evaluated the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) between vonoprazan and lansoprazole. For statistical consistency, studies reporting zero events in either arm were adjusted by adding 0.5 to each cell.¹⁸ Pooled ORs with 95% CIs were calculated using a random-effects model. Heterogeneity was assessed using the Cochran Q test and the I² statistic. Meta-regression was further performed to explore whether vonoprazan dosage influenced the occurrence of adverse events.

Data extraction and management

Data were extracted by the author from each study included in this meta-analysis, capturing demographic details, study design elements, information on nivolumab plus or chemotherapy only treatments, and both primary and secondary outcome values. To maintain accuracy, evaluators carefully verified the direction of effect for each scale used. When data were unavailable in published reports, corresponding authors were contacted for original data. Data extraction, transformation, and consolidation across study arms with differing strategies followed the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions and related medical literature.¹⁹ When multiple post-treatment data points were available, we used the outcome reported at the intervention’s conclusion for statistical analysis. In crossover studies, only data from the initial study period were included to avoid carry-over effects.²⁰

Statistical analysis

Given the variability of the target populations in the studies, we conducted this meta-analysis using a random-effects model with Comprehensive Meta-Analysis software (version 4; Biostat, Englewood, NJ, USA).²¹ We used ORs with 95% CIs to measure primary outcomes (i.e., healing rate). For secondary outcomes (i.e., adverse events), we assessed ORs with their 95% CIs. Study heterogeneity was evaluated using I² and Cochran’s Q statistics, where I² values of 25%, 50%, and 75% indicated low, moderate, and high heterogeneity, respectively.²² We confirmed the meta-analysis’s robustness through sensitivity analyses using the one-study removal method.¹⁸ Publication bias was assessed following Cochrane Handbook guidelines, and funnel plots were visually examined for asymmetry.²³

Results

Study selection and characteristics

Figure 1 shows the PRISMA flowchart outlining the literature search process. After removing duplicates and excluding non-relevant articles based on title and abstract screening, we ultimately included seven RCTs in the final analysis.^10–16 Table S3 lists articles excluded in the final stage along with reasons for exclusion.^24–26 The 7 eligible RCTs comprised 3754 participants, with a mean age of 54.6 ± 3.2 years, of whom 68.54% (n = 2573) were male. Diagnoses are EE.^10–16 The details of these trials are summarized in Table 1.

Figure 1.

The PRISMA flowchart.

Table 1.

Summary of the retrieved trials investigating the effect of vonoprazan in the enrolled participants.

First author and year	Country	Population	Participants (female/male)	Age^a	Study design	Allocation concealment	Randomization	Funding/grants/support
Xiao 2020	Mainland China, South Korea, Taiwan, Malaysia	Erosive oesophagitis	Vonoprazan: 68/176^b Lansoprazole: 58/179	54.1 ± 13.16^b 53.8 ± 12.53	RCT, double-blind	Interactive web response system	1:1 randomization to receive either vonoprazan or lansoprazole	Takeda Pharmaceutical Company
Xiao 2024	China, South Korea, Malaysia	Erosive oesophagitis	Vonoprazan 10 mg: 59/176^b Vonoprazan 20 mg: 61/165 Lansoprazole: 64/178	51.7 ± 11.8^b 52.8 ± 13.0 54.0 ± 12.8	RCT, double-blind	Double dummy design, participants received both tablets and capsules at dosing times	Randomly stratified according to Los Angeles classification grades A/B vs C/D, with a 1:1:1 ratio to treatments	Takeda Development Center Asia
Uemura 2025	Japan	Erosive oesophagitis	Vonoprazan: 38/97 Lansoprazole: 26/41	60.4 ± 11.8^b 61.5 ± 12.2	RCT, open-label	Not mentioned	Not mentioned	Takeda Pharmaceutical Company
Laine 2023	USA and Europe (Poland, Czech Republic, Hungary, Bulgaria, and UK)	Erosive oesophagitis	Vonoprazan: 256/258^b Lansoprazole: 287/223	51 ± 13.4^b, 51.7 ± 14.1	RCT, double-blind	Interactive response technology	Randomized in a 1:1 ratio for the healing phase and a 1:1:1 ratio for the maintenance phase.	Phathom Pharmaceuticals
Ashida 2018	Japan	Erosive oesophagitis	Vonoprazan 10 mg: 42/160^b Vonoprazan 20 mg: 44/160 Lansoprazole: 61/140	55.5 ± 13.8^b 56.8 ± 13.6 57.8 ± 12.9	RCT, double-blind	Independent randomization personnel	1:1:1 ratio using a computer-generated schedule	Takeda Pharmaceutical Company
Ashida November 2015	Japan	Erosive oesophagitis	Vonoprazan: 70/1372 Lansoprazole: 48/154	58.3 ± 13.8^b 57.4 ± 13.2	RCT, double-blind	Not mentioned	Not mentioned	Takeda Pharmaceutical Company
Ashida July 2015	Japan	Erosive oesophagitis	Vonoprazan 5 mg: 41/992 Vonoprazan 10 mg: 32/113 Vonoprazan 20 mg: 39/115 Vonoprazan 40 mg: 32/114 Lansoprazole: 41/99	57.9 ± 12.96^b 57.3 ± 13.01 58.3 ± 13.86 57.6 ± 12.83 55.8 ± 13.92	RCT, double-blind	Not mentioned	Randomized in a 1:1:1:1:1 ratio according to a computer-generated randomization schedule	Takeda Pharmaceutical Company

