Potassium-competitive acid blockers versus proton pump inhibitors: redefining the standards of care in reflux esophagitis

Introduction The introduction of antisecretory drugs, such as H2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) in clinical practice, has transformed the management of acid-related diseases. This advancement has virtually eliminated the need for elective surgery for peptic ulcer disease and limited antireflux surgery to those patients whose reflux symptoms cannot be adequately controlled with medical therapy. Even in the third millennium, PPIs remain the cornerstone of medical management for gastroesophageal reflux disease (GERD) and its associated complications [1–3]. In recent decades, it has become increasingly evident that several clinical needs in the treatment of acid-related conditions remain unmet by the currently available delayed-release PPI formulations [4–7]. Evidence from clinical trials and real-world practice indicates that sustained acid suppression may confer additional therapeutic benefits [8,9]. Consequently, considerable efforts have been directed toward the development of novel therapies – including long-acting PPIs, innovative formulations, and fixed-dose combinations of H2RAs and PPIs – designed to deliver meaningful advances over current treatment options [9,10]. Potassium-competitive acid blockers: a breakthrough in acid suppression therapy An innovative development in acid suppression therapy has been the introduction of H+, K+-ATPase inhibitors, known as potassium-competitive acid blockers (P-CABs) [11,12]. These compounds act by blocking the potassium-binding site of the gastric proton pump, resulting in a rapid, competitive, and reversible inhibition of acid secretion. P-CABs achieve a faster and more substantial increase in intragastric pH compared with delayed-release PPIs, while providing a comparable or even superior antisecretory effect. The duration of their action is primarily determined by the drug’s half-life. Owing to these advantages, P-CABs have attracted considerable interest in pharmaceutical research and development, drawing significant investment from multiple companies. Unlike current PPIs, which are all substituted benzimidazoles, P-CABs belong to distinct chemical classes. Of the four drugs approved by regulatory agencies worldwide and now available on the market, three molecules (i.e. vonoprazan, fexuprazan, and keverprazan) share the sulphonylpyrrole core while tegoprazan retains a benzimidazole backbone (Fig. 1). In addition, two other compounds (i.e. linaprazan glurate and zastaprazan), currently in clinical development, are imidazopyridine derivatives [13]. A recent bibliometric analysis [14] highlighted the ongoing expansion of therapeutic applications for this new class of antisecretory agents, underscoring both their substantial research potential and their growing clinical relevance. Among them, vonoprazan – the first-in-class P-CAB introduced into clinical practice a decade ago – has received approval for a wide range of indications [15]. By contrast, the other P-CABs have thus far concentrated primarily on the management of GERD and the eradication of Helicobacter pylori infection [13].Fig. 1.: Structure and pharmacokinetic as well as pharmacodynamic characteristics of vonoprazan and tegoprazan.Vonoprazan (TAK-436) was initially launched in Japan and later introduced in several other Asian countries. More recently, it received approval from the U.S. Food and Drug Administration and is now available across North, Central, and South America. Similarly, tegoprazan (formerly known as RQ-00000004 or CJ-12420) was first introduced in South Korea in 2019 and has since expanded into various other Asian markets as well as countries in Central and South America [16]. Healing of severe reflux esophagitis: an unmet clinical need The pathogenesis of GERD is complex and multifactorial, though predominantly driven by neuromuscular dysfunction [3]. Importantly, abnormal esophageal acid exposure is not typically the result of gastric acid hypersecretion, which has been demonstrated in only a subset of patients with GERD [17]. Nevertheless, antisecretory agents – including H2RAs and PPIs – remain the cornerstone of GERD management. These therapies act indirectly by reducing the volume and acidity of gastric contents available for reflux, thereby diminishing the corrosive potential of the refluxate [10,18]. In addition, PPIs have been shown to reduce the size of the acid pocket and elevate its pH from approximately 1 to 4 [19]. The clinical efficacy of these drugs has been consistently demonstrated in numerous studies, with the superiority of PPIs over H2RAs firmly established [1,2,20]. An 8-week course of standard-dose PPIs, administered once daily, can achieve healing of reflux esophagitis in over 80% of patients [21], with success rates depending on the severity of mucosal damage [22–24]. This healing rate can be further enhanced by doubling the PPI dosage to twice daily (20–30 min before breakfast and before dinner), with a number needed to treat of 25 [21]. PPIs are also effective in providing symptom relief in both erosive and nonerosive forms of the disease [25]. Their efficacy for the relief