Use Of Histamine-2 Receptor Antagonists Research Articles

Effect of Antacids on the Survival of Patients With Metastatic Urothelial Carcinoma Treated With Pembrolizumab

IntroductionConcomitant medications can affect the efficacy of immune checkpoint inhibitors. The association between histamine-2 receptor antagonists (H2RAs), major antacids similar to proton pump inhibitors (PPIs), and the efficacy of pembrolizumab for metastatic urothelial carcinoma (mUC) treatment has been poorly evaluated. We evaluated the impact of PPIs and H2RAs on oncological outcomes in mUC patients treated with pembrolizumab. Patients and MethodsThis retrospective multicenter study included patients with mUC treated with pembrolizumab. Patients prescribed PPIs or H2RAs within 30 days before and after the initial administration were extracted. The overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), and objective response rates (ORR) were assessed. Kaplan–Meier survival curve analysis and multivariable Cox proportional hazard models were employed to assess the association between PPIs or H2RAs and survival outcomes. ResultsOverall, 404 patients were eligible for this study; 121 patients (29.9%) used PPIs, and 34 (8.4%) used H2RAs. Kaplan–Meier analysis showed significantly worse OS, CSS, and PFS in patients using PPIs compared to no PPIs (P = .010, .018, and .012, respectively). In multivariable analyses, the use of PPIs was a significant prognostic factor for worse OS (HR = 1.42, 95% CI 1.08-1.87, P = .011), CSS (HR = 1.45, 95% CI 1.09-1.93, P = .011), and PFS (HR = 1.35, 95% CI 1.05-1.73, P = .020). PPIs were not associated with ORRs. The use of H2RAs was not associated with survival or ORRs. ConclusionPPIs were significantly associated with worse survival of patients with mUC treated with pembrolizumab, and H2RAs could be an alternative during administration. Both the oncological and gastrointestinal implications should be carefully considered when switching these antacids.

Effects of H2-Receptor Antagonists on the Exposure of Dacomitinib.

Dacomitinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) and EGFR-activating mutations. Proton-pump inhibitors decreased dacomitinib exposure. This analysis summarizes the effect of Histamine-2 receptor antagonists (H2RAs) on dacomitinib exposure. A within-patient comparison of the steady-state trough concentrations (Ctrough,ss) of dacomitinib and its active metabolite and active moiety with and without concomitant use of H2RAs was conducted using a linear mixed effects model with pooled data from 11 clinical studies in patients with NSCLC. An oral absorption physiologically based pharmacokinetic (PBPK) model was constructed and verified using clinical pharmacokinetic (PK) data after a single dose of dacomitinib in healthy volunteers to estimate the effect of gastric pH altered by an H2RA on dacomitinib's PKs. The adjusted geometric mean of the dacomitinib Ctrough,ss of the dacomitinib parent, metabolite and active moiety following co-administration with an H2RA was approximately 86%, 104% and 100% relative to that following dacomitinib 45 mg administration without an H2RA (p > 0.05). The PBPK modeling showed negligible change in dacomitinib maximum concentration (Cmax) and area under the drug concentration-time curve (AUC) over 0-24 h after H2RA administration when compared with those administered dacomitinib alone. Co-administration of an H2RA with dacomitinib is not expected to have any clinically relevant effect on dacomitinib exposure.

Association between proton pump inhibitors use and risk of asthma in Korea: A prevalent new-user cohort study.

There have been conflicting mechanisms that proton pump inhibitors (PPIs) may promote or prevent asthma development. However, the evidence on the association of PPI use with the risk of asthma and its exposure-response relationship has been limited. We aim to identify the association between the use of PPIs and the incidence of asthma, compared with use of histamine 2 receptor antagonists (H2RAs). A nationwide, prevalent new-user cohort study was conducted using Korea's National Sample Cohort database. Patients were defined as PPI or H2RA users between 2003 and 2019. PPI users matched to H2RA users based on time-conditional propensity score. Cox proportional hazards model was used to estimate adjusted hazard ratios with 95% confidence intervals of incident asthma associated with PPI use by duration of use, cumulative dose, and average dose per duration. Among the 250,041 pairs, PPI users (51.3% male; mean [SD] age, 42.6 [16.5]; mean follow-up, 6.7 years) showed a higher incidence rate of asthma (7.94 events per 1000 person-year) compared to H2RA users (3.70 events per 1000 person-year) with adjusted hazard ratio of 2.15 (95% confidence interval = 2.08-2.21). The risk of asthma was significantly increased across all observed groups of duration of use, cumulative dose, and average dose per duration. This study suggested that PPI use is associated with an increased risk of developing asthma compared to H2RA use.

