Inhibitor Users Research Articles

Effect of Biological Therapy for Psoriasis on the Development of Psoriatic Arthritis: A Population-Based Cohort Study.

Evidence comparing the impact of various biologics for psoriasis on the progression to psoriatic arthritis (PsA) is limited. We therefore assessed the risk of PsA associated with interleukin (IL)-23 inhibitor, IL-17 inhibitor, or IL-12/23 inhibitor use compared with tumor necrosis factor (TNF) inhibitor use among patients with psoriasis. This population-based cohort study used the nationwide claims database from South Korea (2007-2023). New users of IL or TNF inhibitors with psoriasis who did not have PsA or other inflammatory arthritis were categorized into each class of the IL inhibitors for comparison with TNF inhibitor users. The outcome measured was the development of incident PsA. We calculated multinomial overlap weights to balance predefined covariates. Hazard ratio (HR) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. We identified 9499 patients with psoriasis (mean age 45.1 years; 33.6% female), of whom 3913 (41.2%), 2126 (22.4%), 2773 (28.8%), and 727 (7.7%) were exposed to IL-23 inhibitor, IL-17 inhibitor, IL-12/23 inhibitor, and TNF inhibitor, respectively. PsA developed in 281 (3.0%) patients during 23,275 person-years. The weighted HR for any IL inhibitors was 0.40 (95% CI 0.25-0.62), with specific HRs of 0.22 (95% CI 0.13-0.37), 0.47 (95% CI 0.28-0.80), and 0.46 (95% CI0.29-0.74) for IL-23 inhibitor, IL-17 inhibitor, and IL-12/23 inhibitor, respectively. IL-23 inhibitors exhibited the greatest rate difference of - 2.61 (95% CI - 3.67 to - 1.55) cases of PsA per 100 person-years. The use of IL inhibitors, particularly IL-23 inhibitors, compared with TNF inhibitors, was associated with a lower risk of developing PsA.

Validation of an interactive process mining methodology for clinical epidemiology through a cohort study on chronic kidney disease progression.

Process mining holds promise for analysing longitudinal data in clinical epidemiology, yet its application remains limited. The objective of this study was to propose and evaluate a methodology for applying process mining techniques in observational clinical epidemiology. We propose a methodology that integrates a cohort study design with data-driven process mining, with an eight-step approach, including data collection, data extraction and curation, event-log generation, process discovery, process abstraction, hypothesis generation, statistical testing, and prediction. These steps facilitate the discovery of disease progression patterns. We implemented our proposed methodology in a cohort study comparing new users of proton pump inhibitors (PPI) and H2 blockers (H2B). PPI usage was associated with a higher risk of disease progression compared to H2B usage, including a greater than 30% decline in estimated Glomerular Filtration Rate (eGFR) (Hazard Ratio [HR] 1.6, 95% Confidence Interval [CI] 1.4-1.8), as well as increased all-cause mortality (HR 3.0, 95% CI 2.1-4.4). Furthermore, we investigated the associations between each transition and covariates such as age, gender, and comorbidities, offering deeper insights into disease progression dynamics. Additionally, a risk prediction tool was developed to estimate the transition probability for an individual at a future time. The proposed methodology bridges the gap between process mining and epidemiological studies, providing a useful approach to investigating disease progression and risk factors. The synergy between these fields enhances the depth of study findings and fosters the discovery of new insights and ideas.

Effects of Medication Period and Gastrin Levels on Endoscopic Gastric Mucosal Changes in Long-Term Proton Pump Inhibitor Users