of regurgitation is, however, modest, and considerably lower than that achieved for heartburn [26]. Alongside other limitations – such as inconsistent and unreliable symptom relief in all patients, inadequate control of nocturnal acid secretion, and limited efficacy in managing extra-esophageal manifestations – the inability to achieve complete healing of severe erosive esophagitis remains an significant unmet clinical need in the treatment of GERD [11]. A meta-analysis evaluating the effectiveness of standard-dose PPIs for healing Los Angeles grade C and D esophagitis revealed that 51% of patients remained unhealed after 4 weeks of therapy, and 27% after 8 weeks [27]. These findings underscore the need for more potent acid suppression in this subgroup of patients. Further support comes from a study in patients with moderate to severe reflux esophagitis, which prospectively demonstrated a significant positive correlation between 24-h intragastric acid control (pH > 4.0) and mucosal healing [28]. Moreover, a comprehensive meta-analysis of 95 studies reporting intragastric pH data and 109 studies reporting healing outcomes identified an inverse linear relationship between intragastric acidity and healing rates across treatments with PPIs, H2RAs, and placebo [29]. This evidence suggests that, by determining the percentage of time during which intragastric pH remains below 4, the healing potential of any new or existing antisecretory regimen can be accurately predicted. Potassium-competitive acid blockers for reflux esophagitis Pharmacological studies and clinical trials have consistently shown that P-CABs overcome many of the limitations associated with PPIs [11]. As predicted [29], an 8-week treatment with vonoprazan achieved an almost 100% healing rate for reflux esophagitis. Notably, while healing rates were comparable between vonoprazan (20 mg daily) and lansoprazole (30 mg daily) in patients with Los Angeles grade A and B esophagitis, vonoprazan demonstrated significantly superior healing in those with grade C and D esophagitis [30], a benefit that persisted even in patients who are extensive metabolizers of CYP2C19 [31]. The superiority of vonoprazan over lansoprazole in healing severe esophagitis was further confirmed in a more recent large multicenter clinical trial involving 468 Asian patients [32]. As a more recent agent, tegoprazan has been the subject of fewer studies to date. In this context, the meta-analysis by Nayyer et al. [33], published in this issue of the European Journal of Gastroenterology & Hepatology, offers valuable insights and represents a welcome contribution to the growing body of evidence. These findings suggest that tegoprazan is noninferior to PPIs in achieving healing of reflux esophagitis at both 4 and 8 weeks; however, these conclusions are drawn from only three randomized controlled trials (RCTs), which included too few patients with severe esophagitis to allow for meaningful analysis of healing rates by esophageal lesion grade. Notably, the RCT conducted by Shin et al. [34] reported a higher healing rate with tegoprazan compared with lansoprazole in patients with severe esophagitis (88.9 vs. 70.0% at 4 weeks). Nevertheless, the small sample size limited the ability to achieve statistical significance for this apparent benefit. To address this gap, an ongoing study in Mexico – the TOP-GERD trial – is comparing tegoprazan with pantoprazole for the treatment of reflux esophagitis [35]. This trial is specifically designed to enroll a sufficient number of patients with Los Angeles classification grades C and D esophagitis, which may provide the statistical power necessary to better define the comparative efficacy of tegoprazan in more severe disease. We recently developed a mathematical model to investigate the relationship between pH holding time ratios (HTRs) and the healing rates of erosive esophagitis across the three principal classes of antisecretory agents: H2RAs, PPIs, and P-CABs [36]. This analysis incorporated data from 82 studies reporting steady-state mean pH greater than 4 HTRs and 104 clinical trials documenting healing rates of esophagitis. Using nonlinear mixed effects modeling, we identified a clear correlation between pH holding time and healing rates for each drug class (Fig. 2). The final model demonstrated excellent accuracy, with a strong agreement between observed and predicted healing outcomes. Through this model, we estimated the likelihood of achieving specific healing targets with each class of antisecretory drugs. The findings clearly demonstrate that, regardless of the chosen therapeutic target, P-CABs emerge as the most effective agents for promoting the healing of reflux esophagitis.Fig. 2.: Correlation between pH holding time and esophagitis healing rate: nonlinear mixed effects fitting (from Howden et al. [35]). H2RA, H2-receptor antagonists; P-CAB, potassium-competitive acid blocker; PPI, proton pump inhibitor.A recent meta-analysis of Fass’ team [37] demonstrated that vonoprazan is highly effective in both the healing and maintenance of PPI-resistant erosive esophagitis and shows moderate efficacy in improving symptoms as measured by the Frequency Scale for the Symptoms of GERD. The therapeutic