Effect Of Proton Pump Inhibitors Research Articles

Interaction between the effects of proton pump inhibitors and aspirin on gastric wall sestamibi uptake on myocardial perfusion imaging

BackgroundIncreased gastric wall activity on myocardial perfusion imaging (MPI) is associated with proton pump inhibitor (PPI) therapy; however, the mechanism is unknown. We proposed a role for gastric mucosal prostaglandin synthesis and asked whether concurrent use of aspirin would antagonize this effect. MethodsAn observational study was performed of 319 patients undergoing technetium-99m sestamibi (MIBI) rest/stress MPI. We assessed the effects of taking PPIs, aspirin and their interaction on the principle outcome of clinically significant gastric wall activity. ResultsThe outcome was observed in 13% of patients taking neither a PPI nor aspirin, 22% of those taking aspirin only, 51% taking a PPI only and 33% of those taking both. Adjusted odd ratios (95% confidence intervals) were 6.3 (CI 2.8-14.0; p < .001) for taking a PPI only, 1.8 (CI 0.8-3.9; p = .16) for taking aspirin only, and 3.0 (CI 1.4-6.5; p = .005) for taking the combination of a PPI and aspirin. There was evidence of negative statistical interaction between the two drug effects using additive (p = .006) and multiplicative (p = .016) scales. ConclusionsPPI use was strongly associated with enhanced gastric wall activity on MPI; however, concurrent aspirin appears to reduce the effect. Enhanced local prostaglandin synthesis may mediate the PPI effect.

S411 Effect of Histamine-2 Receptor Blockers Use on COVID-19 Susceptibility in Patients With Gastroesophageal Reflux Disease (GERD): A Population-Based Study

Introduction: Studies have demonstrated that GERD is among the comorbidities that correlate with poorer outcomes in hospitalized patients with COVID-19. Proton pump inhibitors (PPI) increase the risk for enteric infections likely due to PPI effect on intra-gastric pH. However, evidence regarding the link between PPI use and COVID-19 is still conflicting. On the other hand, famotidine has been shown to correlate with improved clinical outcomes in hospitalized COVID-19 patients. We aimed to examine the relationship between COVID-19 risk and use of H2RB or PPIs in GERD patients. Methods: Data was extracted from a large commercial database (Explorys, IBM) that aggregates electronic health records from 26 large nationwide healthcare systems. Only adult patients with diagnosis of GERD from January 1999-May 2021 and COVID-19 from December 2019-May 2021 were included. Baseline characteristics including race, gender, H2RB or PPI use and health insurance type and status were collected. Incidence of COVID-19 among risk groups were examined. Univariable and multivariable logistic regression analyses were performed.The presence of effect modification by H2RB use was examined. Multivariate model was stratified by H2RB use. Results: We identified 6215670 GERD patients of which 4057825 (65%) were exclusive PPI users. A total of 1626345 (40%) used both H2RBs and PPIs and only 546930 (9%) used H2RBs alone. COVID-19 was diagnosed in 1140 (0.03%) patients using PPIs alone (62% females vs 38% males), 1300 (0.08%) users of both H2RB and PPI (68% females vs 32% males) and 190 (0.03%) patients using H2RBs alone (63% females vs 37% males). In univariate model, H2RB use was significantly associated with COVID-19 diagnosis OR 2.47 [2.29-2.66, P< 0.001]. COVID-19 risk was significantly modified if patient used both PPI and H2RB OR 1.92 [1.72-2.15, P< 0.001]. In multivariate model, after adjusting for covariates, PPI use was independently associated with COVID-19 diagnosis OR 3.4 [3.1-3.76, P< 0.001]. H2RB use alone was significantly associated with COVID-19 diagnosis OR 2.8 [2.35-3.2, P< 0.001]. But the use of both PPI and H2RB significantly reduced the risk of infection OR 0.63 [0.55-0.74, P< 0.001]. If the model was stratified by H2RB use, COVID-19 risk was reduced in PPI users but unchanged in patients regardless of their baseline demographics (Figure 1). Conclusion: In GERD patients, exclusive use of PPIs or H2RBs was significantly associated with COVID-19 diagnosis. Concurrent use may modify susceptibility to COVID-19.Figure 1.: Multivariable regression analysis stratified by histamine-2 receptor blockers (H2RB) use. A forest plot showing odds ratio (OR) and 95% confidence interval (CI) for the association between COVID-19 and select baseline demographic data in patients with gastroesophageal reflux disease (GERD).