Background/Objectives: Proton pump inhibitor (PPI) use has increased worldwide, including in continuous and longer-term users. Recent reports highlight PPI-related endoscopic gastric mucosal changes, including fundic gland polyps, hyperplastic polyps, multiple white and flat elevated lesions, cracked and cobblestone-like mucosa (CCLM), and black spots. PPI use elevates gastrin levels because of acid inhibition, and hypergastrinemia might be relevant to these findings. In this cross-sectional study, we retrospectively examined gastric mucosal changes in long-term PPI users, focusing on medication period and gastrin levels. Methods: We enrolled 57 patients who received a PPI (>1 year) at two clinics between January 2021 and March 2022. Participants were classified according to medication period: 1 < 5, 5–10, and ≥10 years. Gastrin levels were categorized as low, middle, and high (<250, 250–500, and ≥500 pg/mL, respectively). Odds ratios (OR) were estimated to assess the risk of endoscopic findings. Results: Of the 57 patients, 6 (10.5%), 25 (43.9%), and 26 (45.6%) were PPI users of 1 < 5, 5–10, and ≥10 years, respectively. There were no significant differences in the incidence of endoscopic findings among the medication periods. Low, middle, and high gastrin groups included 21 (36.8%), 21 (36.8%), and 15 (26.3%) patients, respectively. CCLM incidence was significantly elevated in higher gastrin level groups: middle (OR, 6.60; 95% confidence interval [CI], 1.46–29.75; p = 0.014) and high (OR, 9.00; 95% CI, 1.79–45.23; p = 0.0008) (p-trend = 0.0171). No significant differences were observed for other findings. Conclusions: No elevated risk of PPI-related gastric epithelial changes in long-term PPI users was observed time-dependently. Notably, higher gastrin levels were positively associated with CCLM development, irrespective of the medication period.

Abstract 4140140: Cardiology Follow-Up as a Determinant of LDL-C Management Success in Secondary Cardiovascular Prevention

Managing low-density lipoprotein (LDL) cholesterol is crucial for secondary cardiovascular prevention. Despite ACC/AHA recommendations for maintaining LDL below 70 mg/dL, achieving this target remains suboptimal. This study investigates the impact of consistent cardiologist involvement on LDL cholesterol management. Methods: We conducted a multicenter, cross-sectional cohort study within the Steward Healthcare System in Massachusetts, analyzing data from 10,211 patients hospitalized from January 2019 to March 2024. This study offers a detailed snapshot of data across the study period, capturing both recent and long-standing cases identified through ICD codes for conditions like NSTEMI, CAD, STEMI, or CABG, specifically as markers for secondary cardiovascular prevention. We utilized the most recent LDL cholesterol measurements for our analysis and compared the distribution of lipid-lowering medications across groups. Notably, follow-ups with cardiologists outside our network were not tracked, potentially omitting relevant data. Statistical analysis employed the Chi-square test for categorical variables and binary logistic regression to adjust for confounders. Results: showed that patients with regular cardiology visits more often achieved LDL levels below 70 mg/dL (57.45% vs. 46.67%; OR 1.54, 95% CI: 1.42-1.68; P<0.0001). These patients also had lower mean LDL levels (68.72 ± 27.02) compared to those without cardiology follow-up (75.82 ± 30.27; P<0.0001). Higher usage of PCSK9 inhibitors and non-statin medications was noted among the visiting group, with an adjusted OR of 1.43 (95% CI: 1.29-1.59; P<0.0001). Conclusion: Our study shows that cardiologist involvement significantly enhances cholesterol management in CAD patients, as evidenced by a higher proportion achieving optimal LDL levels and more aggressive use of lipid-lowering medications. Despite these benefits, some patients discontinue their follow-ups with cardiologists after coronary events, shifting cholesterol management to primary care providers (PCPs). This transition often results in less aggressive treatment strategies, evidenced by elevated LDL levels in patients lacking recent cardiology care. To sustain effective cholesterol management and stringent LDL targets, long-term follow-up with a cardiologist is crucial. Furthermore, equipping PCPs with the necessary tools and protocols to adopt more aggressive treatment approaches could bridge the care gap when specialist visits are infrequent.

Abstract 4134947: Explainable Machine Learning to Predict Heart Failure Outcomes Using Exercise and Clinical Data

