Gong EJ, Bang CS, Lee JJ, Baik GH. Comparative efficacy and pharmacological heterogeneity of individual potassium-competitive acid blockers: A systematic review and network meta-analysis. World J Gastroenterol 2026; 32(39): 121372 [DOI: 10.3748/wjg.121372]
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Chang Seok Bang, MD, PhD, Department of Internal Medicine, Hallym University College of Medicine, Sakju-ro 77, Chuncheon 24253, Gangwon-do, South Korea. cloudslove@naver.com
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Gong EJ, Bang CS, Lee JJ, Baik GH. Comparative efficacy and pharmacological heterogeneity of individual potassium-competitive acid blockers: A systematic review and network meta-analysis. World J Gastroenterol 2026; 32(39): 121372 [DOI: 10.3748/wjg.121372]
World J Gastroenterol. Oct 21, 2026; 32(39): 121372 Published online Oct 21, 2026. doi: 10.3748/wjg.121372
Comparative efficacy and pharmacological heterogeneity of individual potassium-competitive acid blockers: A systematic review and network meta-analysis
Eun Jeong Gong, Chang Seok Bang, Department of Internal Medicine, Hallym University College of Medicine, Chuncheon 24253, Gangwon-do, South Korea
Jae Jun Lee, Institute of New Frontier Research, Hallym University College of Medicine, Chuncheon 24253, Gangwon-do, South Korea
Gwang Ho Baik, Department of Gastroenterology, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon 24253, Gangwon-do, South Korea
Co-corresponding authors: Chang Seok Bang and Jae Jun Lee.
Author contributions: Gong EJ and Bang CS were responsible for writing-original draft; Bang CS was responsible for conceptualization, formal analysis, methodology, project administration, and resources; Bang CS and Lee JJ were responsible for writing-review and editing as co-corresponding authors; Gong EJ, Bang CS, Lee JJ, and Baik GH were responsible for data curation, investigation; Lee JJ was responsible for funding acquisition.
AI contribution statement: After all point-by-point responses were written, the English proofreading was performed by the LLM. This was done by Grammarly and Gemini.
Supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT), No. RS-2023-00223501.
Conflict-of-interest statement: All authors declare no conflict of interest in publishing the manuscript.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Corresponding author: Chang Seok Bang, MD, PhD, Department of Internal Medicine, Hallym University College of Medicine, Sakju-ro 77, Chuncheon 24253, Gangwon-do, South Korea. cloudslove@naver.com
Received: March 24, 2026 Revised: April 17, 2026 Accepted: June 5, 2026 Published online: October 21, 2026 Processing time: 171 Days and 0.6 Hours
Abstract
BACKGROUND
Vonoprazan consistently demonstrates superior Helicobacter pylori eradication (HPE) rates compared to other potassium-competitive acid blockers (P-CABs), yet the pharmacological basis for this heterogeneity remains unclear. We hypothesized that the acid dissociation constant (pKa) – which determines acid stability and parietal cell accumulation – may explain the differential efficacy among individual P-CABs.
AIM
To examine whether pKa values predict clinical efficacy of P-CABs for HPE and erosive esophagitis healing.
METHODS
A systematic review and network meta-analysis were conducted. Randomized controlled trials (RCTs) comparing P-CABs with proton pump inhibitors (PPIs) were identified from core databases (up to January 2026). Risk of bias was assessed using RoB 2.0 and certainty of evidence using GRADE.
RESULTS
Thirty RCTs (7639 patients) were included for HPE. High-pKa P-CABs (vonoprazan of 9.06, keverprazan of 9.12) achieved 82%-84% eradication in clarithromycin-resistant infections vs 32%-40% with PPIs, while low-pKa P-CAB achieved only 47.8% (not significant vs PPI). For erosive esophagitis (10 RCTs; 4196 patients), high-pKa zastaprazan (9.95) achieved 100% Los Angeles classification grade C/D healing vs 83.3% with esomeprazole, whereas low-pKa P-CABs showed inferior outcomes. Spearman correlation analysis revealed a positive association between pKa and efficacy (ρ = 0.80). However, fexuprazan (pKa of 9.04) showed PPI-equivalent outcomes despite high-pKa, highlighting pKa as necessary but not sufficient for clinical efficacy. Network ranking confirmed high-pKa P-CABs as top-ranked agents. No publication bias was detected.
CONCLUSION
P-CAB efficacy may not be uniform across the class. High-pKa P-CABs (≥ 9.0) were associated with higher eradication rates in clarithromycin-resistant infections and superior healing in severe esophagitis, whereas low-pKa P-CABs showed limited advantages over PPIs. The pKa may serve as a hypothesis-generating pharmacological parameter, though all P-CAB comparisons were indirect and prospective validation is needed.
Core Tip: Potassium-competitive acid blockers (P-CABs) suppress acid faster and more consistently than proton pump inhibitors. Over 30 meta-analyses pooled all P-CABs as a single class. Guidelines treat individual P-CABs as interchangeable. Individual P-CABs differ substantially in clinical outcomes, suggesting that efficacy may not be uniform across the class. Acid dissociation constant (pKa) values showed a positive correlation with clinical efficacy, with high-pKa P-CABs (vonoprazan, keverprazan) achieving 82%-84% eradication in clarithromycin-resistant Helicobacter pylori vs 47.8% for low-pKa tegoprazan. However, fexuprazan (pKa of 9.04) did not follow this pattern, demonstrating that pKa alone is insufficient to predict outcomes. The pKa may be one contributing factor but is not sufficient alone. Multiple pharmacological properties likely contribute to antisecretory effectiveness and clinical outcomes. These findings generate the hypothesis that pKa may inform P-CAB selection, particularly for clarithromycin-resistant infection and severe esophagitis, pending prospective validation.