Proton pump inhibitors and chronic kidney disease risk: a comparative study with histamine-2 receptor antagonists

This observational study explored the association between proton pump inhibitor (PPI) and histamine-2 receptor antagonist (H2RA) use and the risk of chronic kidney disease (CKD). Using the National Health Insurance Service-National Sample Cohort (NHIS-NSC) and six-hospital electronic health record (EHR) databases, CKD incidence was analyzed among PPI and H2RA users. Propensity score matching was used to balance baseline characteristics, with 1,869 subjects each in the PPI and H2RA groups from the NHIS-NSC, and 5,967 in EHR databases. CKD incidence was similar for both groups (5.72/1000 person-years vs. 7.57/1000 person-years; HR = 0.68; 95% CI, 0.35–1.30). A meta-analysis of the EHR databases showed no significant increased CKD risk associated with PPI use (HR = 1.03, 95% CI: 0.87–1.23). These results suggest PPI use may not increase CKD risk compared to H2RA use, but the potential role of PPI-induced CKD needs further research. Clinicians should consider this when prescribing long-term PPI therapy.

Gastric Acid Suppression Therapy and Its Association with Peritoneal Dialysis-Associated Peritonitis in the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS).

Peritonitis is a major peritoneal dialysis (PD) related complication. We determined whether gastric acid suppression (GAS) (proton pump inhibitor (PPI) or histamine-2 receptor antagonists (H2RA)) use was associated with all-cause and organism-specific peritonitis in PD patients. In the Peritoneal Dialysis Outcomes and Practice Patterns Study (595 facilities, 8 countries, years 2014-2022), associations between GAS use and time to first episode of all-cause peritonitis were examined using Cox proportional hazards models. The primary exposure of interest was GAS, and secondarily PPI or H2RA use. Secondary outcomes were organism-specific peritonitis, peritonitis cure rates, and death. Among patients (n=23 797) at study baseline, 6020 (25.3%) used PPIs, and 1382 (5.8%) used H2RAs. Overall risks of GAS use and peritonitis risk [adjusted hazard ratio (AHR)=1.05 (95% CI 0.98-1.13)], and use of PPI [AHR 1.06 (95% CI 0.99-1.14)] or H2RA [AHR 1.02 (95% CI 0.88-1.18)] did not reach statistical significance. In organism-specific analyses, GAS users displayed higher peritonitis risks for gram-negative (AHR 1.29, 95% CI 1.05-1.57), gram-positive (AHR 1.15, 95% CI 1.01-1.31), culture-negative (AHR 1.20, 95% CI 1.01-1.42), enteric (AHR 1.23, 95% CI 1.03-1.48), and particularly Streptococcal (AHR 1.47, 95% CI 1.15-1.89) peritonitis episodes. GAS was also associated with higher overall mortality [AHR 1.13 (95% CI 1.05-1.22)]. The association between GAS use and peritonitis risk was weaker (HR 1.05 [0.98-1.13]) than for streptococcal (HR 1.57 [1.15-1.89]) and gram-negative (HR 1.29 [1.05-1.57]) peritonitis. A better understanding of mechanisms surrounding the differential effects of GAS subtype on peritonitis risks is needed. Clinicians should be cautious when prescribing GAS. The impact of GAS deprescribing on peritonitis risk requires further evaluation.