Background: Heart failure (HF) hospitalizations are associated with disease burden and cardiovascular mortality. International guidelines highlight cardiopulmonary testing (CPET) for risk stratification and prognosis in HF. Identifying individuals at risk could direct interventions to prevent admissions. This study uses explainable machine learning (XML) tools to identify CPET and clinical variables predictive of HF hospitalizations. Hypothesis: XML analysis of CPET parameters and clinical factors can yield accurate, patient-specific prediction of HF admission within one year. Methods: A retrospective single center review of 178 CPETs in patients referred for HF was completed. Clinical data within one year of CPET trained a boosted machine learning model (XGBoost). SHAP (Shapley Additive Explanations) explainability analysis emphasized key features for model predictions. Results: 44 (24.7%) patients with CPET were admitted for HF within one year. The model predicted this outcome with an area under the receiver operating characteristic curve (AUC) of 0.772. SHAP analysis (Figure 1) selected factors for decision making: pulmonary artery systolic pressure (PASP) via cardiac catheterization or echocardiogram; oxygen consumption at the ventilatory threshold (VO 2 at VT); O 2 pulse at rest; ventilatory efficiency (VE/VCO 2 slope); minute ventilation per oxygen consumption at maximal exercise (VE/VO 2 max) during CPET; left ventricle end diastolic volume by echocardiogram; and sodium-glucose cotransporter-2 inhibitor usage. Peak VO2, predicted VO2, predicted O2 pulse, and VE/VCO2 slope were significant, consistent with past studies (Table 1). Conclusion: Our XML analysis emphasizes PASP (partially related to high left ventricular filling pressures) and VO 2 (at ventilatory threshold) as predictive for HF hospitalization within one year of CPET testing. Studies to prospectively evaluate these highlighted factors are needed to continue exploring predictive capabilities to tailor interventions.

DDDR-42. LEVERAGING GENOME-WIDE CRISPR/CAS9 KNOCKOUT DRUG SCREENS TO IDENTIFY SENSITIZERS FOR PROTEOSOME INHIBITORS IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is the most common primary brain tumor with a poor prognosis despite aggressive treatment. Patient outcomes remain abysmal with 95% of patients relapsing and a median overall survival of 15 months. This necessitates the rapid search for personalized therapeutics and agents to enhance current treatments. One pathway that demonstrates dysregulated functioning is the ubiquitin-proteasome pathway (UPP). Literature has shown that UPP dependent proteolysis remains constitutively upregulated in cancer cells leading to the rapid degradation of proteins that regulate oncogenic pathways. Despite robust preclinical evaluations for the usage of proteasome inhibitors against GBM, most proteasome inhibitors failed in clinical trials, indicating resistance. We conducted an unbiased genome wide CRISPR-Cas9 screen in HAP1 cells treated with the proteasome inhibitor, Bortezomib (BTZ), to identify genes leading to a BTZ-resistant phenotype. We identified several genes that when perturbed, sensitized cells to BTZ including N-glycanase-1 (NGLY-1), Nuclear factor Erythroid 2-Like-1 (NFE2L1), and DNA damage inducible 1 homolog 2 (DDI2). Herein, we sought to evaluate the effects of perturbing these identified genes in our patient derived GBM cell lines by utilizing CRISPR/Cas9 knockout technology in vitro and in vivo. The generation of NGLY-1, DDI2, and NFE2L1 KO cell lines demonstrated functional sensitivity to the proteasome inhibitor Marizomib (MZB) as observed through a significant reduction of the IC50 in the KO cell lines compared to an adeno-associated virus integration site 1 (AAVS1) control. Functional evaluation also demonstrated reduced proliferation capacity and sphere formation in our KO GBM lines. Ongoing in vivo work will aim to evaluate the mitigation of this resistant pathway in our NSG mouse models orthotopically transplanted with our patient derived KO cell lines. In an ongoing collaborative effort, we aim to functionally assess a novel small molecule NGLY-1 inhibitor for preclinical sensitivity to MZB in our in vitro and in vivo models.

Minimal disease activity and associated factors in patients with psoriatic arthritis: cross-sectional study from a single center