Age is presented as means ± standard deviations or as medians (ranges).

Allocated participants.

RCT, randomized controlled trial.

Risk of bias and quality of evidence

In evaluating the overall methodological quality of the included studies, we found that 71.42% were rated as low risk of bias, 28.57% as having some risk of bias, and none as high risk of bias (Figure 2). More specifically, two studies were classified as having “some” risk of bias in the intervention adherence and missing outcome data due to an open-label study and voluntary withdrawal.^14,16 The details of the risk of bias assessment are summarized in Table 2.

Figure 2.

Summary of quality assessment of studies included in the meta-analysis using the Cochrane risk of bias 2 tool.

Table 2.

Detailed quality assessment of included studies using the Cochrane risk of bias 2 tool.

First author	Year	Randomization process	Intervention adherence	Missing outcome data	Outcome measurement	Selective reporting	Overall RoB
Xiao	2020	L	L	L	L	L	L
Xiao	2024	L	L	S^a	L	L	S
Uemura	2025	L	S^b	L	L	L	S
Laine	2023	L	L	L	L	L	L
Ashida	2018	L	L	L	L	L	L
Ashida	2015 November	L	L	L	L	L	L
Ashida	2015 July	L	L	L	L	L	L

The study excluded one subjects from each group because of voluntary withdrawal.

An open-label study. The participants were aware of the intervention they received.

H, high risk of bias; L, low risk of bias; RoB, risk of bias; S, risk of bias.

Primary outcome: Evaluation of healing rate, maintenance of healing, and gastrin level

Across seven clinical trials (Figure 3), vonoprazan showed significant superiority over lansoprazole in both healing and maintenance of mucosal healing. The pooled OR for healing rate was 1.855 (95% CI: 1.386–2.482, p < 0.001; I² = 8.38%), and for recurrence-free rate 2.920 (95% CI: 1.636–5.211, p < 0.001; I² = 70.99%). Vonoprazan also produced higher serum gastrin levels (pooled OR = 2.707, 95% CI: 1.430–5.123, p = 0.002; I² = 87.31%).

Figure 3.

Forest plot illustrating the comparison of healing rate, recurrence-free rate, and gastrin level between the vonoprazan and lansoprazole groups. (a) Healing rate: OR = 1.855 (95% CI: 1.386–2.482, p < 0.001, I² = 8.38%). (b) Recurrence-free rate: OR = 2.920 (95% CI: 1.636–5.211, p < 0.001, I² = 70.99%). (c) Gastrin elevation: OR = 2.707 (95% CI: 1.430–5.123, p = 0.002, I² = 87.31%).

Meta-regression analyses (Figure 4(a) and (b)) demonstrated that longer treatment duration (coefficient = 0.0163 per day, p < 0.0001) and higher vonoprazan dosage (coefficient = 0.0293 per mg, p < 0.0001) were significantly associated with improved healing rates. Similarly, both duration (coefficient = 0.001 per day, p = 0.0013) and dose (coefficient = 0.0565 per mg, p = 0.0286) predicted higher recurrence-free rates (Figure 4(c) and (d)), indicating that vonoprazan efficacy increased with longer and more intensive treatment. In addition, meta-regression of serum gastrin elevation (Figure 4(e) and (f)) revealed a significant positive correlation with both treatment duration and vonoprazan dosage, where longer therapy was associated with greater gastrin elevation compared with lansoprazole (coefficient = 1.7972 per week, p < 0.0001) and higher vonoprazan doses showed a significant trend toward increased gastrin levels (coefficient = 9.3422 per mg, p = 0.0093).

