Long-term Proton Pump Inhibitors Users Research Articles

Risk of gastric cancer among long-term proton pump inhibitor users: a population-based cohort study.

To elucidate whether long-term proton pump inhibitor (PPI) users have an increased gastric cancer (GC) risk. We searched the 2009-2019 Korean National Health Insurance Services Database for patients aged > 40years who claimed for Helicobacter pylori eradication (HPE) during 2009-2014. The GC incidence following a PPI exposure of > 180 cumulative defined daily dose (cDDD) and that following an exposure of < 180 cDDD were compared. The outcome was GC development at least 1year following HPE. A propensity score (PS)-matched dataset was used for analysis within the same quartiles of the follow-up duration. Additionally, dose-response associations were assessed, and the mortality rates were compared between long-term PPI users and non-users. After PS matching, 144,091 pairs of PPI users and non-users were analyzed. During a median follow-up of 8.3 (interquartile range, 6.8-9.6) years, 1053 and 948 GC cases in PPI users and non-users, respectively, were identified, with the GC incidence (95% confidence interval (CI)) being 0.90 (0.85-0.96) and 0.81 (0.76-0.86) per 1000 person-years, respectively. The adjusted hazard ratio (aHR) for GC with PPI use was 1.15 (95% CI, 1.06-1.25). Among PPI users, patients in the highest tertile for annual PPI dose showed higher GC development than those in the lowest tertile (aHR (95% CI): 3.87 (3.25-4.60)). GC-related mortality did not differ significantly between PPI users and non-users. In this nationwide analysis in Korea, where the GC prevalence is high, long-term PPI use after HPE showed a significant increase in GC, with a positive dose-response relationship.

CYP2C19 genotypes and osteoporotic fractures in long-term users of proton pump inhibitors: A hospital-based study.

Proton pump inhibitors (PPIs) are commonly prescribed medications. The existing data suggest that individuals at a high risk of fractures have been exposed to high doses of PPIs for prolonged durations. CYP2C19 plays a pivotal role in metabolism of PPIs and thereby influences their pharmacokinetic profile. Hence, we hypothesize that CYP2C19 genotypes may be associated with fragility fracture among PPIs users due to PPI exposure. This study aimed to investigate the association between CYP2C19 genotypes, bone mineral density (BMD), and osteoporotic fracture in a hospital-based population. This retrospective cohort study enrolled patients who were prescribed long-term PPIs at Taichung Veterans General Hospital using data extracted from the Taiwan Precision Medicine Initiative between January 2010 and April 2021. Associations between CYP2C19 phenotypes, comorbidities, and fractures in PPI users were analyzed. We enrolled 1518 long-term PPI users; 571 (38%), 727 (48%), and 220 (14%) CYP2C19 normal metabolizers (NMs), intermediate metabolizers (IMs), and poor metabolizers (PMs), respectively. Among them, 49 (3.2%) patients developed fractures within the 1-year follow-up period; 20 (3.5%) fractures in NMs, 24 (3.3%) in IMs, and 5 (2.3%) in PMs, respectively. No significant difference was observed among CYP2C19 genotypes and fracture. Additionally, BMD measurements during the 1-year follow-up period were made available among 75 participants. No significant difference in BMD between CYP2C19 PMs and non-PMs was found. This real-world, hospital-based study concludes that CYP2C19 PMs/IMs are not associated with an increased risk for fractures or reduced BMD in individuals on long-term PPI therapy.

Abstract PD13-10: PD13-10 Impact of Proton Pump Inhibitors (PPI) on Palbociclib (PAL) Outcomes in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer (HR+/HER2- ABC): Exploratory Analysis of the PARSIFAL Trial