IntroductionPsoriatic arthritis (PsA) is a heterogeneous disease with various manifestations such as dactylitis, enthesitis, spondylitis, and skin involvement. Minimal disease activity (MDA) has been successfully used in daily clinical practice and is considered a reasonable treatment target in patients with PsA. In this study, we aimed to evaluate the MDA status and associated factors in patients with PsA in our tertiary referral clinic.Material and methodsThis cross-sectional study included patients who met the CASPAR classification criteria and had at least 6 months of follow-up data between 2001 and 2021. Patients who met at least 5 of 7 criteria (tender joint count ≤ 1/68, swollen joint count ≤ 1/66, Psoriasis Area Severity Index [PASI] ≤ 1, Visual Analogue Scale [VAS] ≤ 15, patient global VAS ≤ 20, Health Assessment Questionnaire-Disability Index [HAQ-DI] ≤ 0.5, and enthesitis number ≤ 1) were considered to achieve MDA.ResultsData from 172 patients (61% female) were analyzed and included in the study. While most patients had polyarticular involvement (33.7%), mono-oligoarthritis was present in 30.2%, mixed type in 26.2%, isolated distal interphalangeal arthritis in 5.8%, isolated spondylitis in 2.9%, and arthritis mutilans in 1.2%. Overall, 95 (55.2%) of the patients were observed at MDA, which was lower in tumor necrosis factor inhibitor (TNFi) users compared to only conventional synthetic disease-modifying antirheumatic drug users. In univariate analysis, MDA was associated with higher patient age, longer psoriasis duration, late-onset PsA, and continued use of first TNFi. In multivariate analysis, higher patient age, late-onset PsA, and higher continuation rate of first TNFi were associated with MDA.ConclusionsIn the study, more than half of our patients achieved MDA status. A higher MDA rate was associated with a higher continuation rate at first-line TNFi treatment. The relatively large po­pulation who could not reach MDA status in our study indicates an unmet need for monitoring and treatment of PsA.

SGLT-2 inhibitors and mortality among patients with heart failure with reduced ejection fraction: linked database study

ObjectiveTo investigate the association between sodium-glucose cotransporter-2 (SGLT-2) inhibitor use and risk of all cause mortality among patients with heart failure with reduced ejection fraction.DesignLinked database study.SettingNational registers in Denmark,...

A Proton Pump Inhibitor Independently Elevates Gastrin Levels as a Marker for Metachronous Gastric Cancer After Endoscopic Submucosal Dissection.

Background and Objective: Serum markers such as gastrin and pepsinogen are useful for stratifying gastric cancer risk. However, their utility in predicting metachronous gastric cancer after endoscopic submucosal dissection (ESD) in patients with gastric cancer after Helicobacter pylori eradication (GCAE) is unclear. This study aimed to clarify predictive factors for metachronous gastric cancer after ESD with a focus on serum markers. Methods: A retrospective analysis was conducted on 197 patients with 224 GCAE lesions who underwent ESD at Hiroshima University Hospital between April 2010 and December 2019. In total, 63 patients with 74 differentiated-type lesions were classified into metachronous gastric cancer (MG) and non-metachronous gastric cancer (NMG) groups, excluding proton pump inhibitor (PPI) users, female patients, and undifferentiated-type cases. The predictive value of serum markers was assessed using ROC curve analysis, and their association with carcinogenesis was evaluated using multiple logistic regression. Furthermore, the incidence of MG was compared between long-term PPI users and non-users. Results: ROC analysis revealed that serum gastrin had the highest discriminative ability for MG (AUC 0.77, cut-off 99 pg/mL, sensitivity 61.6%, and specificity 80.0%). Severe mucosal atrophy and high gastrin levels were significantly more common in the MG group and were independent predictors (p < 0.01). Although serum gastrin levels were significantly elevated in PPI users, no increased risk of MG was observed. Conclusions: In addition to severe mucosal atrophy, PPI-independent elevated serum gastrin levels may be associated with an increased risk of MG after ESD. Serum gastrin may serve as a valuable marker for post-ESD cancer surveillance in GCAE patients.

Heterologous Versus Homologous COVID-19 Boosters: Immune Response Outcomes in Renal Transplant Recipients.

We aimed to investigate the immune responses to homologous and heterologous COVID-19 booster vaccinations in renal transplant recipients (RTRs) and to identify factors affecting these responses. In this prospective multicenter observational study, we measured the antibody kinetics of 90 RTRs using the chemiluminescent microparticle immunoassay method. The mean age of participants was 45.2 ± 11.4 years, with 35.6% being female. On the 42nd day after the first vaccine dose, the median antibody level was 16.7 (IQR 2.5-249.5) AU/mL, and the seropositivity rate was 60% (n = 36). Mycophenolic acid (MFA) (OR: 0.087, 95% CI: 0.024-0.311) and ACE inhibitor use (OR: 0.203, 95% CI: 0.052-0.794) were identified as independent factors affecting seropositivity. Patients who received the Pfizer/BioNTech booster had significantly higher antibody levels compared to those who received the CoronaVac/Sinovac booster (p = 0.021). Additionally, a significantly higher rate of COVID-19 positivity was observed among patients who received the CoronaVac/Sinovac booster (p = 0.031). Heterologous COVID-19 booster vaccination is significantly more effective than homologous inactivated booster vaccination in enhancing immune responses and preventing new infections in RTRs. MFA and ACE inhibitor usage were independent factors affecting seropositivity. Additional COVID-19 vaccine doses are needed in this patient group.