Figure 4.

Meta-regression analysis of vonoprazan usage on esophagitis outcomes. (a) Longer duration of vonoprazan usage was significantly associated with improved healing rates (coefficient = 0.0163 per day, p < 0.0001). (b) Higher vonoprazan dosage further enhanced the healing rate over time (coefficient = 0.0293 per mg, p < 0.0001). (c) Vonoprazan usage significantly reduced the recurrence of esophagitis (coefficient = 0.001 per day, p = 0.0013). (d) Higher vonoprazan dosage was correlated with an increased recurrence-free rate (coefficient = 0.0565 per mg, p = 0.0286). (e) Longer treatment duration was associated with a greater increase in serum gastrin levels compared with lansoprazole (coefficient = 1.7972 per week, p < 0.0001). (f) Higher vonoprazan dosage was also significantly correlated with elevated serum gastrin (coefficient = 9.3422 per mg, p = 0.0093).

To further delineate categorical modifiers, subgroup analyses were performed according to dosage, treatment duration, and baseline disease severity (Figure 5(a)–(g)).

Figure 5.

Subgroup analyses of healing rate, recurrence-free rate, and gastrin elevation under vonoprazan therapy. Forest plots summarizing subgroup analyses comparing vonoprazan and lansoprazole across multiple clinical parameters. (a–c) Healing rate subgroup analyses by (a) vonoprazan dosage, (b) treatment duration, and (c) baseline disease severity (LA Grade C/D proportion). The healing advantage of vonoprazan increased with dose (up to 20 mg), longer treatment duration, and higher baseline severity. (d–f) Recurrence-free rate subgroup analyses by (d) dosage, (e) treatment duration, and (f) baseline disease severity. Vonoprazan demonstrated consistent superiority in maintaining mucosal healing across all subgroups, with pooled ORs indicating robust benefit over both short-term and long-term treatment horizons. (g) Serum gastrin elevation subgroup analysis by vonoprazan dosage. Both 10 and 20 mg regimens produced significantly higher gastrin levels than lansoprazole, with a greater magnitude of increase at higher doses (10 mg: mean difference = 452.2 pg/mL, 95% CI: 350.1–554.3; 20 mg: pooled mean difference = 113.9 pg/mL, 95% CI: 58.5–169.4; both p < 0.001).

For healing rate, the 20 mg regimen (OR = 1.896, 95% CI: 1.299–2.716, p = 0.001) and >28 days of therapy (OR = 2.379, 95% CI: 1.609–3.518, p < 0.001) yielded the strongest benefit, particularly in cohorts with higher LA Grade C/D proportion (OR = 2.368, 95% CI: 1.652–3.394, p < 0.001).

For the recurrence-free rate, vonoprazan demonstrated consistent superiority across all subgroups, including those stratified by dosage (Figure 5(d)), treatment duration (Figure 5(e)), and baseline disease severity (Figure 5(f)). Specifically, vonoprazan achieved higher recurrence-free rates across all dosing regimens (10 mg: OR = 5.152; 20 mg: OR = 1.852), treatment durations (12 weeks: OR = 5.318; 5 years: OR = 5.062; all p ⩽ 0.001), and both mild (LA A/B: pooled OR = 3.402, p = 0.021) and severe (LA C/D: pooled OR = 2.708, p = 0.045) esophagitis subgroups.

A dose-based analysis of serum gastrin elevation revealed a clear dose-dependent increase (10 mg: Δ = 452.2 pg/mL; 20 mg: Δ = 113.9 pg/mL; both p < 0.001).

Sensitivity testing using the one-study-removal method confirmed the robustness of these results (Figure 6), and funnel-plot symmetry with Egger’s test (p = 0.5748) indicated no publication bias.

Figure 6.

Sensitivity analysis of the effect of vonoprazan. (a) Healing rate, (b) recurrence-free rate, and (c) gastrin level. The analysis demonstrates that significance was maintained across all study removals.