Вибір оптимального інгібітору протонної помпи для пацієнтів з ішемічною хворобою серця, які потребують проведення подвійної антитромбоцитарної терапії

Висока захворюваність і смертність від серцево-судинних захворювань призвели до необхідності широкого використання антитромбоцитарних засобів у клінічній практиці. Найбільш перспективною вважається комбінована антиагрегантна терапія з використанням препаратів, що мають різні механізми впливу на тромбоцитарну ланку гемостазу, за рахунок чого можна досягти вираженого синергічного ефекту. У нашій країні переважно призначається комбінація ацетилсаліцилової кислоти і клопідогрелю, яку часто називають подвійною антитромбоцитарною терапією (ПАТ). Для зменшення ризиків розвитку шлунково-кишкових ускладнень при використанні ПАТ рекомендований прийом інгібіторів протонної помпи (ІПП), проте в деяких дослідженнях згадується, що одночасне призначення ІПП та клопідогрелю в перспективі підвищує ризик виникнення несприятливих серцево-судинних подій, до яких відносять інфаркт міо-карда, інсульт, нестабільну стенокардію, необхідність повторних коронарних втручань і коронарну смерть. У зв’язку з цим представляється актуальною проблема розробки підходів диференційованого застосування ІПП у пацієнтів, які отримують ПАТ. Надано огляд літератури з означеної вище проблематики, наведено результати досліджень із вивчення впливу різних ІПП на клінічні наслідки у хворих, які приймають клопі-догрель.

Effects of Proton Pump Inhibitors on Serum Calcium Level: A Study on Rabbit Model

Background: Proton Pump inhibitors (PPI) are widely used all over the world as therapeutic agents as well as prophylactic agent at different age groups for multiple gastrointestinal disorders etc. it inhibits the hydrogen potassium pump (H/K ATPase Pump). PPI interferes the calcium absorption and thus disturbs acid secretion which leads to decrease the calcium level in the body.&#x0D; Objective: The present design is to evaluate the effects of PPI on serum calcium level in rabbit model.&#x0D; Study Design: Randomized Control Trial/ Study on Rabbit Model.&#x0D; Place and Duration of Study: This experimental study was done at Department of Pharmacology Isra Medical University Hyderabad (November 2020 to March 2021&#x0D; Material &amp; Methods: A total 20 healthy male rabbits with weight between 1-2kg were included in this study. While female rabbits, ill rabbits and rabbits with weight less than 1kg were excluded from study. Ten rabbits were given omeprazole sachet of 20mg orally dissolve in water once a day and 10 rabbits were given sachet of esomeprazole of 20mg dissolve in water once a day upto 90 days regularly. At different levels of study blood samples were obtained from vein near ear of rabbits and samples were centrifuged for 10minutes to obtain the serum. Then serum was sent to Isra Diagnostic Laboratory for analysis of serum calcium levels of all samples at different levels of study.&#x0D; Results: Serum calcium levels of all rabbits were analyzed at three different levels of study, at zero level before starting of experiment, at level I after completion of one month of experiment and level II after the completion of three months of experiment. The normal serum calcium level in rabbits is 13-15mg/dl.8There was a significant decline in serum calcium level in Group A (Omeprazole Group), while in Group B (Esomeprazole Group) there was no significant relation between decreased serum calcium levels.&#x0D; Conclusion: The study concluded that there is significant relation of longterm usage of PPI on serum calcium level.

Effectiveness of PPI treatment and guideline adherence in 236 patients with eosinophilic oesophagitis-Results from the population-based DanEoE cohort shows a low complication rate.