Citation: Gong EJ, Bang CS, Lee JJ, Baik GH. Comparative efficacy and pharmacological heterogeneity of individual potassium-competitive acid blockers: A systematic review and network meta-analysis. World J Gastroenterol 2026; 32(39): 121372
Helicobacter pylori (H. pylori) eradication has entered a new therapeutic era. Potassium-competitive acid blockers (P-CABs) provide faster, more potent, and CYP2C19-independent acid suppression compared to proton pump inhibitors (PPIs), and have been incorporated into treatment algorithms for both first-line and rescue therapy[1,2]. With five P-CABs now clinically available – vonoprazan (VPZ), tegoprazan (TPZ), fexuprazan (FXP), keverprazan (KVP), and zastaprazan (ZPZ) – clinicians might reasonably assume these agents are pharmacologically interchangeable.
The clinical evidence, however, tells a different story. VPZ-based regimens consistently achieve eradication rates exceeding 90%, even in clarithromycin (CLR)-resistant infections where PPI-based therapies fail[3]. In contrast, trials of other P-CABs have produced mixed results: Some demonstrate modest superiority over PPIs, while others show no significant advantage[4,5]. More than 30 meta-analyses have compared “P-CAB” vs “PPI” as a class, yet this approach obscures a fundamental question – why do individual P-CABs perform so differently?
One potential explanation may lie in basic pharmacology, although differences in clinical trial design, patient populations, dosing regimens, and regional resistance patterns may also contribute. P-CABs function as weak bases that accumulate in parietal cell secretory canaliculi through pH-dependent ion-trapping[6]. The efficiency of this accumulation depends critically on the acid dissociation constant (pKa): Compounds with higher pKa values remain protonated and trapped at lower pH, enabling sustained inhibition even under conditions of maximal acid secretion (Supplementary Figure 1). This property directly affects the duration of intragastric pH elevation – and maintaining pH above 6 for extended periods is essential for amoxicillin (AMO) stability and bactericidal activity[7].
This mechanistic framework carries particular significance for CLR-resistant H. pylori, a growing global challenge[8]. When CLR loses efficacy, eradication depends almost entirely on AMO – a time-dependent antibiotic whose bactericidal activity requires prolonged exposure at gastric pH > 5.5[7]. Under these conditions, the margin between therapeutic success and failure narrows considerably, and even modest differences in acid suppression may translate into clinically meaningful differences in eradication rates. Similarly, in severe erosive esophagitis (EE) [Los Angeles classification (LA) grade C/D], where mucosal healing demands sustained nocturnal acid control, the pharmacological ceiling of the acid suppressant becomes the rate-limiting factor.
Remarkably, marketed P-CABs span nearly a fivefold range in pKa, from 5.1 (TPZ) to 9.95 (ZPZ)[6,8]. This degree of pharmacological heterogeneity is unprecedented among drugs within a single therapeutic class (Supplementary Figure 2). If pKa influences clinical efficacy, then P-CABs may not be fully interchangeable, and the “class effect” assumption underlying current prescribing may be overly simplistic.
To date, no study has systematically examined whether pKa predicts clinical outcomes across individual P-CABs. We conducted a systematic review (SR) and network meta-analysis (NMA) comparing all five marketed P-CABs for H. pylori eradication and EE healing, with pre-specified correlation analyses between pKa values and pooled treatment effects. Our hypothesis was that high-pKa P-CABs would demonstrate superior efficacy, particularly in settings requiring profound and sustained acid suppression – CLR-resistant H. pylori and severe EE.
MATERIALS AND METHODS
Study design and registration
This SR and NMA was registered on PROSPERO (CRD420261290164) and conducted following Preferred Reporting Items for Systematic reviews and Meta-Analyses checklist[9,10]. Full methods (including search strategy, eligibility criteria, study selection, data extraction, risk of bias evaluation, statistics) are detailed in Supplementary material.
Information sources and search strategy
PubMed, EMBASE, CENTRAL, and Web of Science were searched from inception through January 15, 2026.
Eligibility criteria
Studies were selected based on the patient, intervention, comparison, outcome framework[11]. We included randomized controlled trials (RCTs) comparing any of five marketed P-CABs (VPZ, TPZ, FXP, KVP, ZPZ) with PPIs for H. pylori eradication (first-line therapy) or EE healing (LA grade A-D). Trials with different antibiotic regimens between arms were excluded.
The pKa values
The pKa values were obtained from published literature and verified with manufacturers: (1) VPZ (9.06)[12]; (2) TPZ (5.1)[6,13]; (3) FXP (9.04)[14]; (4) KVP (9.12)[6]; and (5) ZPZ (9.95) (Supplementary Table 1)[6,8]. These values were derived from published experimental data; as measurement conditions (e.g., potentiometric titration, ultraviolet-spectrophotometry) were not standardized across all agents, minor methodological variation in reported pKa values cannot be excluded.
Risk of bias assessment
Risk of bias was assessed using the Cochrane ROB 2.0 tool for RCTs[15].
Statistical analysis
NMA was performed using frequentist random-effects models with PPI as the common comparator[16]. Treatment rankings used P-scores. The pKa-efficacy correlation was assessed using Spearman’s coefficient; threshold analysis dichotomized P-CABs at pKa = 9.0. Statistical power was estimated via Monte Carlo simulation (3000 iterations). Publication bias was evaluated by funnel plots and Egger’s regression test[17].
RESULTS
Study selection
From 2441 records, 40 RCTs[3,18-56] met inclusion criteria: (1) 30 for H. pylori (n = 7,639)[3,18-46]; and (2) 10 for EE (n = 4196) (Figure 1)[47-56]. Full methods (including exclusion criteria, study selection, data extraction, methodology evaluation, certainty of evidence, statistical analysis etc.) are detailed in Supplementary material.
Figure 1 Preferred Reporting Items for Systematic reviews and Meta-Analyses flow diagram illustrating the study selection process.
The systematic literature search identified 2441 records from four databases (PubMed: n = 111, EMBASE: n = 1107, Cochrane Library: n = 703, Web of Science: n = 520). After removing 1291 duplicates, 1150 unique records were screened by title and abstract. Following full-text review of 445 articles, 405 were excluded (narrative reviews: n = 6, incomplete data: n = 231, study protocols: n = 11, systematic reviews/guidelines: n = 157). Finally, 40 randomized controlled trials were included: (1) 30 studies for Helicobacter pylori eradication; and (2) 10 studies for erosive esophagitis healing.