benefits of vonoprazan in refractory GERD were sustained over the long term [38]. To date, no data are available regarding the efficacy of tegoprazan in PPI-refractory GERD. P-CABs significantly increase the likelihood of heartburn resolution compared with placebo and meaningfully reduce heartburn severity; however, despite their superior healing efficacy, symptom relief achieved with P-CABs in patients with GERD appears comparable to that seen with PPIs [13]. Notably, symptom relief with vonoprazan tends to occur more rapidly [39]. In patients with esophagitis, heartburn resolved earlier with vonoprazan than with lansoprazole: by day 1, complete relief was reported in 31.3% of patients receiving vonoprazan versus 12.5% of those taking lansoprazole. In addition, significantly more patients experienced complete nocturnal heartburn relief with vonoprazan compared with lansoprazole [40]. Unfortunately, the authors of the meta-analysis did not include symptom relief as an additional outcome measure; however, analysis of the three trials included in the meta-analysis [34,41,42] revealed no significant difference in symptom relief between tegoprazan and PPIs, with this P-CAB demonstrating consistent efficacy irrespective of CYP2C19 genotype. Similar to vonoprazan [40], tegoprazan may provide faster relief of nighttime heartburn and associated sleep disturbances in patients with reflux esophagitis compared with PPIs [43]. Nonetheless, despite this favorable trend, the observed difference did not reach statistical significance, likely due to the limited sample size of the study. The safety profile of P-CABs, both in clinical trials and real-world practice, appears comparable to that of PPIs [44]. In studies involving patients with reflux esophagitis and other acid-related conditions, tegoprazan has demonstrated a safety profile similar to that of PPIs [45,46]. Even concerns regarding liver safety – previously raised with first-generation P-CABs – now seem unfounded, with current evidence indicating hepatic safety comparable to that of PPIs [47]. It is therefore surprising that the authors observed a higher, although not markedly elevated yet statistically significant, incidence of adverse events with P-CABs. This unexpected finding is most likely due to the small number of available RCTs (N = 3) and their limited sample sizes, which reduce statistical power, particularly in the detection of rare adverse events [48,49]. Are potassium-competitive acid blockers already adopted by gastroesophageal reflux disease guidelines? Owing to their superior efficacy, P-CABs are now recommended for the healing of mucosal lesions in the most recent clinical guidelines for GERD. These include the Seoul Consensus [50], the Chinese Expert Consensus [51], the Japanese Guidelines [52], and the Mexican Clinical Practice Recommendations [53]. Most recently, the Italian Guidelines have also endorsed the use of P-CABs for this indication [54]. The expert review issued by the American Gastroenterological Association [55] advices that clinicians should generally not use P-CABs as first-line therapy in patients with milder erosive esophagitis, reserving them instead to patients with severe mucosal damage. In contrast, the White Paper from the American Foregut Society [56] provides more definitive guidance, supporting the use of P-CABs across all grades of erosive esophagitis. The paper emphasizes that vonoprazan (the only P-CAB available in the USA) may offer superior efficacy compared with standard, once-daily PPI therapy. Conclusion The development of P-CABs marks a significant advancement in the management of acid-related diseases, particularly GERD and reflux esophagitis. By offering faster, more potent, and longer-lasting acid suppression compared with traditional PPIs, P-CABs effectively address several longstanding limitations of current therapies. Clinical trials consistently demonstrate that P-CABs, particularly vonoprazan, achieve superior healing rates in patients with severe esophagitis and provide faster symptom relief, including nocturnal heartburn, while maintaining a comparable safety profile to PPIs. Although the evidence for newer agents like tegoprazan is still emerging, initial data suggest noninferiority to PPIs and potential benefits in more severe cases; however, the limited number and size of current studies highlight the need for further robust, well-powered clinical trials – especially in populations with severe or PPI-refractory disease. Reflecting their clinical efficacy, P-CABs have been increasingly incorporated into international GERD treatment guidelines, with most expert recommendations advocating their use in patients with more severe forms of erosive esophagitis. As research continues to evolve, P-CABs are poised to play an increasingly prominent role in the personalized management of acid-related disorders, potentially reshaping treatment algorithms in the near future. Acknowledgements None. Conflicts of interest C.S. has served as a speaker, consultant, and advisory board member for Alfasigma, Pfizer, Takeda, Reckitt Benckiser, and Shionogi, and has in the past received funding from Giuliani Pharmaceuticals and Pfizer. For L.G., there are no conflicts of interest.