To the editor

We really appreciated the very informative article by Castellana et al,1 published in this issue of Polish Archives of Internal Medicine (Pol Arch Intern Med), providing an in-depth review on major adverse events observed with the long-term use of proton pump inhibitors (PPIs). We would like to add some information on the association between PPIs and the development of diabetes mellitus (DM) and its related complications.

In a recent prospective analysis of 3 cohorts from the United States in a total of 204 689 subjects without type 2 DM (T2DM) at baseline, it was shown that regular users of PPIs (treatment duration longer than 2 years) had a 26% increase in the risk of T2DM development compared with nonregular users (hazard ratio [HR], 1.26; 95% CI, 1.18–1.35).2 Notably, the result was consistent across the 3 assessed cohorts. However, participants using PPIs up to 2 years did not experience a significantly increased risk compared to nonregular users.2

It is worth emphasizing that previously published observational studies enrolling patients with T2DM have demonstrated that PPIs do not increase the risk of albuminuria or its progression, have conflicting effect on worsening nephropathy, while they definitely increase overall risk of cardiovascular disease.3,4 As Castellana et al1 emphasize, PPIs increase overall cardiovascular disease burden and should be replaced in patients at increased cardiovascular risk. Since the major cause of death among patients with T2DM is cardiovascular disease and its components, it seems crucial for the physician to replace a medication that might accelerate disease progression in this patient population.

Of note, PPIs seem not to have a substantial effect on glycemic control, β-cell function, and insulin resistance, as documented in a recent relevant meta-analysis of observational studies in the T2DM population.5 Therefore, other mechanisms seem to be implicated into the development of DM and related macrovascular complications among regular users. The alteration of gut microbiota might be a potential underlying mechanism, although this remains unclear.2

However, since relevant literature is limited, further prospective studies are required to shed more light on this interesting association with potentially major clinical implications.