Study characteristics
H. pylori eradication studies: A total of 30 RCTs (32 trial comparisons) evaluating P-CAB-based regimens for first-line H. pylori eradication were included (Table 1)[3,18-46]. Studies were conducted across 6 countries: (1) China (n = 19)[22,23,25-30,32,33,35-42,46]; (2) Korea (n = 5)[21,24,31,34,43]; (3) Japan (n = 3)[18-20]; (4) United States/Europe (n = 1)[3]; (5) Taiwan (n = 1)[45]; and (6) Egypt (n = 1)[44]. The total sample size was 7639 patients (P-CAB arms: 4020; PPI arms: 3619). Four P-CAB types were represented: (1) VPZ (21 studies, 22 comparisons)[3,18-20,22,23,25-30,32,33,35,38,40,42,44-46]; (2) TPZ (7 studies, 8 comparisons)[21,24,34,36,39,41,43]; (3) KVP (1 study)[37]; and (4) FXP (1 study)[31]. Treatment regimens included triple therapy (n = 11)[3,18-21,23,31,35,42-44], dual therapy (n = 16)[3,22,26-30,32,33,36,38-41,44,45], bismuth quadruple therapy (n = 4)[24,25,37,46]; and sequential therapy (n = 1)[34]. Treatment duration ranged from 7 days to 14 days, with 14-day regimens predominating (n = 20)[3,23-26,28-31,35-37,39-46] and 7-day regimens limited to early Japanese and Korean studies (n = 4)[18-21]; 10-day regimens accounted for the remaining 8 comparisons[22,27,32-34,38]. PPI comparators included esomeprazole (ESO)-based regimens (n = 18)[23-27,30,33-42,44,46], lansoprazole (LPZ) (n = 5)[3,18,21,31,43], rabeprazole (n = 4)[19,22,28,45], ilaprazole (n = 2)[29,32], and mixed PPI (n = 1)[20].
Table 1 Characteristics of included randomized controlled trials comparing potassium-competitive acid blocker vs proton pump inhibitor for Helicobacter pylori eradication (n = 30 studies, 32 comparisons).
Ten RCTs comparing P-CABs vs PPIs for EE healing were included (Table 2)[47-56]. Studies were conducted in Japan (n = 2)[47,48], South Korea (n = 3)[52,53,55], China (n = 4)[49,51,54,56], and United States/Europe (n = 1)[50]. The total sample size was 4196 patients (P-CAB arms: 2370; PPI arms: 1826). Five P-CAB types were represented: (1) VPZ (4 studies)[47-50]; (2) KVP (1 study)[51]; (3) ZPZ (1 study)[52]; (4) FXP (2 studies)[53,54]; and (5) TPZ (2 studies)[55,56]. All studies evaluated 8-week mucosal healing as the primary endpoint. PPI comparators included LPZ 30 mg (n = 5)[47-51] and ESO 40 mg (n = 5)[52-56]. LA grade C/D subgroup data were adequately reported in 7 studies: (1) Ashida et al[47] (VPZ; n = 245); (2) Ashida et al[48] (VPZ; n = 147); (3) Laine et al[50] (VPZ; n = 351); (4) Chen et al[51] (KVP; n = 49); (5) Xiao et al[49] (VPZ; n = 144); (6) Oh et al[52] (ZPZ; n = 12); and (7) Zhuang et al[54] (FXP; n = 98) reported LA C/D data. Low-pKa P-CAB studies (TPZ[55,56], FXP[53,54]) had limited or unreported LA C/D subgroup data, with FXP notably showing inferior outcomes vs PPI in severe esophagitis (80% vs 91%)[54].
Table 2 Characteristics of included erosive esophagitis randomized controlled trials (n = 10 studies).
Across H. pylori studies, mean patient age ranged from 42 years to 58 years, with male predominance (51%-68%)[18-46]. Baseline H. pylori infection was confirmed by 13C-urea breath test (UBT), rapid urease test, histology, or stool antigen test. Exclusion criteria were generally consistent across trials: (1) Previous eradication attempts; (2) Recent antibiotic or PPI use; and (3) Severe comorbidities. In EE studies, patients had endoscopically confirmed LA grade A-D esophagitis with mean age ranging from 45 years to 56 years[47-56]. The proportion of severe esophagitis (LA grade C/D) varied substantially: 34.3% in PHALCON-EE[50], 20.6% in Chen et al[51], 36.4% in Ashida et al[48], but only 4.3% in Oh et al[52] and ≤ 5% in TPZ studies[55,56], limiting subgroup analyses for low-pKa P-CABs.
Synthesis of results
Overall efficacy of H. pylori eradication: In the NMA of 30 RCTs (32 comparisons, n = 7639)[3,18-46], P-CABs demonstrated significantly higher eradication rates compared with PPIs [pooled odds ratio (OR) = 1.49, 95%CI: 1.27-1.74; Figure 2, Supplementary Figures 3 and 4]. Heterogeneity was low (I² = 15.16%). Among individual P-CABs, VPZ showed the highest efficacy vs PPI (OR = 1.78, 95%CI: 1.47-2.30) (Supplementary Table 2)[3,18-20,22,23,25-30,32,33,35,38,40,42,44-46], followed by KVP (OR = 1.51, 95%CI: 1.08-2.12)[37]. TPZ showed modest benefit (OR = 1.29, 95%CI: 1.04-1.60)[21,24,34,36,39,41,43], and FXP demonstrated a trend toward higher eradication that did not reach statistical significance (OR = 1.49, 95%CI: 0.97-2.29)[31].
Figure 2 Forest plot of network meta-analysis comparing potassium-competitive acid blockers vs proton pump inhibitors for Helicobacter pylori eradication.