BackgroundProton pump inhibitors (PPIs) are often the first drug of choice in the treatment of eosinophilic oesophagitis (EoE), and in Denmark 8 weeks of high‐dose PPI therapy is recommended as first‐line treatment followed by rebiopsying, reflecting international recommendations.AimsTo assess the population‐based effectiveness of PPIs in the treatment of EoE and evaluate whether patients were treated and followed according to the regional guideline.MethodsThis is a retrospective, registry‐based, DanEoE cohort study of 236 adult EoE patients diagnosed between 2007 and 2017 in the North Denmark Region. After patient file revision, the EoE diagnosis was defined according to the AGREE 2 consensus. Symptomatic PPI response was defined as complete symptom resolution and histological remission (<15 eosinophils per high‐power field).ResultsPPI treatment was initiated in 92% of the EoE patients. High‐ and low‐dose PPIs were prescribed in 55% and 45% of the cases, respectively. When treated with high‐dose PPIs, 68% of the patients were completely symptom‐free, and 49% were in histological remission. In 39% of high‐dose PPI‐treated patients, the symptomatic and histological responses were conflicting. While treated with PPIs, complications were rare, with <5% strictures in responders and <10% in non‐responders. Rebiopsying was done in 67% of the EoE patients started on PPIs.ConclusionsHigh‐dose PPI treatment was effective in half of the EoE patients started on PPIs, but conflicting symptomatic and histological PPI responses were common. Complications were rare when PPIs were started. One‐third of the patients were not rebiopsied as recommended.

239P Drug-drug interactions between palbociclib and proton pump inhibitors may significantly affect clinical outcome of metastatic breast cancer patients

Proton pump inhibitors (PPIs) are widely used in cancer patients to mitigate polypharmacy-associated adverse gastroesophageal events. However, drug-drug interactions (DDIs) at absorption level should be considered as it may affect clinical outcome. Palbociclib is a weak base with pH-dependent solubility that rapidly decreases as pH increases above 4.5 (Clin Pharmacol Drug Dev 2017;6:614-6). The current study was aimed at investigating the effect of concomitant PPIs on palbociclib progression-free survival (PFS) in metastatic breast cancer (mBC) patients.

695P Drug-drug interactions between pazopanib and proton pump inhibitors may significantly affect clinical outcome of patients affected by metastatic renal cell carcinoma

Proton pump inhibitors (PPIs) are widely used in cancer patients to mitigate polypharmacy-associated adverse gastroesophageal events. However, pharmacokinetic data showed that concomitant administration of pazopanib and PPIs leads to decreased plasma concentrations and exposure of pazopanib by 40% (Cancer Chemother Pharmacol 2013; 71: 1635–1643). The current study aimed at investigating the effect of concomitant PPIs on pazopanib progression-free survival (PFS) in patients affected by metastatic renal cell carcinoma (mRCC).

Proton Pump Inhibitors and the Risk of Community-Acquired Pneumonia: An Updated Meta-analysis.

Some studies suggested an increased risk of community-acquired pneumonia (CAP) among proton pump inhibitors (PPI) users. However, the published evidence is inadequate to define the association between PPI use and the risk of CAP. The aims of our meta-analysis were to systematically assess the association between the risk of CAP and PPI use in adults to reduce the adverse effects of PPI and ensure the safety of medication for patients. A comprehensive literature search was conducted, published between January 1, 2004, and February 1, 2021. The primary outcome was the incidence of CAP. This meta-analysis was performed using odds ratios (ORs) with 95% CIs as effective measures; 13 studies including 2 098 804 patients were enrolled in our meta-analysis. Our study revealed that the incidence of CAP was higher in PPI users than non -PPI users [OR = 1.37 (95% CI = 1.22-1.53)], especially for PPI duration < 30 days [OR = 1.49 (95% CI = 1.34-1.66)]. Compared with non-PPI use, PPI use increased the incidence of CAP in the stroke disease population [OR = 1.52 (95% CI = 1.33-1.75)], but not in the liver disease population [OR = 1.13 (95% CI = 0.98-1.30)]. Using PPI could increase the risk of CAP when compared to not using PPI. PPI use increased the incidence of CAP in patients with stroke. Clinicians and clinical pharmacists should weigh the benefits before medication and strictly control the indication of the prescription, so as to reduce adverse reactions.