Abstract Background The use of PPI among cancer patients (pts) is quite frequent. PAL is an oral, cyclin-dependent kinase 4 and 6 inhibitor recommended to be taken under fed conditions. PAL showed a reduced solubility when gastric pH is &amp;gt;4.5, a level commonly achieved by PPI. Observational, retrospective studies on concomitant PPI with PAL or ribociclib showed a shorter progression-free survival (PFS) among PPI users than nonusers. In the randomized, phase 2 PARSIFAL trial, PAL plus fulvestrant demonstrated no improvement in PFS and overall survival (OS) versus PAL plus letrozole as frontline treatment in HR+/HER2- ABC pts (Llombart-Cussac et al, JAMA Oncol 2021). Here we assessed the impact of PPI on PAL efficacy and safety in pts included in the PARSIFAL study. Methods Pts with endocrine-sensitive HR+/HER2- ABC and no prior therapy in advanced setting were randomly assigned to receive PAL (hard capsule formulation) plus either fulvestrant or letrozole. Pts with ≥1 PPI received over the entire PAL-based regimen were defined as PPI users, or PPI naïve (N-PPI) if no PPI was administered over the whole study treatment. We carried out two analyses considering early PPI users (E-PPI) –composed by pts who were receiving PPI since the PAL-based regimen initiation– and long-term PPI users (LT-PPI) –composed by pts who received PPI over the entire or ≥⅔ of the PAL-based regimen. PPI users defined as neither E-PPI nor LT-PPI were excluded from the analysis to avoid biases due to the PPI limited exposition. PFS, OS, and safety were compared among groups. Landmark analysis at 3, 6, 12, 18, 24, and 30 months (mo) was used for survival estimates conditional on surviving to certain time points and adjust for immortality bias in comparison between N-PPI and PPI users. Analyses were adjusted by stratification factors and patient characteristics. Results Of 486 pts included in the study, 325 (66.9%) were N-PPI. Among 161 (33.1%) PPI users, 64 (13.2%) were E-PPI and 91 (18.7%) were LT-PPI. Omeprazole was the most prescribed PPI in 80.7% (130 of 161) of PPI users. Median exposition to PPI for PPI users, E-PPI, and LT-PPI was 13.6, 15.9, and 19.4 mo, respectively. Compared with N-PPI, E-PPI and LT-PPI were older (median age, 60.5 vs 66.5 vs 67.0 years, respectively; P&amp;lt; 0.001) and had a worse functional status (ECOG PS of 0, 60.0% vs 34.0% vs 43.0%, respectively; P=0.002). Median follow-up for the whole population was 32 mo. Median PFS was 28.7 mo in N-PPI compared with 23.0 mo in E-PPI (HR 1.5; 95%CI 1.1–2.2; P=0.024) and 23.0 mo in LT-PPI (HR 1.4; 95%CI 1.0–1.9; P=0.035). Both PPI groups had poorer median PFS than N-PPI by landmark analysis at 3 and 12 mo. Subgroup analysis showed a consistent trend regardless of endocrine partner. Three-year OS rate was 81.1% in N-PPI compared with 63.5% in E-PPI (HR 2.2; 95%CI 1.3–3.7; P=0.003) and 62.0% in LT-PPI (HR 2.1; 95%CI 1.4–3.4; P=0.001). Both PPI groups had poorer 3-year OS rate than N-PPI by landmark analysis at 3, 6, 12, and 18 mo. Grade ≥3 hematological adverse events (AEs) occurred in 71.7% (233 of 325 pts) of N-PPI compared with 57.8% (37 of 64 pts; P=0.021) of E-PPI and 54.9% (50 of 91 pts; P=0.003) of LT-PPI. Dose reductions and delays due to hematological AEs were reported in 70.8% (230 of 325 pts) of N-PPI compared with 56.3% (36 of 64 pts; P=0.018) of E-PPI and 52.7% (48 of 91 pts; P=0.002) of LT-PPI. At 3 mo, 45.8% (149 of 325 pts) of N-PPI required a dose reduction or delay due to hematological AEs compared with 39.1% (25 of 64 pts; P=0.42) of E-PPI. Conclusions Early and sustained coadministration of PPI with PAL and endocrine therapy were associated with lower efficacy, hematological toxicities, and dose modifications. Despite the post-hoc nature of the study, these findings suggest pharmacokinetic interactions between PPI and PAL capsules. Further confirmatory studies including the tablet formulation of PAL, which is expected to assure its optimal absorption, are needed. Citation Format: Serena Di Cosimo, José Manuel Pérez-García, Meritxell Bellet Ezquerra, Florence Dalenc, Miguel Gil Gil, Manuel Ruiz Borrego, Joaquín Gavilá, Miguel Sampayo-Cordero, Elena Aguirre, Peter Schmid, Frederik Marmé, Joseph Gligorov, Andreas Schneeweiss, Joan Albanell, Pilar Zamora, Duncan Wheatley, Eduardo Martínez De Dueñas, Vicente Carañana, Kepa Amillano, Andrea Malfettone, Javier Cortés, Antonio Llombart-Cussac. PD13-10 Impact of Proton Pump Inhibitors (PPI) on Palbociclib (PAL) Outcomes in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer (HR+/HER2- ABC): Exploratory Analysis of the PARSIFAL Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-10.

The Effects of Proton Pump Inhibitors in Acid Hypersecretion-Induced Vitamin B12 Deficiency: A Systematic Review (2022).