Each row represents a randomized controlled trial, with squares indicating point estimates of odds ratio and horizontal lines representing 95%CIs. Diamond at the bottom shows the pooled effect estimate. Overall heterogeneity was low (I² = 15.16%). P-CAB: Potassium-competitive acid blocker; PPI: Proton pump inhibitor.
CLR-resistant infections: Four studies (five comparisons) reported CLR resistance subgroup data (Table 3)[3,18,37,43]. High-pKa P-CABs (VPZ pKa of 9.06) achieved markedly superior eradication in CLR-resistant infections: Pooled OR = 3.32 (95%CI: 1.79-6.16, I² = 72.3%; Figure 3)[3,18,37,43]. VPZ-based regimens achieved 65.8%-82.0% eradication in CLR-resistant strains vs 31.9%-40.0% with PPI-based regimens, representing an absolute advantage of +33.9% to +42.0%[3,18]. The VPZ-only subgroup (3 arms) demonstrated OR = 5.07 (95%CI: 3.19-8.06). KVP showed 83.5% vs 77.0% eradication (OR = 1.51, 95%CI: 0.83-2.76)[37], with the attenuated effect likely attributable to the high baseline eradication rate (77.0%) in the Chinese PPI arm. In contrast, low-pKa TPZ (pKa of 5.1) achieved only 47.8% eradication in CLR-resistant infections vs 35.5% with PPI (OR = 1.67, not significant)[43], demonstrating no significant advantage.
Figure 3 Forest plot of individual potassium-competitive acid blockers (vonoprazan, tegoprazan, keverprazan) vs proton pump inhibitor for clarithromycin-resistant Helicobacter pylori eradication.
Each row represents a randomized controlled trial, with squares indicating point estimates of odds ratio (OR) and horizontal lines representing 95%CIs. Diamond at the bottom shows the pooled effect estimate. Five studies reported clarithromycin resistance subgroup data. High-acid dissociation constant; potassium-competitive acid blockers (vonoprazan, keverprazan) and low-acid dissociation constant tegoprazan achieved pooled OR = 3.32 (95%CI: 1.79-6.16) compared with proton pump inhibitors (PPIs). Vonoprazan-based regimens (3 arms) achieved 65.8%-82.0% eradication in clarithromycin-resistant infections vs 31.9%-40.0% with PPIs. Keverprazan showed 83.5% vs 77.0% with a not significant OR of 1.51 (95%CI: 0.83-2.76), likely attenuated by the high baseline eradication rate in the Chinese PPI arm. Tegoprazan showed 47.8% vs 35.5% (OR = 1.67, not significant). Heterogeneity was substantial (I² = 72.3%, P = 0.006), reflecting geographic and methodological differences. P-CAB: Potassium-competitive acid blocker; PPI: Proton pump inhibitor.
Table 3 Results of meta-analysis for the potassium-competitive acid blocker vs proton pump inhibitor efficacy in clarithromycin-resistant Helicobacter pylori infections.
Table 3 summarizes the meta-analysis of CLR-resistant subgroup data[3,18,37,43]. Murakami et al[18] demonstrated OR = 6.83 (95%CI: 3.63-12.86), reflecting VPZ’s substantial advantage in Japanese populations with high CLR resistance rates (approximately 30%-40%). The PHALCON-HP data[3] from Western populations (CLR resistance approximately 25%) showed consistent but somewhat attenuated effects (OR = 4.09 for triple therapy, OR= 4.89 for dual therapy), likely reflecting differences in resistance patterns and patient populations. KVP (Tan et al[37]) showed a not significant OR of 1.51, attributable to the unusually high PPI-arm eradication rate (77.0%) in the Chinese cohort. TPZ (Park et al[43]) achieved only 47.8% vs 35.5% (OR = 1.67, not significant), confirming that low-pKa P-CABs fail to overcome CLR resistance. Overall heterogeneity was substantial (I² = 72.3%, P = 0.006), explained by geographic and methodological differences across studies.
Overall healing rates of EE: In the NMA of 10 RCTs (n = 4,196)[47-56], P-CABs achieved numerically higher 8-week healing rates compared with PPIs (pooled OR = 1.47, 95%CI: 1.03-2.09, Figure 4, Supplementary Figures 5 and 6). Overall healing rates were high across all P-CABs (91.1%-99.1%) and PPIs (84.6%-99.1%), with ceiling effects limiting differentiation in mild-to-moderate esophagitis (LA grade A/B) (Supplementary Table 3).
Figure 4 Forest plot of network meta-analysis comparing potassium-competitive acid blockers vs proton pump inhibitors for 8-week erosive esophagitis healing.
Each row represents a randomized controlled trial, with squares indicating point estimates of odds ratio and horizontal lines representing 95%CIs. Diamond at the bottom shows the pooled effect estimate. Ten randomized controlled trials comparing five potassium-competitive acid blockers [vonoprazan, tegoprazan, fexuprazan (FXP), keverprazan, zastaprazan] with proton pump inhibitors (PPIs) for erosive esophagitis healing are shown. High-acid dissociation constant (pKa) potassium-competitive acid blockers demonstrated significant superiority, while tegoprazan (pKa of 5.1) and FXP (pKa of 9.04, the “FXP paradox”) showed no significant advantage over PPIs. Overall healing rates were high across all treatments (91%-99%), with ceiling effects limiting differentiation in mild-to-moderate esophagitis. Notably, FXP (pKa of 9.04) showed no significant advantage over PPIs (odds ratio = 0.95) despite high-pKa, illustrating the FXP paradox. P-CAB: Potassium-competitive acid blocker; PPI: Proton pump inhibitor.
Severe esophagitis (LA grade C/D): LA grade C/D subgroup data were available in 6 studies (Supplementary Table 4)[48-52,54]. High-pKa P-CABs demonstrated superior healing in severe esophagitis: (1) VPZ achieved 84.0%-100% healing vs 71.8%-87.5% with LPZ (pooled advantage +13.4%)[48-50]; (2) KVP achieved 91.7% vs 80.0% (+11.7%)[51]; and (3) ZPZ achieved 100% vs 83.3% (+16.7%, n = 6 per group)[52]. In contrast, FXP (pKa of 9.04) showed paradoxically inferior outcomes vs ESO in the LA C/D subgroup (80% vs 91%, -11%)[54], and TPZ (pKa of 5.1) lacked adequate LA C/D data for meaningful comparison[55,56].