Risk of Incident colorectal carcinoma in patients with type 2 diabetes on SGLT-2 inhibitor users: a population-based cohort study

Abstract Background Patients with type 2 diabetes (T2D) are at substantially higher risk for developing colorectal carcinoma (CC) than the general population. Clinical studies have investigated the effects of sodium-glucose co-transporter-2 inhibitor (SGLT-2i) use on the development of incident CC in patients with T2D, but the findings are inconsistent. Purpose This study aimed to examine the association between SGLT-2i use and incident CC risk in patients with T2D. Methods We conducted a nationwide retrospective cohort study using the National Health Insurance Research Database (2015–2021). The primary outcome was the risk of incident CC by estimating hazard ratios (HRs) and 95% confidence intervals (CIs). Therefore, multiple Cox regression modeling was conducted to analyze the association between SGLT-2i use and incident CC risk in patients with T2D. Results 268,495 propensity score-matched pairs of patients with T2D using SGLT-2i and non-using SGLT-2i, 1557 and 1264 incident CCs were recorded, respectively. There was a decreased risk of incident CC for SGLT-2i users after adjusting for the index year, sex, age, comorbidities, and concurrent medication (adjusted HR 0.79, 95% CI 0.74–0.84) compared with non-SGLT-2i users. The sensitivity test for the propensity score 1:2-matched analyses showed similar result (adjusted HR 0.79, 95% CI 0.74–0.85). Conclusions This population-based cohort study found that SLGT2i user was associated with a lower risk of CC by 21% compared to non-SGLT-2i users in T2D patients. More studies are needed to credibly evaluate the effects of SGLT-2i therapy on CC prevention in patients with T2D.

Glucagon-like peptide-1 receptor agonists before upper gastrointestinal endoscopy and risk of pulmonary aspiration or discontinuation of procedure: cohort study

ObjectiveTo assess whether use of glucagon-like peptide-1 (GLP-1) receptor agonists before upper gastrointestinal endoscopy is associated with increased risk of pulmonary aspiration or discontinuation of the procedure compared with sodium-glucose...

Sodium-glucose cotransporter 2 inhibitors and cardiovascular events among patients with type 2 diabetes and low-to-normal body mass index: a nationwide cohort study

BackgroundPatients with low-to-normal body mass index (BMI; < 25.0 kg/m2) were underrepresented in major randomized controlled trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors for type 2 diabetes. The present study aims to investigate the effectiveness of SGLT2 inhibitors for cardiovascular outcomes among patients with type 2 diabetes and low-to-normal BMI, using finer stratification than previous trials.MethodsThis cohort study with a target trial emulation framework was conducted using insurance claims and health screening records of more than 30 million working-age citizens in Japan acquired from April 1, 2015 to March 31, 2022. 139,783 new users of SGLT2 inhibitors matched to 139,783 users of dipeptidyl protease (DPP) 4 inhibitors with stratification by BMI category (< 20.0, 20.0–22.4, 22.5–24.9, 25.0–29.9, 30.0–34.9, and 35.0 ≤ kg/m2). The primary outcome was a composite of all-cause death, myocardial infarction, stroke, or heart failure. Secondary outcomes were the components of the primary outcome. Cox proportional hazard models were used to compare SGLT2 inhibitors with DPP4 inhibitors in the whole population and subgroups defined by the BMI category.ResultsAmong participants, 17.3% (n = 48,377) were female and 31.0% (n = 86,536) had low-to-normal BMI (< 20.0 kg/m2, 1.9% [n = 5,350]; 20.0–22.4 kg/m2, 8.5% [n = 23,818]; and 22.5–24.9 kg/m2, 20.5% [n = 57,368]). Over a median follow-up of 24 months, the primary outcome occurred in 2.9% (n = 8,165) of participants. SGLT2 inhibitors were associated with a decreased incidence of the primary outcome in the whole population (HR [95%CI] = 0.92 [0.89 to 0.96]), but not in patients with low-to-normal BMI (< 20.0 kg/m2, HR [95%CI] = 1.08 [0.80 to 1.46]; 20.0–22.4 kg/m2, HR [95%CI] = 1.04 [0.90 to 1.20]; and 22.5–24.9 kg/m2, HR [95%CI] = 0.92 [0.84 to 1.01]).ConclusionsThe protective effect of SGLT2 inhibitors on cardiovascular events among patients with type 2 diabetes appeared to decrease with lower BMI and was not significant among patients with low-to-normal BMI (< 25.0 kg/m2). These findings suggest the importance of considering BMI when initiating SGLT2 inhibitors.Graphical abstract