Gastroesophageal reflux disease (GERD) is the most common disease, for which proton pump inhibitors (PPIs) are a widely used class of drugs. Due to their efficacy and relative safety profile, PPIs are used chronically by GERD patients. Although it is a safe drug, particular attention focuses on the long-term adverse effects of PPI. The association with vitamin deficiencies has received additional focus since chronic PPI treatment increases the incidence of vitamin B12 deficiency, especially in the elderly. However, numerous studies regarding the establishment of an association between PPI and vitamin B12 status revealed conflicting results. In this systematic review, we systematically examined observational studies that focused on the impact of chronic PPI effects on vitamin B12 absorption and diagnostic biomarkers of vitamin B12 deficiency. Our review showed significant changes in diagnostic biomarkers of vitamin B12 status in long-term PPI users, including elevated homocysteine and methylmalonic acid (MMA) concentration levels defining cellular vitamin B12 deficiency. Although there is uncertainty regarding the exact mechanism, it supports the concept that long-term intake of PPI can have clinical implications for vitamins.

Long-term proton pump inhibitor use and risk of osteoporosis and hip fractures: A nationwide population-based and multicenter cohort study using a common data model.

Association between protonpump inhibitors (PPIs) and osteoporosis, hip fractures has not been fully elucidated. We aimed to evaluate the relationship between PPIs use and the risk of osteoporosis and hip fractures in the databases converted to a common data model (CDM) and to compare the results across the databases. This was a population-based, propensity-matched, retrospective cohort study that included patients aged≥50years who were prescribed with PPIs for over 180days. We compared the incidence of osteoporosis and hip fractures between new PPI user and new user of other drugs using the Cox proportional hazards model and performed meta-analysis in the electronic health record (EHR) databases. In the Korean National Health Insurance Service (NHIS)-CDM database, long-term PPI users had greater risk of osteoporosis [PPIs vs non-PPIs groups, 28.42/1000 person-years vs 19.29/1000 person-years; hazard ratio (HR), 1.62; 95% confidence interval (CI), 1.22-2.15; P=0.001]. The meta-analytic results of six EHR databases also showed similar result (pooled HR, 1.57; 95% CI, 1.28-1.92). In the analysis of hip fracture, PPI use was not significantly associated with a hip fracture in the NHIS-CDM database (PPI vs non-PPI groups, 3.09/1000 person-years vs 2.26/1000 person-years; HR, 1.45; 95% CI, 0.74-2.80; P=0.27). However, in the meta-analysis of four EHR databases, the risk of hip fractures was higher in PPI users (pooled HR, 1.82; 95% CI, 1.04-3.19). Long-term PPI was significantly associated with osteoporosis; however, the results of hip fractures were inconsistent. Further study based on better data quality may be needed.

Long-term use of proton-pump inhibitor on Alzheimer's disease: a real-world distributed network analysis of six observational Korean databases using a Common Data Model.

Dementia has a crucial impact on the quality of life of elderly patients and their caregivers. Proton-pump inhibitors (PPIs) are the most frequently prescribed treatment, but they have been shown to be associated with dementia. The data are inconsistent, however. To investigate the association between PPIs use and Alzheimer's disease (AD) or all-cause dementia in six observational Korean databases using a Common Data Model (CDM) and to perform a distributed network analysis. Subjects aged over 18 years between 1 January 2004 and 31 December 2020. Among 7,293,565 subjects from 6 cohorts, 41,670 patients met the eligibility criteria. A total of 2206 patients who were included in both cohorts or with a history of dementia were excluded. After propensity matching, 5699 propensity-matched pairs between the PPIs and histamine-2 receptor antagonist (H2RA) users were included in this study. The primary outcome was the incidence of AD at least 365 days after drug exposure. The secondary outcome was the incidence of all-cause dementia at least 365 days after drug exposure. In the 1:1 propensity score matching, the risk of AD or all-cause dementia was not significantly different between the PPIs and H2RA groups in all six databases. In the distributed network analysis, the long-term PPI users (⩾365 days) were unassociated with AD [hazard ratio (HR) = 0.92, 95% confidence interval (CI) = 0.68-1.23; I 2 = 0%] and all-cause dementia (HR =1.04, 95% CI = 0.82-1.31; I 2 = 0%) compared with H2RA users. In the distributed network analysis of six Korean hospital databases using Observational Medical Outcomes Partnership (OMOP)-CDM data, the long-term use of PPI was not associated with a statistically significantly increased risk of AD or all-cause dementia. Therefore, we suggest that physicians should not avoid these medications because of concern about dementia risk.