Additional analyses
The pKa-efficacy correlation analysis: To explore the pharmacological basis for differential P-CAB efficacy, we analyzed the correlation between P-CAB pKa values and clinical outcomes (Figure 5, Supplementary Figure 7, Supplementary Table 5). Spearman correlation analysis revealed positive associations between P-CAB pKa values and clinical efficacy in both indications (Figure 5A). For H. pylori eradication, pKa correlated positively with pooled OR (ρ = 0.80, P = 0.20); however, with only four marketed P-CABs available for analysis (n = 4), statistical power was fundamentally limited – even a perfect correlation (ρ = 1.0) cannot achieve P < 0.05 at this sample size. Despite this statistical limitation, the observed correlation direction is consistent with the mechanistic hypothesis, and subgroup analysis of CLR-resistant infections provides compelling supporting evidence: High-pKa VPZ (82%) and KVP (84%) dramatically outperformed PPIs (40%), while low-pKa TPZ failed (47.8% vs 35.5%, not significant). For EE healing, Spearman correlation between pKa and pooled OR showed a large positive effect size (ρ = 0.80) but did not reach statistical significance (P = 0.104) due to limited sample size (n = 5, power = 30%). With FXP’s experimentally determined pKa of 9.04[14], four of five P-CABs cluster above pKa of 9.0, precluding meaningful threshold analysis at this cutoff. Notably, the positive correlation was maintained despite FXP being an outlier (Figure 5B): FXP (pKa of 9.04, OR = 0.95) performed at PPI level despite high-pKa, whereas VPZ (pKa of 9.06, OR = 1.80), KVP (pKa of 9.12, OR = 2.56), and ZPZ (pKa of 9.95, OR = 2.51) showed clear superiority. This “FXP paradox” – high-pKa with PPI-equivalent outcomes – strongly suggests that pKa is necessary but not sufficient for P-CAB efficacy, with protein binding (FXP 93% vs VPZ 80%-88%) and intrinsic binding affinity likely serving as additional determinants. In the LA grade C/D subgroup where adequate data were available (n = 4), pKa showed perfect rank correlation with efficacy (Spearman ρ = 1.00). This correlation was consistent across both indications, with high-pKa P-CABs demonstrating consistent superiority in challenging clinical scenarios (CLR-resistant H. pylori, LA grade C/D esophagitis), while low-pKa TPZ (pKa of 5.1) showed no significant advantage (Supplementary Table 6).
Figure 5 The acid dissociation constant-efficacy relationship among potassium-competitive acid blockers.
A: Scatter plot of acid dissociation constant (pKa) vs pooled odds ratio (OR) for Helicobacter pylori eradication [n = 4 potassium-competitive acid blockers (P-CABs), Spearman ρ = 0.80, P = 0.20]; B: Scatter plot of pKa vs pooled OR for erosive esophagitis healing (n = 5 P-CABs, Spearman ρ = 0.80, P = 0.104). In both panels, fexuprazan (FXP) (pKa of 9.04) is highlighted as an outlier with proton pump inhibitor-equivalent efficacy despite high-pKa; C: Individual P-CAB efficacy for erosive esophagitis ordered by pKa, illustrating the FXP paradox: Despite pKa of 9.04, FXP shows OR < 1.0. Dashed line represents ordinary least squares linear regression fit. Error bars represent 95%CIs of pooled ORs. A positive pKa-efficacy trend is observed, but FXP (pKa of 9.04) represents a notable outlier with proton pump inhibitor-equivalent outcomes despite high-pKa. OR: Odds ratio; P-CAB: Potassium-competitive acid blocker; pKa: Acid dissociation constant; PPI: Proton pump inhibitor; TPZ: Tegoprazan; FXP: Fexuprazan; VPZ: Vonoprazan; KVP: Keverprazan; ZPZ: Zastaprazan.
Treatment rankings: Exploratory treatment rankings were assessed using P-scores from the NMA. For H. pylori eradication, VPZ achieved the highest P-score (0.87), followed by KVP (0.63), FXP (0.60), and TPZ (0.38), with PPIs as reference (0.01). For EE, KVP ranked highest (0.80), followed by ZPZ (0.76), VPZ (0.68), TPZ (0.32), and FXP (0.21). While these rankings showed a pattern consistent with the pKa hypothesis, the substantial imbalance in available evidence (21 VPZ studies vs 1 KVP and 1 FXP study), along with differences in study populations, antibiotic regimens, and treatment durations, limits the interpretability of these exploratory rankings (Supplementary Tables 2, 3, and 6, Supplementary Figures 2-4).
Monte Carlo power analysis: Monte Carlo simulation (3000 iterations) demonstrated that with only 5 marketed P-CABs, statistical power to detect a correlation of ρ = 0.80 is limited to 30% (Figure 6, Supplementary Table 7). With the revised FXP pKa of 9.04, threshold analysis at pKa of 9.0 is no longer feasible because four of five P-CABs cluster above this cutoff (only TPZ remains below). The continuous Spearman correlation (ρ = 0.80) remains the primary statistical finding. The limited power underscores the need for head-to-head comparative studies and pH-metry data to complement the indirect clinical comparisons used in this NMA. These findings support the hypothesis that P-CAB pKa may influence clinical efficacy, though the FXP paradox (pKa of 9.04, OR = 0.95 for EE) demonstrates that other pharmacological properties – particularly protein binding and intrinsic H+/K+-ATPase binding affinity – are critical co-determinants (Supplementary Figure 8).
Figure 6 Monte Carlo simulation for statistical power estimation.