The prognosis and incidence of hepatic encephalopathy of patients with liver cirrhosis treated with proton pump inhibitors: A multicenter retrospective study in Japan.

Gastrointestinal bleeding, hepatic encephalopathy (HE), and hepatocarcinogenesis are associated with the prognosis of patients with liver cirrhosis (LC). Proton pump inhibitors (PPIs) have been used to prevent bleeding, however the effects of PPIs on overall survival have not yet been elucidated. Therefore, this multicenter retrospective study aimed to assess the effect of PPI on the prognosis and HE occurrence of the patients with liver cirrhosis in Japan.A total of 456 patients diagnosed with LC at the 4 institutes during the study period (2010–2014) were assessed. PPI-treated and non-treated patients were compared using propensity score matching analysis. Primary and secondary endpoints of the study were set as the occurrence of HE and overall survival, respectively.A comparison of all cases showed a significantly poorer hepatic reserve function in the PPI-treated patients. The propensity-score matching analysis was performed and 120 PPI-treated patients were 1:1 matched with non-treated patients. The analysis revealed a higher incidence of HE in the PPI-treated than in the non-treated patients (P = .032; hazard ratio [HR], 2.162; 95% confidence interval [CI], 1.066–4.176), but the prognosis of PPI-treated patients was no worse than that of non-treated patients (P = .676; HR, 1.101; 95% CI, 0.702–1.726).This retrospective study showed that PPI administration for the patients with liver cirrhosis may partly be related to the increased incidence of HE but not worsen the patient prognosis.

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.

Concomitant Use of Proton Pump Inhibitors With Capecitabine Based Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: Is it Safe?

Capecitabine (Cape) is routinely used for the neoadjuvant chemoradiation treatment (NACRT) of locally advanced rectal cancers (LARCs). Previous reports have suggested that the concomitant use of proton pump inhibitors (PPIs) may affect the efficacy of Cape, although the true effect of PPIs when used with Cape as a radiosensitizer for neoadjuvant radiation is unclear. The aim of our study was to evaluate the impact of concurrent PPI use along with fluorouracil (FU) and Cape based NACRT in terms of pathologic and oncological outcomes, in patients with LARC. LARC patients treated at our center with NACRT from 2010 to 2016 were identified. Postoperative pathology and follow-up outcomes were examined for any differences with relation to the use of PPIs concurrently with FU and Cape based NACRT and adjuvant chemotherapy regimens. Three hundred four and 204 patients received treatment with FU and Cape based NACRT. No difference in pathologic complete response rate was noted between the 2 arms with the concurrent use of PPIs (25.8% and 25%, respectively, P=0.633); or with and without the use of PPIs in the Cape-NACRT arm specifically (20% and 20.7%, P=0.945). At a median follow-up of 5 years, no statistical difference in local or distant control was noted in the Cape-NACRT patients, with and without concomitant PPI use (P=0.411 and 0.264, respectively).Multivariate analysis showed no association of PPI use and NACRT with Cape, in terms of local control (hazard ratio=0.001, P=0.988) or overall survival (hazard ratio=1.179, confidence interval=0.249-5.579, P=0.835). Our study revealed that there was no adverse pathologic or oncological outcome with the concurrent use of PPIs along with Cape-NACRT in the treatment of LARC. We report that it may be safe to use PPIs if essential, in this clinical setting, although it would be wise to exercise caution.