Collectively, these findings demonstrate that vonoprazan’s efficacy and pharmacodynamic response are dose- and duration-dependent, accounting for much of the observed heterogeneity.

Secondary outcome: Adverse events

Of the 2387 participants receiving vonoprazan, 1090 (45.7%) reported TEAEs, including gastric polyps, nasopharyngitis, and hypertension. Similarly, adverse events were reported in the lansoprazole group, affecting 548 of 1367 participants (40.0%).

When stratified by severity, meta-analysis showed no significant difference between vonoprazan and lansoprazole in the incidence of TEAEs (pooled OR = 1.104, 95% CI: 0.922–1.321, p = 0.282, I² = 12.99%) or SAEs (pooled OR = 0.873, 95% CI: 0.584–1.305, p = 0.508, I² = 0%). These findings indicate that vonoprazan demonstrates a safety profile comparable to lansoprazole across all severity levels of adverse events.

Furthermore, meta-regression analysis revealed no significant correlation between higher vonoprazan dosage and the incidence of either TEAEs or SAEs (coefficient = 0.0020 per mg, p = 0.6817; Figure S2).

Discussion

In this systematic review and meta-analysis, we synthesized data from seven RCTs to evaluate the efficacy and safety of vonoprazan in terms of healing rate, recurrence-free rate, gastrin levels, and adverse events. Vonoprazan demonstrated superior efficacy over lansoprazole for both mucosal healing and maintenance of remission. Meta-regression further indicated that longer treatment duration and higher dosage were associated with improved healing and recurrence-free outcomes.

With respect to safety, vonoprazan showed a comparable incidence of treatment-emergent and severe adverse events relative to lansoprazole, indicating that its enhanced acid-suppressive potency does not compromise tolerability. The absence of a dose-dependent increase in adverse events further supports its favorable safety profile across therapeutic regimens.

In addition, vonoprazan produced a greater rise in serum gastrin levels, consistent with its sustained acid suppression. Sensitivity analyses confirmed the robustness of these findings, as the overall trends remained unchanged after sequential exclusion of individual studies.

Vonoprazan is a novel P-CAB designed for the treatment of gastric acid-related disorders.²⁷ Unlike PPIs, vonoprazan directly and reversibly inhibits the H⁺/K⁺-ATPase enzyme in gastric parietal cells, effectively blocking acid secretion.⁴ This competitive inhibition leads to rapid suppression of gastric acid, often within hours of administration. One of vonoprazan’s key advantages is its long-lasting acid suppression, maintaining consistent inhibition without the fluctuations in plasma concentration observed with PPIs. In addition, its stability in acidic conditions eliminates the need for enteric coating, allowing for administration with or without food.³ Due to these pharmacological benefits, vonoprazan has demonstrated superior efficacy in H. pylori eradication therapy and in managing PPI-refractory GERD.^3,28

The findings of this meta-analysis highlight vonoprazan’s clinical advantages over traditional PPIs in the management of EE, particularly in severe cases and PPI-refractory patients. Its superior efficacy in both induction and maintenance therapy establishes vonoprazan as a transformative option for acid suppression.

Vonoprazan demonstrates statistically significant superiority over Lansoprazole in healing severe EE (Los Angeles Grade C/D). With an 8-week healing rate of 98.7% compared to 87.5% for lansoprazole, vonoprazan is well-positioned as a first-line treatment, especially for patients who do not respond adequately to PPIs.^10,16

Vonoprazan provides more effective long-term prevention of EE recurrence than PPIs. At 24 weeks, recurrence rates were significantly lower with vonoprazan (2.0% for 20 mg, 5.1% for 10 mg) compared to lansoprazole (16.8%). This suggests that vonoprazan is particularly beneficial for high-risk patients with frequent relapses, offering sustained acid suppression with lower recurrence rates.^12,25

Vonoprazan’s rapid onset of action further distinguishes it from PPIs. In severe EE cases, it achieved an 88% healing rate at 2 weeks, significantly outperforming lansoprazole (63.9%; p = 0.0008). In addition, in CYP2C19 extensive metabolizers—who often exhibit reduced PPI effectiveness—vonoprazan maintained superior healing rates (90% vs 79.3%; p = 0.0065). These findings underscore its potential for overcoming genetic variability in PPI response.¹² Vonoprazan overcomes limitations of PPIs in genetically predisposed populations and severe EE cases.