Ranitidine Use and Incident Cancer in a Multinational Cohort

Ranitidine, the most widely used histamine-2 receptor antagonist (H2RA), was withdrawn because of N-nitrosodimethylamine impurity in 2020. Given the worldwide exposure to this drug, the potential risk of cancer development associated with the intake of known carcinogens is an important epidemiological concern. To examine the comparative risk of cancer associated with the use of ranitidine vs other H2RAs. This new-user active comparator international network cohort study was conducted using 3 health claims and 9 electronic health record databases from the US, the United Kingdom, Germany, Spain, France, South Korea, and Taiwan. Large-scale propensity score (PS) matching was used to minimize confounding of the observed covariates with negative control outcomes. Empirical calibration was performed to account for unobserved confounding. All databases were mapped to a common data model. Database-specific estimates were combined using random-effects meta-analysis. Participants included individuals aged at least 20 years with no history of cancer who used H2RAs for more than 30 days from January 1986 to December 2020, with a 1-year washout period. Data were analyzed from April to September 2021. The main exposure was use of ranitidine vs other H2RAs (famotidine, lafutidine, nizatidine, and roxatidine). The primary outcome was incidence of any cancer, except nonmelanoma skin cancer. Secondary outcomes included all cancer except thyroid cancer, 16 cancer subtypes, and all-cause mortality. Among 1 183 999 individuals in 11 databases, 909 168 individuals (mean age, 56.1 years; 507 316 [55.8%] women) were identified as new users of ranitidine, and 274 831 individuals (mean age, 58.0 years; 145 935 [53.1%] women) were identified as new users of other H2RAs. Crude incidence rates of cancer were 14.30 events per 1000 person-years (PYs) in ranitidine users and 15.03 events per 1000 PYs among other H2RA users. After PS matching, cancer risk was similar in ranitidine compared with other H2RA users (incidence, 15.92 events per 1000 PYs vs 15.65 events per 1000 PYs; calibrated meta-analytic hazard ratio, 1.04; 95% CI, 0.97-1.12). No significant associations were found between ranitidine use and any secondary outcomes after calibration. In this cohort study, ranitidine use was not associated with an increased risk of cancer compared with the use of other H2RAs. Further research is needed on the long-term association of ranitidine with cancer development.

Association of Proton Pump Inhibitor Use With Incident Dementia and Cognitive Decline in Older Adults: A Prospective Cohort Study

Prior studies have suggested that proton pump inhibitor (PPI) use is associated with increased risk of dementia; however, these have been limited by incomplete assessment of medication use and failure to account for confounders. Furthermore, prior studies have relied on claims-based diagnoses for dementia, which can lead to misclassification. We investigated the associations of PPI and histamine-2 receptor antagonist (H2RA) use with dementia and cognitive decline. We conducted a post hoc analysis of ASPirin in Reducing Events in the Elderly (ASPREE), a randomized trial of aspirin in the United States and Australia, including 18,934 community-based adults ≥65 years of all races/ethnicities. Baseline and recent PPI and H2RA use were determined according to review of medications during annual in-person study visits. Incident dementia was defined according to Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, criteria. Secondary endpoints include cognitive impairment, no dementia (CIND) and changes in cognition. Associations of medication use with dementia and CIND outcomes were examined using Cox proportional hazards models. Changes in cognitive test scores were examined using linear mixed-effects models. Baseline PPI use vs nonuse was not associated with incident dementia (multivariable hazard ratio, 0.88; 95% confidence interval, 0.72-1.08), CIND (multivariable hazard ratio, 1.00; 95% confidence interval, 0.92-1.09), or with changes in overall cognitive test scores over time (multivariable B,-0.002; standard error, 0.01; P= .85). Similarly, no associations were observed between H2RA use and all cognitive endpoints. In adults ≥65 years of age, PPI and H2RA use were not associated with incident dementia, CIND, or decline in cognition over time. These data provide reassurance about the safety of long-term use of PPIs among older adults.

Myopenic Obesity Determined by Fat Mass Percentage Predicts Risk of Aspirin-Induced Bleeding in Chinese Older Adults.

Body mass index (BMI) correlates with aspirin-induced bleeding risk. However, skeletal muscle mass (SMM) loss and fat gain commonly occur with aging, making BMI not a reasonable marker of bleeding risk in older individuals. In the present study, we aimed to investigate the prognostic value of myopenic obesity based on the percent of fat mass (%FM) for aspirin-induced bleeding in Chinese patients over 60 years old. We prospectively analyzed 185 patients taking aspirin for primary and secondary prevention of cardiovascular diseases. Body composition parameters were estimated using bioelectrical impedance analysis. We defined myopenic obesity (MO) as a height-adjusted appendicular SMM <7.0 kg/m2 in males and <5.7 kg/m2 in females with a %FM >29% in males and >41% in females or a BMI ≥25 kg/m2. The patients were categorized into four groups by the presence or absence of myopenia and obesity. Based on the %FM grouping, the bleeding risk was significantly higher in the MO group, followed by the nonmyopenic obesity, myopenic nonobesity, and nonmyopenic nonobesity groups (P = 0.044). No statistically significant differences in the probability of bleeding events were observed among the four BMI-based groups (P = 0.502). Multivariate Cox analysis indicated that MO (hazard ratio [HR] 2.724, 95% confidence interval [CI] 1.073-6.918, P = 0.035), aspirin dose (100 vs 50 mg/day, HR 2.609, 95% CI 1.291-5.273, P = 0.008), concomitant use of histamine-2 receptor antagonists and proton pump inhibitors (HR 1.777, 95% CI 1.007-3.137, P = 0.047), and hemorrhage history (HR 2.576, 95% CI 1.355-4.897, P = 0.004) were associated with bleeding events independently. %FM-based MO was an independent predictor of aspirin-induced bleeding in older Chinese individuals. Reducing %FM rather than BMI should be an optimal strategy for the management of myopenic obesity.