English

BACKGROUND Laryngopharyngeal reflux (LPR) is found to be a common disease encountered in Otolaryngology practice. LPR presents clinically with symptoms of laryngeal irritation, frequent throat clearing, cough, and hoarseness of voice. The main diagnostic methods currently used are Fiber-optic laryngoscopy and in some centers pH monitoring. Proton pump inhibitors (PPIs) are used and found to be cost-effective and useful for the treatment of LPR. The main objective of this study was to study the effectiveness of PPIs in alleviating the symptoms assessed using Reflux Symptom Index (RSI) score and Reflux Finding Scores (RFS). METHODS A prospective study was carried out on 100 patients attending the ENT OPD of Government Medical College and Hospital, Thrissur, Kerala. Patients were evaluated for improvement in symptoms of Laryngopharyngeal reflux disease following use of proton pump inhibitors, using Reflux symptom index and Reflux finding scores using 70 degree / flexible nasopharyngolaryngoscopy. Patients with clinical findings of LPRD with RSI score &gt; 13 and RFS score &gt; 7 were given a standard treatment protocol followed in our ENT department using Tab. Pantoprazole 40 mg twice daily before food and the treatment response was assessed by proper follow up at 6 weeks and 12 weeks. On each follow up visit, improvement in RSI and RFS scores with Proton pump inhibitor therapy was assessed. Data collected was then tabulated and analysed. RESULTS The study was conducted in 100 patients, 59 % of whom were females and 41 % males. Mean RSI score changed from 18.9 at the beginning to 14.5 at 6 weeks of treatment and 9.0 at 12 weeks of treatment with Proton pump inhibitor. Mean RFS score changed from 10.7 at the beginning to 8.7 at 6 weeks of treatment and to 5.9 at 12 weeks of treatment. Comparison of mean Reflux Symptom Index and mean Reflux Finding Scores before and after treatment revealed improvement and the result was statistically significant (p value &lt; 0.001). CONCLUSIONS The use of RSI and RFS scores in the assessment of PPIs at fixed intervals is cost effective and avoids time consuming and cost intensive examinations. These scores also help in early diagnosis and long term follow up of LPR patient. Fixed time interval PPI treatment significantly improved RSI and RFS scores in LPR patients. The mean RSI score changed from 18.9 at the beginning of treatment to 14.5 at 6 weeks after treatment (p value &lt; 0.001) and 9.0 after 12 weeks of treatment; (p value &lt; 0.001) The mean RFS score changed from 10.7 at the beginning of treatment to 8.7 at 6 weeks after treatment (p value &lt; 0.001) and 5.9 after 12 weeks of treatment; (p value &lt; 0.001). KEYWORDS Laryngopharyngeal Reflux, Reflux Symptom Index, Reflux Finding Score

Proton Pump Inhibitors Inhibit PHOSPHO1 Activity and Matrix Mineralisation In Vitro

Proton pump inhibitors (PPIs) have been associated with an increased risk of fragility fractures in pharmaco-epidemiological studies. The mechanism is unclear, but it has been speculated that by neutralising gastric acid, they may reduce intestinal calcium absorption, causing secondary hyperparathyroidism and bone loss. Here we investigated that hypothesis that the skeletal effects of PPI might be mediated by inhibitory effects on the bone-specific phosphatase PHOSPHO1. We found that the all PPIs tested inhibited the activity of PHOSPHO1 with IC50 ranging between 0.73 µM for esomeprazole to 19.27 µM for pantoprazole. In contrast, these PPIs did not inhibit TNAP activity. We also found that mineralisation of bone matrix in primary osteoblast cultures was inhibited by several PPIs in a concentration dependent manner. In contrast, the histamine-2 receptor antagonists (H2RA) nizatidine, famotidine, cimetidine and ranitidine had no inhibitory effects on PHOSPHO1 activity. Our experiments show for the first time that PPIs inhibit PHOSPHO1 activity and matrix mineralisation in vitro revealing a potential mechanism by which these widely used drugs are associated with the risk of fractures.