The 5-year VISION study confirmed the long-term safety of vonoprazan, with no malignant gastric mucosal changes observed despite persistently elevated serum gastrin levels. Although enterochromaffin-like (ECL) cell hyperplasia occurred more frequently with vonoprazan than with PPIs, no progression to neoplasia was documented, supporting its overall suitability for chronic use.¹⁴ Consistent with these findings, our pooled analysis showed comparable rates of treatment-emergent and SAEs between vonoprazan and lansoprazole, indicating that its potent and sustained acid suppression does not compromise overall tolerability or increase the risk of severe complications.

Nevertheless, the biological relevance of sustained hypergastrinemia should not be overlooked. Prolonged gastrin elevation can induce ECL cell proliferation, foveolar hyperplasia, and parietal cell hypertrophy. Long-term potent acid inhibition has also been associated with the development of benign fundic gland polyps, likely secondary to mucosal remodeling under chronic hypergastrinemic stimulation. Previous studies have suggested potential associations between profound acid inhibition induced hypergastrinemia and the development of gastric or neuroendocrine neoplasia.²⁹ While current evidence does not indicate an established causal relationship, periodic surveillance and monitoring of gastrin levels during long-term PCAB therapy remain advisable. Pharmacologic modulation—such as co-administration of agents like pirenzepine or gastrin receptor antagonists (e.g., netazepide)—may further help mitigate persistent hypergastrinemia while maintaining adequate acid control.³⁰

Vonoprazan provides rapid and sustained symptom relief, particularly for nighttime heartburn, improving sleep quality in patients with EE. By day 1, 31.3% of vonoprazan-treated patients achieved sustained relief (⩾7 consecutive days) compared to 12.5% with lansoprazole. This rapid and stable acid suppression highlights vonoprazan’s potential as a preferred alternative to PPIs in GERD management.⁴

Among the seven studies included, only one RCT evaluated the 40 mg vonoprazan dose in a dose-ranging design. Meta-regression demonstrated a dose-dependent trend in healing efficacy (coefficient = 0.0293 per mg; p < 0.001), with numerically higher healing rates observed at 40 mg (97.0% at Week 4). However, in the corresponding subgroup analysis, the 40 mg regimen did not reach statistical significance because of the small sample size and wide CI. Consistent with the pivotal evidence that established 20 mg as the standard dose, the pooled data suggest that 20 mg achieves near-ceiling efficacy, including in patients with severe EE (LA C/D), while maintaining an excellent safety profile. Therefore, routine escalation to 40 mg is not warranted for low-grade disease, although higher doses may be reserved for refractory or high-acid-burden phenotypes pending further trials.¹¹

To further examine whether the optimal vonoprazan regimen varies by disease severity, we performed subgroup analyses stratified by the study-level proportion of patients with LA grade C/D esophagitis (median-split approach).

For healing rate, vonoprazan demonstrated a markedly greater benefit over lansoprazole in studies with a higher proportion of severe cases (pooled OR = 2.368, p < 0.001), whereas the effect was smaller and not significant in studies dominated by mild (A/B) cases (pooled OR = 1.381, p = 0.107). This suggests that the therapeutic margin of vonoprazan becomes more clinically evident in patients with advanced mucosal injury, consistent with its stronger acid suppression profile.

By contrast, for recurrence-free rate, vonoprazan maintained a significant advantage in both strata (A/B: pooled OR = 3.402, p = 0.021; Grade C/D: pooled OR = 2.708, p = 0.045). These findings indicate that vonoprazan provides sustained mucosal protection across all severities, and its long-term efficacy is not limited to severe EE. In clinical practice, this implies that dose escalation (e.g., 40 mg) is generally unnecessary once healing is achieved, whereas treatment duration and maintenance dosing play a more pivotal role in preventing relapse.

Overall, the observed pattern suggests that vonoprazan 20 mg daily offers an optimal balance between efficacy and safety across severities, while prolonged maintenance or selective dose escalation may be reserved for refractory or high-acid-output phenotypes.