Proton Pump Inhibitors and Gastric Cancer

Concerns have been raised regarding the long-term use of proton pump inhibitors (PPIs) as an important risk factor for gastric cancer in clinical practice. PPIs can cause hypergastrinemia at clinical doses, and hypergastrinemia has been reported to induce malignant neoplasms in the stomach in previous animal studies. In humans, the proliferation of enterochromaffin-like (ECL) cells induced by hypergastrinemia is suspected as a potential mechanism of gastric cancer. Meanwhile, persistent Helicobacter pylori (H. pylori) infection causes gastric atrophic change, which itself is a major cause of gastric cancer, and it can further increase the risk of gastric cancer by strengthening corpus atrophy through interaction with PPIs. Recent epidemiologic studies have reported an important link between long-term PPI intake and gastric cancer risk even after successful eradication of H. pylori. However, due to the methodological limitations of observational clinical studies, the causal relationship is still not clear, and a recent big data-based study reported that long-term PPI use was not related to gastric cancer incidence. Taken together, despite the potential detrimental effects of PPIs, it is currently difficult to draw a definite conclusion about its association with gastric cancer. To minimize the possibility of gastric cancer in H. pylori-infected patients or precancerous lesions in long-term PPI users, long-term PPI administration should be limited to the minimum effective dose, and antibacterial treatment for H. pylori should be considered.

Correlation of Long Term Proton Pump Inhibitors (PPI) Use with Iron and Vitamin B12 Deficiency Anaemia

The Suppression of gastric acid by long term use of PPI may decrease iron and vitamin B12 absorption and might be causing iron and vitamin B12 deficiency anaemia. This comparative cross-sectional study was conducted among patients with peptic ulcer disease from November 2017 to March 2020; attending in the Internal Medicine department of Bangabandhu Sheikh Mujib Medical University (BSMMU). A total of 80 patients were included and divided into group-A (PPIs user) and group-B (non-PPI user), each group containing 40 patients each. The group-A included patients who were taking PPIs for more than one year and aged from 18 to 70 years and group-B the control group who were not taking PPIs for atleast 1(one) year. The data were analysed by Statistical Package for the Social Sciences (SPSS) version 20.0 (SPSS Inc., Chicago, IL, USA).The study shown that male were 18(45%) and 19(47.5%) in group A and B respectively and female were 22(55%) and 21(52.5%) in group A and B respectively. The mean age of male and female was (year) 45.35 ± 12.46, 44.85 ± 15.24, respectively. Most of the patient took omeprazole 62.5% follwed by, esomeprazole 20%, pantoprazole 12.5%, rabeprazole 5%. About 47.5% of the patient took PPI for more than 2 years, and 52.5% took between 1-2 years. The mean (±SD) haemoglobin (Hb) level was 10.93±2.00 g/dl amongst group-A and 13.16±1.68g/dl in group-B, the difference is statistically significant (P&lt;0.001). The mean serum iron of the PPI users (group-A) was 46.43±22.79, and of non-PPI users (group-B) was 84.95±33.18, the difference between iron level between two group was statistically significant (odds ratio -6.38 ; CI-2.28-17.84 and P-value &lt;0.001). The PPI user group, mean vitamin B12 was 449±166.99 and in non-PPI group it was 432.85±175.93, which was statistically nonsignificant (P-value -1.00). Amongst all the participant low serum concentrations of iron, ferritin and transferrin were found 23(57.5%), 18(45%) and 27(67.5%), respectively in Group-A (PPI user group) and 7(17.5%), 7(17.5%) and 8(20%) respectively in Group-B (PPI-non user).The difference was statistically significant (p&lt;0.05) between the two groups. But the value of TIBC was found to be high in 36 (90.0%) participants in both groups, which was statistically non-significant(p=0.33). Hematocrit (HCT) were low in 35 (87.5%) participants in Group-A and 25(62.5%) in Group-B. The difference was statistically significant (p&lt;0.05). Low MCV was found in 10(25%) in the PPI user group and 4(10%) in the non-user group, whish was statistically non-significant. No significant differences in vitamin B12 concentrations (pg/ml) 449±166.99 vs 432.85±175.93 were found between groups A and group B, respectively. There was a weak negative Pearson’s correlation shown in ascatter diagram between duration of PPI use, and the iron level of group A (n=40) (r=-.311, p=.051). A negligible Pearson’s correlation was seen in the scatter diagram between the duration of PPI use, and vitamin B12 level of group A (r=+.05 p=.977). This study showed a significant decrease in haemoglobin, haematocrit, iron, ferritin, transferrin saturation in participants taking PPIs for more than one year, compared with age and gender-matched controls. No significant change of MCV, TIBC (Total Iron Binding Capacity) and vitamin B12 were noticed between groups. In conclusion, the study found a significant decrease in hematologic indices and iron profile among patients receiving PPIs for longer than one year. There was no substantial change of Vitamin B12 levels was detected between long-term PPIs users and non PPIs user groups. So, from the study it is suggested that judicial prescription of long-term PPIs must be practiced. However, the small sample size and short study duration were the limitation of the study.&#x0D; Bangladesh Med J. 2021 January; 50(1) : 27-32

Gastric neuroendocrine tumours from long-term proton pump inhibitor users are indolent tumours with good prognosis.