Abstract CT125: Evaluation of potential drug-drug interactions (DDIs) between futibatinib and CYP3A inhibitors/inducers, CYP3A substrates, or proton pump inhibitors (PPIs)

Abstract Background Futibatinib is an oral, irreversible FGFR1-4 inhibitor with clinical activity in cholangiocarcinoma and other FGFR-aberrant tumors. The recommended futibatinib dosage is 20 mg once daily (QD). In vitro studies have shown that futibatinib is predominantly metabolized by and inhibits cytochrome p450 3A (CYP3A); futibatinib is also a P-glycoprotein substrate. Two phase 1 studies were performed in healthy volunteers to evaluate potential DDIs between futibatinib and CYP3A substrates (midazolam; study 1) or CYP3A inhibitors/inducers (itraconazole/rifampin; study 2). As the solubility of futibatinib is pH dependent, study 3 assessed the effect of PPI (lansoprazole) coadministration on futibatinib pharmacokinetics (PK). Methods All 3 studies, conducted in adult nonsmokers, were open-label, fixed-sequence, 2-period cross-over studies with a 1- or 2-d washout between each period. In study 1, midazolam 2 mg was given on d1 of period 1 (-futibatinib) and on d7 of period 2 (+futibatinib 20 mg QD d1-7). In study 2, futibatinib 20 mg was given on d1 of period 1 (alone) and on d5 (+itraconazole 200 mg QD d1-6) or d8 (+rifampin 600 mg QD d1-9) of period 2. In study 3, futibatinib 20 mg was given on d1 of period 1 (-lansoprazole) and d5 of period 2 (+lansoprazole 60 mg QD d1-5). Plasma samples for PK assessment were collected predose through 24 h post-midazolam dosing (study 1) and predose through 48 h post-futibatinib dosing (studies 2 and 3). Results In study 1 (N=24), coadministration of futibatinib did not result in clinically significant changes in midazolam PK, based on the area under the concentration curve extrapolated to the last measurable time (AUC0-t; -9%) or infinity (AUC0-inf; -9%) or maximum plasma concentration (Cmax; -5%), compared with midazolam alone. In study 2 (N=40), relative to futibatinib administered alone, coadministration with itraconazole increased futibatinib Cmax (+51%) and plasma exposure (AUC0-t and AUC0-inf +41% each), whereas coadministration with rifampin decreased futibatinib Cmax (-53%) and plasma exposure (AUC0-t and AUC0-inf -64% each). In study 3 (N=20), coadministration of lansoprazole did not result in clinically significant changes in futibatinib PK parameters vs futibatinib alone (AUC0-t +5%; AUC0-inf +5%; Cmax +8%). Agents were well tolerated, and all 3 studies were completed with no clinically relevant safety signals. Conclusions Futibatinib is not expected to affect the exposure of concomitant medications metabolized via CYP3A, the most common drug metabolism pathway. Caution should be exercised when coadministering strong CYP3A inducers or inhibitors with futibatinib, as significant DDIs were observed with itraconazole and rifampin. Futibatinib can be concomitantly administered with PPIs with no clinically relevant impact on futibatinib exposure. Citation Format: Ikuo Yamamiya, John Laabs, Allen Hunt, Toru Takenaka, Daryl Sonnichsen, Mark Mina, Yaohua He, Karim Benhadji. Evaluation of potential drug-drug interactions (DDIs) between futibatinib and CYP3A inhibitors/inducers, CYP3A substrates, or proton pump inhibitors (PPIs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT125.

Effects of Proton Pump Inhibitors on Glycemic Control and Incident Diabetes: A Systematic Review and Meta-analysis.

Whether proton pump inhibitors (PPI) can improve glycemic control among individuals with diabetes or decrease the risk of incident diabetes in the general population is unclear. To evaluate the impact of PPI therapy on glycemic control among individuals with diabetes and the risk of diabetes among those without diabetes. PubMed, Embase, Scopus, and ClinicalTrials.gov were searched from inception to November 21, 2020. We included studies comparing glycosylated hemoglobin (HbA1c) or fasting blood glucose (FBG) among individuals with diabetes treated with and without PPI therapy as an add-on to standard therapy. Studies evaluating the risk of incident diabetes among individuals taking PPI were assessed. We performed dual independent review, data extraction, and quality assessment. Weighted mean differences between groups or relative risks were imputed using random-effects models. Seven studies (n = 342) for glycemic control and 5 studies (n = 244 439) for risk of incident diabetes were included. Compared with standard therapy, add-on PPI was associated with a significant decrease in HbA1c (WMD, -0.36 %; 95% CI, -0.68 to -0.05; P = 0.025) and FBG (WMD, -10.0 mg/dL; 95% CI, -19.4 to -0.6; P = 0.037). PPI use did not reduce the risk of incident diabetes (pooled RR, 1.10; 95% CI, 0.89 to 1.34; P = 0.385). Add-on PPI improved glycemic indices among individuals with diabetes but did not alter the risk of incident diabetes. The effects of PPI on glycemic control should be considered when prescribing antacids to patients with diabetes.