Power curves showing the relationship between sample size [number of potassium-competitive acid blockers (P-CABs)] and statistical power to detect acid dissociation constant-efficacy correlations at different effect sizes (ρ = 0.60, ρ = 0.70, ρ = 0.80, ρ = 0.90). With only 5 marketed P-CABs, power to detect ρ = 0.80 is limited to 30% (horizontal dashed line indicates 80% power threshold); with n = 4 (Helicobacter pylori), power is 30%. These simulations illustrate that the inherent limitation of 5 marketed P-CABs constrains statistical power for correlation testing, emphasizing the importance of mechanistic plausibility and supporting evidence from subgroup analyses. P-CABs: Potassium-competitive acid blockers.
Sensitivity and subgroup analyses: Sensitivity analyses excluding open-label (OL) studies or restricting to non-inferiority trials did not materially alter the results. Subgroup analysis by treatment duration showed consistent P-CAB superiority for both 7-day[18-21] and 14-day regimens[3,23-26,28-31,35-37,39-46], though effect sizes were larger with shorter duration (OR = 2.31 vs 1.38), likely reflecting greater differentiation when baseline eradication rates are lower. Geographic subgroup analysis showed consistent results across Asian[18-43,45,46] and Western populations[3,44].
Risk of bias assessment
Risk of bias was assessed using the Cochrane ROB 2.0 tool across five domains (Table 4, Supplementary Table 8)[3,18-56]. Among 30 H. pylori eradication trial comparisons[3,18-46], six double-blind trials (Murakami et al[18], Chey et al[3] triple-therapy arm, Choi et al[21], Kim et al[24], Tan et al[37], Park et al[43]) were judged as low risk of bias across all domains. The remaining 26 OL trials[3,18,20,22,23,25-36,38-46] were rated as “some concerns” overall, primarily due to lack of participant and personnel blinding (Domain 2). However, the risk of bias in outcome measurement (Domain 4) was judged low for all studies because eradication was assessed by UBT, an objective endpoint evaluated by blinded laboratory personnel. One study (Maruyama et al[19]) had additional concerns for randomization (Domain 1) due to quasi-random allocation using odd/even medical record numbers. All 10 EE RCTs[47-56] employed double-blind designs and were rated as low risk of bias. No studies were judged as high risk of bias. While these assessments provide fair to moderate support for the validity of the included studies, reliance on 13C-UBT alone for H. pylori eradication confirmation – without corroboration by histology, rapid urease test, or immunological stool antigen test – may introduce some diagnostic uncertainty in individual studies. Diagnostic accuracy varies meaningfully across modalities (UBT sensitivity 92%-96%/specificity 89%-93%; stool antigen test 87%-94%/70%-91%; histology with Giemsa staining approximately 93%/> 90%; rapid urease test > 90%/> 95%), and recent use of PPIs, antibiotics, or bismuth within 2-4 weeks of testing can produce false-negative results; included trials applied protocol-specified washout intervals to mitigate this risk. Overall, the predominance of objective outcomes (UBT for H. pylori, endoscopic healing for EE) mitigates concerns arising from OL designs.
Table 4 Risk of bias assessment for Included randomized controlled trials.
Ref.
Design
D1: Randomization
D2: Deviations
D3: Missing data
D4: Measurement
D5: Reporting
Overall
H. pylori eradication RCTs (n = 30, 32 comparisons)
The certainty of evidence was assessed using GRADE methodology (Table 5, Supplementary Table 9)[3,18-56]. For H. pylori eradication, the certainty was rated as high. Although some studies used OL designs, this was not downgraded because the primary outcome (UBT) is an objective measure unlikely to be influenced by lack of blinding. No serious concerns were identified for inconsistency, indirectness, imprecision, or publication bias.
For EE healing, the certainty was rated as moderate, downgraded one level for serious imprecision because some individual P-CABs (ZPZ, KVP) had only single RCTs with wide confidence intervals.
In summary, the evidence supports the overall superiority of P-CABs (particularly VPZ, which has the most extensive data) over PPIs for H. pylori eradication, with the strongest evidence in CLR-resistant infections. Evidence for EE healing is of moderate certainty due to limited data for newer P-CABs, though VPZ demonstrates consistent benefit across multiple trials. The interpretation of certainty ratings should account for the indirect nature of all P-CAB comparisons and the imbalanced evidence base across individual agents.
Publication bias
Visual inspection of funnel plots showed no obvious asymmetry for either H. pylori eradication (Figure 7A) or EE healing outcomes (Figure 7B, Supplementary Table 10). Egger’s regression test was not statistically significant for H. pylori studies (P = 0.97). For EE studies, Egger’s test was not significant (P = 0.14); however, interpretation is limited by the small number of studies (n = 10), and visual inspection of the funnel plot did not suggest meaningful asymmetry.
Figure 7 Funnel plots for assessment of publication bias.
A: Funnel plot for Helicobacter pylori eradication studies (30 randomized controlled trials, 32 comparisons). Each point represents one study, plotted by effect size (log odds ratio, X-axis) against precision (standard error, Y-axis). Visual inspection shows symmetric distribution around the pooled effect estimate (vertical line). Egger’s regression test was not significant (P = 0.97), indicating no evidence of publication bias; B: Funnel plot for erosive esophagitis healing studies (10 randomized controlled trials). Distribution appears symmetric upon visual inspection. Egger’s test was not significant (P = 0.14); however, interpretation is limited by the small number of studies (n = 10), and funnel plot asymmetry was not visually apparent. Dashed diagonal lines represent pseudo-95% confidence limits. H. pylori: Helicobacter pylori; OR: Odds ratio.