Proton pump inhibitors (PPIs) are among the most widely used medications in the United States. Most PPI users have persistent hypergastrinaemia during treatment. However, gastric neuroendocrine tumours diagnosed in long-term PPI users are rarely reported. Their clinicopathological features and prognosis are not characterised. It remains unclear whether or not they can be classified as Type III sporadic tumours. We retrospectively characterised 66 gastric neuroendocrine tumours from patients without atrophic gastritis and gastrinoma from two tertiary care medical centres, including 38 tumours in patients who had used PPIs for at least 1year and 28 tumours from patients without long-term PPI use (control group, Type III tumours). Compared to controls, tumours from long-term PPI users tended to be in the pT1-2 category (98% versus 79%, P=0.09) and less often invaded the serosa (3% versus 18%, P=0.08) or lymphovascular spaces (11% versus 32%, P=0.06). Using Kaplan-Meier analysis, long-term PPI users had significantly longer overall survival than controls (P=0.035). While three control patients developed distant metastasis and seven died, long-term PPI users were without distant metastasis (P=0.06) or death (P=0.002) during follow-up. However, five long-term PPI users developed additional gastric neuroendocrine tumour(s), while none of the controls did (P=0.07). Our results show that gastric neuroendocrine tumours of long-term PPI users are probably less aggressive compared to Type III sporadic tumours and have an indolent disease course. Our findings support the classification of gastric neuroendocrine tumours in long-term PPI users as a separate subtype.

Genotoxicity in Patients on Long-term Proton Pump Inhibitor Therapy in Korea: A Nested Case-control, Prospective, Pilot Study

Background/Aims: Although proton pump inhibitors (PPIs) remain a mainstay for the suppression of gastric acid secretion, long-term PPI use is associated with side effects. However, the genotoxicity associated with long-term PPI use is unclear.Materials and Methods: This prospective observational pilot study enrolled patients who had been on PPIs for &gt;1 year and healthy controls from July 2015 to August 2016. The subjects completed self-report questionnaires pertaining to their drug and medical history, and only those with no medical history and a ≥2-year wash-out period (for drugs other than PPIs) were included. We collected peripheral-blood lymphocytes from long-term PPI users and healthy controls and analyzed the genotoxicity by using the cytokinesis-block micronucleus cytome assay; we also determined the fasting serum levels of pyridoxine, folate, cobalamin, and homocysteine.Results: Ten long-term PPI users and 40 healthy control subjects were enrolled. The median serum pyridoxine, folate, cobalamin, and homocysteine levels were not significantly different between the groups. The median frequencies of micronuclei (MNi), nucleoplasmic bridges (NPBs), and nuclear buds (Nbuds) per 1,000 binucleated cells, in long-term PPI users and healthy controls, were 30.3 and 16.3 (&lt;i&gt;P&lt;/i&gt;&lt;0.005), 2.5 and 1.8 (&lt;i&gt;P&lt;/i&gt;&lt;0.005), and 9.3 and 5.0 (&lt;i&gt;P&lt;/i&gt;&lt;0.005), respectively. Even after adjustment for confounding factors, the OR of the MNi, NPBs, and Nbuds for long-term PPI users compared with healthy control subjects were 14.1 (&lt;i&gt;P&lt;/i&gt;&lt;0.001), 2.0 (&lt;i&gt;P&lt;/i&gt;=0.001), and 1.3 (&lt;i&gt;P&lt;/i&gt;=0.3), respectively.Conclusions: Long-term PPI use was significantly associated with an increased risk of genotoxicity after adjustment for age, sex, body mass index, medical history, drug history, and the serum levels of vitamins.

Proton Pump Inhibitor Use, Hypergastrinemia, and Gastric Carcinoids-What Is the Relationship?

