Use of proton pump inhibitors in older subjects: Risk of adverse clinical outcomes and potential mechanisms

Abstract

Background In the last 2 decades, it was observed a widely increased use of proton pump inhibitors (PPIs) especially in older populations. Despite the fact that PPIs are superior to histamine receptor antagonists in treating gastroesophageal reflux disease (GERD) and peptic ulcers, the chronic use of PPIs has been associated with adverse clinical outcomes including higher risk of fractures and Clostridium difficile infections. In vitro studies have shown that PPIs negatively modulate the bioactivity of insulin-like growth factor-1 (IGF-1), anabolic hormone and nutritional marker. However, whether or not PPIs use has negative influence on survival and independence of activities of daily living (ADL) and the mechanisms underlying these hypothesized associations are still poorly known. Aims of the study The aims of the study were to test the relationship between the use of PPIs and adverse clinical outcomes (mortality and rehospitalization, loss of ADL) and the association between use of PPIs and cortical and trabecular bone mineral density, IGF-1 bioactivity in older patients of 2 different populations. Methods In 491 patients (mean age 80.1 ± 5.9 years), categorized as PPI users and non users, discharged from 11 acute care medical wards and 3 long-term care/rehabilitation units, we tested the relationship between use of PPIs and 1- year mortality or combined end-point mortality and rehospitalization and incident dependency by using time-dependent Cox proportional hazard regression models and after propensity score matching. The association between use of PPIs, IGF-1 and bone mineral density was estimated by multivariate regression model adjusted for multiple confounders in 938 subjects (413 men and 525 women) aged ≥ 65 years, from the InCHIANTI Study, with complete information on tibial pQCT, IGF-1, IGF-binding protein-1 (IGFBP-1) and medications. Results In the hospitalized population the use of PPIs was independently associated with mortality (hazard ratio, 1.51 [95% CI, 1.03–2.77]) but not with the combined end point (1.49 [0.98–2.17]). An increased risk of mortality was observed among patients exposed to high-dose PPIs vs none (hazard ratio, 2.59 [95% CI, 1.22–7.16]). Use of PPIs was significantly associated with functional decline either before (OR = 1.75; 95% CI = 1.17–2.60) and after propensity score matching (OR = 2.44; 95% CI = 1.36–4.41). In the InCHIANTI population, PPI users showed age- and sex-adjusted lower vBMDt than nonusers (180.5 ± 54.8 vs. 207.9 ± 59.4, P = 0.001). The inverse association between PPI use and vBMDt remained almost unchanged after adjustment for multiple confounders. There was no statistically significant difference in vBMDc between PPI users and nonusers. PPI users had lower IGF-1 levels (81,9 [61,1-113,8]) than non-users (110 [77,8–148,6]), P = 0.02. After further adjustment for BMI, liver function, number of medications, caloric intake and IGFBP-1, the relationship between use of PPI and IGF-1 remained statistically significant (β ± SE = –18,09 ± 9,38, P = 0,05). Conclusions In older persons discharged from acute care hospitals, the chronic use of PPIs is associated with increased 1-year mortality and functional decline. The lower trabecular bone mineral density and IGF-1 levels found in PPI users are potential mechanisms explaining this association.