Proton Pump Inhibitor Usage in Urban vs. Rural Intensive Care Units: A Narrative Review of Implications for Standardization of Care.

Intensive care unit (ICU) patients frequently require and benefit from stress ulcer prophylaxis (SUP) using proton pump inhibitors (PPIs). Despite recognized benefits, PPIs are overutilized in patients who do not have high-risk factors predisposing them to clinically significant gastrointestinal bleeding (CSGIB), including mechanical ventilation and coagulopathy. This overuse increases the risk of adverse effects associated with PPIs. Several urban healthcare systems have created educational initiatives aimed at reducing PPI usage in patients who do not meet recommendations or who are outside the period for serious risk of CSGIB. However, there was no available literature exploring PPI use or educational trends in rural hospitals. This situation presents an opportunity to investigate the disparities in PPI use between rural and urban healthcare settings. This narrative review aimed to assess current data on PPI usage in both urban and rural critical care environments, and to appraise existing practices, ultimately identifying gaps in current literature and informing future guidelines. With these evaluations, this review intended to provide a comprehensive overview of current PPI prescribing practices in the ICU and improve patient care across diverse healthcare settings.

Salivary microbiota composition before and after use of proton pump inhibitors in patients with laryngopharyngeal reflux: a self-control study

BackgroundIssues associated with proton pump inhibitor (PPI) usage have been documented. PPIs affect the gastrointestinal microbiome, as well as the saliva microbiota of healthy individuals. However, the alterations in the saliva microbiota of laryngopharyngeal reflux (LPR) patients remain unclear. This study aims to examine the composition of saliva microbiota in LPR patients before and after PPI usage through a self-controlled study.MethodsThirty-two adult LPR patients participated in the study. Saliva samples were collected before and after an 8-week regimen of twice-daily administration of 20-mg esomeprazole. The impact of PPI administration on bacterial communities was assessed using 16 S rRNA gene sequencing. The functional and metabolic changes in saliva microbial communities after PPI usage were analyzed using PICRUSt2 based on our 16 S rRNA gene sequencing results.ResultsThe alpha diversity within the salivary microbiota, as measured by the PD-whole-tree index, exhibited a significant difference between samples collected before and after PPI application (P = 0.038). Additionally, PCoA analysis of unweighted UniFrac distances (beta diversity) revealed distinct separation of saliva sample microbiota structures before and after PPI application in LPR patients, with statistical significance (Adonis test, R2 = 0.063, P< 0.010). Taxon-based analysis indicated that PPI administration increased the abundance of Epsilonproteobacteria, Campylobacterales, Campylobacteraceae, Campylobacter, and Campylobacter_gracilis, while reducing the abundance of Lactobacillaceae and Lactobacillus in salivary samples ( P< 0.050). Using LEfSe to compare bacterial abundances, Bacillaceae and Anoxybacillus were found to be enriched before PPI usage in LPR patients. Furthermore, the proportion of genes responsible for indole alkaloid biosynthesis in the salivary microbiota of LPR patients significantly increased after PPI therapy (P< 0.050).ConclusionsThese findings indicate that PPIs induce alterations in the salivary microbiota of LPR patients.Chinese clinical trial registryNo. ChiCTR2300067507. Registered on January 10,2023 retrospectively.Level of evidence4.