Neuroendocrine tumors (NETs) throughout the body are the focus of much current interest. Most occur in the gastrointestinal tract and have shown a major increase in incidence over the past 30 years, roughly paralleling the world-wide increase in the use of proton pump inhibitor (PPI) drugs. The greatest rise has occurred in gastric carcinoids (g-NETs) arising from enterochromaffin-like (ECL) cells. These tumors are long known to occur in auto-immune chronic atrophic gastritis (CAG) and Zollinger-Ellison syndrome (ZES), with or without multiple endocrine neoplasia type-1 (MEN-1), but the incidences of these conditions do not appear to have increased over the same time period. Common to these disease states is persistent hypergastrinemia, generally accepted as causing g-NETs in CAG and ZES, and postulated as having similar tumorigenic effects in PPI users. In efforts to study the increase in their occurrence, g-NETs have been classified in a number of discussed ways into different grades that differ in their incidence and apparent pathogenesis. Based on a large amount of experimental data, tumorigenesis is mediated by gastrin’s effects on the CCK2R-receptor on ECL-cells that in turn leads to hyperplasia, dysplasia, and finally neoplasia. However, in all three conditions, the extent of response of ECL-cells to gastrin is modified by a number of genetic influences and other underlying risk factors, and by the duration of exposure to the hormonal influence. Data relating to trophic effects of hypergastrinemia due to PPI use in humans are reviewed and, in an attached Appendix A, all 11 reports of g-NETs that occurred in long-term PPI users in the absence of CAG or ZES are summarized. Mention of additional suspected cases reported elsewhere are also listed. Furthermore, the risk in humans may be affected by the presence of underlying conditions or genetic factors, including their PPI-metabolizer phenotype, with slow metabolizers likely at increased risk. Other problems in estimating the true incidence of g-NETs are discussed, relating to non-reporting of small tumors and failure of the Surveillance, Epidemiology, and End Results Program (SEER) and other databases, to capture small tumors or those not accorded a T1 rating. Overall, it appears likely that the true incidence of g-NETs may be seriously underestimated: the possibility that hypergastrinemia also affects tumorigenesis in additional gastrointestinal sites or in tumors in other organ systems is briefly examined. Overall, the risk of developing a g-NET appears greatest in patients who are more than 10 years on drug and on higher doses: those affected by chronic H. pylori gastritis and/or consequent gastric atrophy may also be at increased risk. While the overall risk of g-NETs induced by PPI therapy is undoubtedly low, it is real: this necessitates caution in using PPI therapy for long periods of time, particularly when initiated in young subjects.

Long-term proton pump inhibitor usage and the association with pancreatic cancer in Sweden

BackgroundThe long-term safety of proton pump inhibitors (PPIs) is increasingly questioned. The aim of our study was to assess the risk of pancreatic cancer among long-term PPI users in Sweden.MethodsThis population-based nationwide Swedish cohort study including 796,492 adult long-term PPI users has been used to calculate the standardized incidence rate ratios (SIRs) and 95% confidence intervals (CI) for pancreatic cancer, stratifying by indications of use, age, sex, and duration of use. The risk among all 20,210 long-term H2-receptor antagonist users was assessed as comparison.ResultsPancreatic cancer was found in 1733 long-term PPI users, and 25 H2-receptor antagonist users. For PPI users, the risk of pancreatic cancer was increased overall (SIRs = 2.22; 95% CI 2.12–2.32) and in all subgroup analyses, with the highest risk among PPI-users younger than 40 years (SIR = 8.90, 95% CI 4.26–16.37), and among individuals with a history of Helicobacter pylori (SIR = 2.99, 95% CI 2.54–3.49). After the first year after enrolment (during which PPI use may be because of early symptoms of pancreatic cancer), the risk remained increased over time, with SIR = 1.57 (95% CI 1.38–1.76) after 5 years. No associations were found for H2-receptor antagonists (SIR = 1.02, 95% CI 0.66–1.51).ConclusionsThis large study showed an increased risk of pancreatic cancer in long-term users of PPIs in Sweden, in particular among the youngest users.

Discontinuing Long-Term PPI Therapy: Why, With Whom, and How?

Proton pump inhibitors (PPIs) are among the most widely used class of drugs prescribed over the long term in all of clinical medicine with 8-10% of ambulatory adults have been prescribed a PPI in the past 30 days. However, numerous studies have raised doubts about the long term safety of PPI use. The purpose of this review is threefold: (i) To provide an overview of the current evidence demonstrating associations between PPI use and adverse health outcomes and the likelihood of the associations being causal (Why?); (ii) To be able to identify long-term PPI users in whom the intensity of PPI therapy could be reduced or in whom PPIs could be eliminated outright (Who?); and (iii) To provide strategies on how to reduce or stop chronic PPI therapy while maintaining symptom control and reducing the risk for symptom or upper GI disease recurrence (How?).

Maintenance proton pump inhibition therapy and risk of oesophageal cancer

BackgroundThe association of long-term use of proton pump inhibitors (PPIs) with oesophageal adenocarcinoma has been poorly defined. Our aim was to assess the risk of oesophageal cancer assessing confounding by indication. MethodsThis population-based cohort study included all 796,492 adults exposed to maintenance therapy with PPIs in Sweden in 2005–2012. Standardised incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated to assess the risk of oesophageal adenocarcinoma (and squamous cell carcinoma as a comparison) among long-term PPI users relative to the corresponding background population. The different indications for maintenance PPI therapy were analysed separately. ResultsAmong all individuals using maintenance PPI therapy, the overall SIR of oesophageal adenocarcinoma was 3.93 (95% CI 3.63–4.24). The SIRs of adenocarcinoma were increased also among individuals without gastro-oesophageal reflux disease who used PPIs for indications not associated with any increased risk of oesophageal adenocarcinoma. For example, the SIRs among participants using maintenance PPI therapy because of maintenance treatment with non-steroidal anti-inflammatory drugs and aspirin were 2.74 (95% CI 1.96–3.71) and 2.06 (95% CI 1.60–2.60), respectively. The SIRs of oesophageal squamous cell carcinoma were increased for most investigated indications, but to a lesser degree than for oesophageal adenocarcinoma. ConclusionIn conclusion, the long term use of PPIs is associated with increased risk of oesophageal adenocarcinoma in the absence of other risk factors. Long term use of PPIs should be addressed with caution.