A key strength of this meta-analysis lies in its comprehensive evaluation of vonoprazan across all grades of EE, extending beyond previous studies that primarily focused on severe cases (LA Grade C/D). By encompassing a broader spectrum of disease severity, our findings provide more generalizable evidence of vonoprazan’s therapeutic efficacy. In addition, the inclusion of both healing and recurrence-free outcomes, as well as serum gastrin analyses, offers novel insights into its long-term pharmacodynamic profile. The subgroup and meta-regression analyses further elucidate dose–response and duration-dependent trends, suggesting that vonoprazan’s acid-suppressive effects may confer sustained mucosal protection.

Nevertheless, several limitations should be acknowledged. The relatively short follow-up durations of most included trials restrict the assessment of long-term safety, particularly regarding mucosal alterations such as gastric polyps and ECL cell hyperplasia. Variations in study design, treatment protocols, and patient characteristics may have contributed to heterogeneity across analyses. Moreover, vonoprazan dose and treatment duration are often intensified concurrently in more severe or refractory cases, indicating that these variables may not be fully independent. With only seven available studies, our meta-regression was underpowered for robust multivariable modeling and should therefore be regarded as exploratory. To complement this, dose- and duration-based subgroup analyses were additionally performed, which demonstrated consistent trends supporting the meta-regression findings. Although random-effects models were applied to reduce potential bias, further prospective trials directly comparing different dose–duration strategies are needed to clarify their independent effects. Finally, additional long-term and real-world evidence, including head-to-head comparisons with other PPIs, will be essential to confirm vonoprazan’s sustained efficacy and safety.

To the best of our knowledge, a previous meta-analysis primarily focused on clinical recommendations, suggesting that vonoprazan should be prioritized for patients with severe EE (LA Grade C/D) due to its superior healing rates, particularly during the early treatment phase.² Our study presents not only severe EE, but also all types of EE have benefited from vonoprazan. By contrast, our study extends these findings by demonstrating that vonoprazan benefits not only patients with severe EE but also those with all EE grades. In addition, we conducted analyses on recurrence rates and gastrin levels, both of which further supported the advantages of vonoprazan. Moreover, our meta-regression revealed a dose-dependent effect and long-term protective benefits of vonoprazan, reinforcing its potential as a preferred treatment option.

Conclusion

This systematic review and meta-analysis of seven RCTs provides strong evidence supporting the superiority of vonoprazan over lansoprazole in the treatment of EE. Vonoprazan significantly improves healing rates, reduces recurrence, and leads to higher gastrin levels, with a clear dose-dependent and time-dependent relationship. Notably, these benefits are achieved without an increase in adverse events, confirming its safety profile.

Vonoprazan’s rapid acid suppression, sustained therapeutic effect, and effectiveness in CYP2C19 extensive metabolizers position it as a preferred treatment, especially for patients with severe or refractory EE. Long-term safety data further support its potential for chronic use without significant risks. Given these findings, vonoprazan should be considered a first-line therapy for severe EE and a viable alternative to PPIs for broader patient populations.

Future research should focus on real-world studies, direct comparisons with other PPIs, and long-term outcomes to further establish vonoprazan’s clinical role. Nonetheless, the current evidence underscores its transformative impact on acid suppression therapy, offering a more effective and reliable option for managing EE.

Supplemental Material

sj-docx-1-tag-10.1177_17562848251406098 – Supplemental material for Dose and duration shape the efficacy of vonoprazan versus lansoprazole for erosive esophagitis: insights from meta-regression

Supplemental material, sj-docx-1-tag-10.1177_17562848251406098 for Dose and duration shape the efficacy of vonoprazan versus lansoprazole for erosive esophagitis: insights from meta-regression by Po-Feng Huang, Hsuan-Wei Chen and Yao-Jen Liang in Therapeutic Advances in Gastroenterology

Supplemental Material

sj-docx-2-tag-10.1177_17562848251406098 – Supplemental material for Dose and duration shape the efficacy of vonoprazan versus lansoprazole for erosive esophagitis: insights from meta-regression

Supplemental material, sj-docx-2-tag-10.1177_17562848251406098 for Dose and duration shape the efficacy of vonoprazan versus lansoprazole for erosive esophagitis: insights from meta-regression by Po-Feng Huang, Hsuan-Wei Chen and Yao-Jen Liang in Therapeutic Advances in Gastroenterology

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Po-Feng Huang

Supplemental material

Supplemental material for this article is available online.

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