Proton Pump Inhibitors Directly Block hERG-Potassium Channel and Independently Increase the Risk of QTc Prolongation in a Large Cohort of US Veterans

[Figure: see text].

Effect of a proton-pump inhibitor on intestinal microbiota in patients taking low-dose aspirin.

Low-dose aspirin (LDA) administration prevents cerebral infarction and myocardial infarction, but many studies found an association with mucosal injury. Proton-pump inhibitors (PPIs) can prevent gastric and duodenal mucosal damage, but they may exacerbate small-intestinal mucosal injury by altering the microbiota. We aimed to assess the effect of PPIs on the intestinal flora of LDA users. Thirty-two recruited patients, who received LDA (100mg/day) but did not take PPIs, were divided into 15 patients additionally receiving esomeprazole (20mg/day) and 17 patients additionally receiving vonoprazan (10mg/day). On days 0, 30, 90, and 180, the microbiota of each patient was examined by terminal restriction fragment length polymorphism analysis, and the serum gastrin, hemoglobin, and hematocrit levels were measured. Additional PPI administration increased the proportion of Lactobacillales in the microbiota of LDA users. This trend was more prevalent in the vonoprazan group (p < 0.0001) than in the esomeprazole group (p = 0.0024). The Lactobacillales proportion was positively correlated with the gastrin level (r = 0.5354). No significant hemoglobin or hematocrit level reduction was observed in subjects receiving LDA with additional PPI. Additional PPI administration increased the Lactobacillales proportion in the microbiota of LDA users. The positive correlation between the gastrin level and the proportion of Lactobacillales suggested that the change in the intestinal flora was associated with the degree of suppression of gastric acid secretion. Additional oral PPI did not significantly promote anemia, but the risk of causing PPI-induced small-intestinal mucosal injury in LDA users should be considered.

180-LB: Effects of Proton Pump Inhibitors on Glycemic Control and Risk of Incident Diabetes: A Systematic Review and Meta-analysis

Background and Aims: Whether proton pump inhibitors (PPI) can improve glycemic control is unclear. Also, incident diabetes from PPI use has not been elucidated. We conducted a meta-analysis and systematic review to determine the impact of PPI on glycemic control in individuals with diabetes and the risk of diabetes in those without diabetes. Methods: PubMed, Embase, Scopus, and ClinicalTrials.gov were searched from inception to November 21, 2020. Studies reporting a change of glycemic indices, including glycosylated hemoglobin (HbA1c) or fasting blood glucose (FBG), in individuals with diabetes taking add-on PPI compared to standard therapy were included. Also, studies evaluating risk of incident diabetes in individuals taking PPI were assessed. We performed dual independent review, data extraction, and quality assessment. Weighted mean differences or relative risks were imputed using random-effects models. Results: Seven studies (n = 342) for glycemic control, and five studies (n = 244,439) for risk of incident diabetes were included. Compared to standard therapy, add-on PPI was associated with a significant decrease in HbA1c (WMD = −0.36 %; 95% CI: −0.68 to −0.05; p = 0.025), and FBG (WMD = −10.0 mg/dL; 95% CI: −19.4 to −0.6; p = 0.037). However, PPI use was not significantly associated with the risk of incident diabetes (pooled RR = 1.10; 95% CI: 0.89 to 1.34; p = 0.385). Conclusions: PPI along with standard care improved glycemic indices in individuals with diabetes but did not alter the risk of incident diabetes. The effects of PPI on glycemic control should be considered when treating upper gastrointestinal symptoms in patients with diabetes. Disclosure C. Peng: None. K. Bukhari: None. H. Huang: None. Y. Tu: None. G. Lee: None. H. Chang: None. Y. Huang: None. Y. Fu: None. K. M. Munir: None.