A66 PROTON PUMP INHIBITORS AND THE RISK OF INFLAMMATORY BOWEL DISEASE: A REAL WORLD POPULATION-BASED COHORT STUDY

Abstract Background Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) are acid suppressant drugs indicated in highly prevalent conditions such as gastroesophageal reflux disease and peptic ulcer disease. A recent observational study reported an increased risk of inflammatory bowel disease (IBD) with the use of PPIs. However, this association may have been driven by certain methodological shortcomings, such as failure to properly account for protopathic bias, a conclusion-altering bias. Purpose To determine whether the use of PPIs compared with the use of H2RAs is associated with an increased risk of IBD. Method Using the longitudinal primary care records from the United Kingdom Clinical Practice Research Datalink database, we identified 1,498,416 initiators of PPIs and 322,474 initiators of H2RAs from January 1, 1990, through December 31, 2018, with follow-up until December 31, 2019. Standardized morbidity ratio weighted Cox proportional hazards models were used to estimate marginal hazard ratios (HRs) and 95% confidence intervals (CIs). Patients were analyzed according to the timing of the IBD events after treatment initiation (early versus late). In the early-event analysis, IBD events were assessed within the first two years of treatment initiation, an analysis subject to potential protopathic bias. In the late-event analysis, all exposures were lagged by two years to account for latency and minimize protopathic bias. Result(s) In the early-event analysis, the use of PPIs was associated with an increased risk of IBD within the first two years of treatment initiation, compared with H2RAs (HR: 1.39, 95% CI: 1.14-1.69). In contrast, the use of PPIs was not associated with an increased risk of IBD in the late-event analysis (HR: 1.05, 95% CI: 0.90 to 1.22). The results remained consistent in several sensitivity analyses. Image Conclusion(s) Compared with H2RAs, PPIs were not associated with an increased risk of IBD, after accounting for protopathic bias. Please acknowledge all funding agencies by checking the applicable boxes below CIHR Disclosure of Interest R. Yanofsky: None Declared, D. Abrahami Employee of: pfizer, R. Pradhan: None Declared, H. Yin: None Declared, E. McDonald: None Declared, A. Bitton Consultant of: Member of Advisory Boards for Abbie, Pfizer, Takeda, Jansen, and Merck, Speakers bureau of: Has received speaker fees for Abbie, Jansen, Takeda, and Pfizer, L. Azoulay Consultant of: Has received consults fees from Jansen, Pfizer, and Roche, Speakers bureau of: Has received speaker fees from Jansen, Pfizer, and Roche

Proton pump inhibitors and the risk of inflammatory bowel disease: population-based cohort study

ObjectiveTo determine whether the use of proton pump inhibitors (PPIs) compared with the use of histamine-2 receptor antagonists (H2RAs) is associated with an increased risk of inflammatory bowel disease (IBD).DesignPopulation-based...

Maintenance Proton Pump Inhibitor Use Associated with Increased All-Cause and Cause-Specific Mortality in Sweden