DISCUSSION
Principal findings
This NMA of 40 RCTs (n = 11835)[3,18-56] suggests that P-CAB efficacy varies substantially among individual agents and is positively correlated with pKa values (Spearman ρ = 0.80). High-pKa P-CABs (VPZ of 9.06, KVP of 9.12, ZPZ of 9.95) achieved 82%-84% eradication in CLR-resistant infections vs 47.8% with low-pKa TPZ (pKa of 5.1). However, FXP (pKa of 9.04) represents a notable exception: Despite high-pKa, it achieved EE healing rates equivalent to PPIs (OR = 0.95) and showed no significant advantage for H. pylori eradication (OR = 1.49, 95%CI: 0.97-2.29). This “FXP paradox” demonstrates that pKa alone is insufficient to predict clinical outcomes, and that additional pharmacological properties – including protein binding (FXP of 93% vs VPZ of 80%-88%), intrinsic H+/K+-ATPase binding affinity, and effects on gastric emptying – are critical co-determinants. Regarding gastric emptying, VPZ has been reported to delay gastric emptying, which may prolong antibiotic contact time with H. pylori in the gastric mucosa and independently contribute to higher eradication rates beyond acid suppression alone; however, this effect has not been systematically evaluated for other P-CABs, and its relative contribution to the observed efficacy differences remains uncertain. This association does not establish causation, and multiple confounding factors including imbalanced study numbers, differences in patient populations and H. pylori strains, and varying dosing regimens may also contribute. While a positive pKa-efficacy correlation exists, the FXP paradox invalidates a simple pKa threshold model and supports a multi-factor framework where pKa, protein binding, and intrinsic binding affinity collectively determine clinical outcomes.
Comparison with previous literature
Over 30 meta-analyses have compared P-CABs vs PPIs as a unified class. Rokkas et al[57] ranked VPZ-triple therapy first among all regimens but pooled all P-CABs together. The recent NMA analyzing 25 RCTs reported P-CAB-dual therapy achieved the highest SUCRA (92.7%), again without differentiating individual agents[58].
Our findings suggest a potential pharmacological explanation for previously observed heterogeneity, with pKa as one candidate differentiating factor among several that may contribute. The PHALCON-HP trial[3] demonstrated VPZ achieved 65.8% eradication in CLR-resistant strains vs 31.9% with LPZ – potentially related to differences in acid suppression potency, although the relative contributions of pKa-dependent ion trapping, protein binding, intrinsic binding affinity, effects on gastric emptying, and dosing differences remain to be established.
Current guidelines have not differentiated individual P-CABs. The ACG 2024 guideline[2] and the AGA Clinical Practice Update 2024[59] recommend P-CAB-based regimens but treat them interchangeably. Our data generate the hypothesis that pKa-based pharmacological differentiation may help address this evidence gap, although prospective head-to-head comparisons and pH-metry studies are needed for confirmation.
Precedents of pKa as a clinical predictor
An important consideration is that the efficacy of gastric antisecretory drugs has traditionally been compared using intragastric pH threshold and holding time parameters, which over the past 50 years have become the established standard for evaluating acid suppression potency. Our study used clinical endpoints (eradication rate and endoscopic healing) rather than pH-metry data, a design choice that merits discussion. While clinical outcomes represent the ultimate measure of therapeutic effectiveness, they are influenced by numerous factors beyond acid suppression alone. A recent pharmacometric analysis has modeled the pH profiles of individual P-CABs and PPIs, providing a quantitative framework for comparing antisecretory activity that could complement our clinical findings[60]. Future studies integrating pKa values with pH-metry parameters and clinical outcomes would strengthen the pharmacological basis for differentiating individual P-CABs. Our use of pKa to predict clinical efficacy extends established pharmacological principles. In local anesthetics, pKa determines onset time: Lidocaine (pKa of 7.8) achieves faster onset than bupivacaine (pKa of 8.1) because more molecules exist in the membrane-permeable unionized form at physiological pH[61]. In opioids, alfentanil (pKa of 6.5) has the fastest onset among fentanyl derivatives because 89% is unionized at pH 7.4[62]. Recent work demonstrates that lowering fentanyl derivative pKa restricts analgesia to inflamed acidic tissues, reducing systemic side effects – positioning pKa as a design criterion for safer opioids[63]. Conversely, for NSAIDs, pKa predicts toxicity: Aspirin (pKa of 3.5) accumulates in gastric mucosa through ion-trapping more readily than less acidic NSAIDs, directly correlating with mucosal damage severity[64].
These precedents share a unifying principle: PKa governs drug distribution across pH gradients. For P-CABs, high-pKa compounds remain protonated and trapped in acidic parietal cell canaliculi regardless of secretory status, whereas low-pKa compounds require active acid secretion for accumulation.
The pKa threshold: Mechanistic framework
The pKa-efficacy correlation reflects fundamental acid-base chemistry. According to Henderson-Hasselbalch principles, a drug with pKa of 9.0 achieves > 99.99% protonation at canalicular pH of 1.0 (pKa sources detailed in Supplementary Table 11), whereas pKa of 5.1 compounds show substantially less efficient trapping[6,13,14].
This differential accumulation translates into clinical outcomes through two mechanisms.
The pH-dependent antibiotic efficacy: H. pylori enters a non-replicating, antibiotic-resistant state at pH < 4.5[65]. AMO requires sustained pH > 5.5 for bactericidal activity[66]. High-pKa P-CABs maintain pH > 6 longer, keeping H. pylori susceptible – explaining why VPZ achieves 82%-84% eradication in CLR-resistant infections while TPZ achieves only 47.8%.
Acid suppression consistency: VPZ achieved 87.8% time with pH > 4 on day 7 vs 42.3% with LPZ[67]. Unlike PPIs, P-CABs bind both active and inactive proton pumps[68], but high-pKa compounds may additionally accumulate in resting parietal cells. However, several important caveats apply to this mechanistic interpretation. Unlike PPIs, P-CABs do not require acid activation within the canaliculus to inhibit proton pumps; unprotonated P-CABs can cross cell membranes to inactivate both active and inactive proton pumps. Furthermore, most P-CABs have substantially longer plasma half-lives than PPIs, providing prolonged systemic availability for pump inhibition even without canalicular trapping. Therefore, the relative contribution of pKa-dependent ion trapping vs other pharmacokinetic properties (plasma half-life, protein binding, intrinsic binding affinity, effects on gastric emptying) to the observed clinical differences remains to be established through dedicated pharmacological studies including isolated gastric gland and parietal cell experiments.