8722 Sodium-Glucose Cotransporter 2 Inhibitors And The Risk Of Kidney Cancer Among Patients With Type 2 Diabetes: A Population-Based Cohort Study

Abstract Disclosure: M. Lee: None. H. Kim: None. R. Kim: None. Y. Yang: None. S. Lee: None. E. Kang: None. There is an important need to develop clinical strategies to reduce the risk of incident kidney cancer, especially in patients with type 2 diabetes (T2D) and concomitant chronic kidney disease. Here, we investigated kidney cancer risk associated with sodium-glucose cotransporter 2 (SGLT2) inhibitor use in patients with T2D, using a nationwide cohort of the Korean National Health Insurance claims and health examination database. After 1:1 propensity score matching, 83,531 SGLT2 inhibitor users and 83,531 non-users on other oral glucose-lowering drugs were selected from 814,685 cancer-free participants, aged 20 to 79 years, who started oral glucose-lowering drugs for T2D from 2014 to 2018. During 559,738 person-years of follow-up, 143 (25.5 per 100,000 person-years) new kidney cancer events occurred. SGLT2 inhibitor use was associated with a 37% reduced risk of kidney cancer compared with other oral glucose-lowering drug use (18.1 vs. 29.9 per 100,000 person-years; hazard ratio [HR], 0.63; 95% CI, 0.43 to 0.92). The reduced kidney cancer risk by SGLT2 inhibitor use was consistent even after additional adjustment for all variables composing the propensity scores (HR, 0.64; 95% CI, 0.43 to 0.93) and regardless of age, sex, BMI, comorbidities, or diabetic complications including nephropathy (all p &amp;gt; 0.1 for interaction). SGLT2 inhibitor use may be a preferable option for patients with T2D at high risk of kidney cancer. Presentation: 6/3/2024

Association of PCSK9 inhibitors with mortality: insights from a retrospective cohort analysis.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are effective in reducing cardiovascular events, but their impact on all-cause mortality and medical utilization compared to statins is unclear. This study investigated PCSK9 inhibitor use and its impact on mortality and medical utilization vs. statins, using TriNetX database data with up to 9 years of follow-up. This retrospective cohort study analysed TriNetX data spanning 1 July 2015, to 31 December 2023, including 79194 PCSK9 inhibitor users (alirocumab, evolocumab, inclisiran) and 5437513 statin users with hyperlipidaemia. The primary outcomes were all-cause mortality and medical utilization, including hospital inpatient services, emergency department visits, critical care, and mechanical ventilation. Propensity score matching showed that PCSK9 inhibitor use was associated with a 28.3% lower risk of all-cause mortality [adjusted hazard ratio (aHR) 0.717, 95% confidence interval (CI): 0.673-0.763] and significant reductions in medical utilization (hospital inpatient services usage: aHR 0.692, 95% CI: 0.664-0.721; emergency department services: aHR 0.756, 95% CI: 0.726-0.788; critical care services: aHR 0.619, 95% CI: 0.578-0.664; and mechanical ventilation: aHR 0.537, 95% CI: 0.484-0.596) compared to statins. These findings were consistent across various demographics and clinical subgroups. The sensitivity analyses supported the robustness of the findings. PCSK9 inhibitors significantly reduced all-cause mortality and medical utilization compared to statins, suggesting their important role in dyslipidaemia management, particularly for statin-naïve or intolerant patients. Further research, including randomized controlled trials, is needed to confirm these findings and explore the underlying mechanisms.

Association between risk of Alzheimer’s disease and related dementias and angiotensin receptor Ⅱ blockers treatment for individuals with hypertension in high-volume claims data