BackgroundProton pump inhibitor (PPI) use has increased over the last decades and has been associated with multiple adverse events and potentially even overall survival.AimsWe aimed to investigate the association between proton pump inhibitor maintenance use and all-cause and cause-specific mortality, addressing confounding by indication and duration of use.MethodsThis Swedish population-based cohort study included all adult (N = 935,236) PPI and histamine-2 receptor antagonist maintenance users (≥ 180 days use) during 2005–2014. Standardised mortality ratios (SMRs) and 95% confidence intervals were calculated for all-cause and cause-specific mortality comparing the risk among PPI/H2RA users to that of the Swedish background population, stratified by age, sex, calendar period, indication and duration of use. Multivariable Poisson regression models were used to compare PPI use to H2RA use, expressed as incidence rate ratios and 95% confidence intervals.ResultsPPI and histamine-2 receptor antagonist use were associated with an increased risk of all-cause mortality (SMR = 1.35; 1.34–1.36; SMR = 1.31; 1.27–1.36, respectively). The highest SMRs were found in the youngest age groups. In direct comparison, PPI use showed a higher mortality risk than histamine-2 receptor antagonist use (incidence rate ratios = 1.42; 1.38–1.46). PPIs were related to increased cancer (SMR = 1.21; 1.20–1.22), and cardiovascular mortality (SMR = 1.36; 1.35–1.37). Increased SMRs were observed for most indications. Longer duration of use was associated with a higher mortality among PPI users but not among histamine-2 receptor antagonist users.ConclusionMaintenance PPI use was associated with an increased risk of all-cause and cause-specific mortality, and the risk increased with prolonged duration.

Histamine-2 Receptor Antagonists and Proton Pump Inhibitors Are Associated With Reduced Risk of SARS-CoV-2 Infection Without Comorbidities Including Diabetes, Hypertension, and Dyslipidemia: A Propensity Score-Matched Nationwide Cohort Study.

This study aimed to identify the effect of histamine-2 receptor antagonist (H2RA) and proton pump inhibitor (PPI) use on the positivity rate and clinical outcomes of coronavirus disease 2019 (COVID-19). We performed a nationwide cohort study with propensity score matching using medical claims data and general health examination results from the Korean National Health Insurance Service. Individuals aged ≥ 20 years who were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between 1 January and 4 June 2020 were included. Patients who were prescribed H2RA or PPI within 1 year of the test date were defined as H2RA and PPI users, respectively. The primary outcome was SARS-CoV-2 test positivity, and the secondary outcome was the instance of severe clinical outcomes of COVID-19, including death, intensive care unit admission, and mechanical ventilation administration. Among 59,094 patients tested for SARS-CoV-2, 21,711 were H2RA users, 12,426 were PPI users, and 24,957 were non-users. After propensity score matching, risk of SARS-CoV-2 infection was significantly lower in H2RA users (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.74-0.98) and PPI users (OR, 0.62; 95% CI, 0.52-0.74) compared to non-users. In patients with comorbidities including diabetes, dyslipidemia, and hypertension, the effect of H2RA and PPI against SARS-CoV-2 infection was not significant, whereas the protective effect was maintained in patients without such comorbidities. Risk of severe clinical outcomes in COVID-19 patients showed no difference between users and non-users after propensity score matching either in H2RA users (OR, 0.89; 95% CI, 0.52-1.54) or PPI users (OR, 1.22; 95% CI, 0.60-2.51). H2RA and PPI use is associated with a decreased risk for SARS-CoV-2 infection but does not affect clinical outcome. Comorbidities including diabetes, hypertension, and dyslipidemia seem to offset the protective effect of H2RA and PPI.

Impact of Acid Suppression Therapy on Renal and Survival Outcomes in Patients with Chronic Kidney Disease: A Taiwanese Nationwide Cohort Study.

Histamine-2-receptor antagonist (H2RA) has shown beneficial effects on the kidney, heart, and sepsis in animal models and on the heart and COVID-19 infection in clinical studies. However, H2RAshave been used as a reference in most epidemiological studies examining the association of proton pump inhibitors (PPI) with outcomes. Therefore, we aimed to evaluate the effect of H2RA on renal and survival outcomes in chronic kidney disease (CKD) patients. We used a Taiwanese nationalhealth insurance database from 2001 to 2016 to screen 45,767 CKD patients for eligibility. We identified new users of PPI (n = 7121), H2RA (n = 48,609), and users of neither PPI nor H2RA (as controls) (n = 47,072) during follow-up, and finally created 1:1:1 propensityscore-matchedcohorts; each cohort contained 4361 patients. Participants were followed up after receivingacid-suppression agents or on the corresponding date until the occurrence of end-stage renal disease (ESRD) in the presence of competing mortality, death, or through the end of 2016. Compared toneither users, H2RAand PPI users demonstrated adjusted hazard ratios of 0.40 (95% confidence interval, 0.30–0.53) for ESRDand 0.64 (0.57–0.72) for death and 1.15 (0.91–1.45) for ESRD and 1.83 (1.65–2.03) for death, respectively. A dose-response relationship betweenH2RA use with ESRD and overall, cardiovascular, and non-cardiovascular mortality was detected. H2RA consistently provided renal and survival benefits on multivariable stratified analyses and multiple sensitivity analyses. In conclusion, dose-dependent H2RA use was associated with a reduced risk of ESRD and overall mortality in CKD patients, whereas PPI use was associated with an increased risk of overall mortality, not in a dose-dependent manner.