Future perspectives
Drug development: Six P-CABs are now approved globally, spanning a wide pKa range. Pipeline compounds include linaprazan glurate (Cinclus Pharma), which achieved 89% LA C/D healing in phase II. If our hypothesis is confirmed, future development may benefit from considering pKa alongside other relevant physicochemical properties including protein binding, intrinsic binding affinity, and effects on gastric motility.
Precision acid suppression: P-CABs bypass CYP2C19 metabolism, eliminating genotype-dependent variability[69]. However, within the P-CAB class, our data suggest pKa may be one determinant of the clinical ceiling alongside other pharmacological properties. If confirmed by prospective studies including pH-metry validation, selecting P-CABs based on physicochemical properties could complement genotype-based approaches to precision acid suppression[70].
Guideline implications: In regions with CLR resistance > 15%, high-pKa P-CABs may warrant preferential consideration, pending validation through direct comparative studies. Head-to-head trials comparing individual P-CABs, coupled with pH-metry studies directly correlating pKa values with intragastric pH profiles and holding times, are essential to confirm these indirect comparisons.
Strengths and limitations
Strengths include the first NMA comparing individual P-CABs rather than pooling them as a class, pre-specified pKa-efficacy correlation analyses, inclusion of 40 RCTs with 11835 patients, and the use of objective outcomes (UBT for H. pylori, endoscopic healing for EE). Systematic quality assessment using RoB 2.0 and GRADE methodology enhances methodological transparency.
Several limitations warrant careful consideration. First, no head-to-head P-CAB trials exist – all comparisons derive indirectly through PPI common comparators, introducing potential bias. This is a fundamental limitation because observed differences between P-CABs may reflect confounding factors unrelated to pKa, including: (1) Differences in patient populations across geographic regions; (2) Variation in H. pylori strain virulence and CLR resistance rates; (3) Differing P-CAB dosing regimens and treatment durations; (4) Different antibiotic combination partners; (5) Substantial imbalance in available evidence, with VPZ studied for over a decade across 21 trials while KVP and FXP each have only a single study; and (6) Physicochemical factors beyond pKa, including variations in protein binding (particularly at the secretory canaliculus level), effects on gastrointestinal motility (notably the delay in gastric emptying reported with VPZ, which may meaningfully contribute to eradication success), and differences in intrinsic H+/K+-ATPase binding affinity and kinetics.
Second, the pKa-efficacy correlation, while mechanistically plausible, requires cautious interpretation. The FXP paradox is the most compelling illustration: With an experimentally determined pKa of 9.04[14] (data from Daewoong Pharmaceutical Investigator’s Brochure), FXP should classify as a high-pKa agent, yet it achieves pH > 4 holding time ratios (55%-65%) comparable to ESO (61%) rather than VPZ (88%-94%), and its EE healing OR (0.95) is essentially PPI-equivalent. Two factors likely explain this discrepancy. First, FXP exhibits the highest protein binding among P-CABs (92.8%-94.3% vs VPZ of 80%-88%), reducing free drug available for parietal cell uptake by 2-3 fold. Second, FXP’s intrinsic H+/K+-ATPase binding kinetics (Ki, koff) remain unpublished (Supplementary Table 12), preventing direct comparison with VPZ’s exceptionally tight binding (Ki of 3.0 nM). Our findings therefore demonstrate that pKa is necessary but clearly not sufficient for P-CAB efficacy: High-pKa may enable canalicular accumulation, but adequate free drug fraction and intrinsic binding affinity are required to translate accumulation into sustained acid suppression. This multi-factor model explains why a simple pKa threshold cannot reliably predict clinical outcomes.
Third, with only five marketed P-CABs, our correlation analysis has limited statistical power (30% for detecting ρ = 0.80) (Supplementary Table 13) and cannot exclude confounding by regional differences in CLR resistance rates, dosing regimens, or study design heterogeneity. With the revised FXP pKa of 9.04, the previously reported threshold analysis at pKa 9.0 is no longer feasible (4 of 5 P-CABs cluster above this cutoff). The Spearman correlation (ρ = 0.80) remains the primary statistical finding but should be interpreted cautiously given the small sample (n = 4-5).
Fourth, we used clinical endpoints (eradication rate and endoscopic healing) rather than pH-metry outcomes (intragastric pH threshold and holding time), which have been the established standard for comparing antisecretory drug efficacy for over 50 years. Future studies should directly correlate pKa values with pH-metry parameters to determine whether pKa-dependent differences in acid suppression mediate the observed clinical differences. Fifth, while the Spearman correlation supports a positive pKa-efficacy association, the FXP paradox (pKa of 9.04, OR = 0.95) demonstrates that a simple pKa cutoff cannot serve as a reliable predictor. A multi-factor model incorporating protein binding, intrinsic binding affinity, and pharmacokinetic properties alongside pKa requires prospective validation through pH-metry studies and parietal cell experiments. Sixth, the molecular structures of P-CABs are more variable than those of PPIs (which are all based on substituted benzimidazoles), and this structural diversity may contribute to pharmacological differences beyond what pKa alone can explain.
Finally, ZPZ and KVP data remain limited to single Asian RCTs, restricting generalizability.
CONCLUSION
P-CAB efficacy correlates with pKa values in this SR and NMA of 40 RCTs. High-pKa P-CABs (≥ 9.0) were associated with higher eradication rates in CLR-resistant infections and superior healing in severe esophagitis, whereas low-pKa P-CABs showed more limited advantages over PPIs in the available indirect comparisons. While all P-CABs share the fundamental mechanism of potassium-competitive acid suppression, our findings suggest that individual agents may differ in clinical effectiveness. In high CLR-resistance regions, clinicians may consider pKa as one factor when selecting among available P-CABs. However, these findings remain hypothesis-generating, and prospective validation through head-to-head trials, pH-metry studies correlating pKa with intragastric pH profiles, and parietal cell pharmacological experiments is needed to establish whether the observed associations reflect a causal relationship.
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