Findings regarding the protective effect of Angiotensin II receptor blockers (ARBs) against Alzheimer's disease and related dementias (AD/ADRD) and cognitive decline have been inconclusive. Individuals with hypertension who do not have any prior ADRD diagnosis were included in this retrospective cohort study from Optum's de-identified Clinformatics® Data Mart. We identified antihypertensive medication (AHM) drug classes and subclassified ARBs by blood-brain barrier (BBB) permeability. We compared baseline characteristics and used the Kaplan-Meier (KM) survival curve and adjusted Cox proportional hazards (PH) model for survival analyses. From 6,390,826 individuals with hypertension, there were 1,839,176 ARB users, 3,366,841 non-ARB AHM users, and 1,184,809 AHM non-users. The unadjusted KM curve showed that ARB users had lower cumulative hazard than other AHM users or AHM non-users (P<0.0001). In Cox PH analysis, ARB users showed a 20% lower adjusted hazard of developing ADRD compared to angiotensin-converting enzyme inhibitor (ACEI) users and a 29% and 18% reduced hazard when compared to non-ARB/ACEI AHM users and AHM non-users (all P<0.0001). Consumption of BBB-crossing ARBs was linked to a lower hazard of ADRD development than non-BBB-crossing ARBs, undetermined ARBs, and non-consumption of AHMs by 11%, 25%, and 31% (all P<0.0001). This study suggests that ARBs are superior to ACEIs, non-ARB/ACEI AHMs, or non-use of AHMs in reducing the hazard of ADRD among patients with hypertension. Also, BBB-permeability in ARBs was associated with lower ADRD incidence. There is no cure for AD, ADRD, or vascular dementia; hence, these findings are significant in preventing those disorders in an inexpensive, convenient, and safe way. Limitations in claims data should be considered when interpreting our findings. This research was supported by the National Institute on Aging grants (R01AG084236, R01AG083039, RF1AG072799, R56AG074604).

Poor muscle health and cardiometabolic risks associated with antidepressant treatment.

This study aims to investigate whether antidepressant users display differences in fat distribution and muscle composition relative to non-users and to explore risk factors for developing cardiovascular disease (CVD) and type 2 diabetes. The study used quantitative adipose and muscle tissue measures derived from magnetic resonance imaging data from UK Biobank (N = 40,174). Fat distribution and muscle composition of selective serotonin reuptake inhibitor (SSRI) and tricyclic antidepressant (TCA) users were compared with sex-, age-, and BMI-matched control individuals. Cox regression models were used to test for increased risk of developing CVD and type 2 diabetes. SSRI users had more visceral fat, smaller muscle volume, and higher muscle fat infiltration compared with matched control individuals. Female users showed a larger increase in BMI over time compared with male users. However, male users displayed an unhealthier body composition profile. Male SSRI users also had an increased risk of developing CVD. Both male and female TCA users showed lower muscle volume and an increased risk of developing type 2 diabetes. Adverse changes in body composition of antidepressant users are not captured by tracking the body weight or the BMI of the patients. These changes may lead to a worsened cardiometabolic risk profile.

Hospitalized patients on proton pump inhibitors for stress ulcer prophylaxis have a higher risk of Clostridioides difficile infection compared with those on histamine-2 receptor antagonists

Previous studies on Clostridioides difficile infection (CDI) in proton pump inhibitor (PPIs) users generally enrolled a heterogeneous population and did not include a control group of histamine H2 receptor antagonists (H2RAs) users or adjust for confounding variables, such as previous antibiotics. It is uncertain whether hospitalized patients using PPIs for stress ulcer prophylaxis (SUP) are at a higher risk of CDI compared to those using H2RAs. This study aimed to compare the association between CDI and the usage of antisecretory drugs (ASDs): PPIs and H2RAs, for stress ulcer prophylaxis (SUP) among hospitalized patients, and the impact of the duration of their use on CDI. In this nationwide population-based cohort study using the Taiwan National Health Insurance Database, hospitalized patients using ASDs for SUP were identified between 2017-2018. A total of 63,266 and 69,269 individuals were included in the PPI and H2RA groups, respectively. The primary endpoint was a 90-day monitoring of CDI occurrence. The incidences of CDI were 1·6/10,000 and 0·5/10,000 person-days in the PPIs and H2RAs groups, respectively. After adjusting for confounding factors, the risk of infection in the PPIs group remained significantly higher than in the H2RAs group (Hazard ratio [HR], 2·49; 95% Confidence Interval [CI], 1·63-3·81). In the subgroup analysis, during hospitalization, the risk of CDI for patients using high-risk antibiotics or admitted intensive care unit (ICU), as well as patients with immunodeficiency, using PPIs for SUP, was higher than using H2RAs. Furthermore, the risk of CDI was higher in patients using ASDs for durations > 14 days than in those using them for < 7 days (adjusted HR, 3·66; 95% CI, 2·34-5·75). The risk of occurrence CDI for hospitalized patients using PPIs for SUP was higher than using H2RAs. It is recommended not to exceed 14 days of any gastric ASDs for SUP during hospitalization, especially for patients who have used high-risk antibiotics, been admitted to the ICU, or have immunodeficiency.