Pharmaceutical prescription of proton pump inhibitors and ranitidine in the general population living in the area of the Healthcare Authority and University of Udine (Friuli Venezia Giulia, Northeastern Italy)

to describe the use of proton pump inhibitors (PPI) and ranitidine in the general population living in the area of the Healthcare Authority and University of Udine (Friuli Venezia Giulia, Northeastern Italy) and to evaluate whether there are any cases of co-prescription of medications in those classes. analysis of health-related administrative databases (list of potential healthcare beneficiaries, prescriptions of medications, exemption from medical charges because of chronic conditions, list of general practitioners). population of the Italian area of the Healthcare Authority and University of Udine (approximately 250,000 inhabitants) ≥1 year of age as of January 1st, 2016. prevalence of PPI or H2RA use (>1 prescription in 2016), overall and stratified by drug, age class and sex; duration of the theoretical period covered by prescriptions; prevalence of co-prescriptions; association of co-prescriptions and clinical and demographic characteristics of patients (odds ratio and 95% confidence intervals). in 2016, 162 persons per 1,000 used those medications; in particular, 158/1,000 used PPIs. Prevalence of use increased with age, as did the median treatment duration with PPIs. Co-prescription of two medications of the same class were observed in 0.43% of antacid users. The likelihood of receiving co-prescriptions was higher among non-elderly subjects, long-term PPI users, and those with chronical diseases, such asthma. in the considered Italian area, PPIs and ranitidine were frequently used, although less than in the rest of Italy. We observed occasionally non-recommended practices, such as the co-prescription of different medications of the same class or with the same indications.

Hypergastrinemia in Long-Term Use of Proton Pump Inhibitors

Background/Aim: The use of proton pump inhibitors (PPIs) is known to lead to hypergastrinemia; however, the data in patients with atrophic gastritis is still lacking. The aim of this study was to investigate the effects of long-term PPIs use on the gastrin levels in patients with atrophic gastritis and to determine factors affecting hypergastrinemia in long-term users of PPIs. Methods: Serum Helicobacter pylori IgG, gastrin and pepsinogen levels were measured. Atrophic gastritis was assessed by upper gastrointestinal endoscopies based on the Kimura-Takemoto classification and pepsinogen levels. CYP2C19 polymorphisms were assessed using DNA extracted from peripheral blood. Results: A total number of 382 patients (275 men and 107 women) were enrolled. Median serum gastrin levels were higher in PPI users than in non- users (234 vs. 113 pg/mL, p < 0.001) and in women than in men (252 vs. 155 pg/mL, p = 0.006). Gastrin levels were significantly associated with corpus atrophy only in the subgroup of non-users of PPIs. Multivariate analysis revealed that hypergastrinemia (over 150 pg/mL) was significantly associated with PPI use (OR 5.30; 95% CI 3.32–8.47), women (OR 2.22; 95% CI 1.33–3.72) and corpus atrophy (OR 1.82; 95% CI 1.14–2.90). Conclusion: PPI use, women and corpus atrophy were risk factors for hypergastrinemia. Gender, but not corpus atrophy, affected the gastrin levels in long-term users of PPIs.

Long-term use of proton pump inhibitors, dose-response relationship and associated risk of ischemic stroke and myocardial infarction.

Use of proton pump inhibitors (PPIs) has been associated with cardiovascular disease amongst patients not on antiplatelet therapy. The associations of PPI use, duration and dose, with risk of first-time ischemic stroke and myocardial infarction (MI) are poorly understood. All Danish individuals with no prior history of MI or stroke, who had an elective upper gastrointestinal endoscopy performed between 1997 and 2012, were identified from nationwide registries. We used multiple Poisson regression to test associations with current PPI use and its dose and used multiple cause-specific Cox regression and g-formula methods to analyze long-term use. Amongst 214998 individuals, during a median follow-up of 5.8years, there were 7916 ischemic strokes and 5608 MIs. Current PPI exposure was associated with significantly higher rates of both ischemic stroke (Hazard ratio (HR) 1.13; 95% confidence interval (CI) 1.08-1.19) and MI (HR 1.31, CI 1.23-1.39) after adjusting for age, sex, comorbidities and concomitant medication. High-dose PPI was associated with increased rates of ischemic stroke (HR 1.31, CI 1.21-1.42) and MI (HR 1.43, CI 1.30-1.57). Histamine H2 receptor antagonists (H2RAs) use was not significantly associated with ischemic stroke (HR 1.02, CI 0.84-1.24) or MI (HR 1.15, CI 0.92-1.43). Long-term users of PPIs, compared with nonusers, had a 29% (CI 5%-59%) greater absolute risk of ischemic stroke and a 36% (CI 7%-73%) greater risk of MI within a 6-month period. Use of PPIs was associated with increased risks of first-time ischemic stroke and MI, particularly amongst long-term users and at high doses.