Acid suppressants use and risk of atherosclerotic cardiovascular disease in middle-aged and older adults

Background and aimsConcerns regarding adverse events associated with the use of acid suppressants have increased. However, the impact of proton pump inhibitors (PPIs) and histamine‐2 receptor antagonists (H2RAs) on the risk of atherosclerotic cardiovascular disease (ASCVD) remains unknown. This study aimed to estimate the risk of ASCVD in association with the use of PPIs and H2RAs. MethodsThis prospective cohort study included participants without cardiovascular diseases or anti-hypertensive treatment at baseline (2006–2010) in the UK Biobank. The outcomes were ASCVD and each subtype (coronary artery disease, myocardial infarction, peripheral artery disease, and ischemic stroke). The association was estimated by Cox proportional-hazards models. ResultsAmong 316,730 individuals (aged 50–88 years), during a median of 12.5 years of follow-up, we documented 13,503 (4.3%) incident ASCVD. Regular PPIs use was associated with a higher risk of ASCVD (HR: 1.16, 95% CI: 1.09–1.23) and every subtype of ASCVD. Among each type of PPIs, omeprazole (HR: 1.19, 95% CI: 1.11–1.28), lansoprazole (HR: 1.11, 95% CI: 1.02–1.22), and pantoprazole (HR: 1.40, 95% CI: 1.00–1.97) were associated with a higher risk of ASCVD. Stratification analysis showed that PPIs use was associated with a higher risk of ASCVD among individuals without indications of medications for PPIs. In addition, use of H2RAs was not related to the risk of ASCVD (HR: 0.97, 95% CI: 0.85–1.11). ConclusionsPPIs were associated with increased risk of ASCVD, particularly amongst participants without indications for medication. Our findings are of important practical significance and suggest that clinicians should be cautious in prophylactic use of PPIs.

Proton Pump Inhibitor Use and Obesity-Associated Cancer in the Women’s Health Initiative

Proton pump inhibitors (PPIs) have off-target activity on fatty acid synthase (FASN), a critical enzyme in energy balance and cancer growth. We evaluated risk of common obesity-related cancers: breast, colorectal (CRC), and endometrial, with use of PPI and histamine-2 receptor antagonists (H2RA) in 124,931 postmenopausal women enrolled in the Women’s Health Initiative. Incident cancer cases were physician-adjudicated. Cox proportional hazards models were used to estimate multivariable hazard ratios (HR) and 95% confidence intervals (CI) for cancer incidence after year 3. There were 7956 PPI ever users and 9398 H2RA only users. Ever use of either PPI or H2RA was not associated with risk of breast cancer (n = 9186) nor risk of endometrial cancer (n = 1231). The risk of CRC (n = 2280) was significantly lower in PPI users (HR = 0.75, 95% CI = 0.61–0.92), but not in H2RA users (HR = 1.13, 95% CI = 0.97–1.31). The association of PPI use with CRC was apparent regardless of BMI or NSAID use, and was stronger with longer PPI duration (p = 0.006) and potency (p = 0.005). The findings that PPI use, but not H2RA use, demonstrate an inverse dose-response relationship with risk of CRC is consistent with preclinical data showing FASN inhibition prevents colon cancer progression and supports a role of PPI in CRC prevention.

Proton Pump Inhibitor Use and Obesity-Associated Cancers in the Women's Health Initiative