Performance of the faecal immunochemical test for the detection of colorectal neoplasms and the role of proton pump inhibitors in their diagnostic accuracy.

The faecal immunochemical test (FIT) is currently utilized in both symptomatic and screening populations, but little is known about factors that affect its performance. For example, proton pump inhibitor (PPI) therapy has been purported to increase false negative rates. This has significant implications given the extent of PPI prescriptions. The aim of this work was to evaluate the performance of the FIT for the detection of colorectal neoplasms and the impact of PPI therapy on its diagnostic accuracy. Symptomatic patients referred on the suspected cancer pathway and those on polyp surveillance between 2015 and 2019 were approached to participate. Estimates of the accuracy of FIT at different cut-off levels in diagnosing colorectal neoplasms were made. Logistic regression was used to assess the effect of PPIs on the FIT results. A total of 667 participants were eligible for the final analysis. At a cut-off of 10μg/g faeces, the overall sensitivity and specificity of FIT for the detection of colorectal cancer (CRC) was 0.85 (95% CI 0.71-0.94) and 0.81 (95% CI 0.78-0.84), respectively. For the detection of advanced neoplasia, the sensitivity was 0.70 (95% CI 0.58-0.79) and the specificity was 0.83 (95% CI 0.80-0.86). At higher thresholds, the sensitivity steadily declined whilst specificity increased. PPI therapy did not have a significant effect on performance of the FIT. FIT is a good rule-out test for the detection of CRC and advanced neoplasia at lower thresholds. PPI therapy does not appear to have an effect on its diagnostic performance.

Esomeprazole attenuates inflammatory and fibrotic response in lung cells through the MAPK/Nrf2/HO1 pathway

IntroductionIdiopathic pulmonary fibrosis (IPF) is an orphan disease characterized by progressive loss of lung function resulting in shortness of breath and often death within 3–4 years of diagnosis. Repetitive lung injury in susceptible individuals is believed to promote chronic oxidative stress, inflammation, and uncontrolled collagen deposition. Several preclinical and retrospective clinical studies in IPF have reported beneficial outcomes associated with the use of proton pump inhibitors (PPIs) such as esomeprazole. Accordingly, we sought to investigate molecular mechanism(s) by which PPIs favorably regulate the disease process.MethodsWe stimulated oxidative stress, pro-inflammatory and profibrotic phenotypes in primary human lung epithelial cells and fibroblasts upon treatment with bleomycin or transforming growth factor β (TGFβ) and assessed the effect of a prototype PPI, esomeprazole, in regulating these processes.ResultsOur study shows that esomeprazole controls pro-inflammatory and profibrotic molecules through nuclear translocation of the transcription factor nuclear factor-like 2 (Nrf2) and induction of the cytoprotective molecule heme oxygenase 1 (HO1). Genetic deletion of Nrf2 or pharmacological inhibition of HO1 impaired esomeprazole-mediated regulation of proinflammatory and profibrotic molecules. Additional studies indicate that activation of Mitogen Activated Protein Kinase (MAPK) pathway is involved in the process. Our experimental data was corroborated by bioinformatics studies of an NIH chemical library which hosts gene expression profiles of IPF lung fibroblasts treated with over 20,000 compounds including esomeprazole. Intriguingly, we found 45 genes that are upregulated in IPF but downregulated by esomeprazole. Pathway analysis showed that these genes are enriched for profibrotic processes. Unbiased high throughput RNA-seq study supported antifibrotic effect of esomeprazole and revealed several novel targets.ConclusionsTaken together, PPIs may play antifibrotic role in IPF through direct regulation of the MAPK/Nrf2/HO1 pathway to favorably influence the disease process in IPF.