Editorial: PCAB Safety: Balancing Potential Long-Term Risks With Short-Term Benefits

Abstract

Potassium-competitive acid blockers (PCABs), such as vonoprazan, provide more rapid, potent and prolonged acid suppression than proton pump inhibitors (PPIs), and as such may offer advantages in the treatment of GERD and other acid-related disorders. PPI-related adverse effects, including enteric infection, pneumonia, and micronutrient deficiencies, have been attributed primarily to gastric acid suppression [1], which raises concerns that treatment-emergent adverse events (TEAEs) could be more profound with PCAB use.

The current study by Howden et al. [2] found that vonoprazan is well-tolerated, with a safety profile comparable to PPIs. This is based on an assessment of TEAEs across 14 clinical trials of vonoprazan compared with lansoprazole, esomeprazole or placebo, in addition to post-marketing data from 2014–2023. While the short-term safety of vonoprazan seems supported, the study's mean exposure duration of 142 days (20 weeks/5 months) and maximum duration of 260 weeks (5 years) may offer an incomplete assessment of the longer-term safety profile. Notably, several PPI-associated TEAEs can only be fully evaluated after chronic exposure, including bone fracture, vitamin B12 deficiency and gastric malignancy.

Bone fracture has been associated with PPI use of at least 7 years, but not less than 6 years [3]; thus, the duration of vonoprazan exposure in this analysis may not be sufficient to detect an increased incidence of fractures. The associated mechanism may be due to calcium and magnesium malabsorption, which occurs over 5–10 years [4]. Additionally, while the impact of PPI on bone mineral density is controversial, the timing of osteoporosis development in women can exceed 10 years [5].

Vitamin B12 can take 3–5 years to deplete in the body, usually presenting with no or minimal symptoms in the short term and can take additional years to decades to manifest clinically as glossitis, anaemia or neuropsychiatric dysfunction [6], though the association between chronic PPI use and dementia remains controversial [7].

Gastric malignancy often arises as a subacute process, with a median time to progression of 6.1 years from nondysplastic gastric intestinal metaplasia to adenocarcinoma [8]. Risk of gastric cancer increased with cumulative PPI dose as well as longer duration of therapy (> 3 years) [9], though this association was inconsistent across studies and may involve various mechanisms, including H. pylori infection and alterations in GI microbiota [10].

Of note, other serious adverse events that were identified as potentially related to vonoprazan use by investigators included acute cholangitis, diverticulitis, malignancies, acute thyroiditis, atrial fibrillation and transient loss of consciousness. Additional evaluation is needed to determine the frequency, causality and potential mechanisms of action.

Despite the concerns associated with chronic use, PPIs remain a mainstay of treatment for numerous GI conditions because, ultimately, the absolute risk is low, causality is debated, and few therapeutic alternatives exist. While there is not yet sufficient data on long-term PCAB use to draw the same conclusions, we believe that PCABs likely have a role in the treatment of acid-related conditions, particularly those in which PPIs have failed, and that future evaluations of real-world clinical application will clarify the longer-term harms and benefits that may presently remain underappreciated.

Stephanie Owyang: conceptualization, writing – original draft, writing – review and editing. Wai-Kit Lo: conceptualization, writing – review and editing, supervision.

This article is linked to Howden et al paper. To view this article, visit https://doi.org/10.1111/apt.18458.