Purpose: Proton pump inhibitors (PPIs) inhibit fatty acid synthase (FAS), a critical enzyme in lipogenesis, energy balance, and cancer cell survival. We aimed to evaluate the association of PPI use with incidence of common obesity- related cancers in women: postmenopausal breast, colorectal, and endometrial cancers. Methods: Our study included 124,931 postmenopausal who were enrolled in the Women's Health Initiative (WHI) observational study and clinical trials, and had responded to a year 3 follow-up assessment. We examined prescription and over the counter use of PPI and/or histamine 2 receptor antagonists (H2RA) at baseline and year 3, to isolate potential effects of FAS inhibition by PPI rather than simply acid suppression. Incident cancer cases were physician-adjudicated. Cox proportional hazard regression models were used to estimate multivariable hazard ratios (HR) and 95% confidence intervals (CI) for associations between PPI and/or H2RA use and cancer incidence after year 3. Results: There were 7956 PPI ever users (with or without H2RA use) and 9398 H2RA only users. PPI or H2RA use was not associated with risk of breast cancer (n=9186 cases), compared to women who did not use either agent (HR 1.01, 95% CI 0.93-1.10 and HR 0.95 95% CI 0.87-1.03, respectively). The incidence of colorectal cancer (n=2280) was significantly lower in PPI users (HR 0.75, 95% CI 0.61-0.92), but not in H2RA users (HR 1.13, 95% CI 0.97-1.31). This association was strengthened with increasing duration (p=0.006) and potency (p=0.005) of PPI use and held regardless of BMI or NSAID use. PPI or H2RA use was not associated with endometrial cancer (n=1231) (HR 0.81, 95% CI 0.61-1.07 and HR 1.13, 95% CI 0.91-1.40, respectively), but showed a trend in decreased risk with increasing PPI potency (P=0.048). Conclusions: Among postmenopausal women, PPI use, but not H2RA use, demonstrated an inverse, dose-responsive association with colorectal cancer incidence. This was consistent with preclinical data that FAS inhibition prevents colon cancer progression and supports further investigation of this commonly used medication as a cancer preventive agent. PPI use was not associated with incidence of breast or endometrial cancer.

Acid Lowering Agents and Trajectory of Vitamin B-12 Deficiency in the Boston Puerto Rican Health Study

ObjectivesStudies have reported an association between acid lowering agents (ALAs) such as proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) and malabsorption of vitamin B-12 (B-12). Therefore, we sought to examine the association between ALA use, including PPI and H2RA, and B-12 deficiency in a cohort of older Puerto Rican adults residing in the Boston MA metropolitan area.MethodsThis analysis was conducted within the Boston Puerto Rican Health Study (BPRHS), an ongoing longitudinal cohort that enrolled 1502 self-identified Puerto Rican adults aged 45–75 y at baseline. Our study was comprised of 1428 participants at baseline, with complete baseline data on plasma B-12 concentration, of whom 1155 and 647 participated in wave-2 (mean 2.2 y from baseline ± 0.61 y), and wave-3 (mean 6.2 y ± 0.98 y), collections, respectively. B-12 deficiency was defined as plasma cobalamin <148 pmol/L or methyl malonic acid (MMA) >271 nmol/L. Covariate-adjusted logistic regression was used to examine the association between overall ALA, PPI and H2RA use and B-12 deficiency at baseline and wave-3 (mean 6.2 y) as well as between long-term use (mean 6.2 y) and B-12 deficiency at 6.2 y of follow-up. Logistic mixed effects models were used to examine associations between baseline ALA, PPI and H2RA use and trajectory of B-12 deficiency over 6.2 y of follow-up. Analyses were further stratified for B-12 supplement use, based on food frequency questionnaire.ResultsOf 1428 participants at baseline, 455 were ALA users, of which 361 were PPI, 112 H2RA and 18 concomitant users. In baseline cross-sectional analyses, including analyses stratified for B-12 supplement use, we did not observe an association between ALA, PPI, H2RA use and B-12 deficiency. We also did not observe an association between long-term ALA, PPI, H2RA use and B-12 deficiency at 6.2 y. Further, in trajectory analyses, we did not observe an association between baseline ALA, PPI, H2RA use and trajectory of B-12 deficiency from baseline through 6.2 y follow-up, including in analyses stratified for B-12 supplement use.ConclusionsIn this study we did not observe an association between ALA, PPI, H2RA use and B-12 deficiency over wave-3 (6.2 y) follow-up. Larger studies with more detailed exposure information are needed to further examine these associations.Funding SourcesNIH.

