Commentary: a gastrin antagonist against carcinoids – implications for PPI-induced hypergastrinaemia


In 8 patients with chronic atrophic gastritis (CAG) and type-1 gastric carcinoids (T1GC), Fossmark et al.[1] have shown that short-term therapy with the experimental, orally-administered gastrin receptor antagonist drug netazepide caused significant regression in these tumours during therapy. Tumours recurred when drug was discontinued, a phenomenon also observed following parenteral somatostatin or octreotide therapy. As reviewed, most TIGCs are relatively benign, but a small number develop into cancers that metastasize. This occurrence is unpredictable in individual cases, creating much controversy as to surveillance and management.

During a time when CAG is diminishing in western countries, increases in population incidences of T1GCs have accelerated markedly over 3 decades, in parallel with increasing use of proton pump inhibitor drugs (PPIs).[2] Unfortunately, PPI use was not recorded in epidemiological analyses showing this, precluding case–control or cohort studies that clearly indicated an association. The percentage of carcinoids arising in stomach has risen markedly, and possible impact of netazepide on such lesions in PPI-users is of great interest, but although much discussed, the number of malignant carcinoids reported in PPI users remains very small or unproven, and any real risk is of uncertain magnitude.[2]

Elevations of serum gastrin and chromogranin-A are equally common in CAG patients and PPI users. Major studies of T1GC development in pernicious anaemia indicate that it usually occurs only when CAG is of very long duration, and is uncorrelated with the degree of hypergastrinaemia[3, 4]: trophic effects of gastrin on ECL cells begin at serum concentrations of about 40 pmol/L, and are maximal in the range of 250–500 pmol/L.[5] Thus, very high concentrations are not needed for T1GC development. However, the concentrations occurring in most PPI users are at the lower end of this range and the durations of use shorter in most cases. Nevertheless, potent acid secretory inhibition by netazipide may offer a therapy, clinically as effective as PPIs, but free of the risks of carcinoid development, recurrence or progression. However, to date, knowledge of the pharmacology of netazipide remains limited, but is clearly of considerable interest.[6]


Declaration of personal and funding interests: None.