The risk of Clostridium difficile infection in patients with pernicious anaemia: a retrospective cohort study using primary care database.

Studies have found an association between proton pump inhibitor (PPI) use and Clostridium difficile infection. The purpose of this study was to determine whether the mechanism by which PPIs induce an increased risk of C. difficile infection is supported by the same mechanism acting in another cause of achlorhydria, pernicious anaemia. Using a database of anonymised primary care records between 1990 and 2013, we selected exposed patients with a diagnosis of pernicious anaemia treated with vitamin B12 therapy. Each exposed patient was matched by age, gender and general practice to up to 10 controls. Cox regression analysis was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for C. difficile infection with pernicious anaemia, adjusted for potential confounders. We identified 45,467 exposed patients matched to 449,635 controls. The crude incidence rate of C. difficile infection was 1.85/1000 person-years for the exposed cohort and 1.09/1000 person-years for controls. Patients with pernicious anaemia had a greater risk of C. difficile infection than the controls (adjusted HR 1.57, 95% CI 1.40-1.76). Pernicious anaemia patients have an increased risk of C. difficile infection. This supports the theory that severe achlorhydria is the mechanism that increases the risk of C. difficile infection in long-term PPI users.

Proton Pump Inhibitor Induction of Gastric Cobblestone-like Lesions in the Stomach.

Objective The long-term use of proton pump inhibitors (PPIs) may induce adverse events in many organs, including the stomach. The chronic use of PPIs has been associated with the growth of fundic gland polyps (FGPs) and of gastric black spots. This study assessed the incidence of gastric lesions with cobblestone-like appearance in PPI users. Methods The clinical characteristics and endoscopic findings of patients who underwent upper gastrointestinal endoscopy after using PPIs for at least six months were analyzed. The biopsy specimens from patients with gastric cobblestone-like lesions (GCLLs) were examined histopathologically. Patients This study analyzed 171 patients who underwent upper gastrointestinal endoscopy after more than 6 months of PPI use in Mitsugi Public General Hospital from January 1, 2015, to March 31, 2016. Results Of the 171 patients, 60 (35.1%) had GCLLs and 111 (64.9%) did not. There were no significant between-group differences in age, sex, duration of PPI use, and receipt of Helicobacter pylori eradication therapy. Atrophic gastritis of the corpus was significantly less frequent in the GCLL than in the non-GCLL group (55.0% vs. 47.8%, p=0.0097). Among the GCLL group, histological examinations of 24 patients revealed cystic dilation of the fundic gland in 19 (79.2%), parietal cell hyperplasia in 18 (75.0%), and cytoplasmic vacuolation in 7 (29.2%). Conclusion GCLLs occurred frequently in long-term PPI users, especially in patients without atrophic gastritis. The pathological findings of GCLLs included parietal cell hyperplasia and fundic gland cysts. The clinical importance of these new lesions remains uncertain, but they should be observed carefully.

Long-Term Proton Pump Inhibitor Use Is Not Associated With Changes in Bone Strength and Structure.

Multiple studies have reported an association between proton pump inhibitor (PPI) use and fracture. However, the causality of this association is questionable, as there is not a well defined mechanism of action, nor is there evidence of an effect on PPIs on areal bone mineral density (aBMD) using dual photon X-ray absorptiometry (DXA). It is possible that PPIs may induce changes in bone structure which would predispose to fracture in the absence of changes in aBMD. We used three-dimensional quantitative computed tomography (3D-QCT) imaging to determine if long-term PPI use was associated with structural changes in bone independent of aBMD. We enrolled a sample of long-term (≥5 years) PPI users matched to a similar cohort of persons with no PPI use in the previous 5 years. All subjects underwent assessment of aBMD using DXA, volumetric BMD using 3D-QCT, as well as markers of bone metabolism. Measures of bone strength, including buckling ratio and section modulus, were also compared between the two samples. 104 subjects were enrolled (52 PPI users and 52 PPI non-users). There were no differences detected in standard BMD, volumetric BMD, markers of bone metabolism or measures of bone strength between the two groups. Long-term PPI use is not associated with any changes in bone mineral density or bone strength that would predispose to an increased risk of fracture. These findings provide further evidence that the association between PPI use and fracture is not causal.