Comparative risk of incidence and clinical outcomes of COVID-19 among proton pump inhibitor and histamine-2 receptor antagonist short-term users: a nationwide retrospective cohort study

BackgroundThis study aimed to evaluate incidence risk and adverse clinical outcomes in COVID-19 disease among short-term users of acid-suppressants in South Korea.MethodsThis retrospective cohort study, conducted using a nationwide claims database for South Korea, used data from patients with COVID-19 tested between January 1 and May 15, 2020. Patients aged over 18 years and prescribed proton pump inhibitors (PPI) or histamine-2 receptor antagonist (H2RA) for more than 7 days were identified. Primary outcome was COVID-19 while secondary outcomes were all-cause mortality, hospitalization with respiratory disease, or intensive respiratory intervention. Large-scale propensity scores were used to match patients, while the Cox proportional hazard model was utilized to evaluate any association between exposure and outcome(s). The risk estimates were calibrated by using 123 negative control outcomes.ResultsWe identified 26,166 PPI users and 62,117 H2RA users. After propensity score matching, compared to H2RA use, PPI use was not significantly associated with lower risk of COVID-19 (calibrated hazard ratio [HR], 0.81 [95% confidence interval (CI), 0.30–2.19]); moreover, PPI use was not associated with adverse clinical outcomes in COVID-19, namely, hospitalization with respiratory disease (calibrated HR, 0.88 [95% CI, 0.72–1.08]), intensive respiratory interventions (calibrated HR, 0.92 [95% CI, 0.46–1.82]), except for all-cause mortality (calibrated HR, 0.54 [95% CI, 0.31–0.95]).ConclusionsIn this study, we found that the PPI user was not associated with risk of COVID-19 compared to H2RA users. There was no significant relationship between severe clinical outcomes of COVID-19 and exposure to PPI compared with H2RA, except for all-cause mortality.

Proton pump inhibitor therapy and risk of knee replacement surgery: a general population-based cohort study

Proton pump inhibitors (PPIs) are among the most commonly used medications for patients with osteoarthritis (OA). Various types of PPIs have different impacts on lowering serum magnesium level that may affect knee OA progression. We aimed to compare the risk of clinically relevant endpoint of knee replacement (KR) among initiators of five different PPIs with that among histamine-2 receptor antagonist (H2RA) initiators. Among patients with knee OA (≥50 years) in The Health Improvement Network database in the UK we conducted five sequential propensity-score matched cohort studies to compare the risk of KR over 5-year among patients who initiated omeprazole (n=2,672), pantoprazole (n=664), lansoprazole (n=3,747), rabeprazole (n=751), or esomeprazole (n=827) with those who initiated H2RA. The prevalence of PPI prescriptions among participants with knee OA increased from 12.7% in 2000-44.0% in 2017. Two-hundred-and-seventy-four KRs (30.8/1,000 person-years) occurred in omeprazole initiators and 230 KRs (25.4/1,000 person-years) in H2RA initiators. Compared with H2RA initiators, the risk of KR was 21% higher in omeprazole initiators (hazard ratio [HR]=1.21,95% confidence interval [CI]:1.01-1.44). Similar results were observed when pantoprazole use was compared with H2RA use (HR=1.38,95%CI:1.00-1.90). No such an increased risk of KR was observed among lansoprazole (HR=1.06,95%CI:0.92-1.23), rabeprazole (HR=0.97,95%CI:0.73-1.30), or esomeprazole (HR=0.83,95%CI:0.60-1.15) initiators compared with that among H2RA initiators. In this population-based cohort study, initiation of omeprazole or pantoprazole use was associated with a higher risk of KR than initiation of H2RA use. This study raises concern regarding an unexpected risk of omeprazole and pantoprazole on accelerating OA progression.

Gastric acid suppressants and cognitive decline in people with or without cognitive impairment.

IntroductionStudies suggest associations between proton pump inhibitors (PPIs) and dementia risk; however, many neither considered histamine‐2 receptor antagonists (H2RAs) nor baseline cognitive status.MethodsParticipants (National Alzheimer's Coordinating Center Database; 2005–2021) using a PPI or H2RA were compared. Covariate‐adjusted Cox regression was used to estimate hazard ratios (HR) for progression from normal cognition to mild cognitive impairment (MCI), and from MCI to dementia over 5 years. In a propensity‐score–matched subsample of mild–moderate Alzheimer's disease (AD), mixed‐effects negative binomial regression was used to estimate decline in delayed recall memory.ResultsCompared to PPI, H2RA use was associated with earlier progression from MCI to dementia (HR = 1.40 [1.09–1.81]; n = 1701), and with faster memory decline in AD over time (rate ratio = 0.76 [0.64–0.92]; n = 628), but not with progression from normal cognition to MCI (HR = 0.94 [0.71–1.24]; n = 2784).DiscussionCompared to PPIs, H2RAs were associated with cognitive decline, specifically among people with pre‐existing cognitive impairment.