Background:Promoting at-home tests (e.g., for COVID-19) using chatbots may be a novel and scalable way to improve uptake across underserved populations. Objective:The objective of this study was to assess the navigational patterns (i.e., sequence of interactions) of underserved populations when using a chatbot designed to provide education on COVID-19 testing and free order access for at-home COVID-19 test kits. Methods:The study was a descriptive analysis of the original data of the chatbot intervention of the SCALE-UP II trial, which compared different digital health modalities (i.e., chatbots versus simple text messages) to deliver free at-home COVID-19 test kits to minority populations in Utah. SCALE-UP II (registration numbers NCT05533918 ; NCT05533359 ) was a multisite, pragmatic clinical trial with patients randomized in a 2×2×2 factorial design (smartphone study) to receive (1) chatbot or text messaging, (2) the option to request patient navigation, and (3) intervention frequency every 10 or 30 days. All other participants were randomized in a 2×2 factorial design (nonsmartphone study) to receive the option to request patient navigation and intervention frequency every 10 or 30 days. Eligible patients (1) had an appointment at one of the participating community health centers (CHC) in the last 3 years, (2) were 18 years and older, and (3) had a valid cellphone number recorded in the CHC electronic health record (EHR).The trial enrolled 2117 in the smartphone study and 31,439 in the nonsmartphone study. In the smartphone study, the proportion of participants who requested test kits in the Chatbot arm was lower than in SMS text messaging. In the nonsmartphone study, test kits was higher if they were messaged every 10 days.Sources of funding included the National Institute on Minority Health and Health Disparities (NIMHD) of the US National Institutes of Health (NIH) grant number 5U01MD017421 and by awards from the National Cancer Institute of the NIH (P30CA042014) and the Huntsman Cancer Foundation. Results:Of 1,051 patients randomized to the chatbot intervention, 309 (29%) launched the chatbot, 196 (63%) interacted with it, and 186 (60%) started the COVID-19 test kit ordering process. Among those who launched the chatbot, 170 (55%) completed a test kit order. One patient (0.3%) accessed the chatbot educational content. The median age was 51, with 66% female, 54% Latino/a, 55% uninsured, and 86% located in an urban area. Conclusion:Ordering of COVID-19 test kits among underserved patients who interacted with the chatbot was high. Thus, chatbots may represent a viable approach to reach underserved populations as a part of public health response in a pandemic. All patients except one placed orders without reviewing educational content. Chatbot design should identify and minimize the number of steps for patients to achieve a specific goal.

Sleep duration < 7 h increases risk for chronic disease, which makes identifying short sleep duration critical to public health. The goal of this study is to evaluate objective short sleep duration among individuals who self-report insufficient sleep to test and evaluate predictors of the subjective–objective sleep duration difference. This study presents baseline data from a sleep extension study involving adults aged 18–65, fluency in English, and self-reported sleep duration ≤ 7 h and elevated blood pressure. Objective sleep duration was measured with actigraphy, and subjective–objective sleep difference was calculated as the difference between self-reported habitual sleep duration and actigraphically measured sleep duration. Data were analyzed using regression models, Bland–Altman plots and exploratory spline-based logistic regression models. Among 195 adults (age m = 42 ± 11 years), 54

Background:Mechanical ventricular unloading and systemic circulatory support with left ventricular assist devices (LVADs) enable myocardial recovery in a subset of advanced heart failure (HF) patients, but predictors and mechanisms of recovery are not well understood. Integrating clinical and molecular data may improve identification of patients most likely to recover and uncover biologically relevant targets in HF. Methods:We collected and analyzed left ventricular apical myocardial tissue and clinical data from 208 patients undergoing LVAD implantation across five centers. Pre-implant transcriptomic profiles (22,373 mRNA transcripts) were integrated with 59 clinical variables using supervised machine learning with repeated cross-validation to identify and prioritize features associated with myocardial recovery, defined as a binary outcome based on improvement in left ventricular ejection fraction (LVEF ≥40%) and left ventricular end-diastolic diameter (LVEDD ≤5.9 cm). We also modeled functional (LVEF) and structural (LVEDD) improvement as a continuous outcome without any predefined LVEF and LVEDD pathological thresholds. Feature prioritization was followed by validation in human myocardial tissue and mechanistic interrogation in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Results:Integrative models achieved modest discrimination for myocardial recovery as a binary categorical outcome (maximum mean cross-validated area under the curve 0.73±0.15), identifying clinical features such as HF duration, LVEDD, HF pharmacologic therapy, and device configuration. Leucine-rich repeat neuronal 4C-like ( LRRN4CL ), measured in human myocardium, consistently emerged as a top transcriptomic predictor across both binary and continuous metric models (functional and structural). Higher pre-LVAD LRRN4CL expression was associated with reduced likelihood of myocardial recovery and localized primarily to cardiomyocytes. In iPSC-CMs, LRRN4CL overexpression localized to the sarcoplasmic reticulum, induced transcriptional remodeling characterized by suppression of contractile pathways and activation of stress programs, impaired calcium handling, impaired contraction-relaxation kinetics, and diminished mitochondrial respiratory reserve capacity. Conclusions:Integration of clinical and myocardial transcriptomic data identifies LRRN4CL as a novel marker associated with impaired myocardial recovery following LVAD-mediated ventricular unloading and systemic circulatory support. These findings move beyond predictive modeling, linking integrative computational discovery to cardiomyocyte dysfunction and providing a translational framework for biologically informed risk stratification and therapeutic targeting for myocardial recovery. CLINICAL PERSPECTIVE:What Is New?: Integrative clinical and myocardial transcriptomic modeling identifies LRRN4CL as a novel molecular determinant of structural and functional changes after LVAD-mediated ventricular unloading and enhanced systemic circulatory support. Elevated LRRN4CL expression is associated with adverse remodeling signatures, impaired calcium handling, and stress responses in human iPSC-derived cardiomyocytes. Experimental overexpression of LRRN4CL directly disrupts calcium cycling, contractile performance, and mitochondrial respiration linking molecular signature to functional phenotype. What Are the Clinical Implications?: Identification of LRRN4CL as a marker associated with impaired myocardial recovery supports future efforts toward biologically informed risk stratification for patients undergoing LVAD therapy. LRRN4CL as a marker of cardiac improvement potential may extend beyond advanced HF to earlier stage disease patients and inform prognosis, risk stratification, and response to medical therapies. These findings highlight LRRN4CL -associated pathways as potential therapeutic targets and demonstrate how integrative clinical-transcriptomic approaches can move beyond clinical prediction toward identification of new biologically precise therapeutic targets in HF following a bedside to bench and back approach.

BACKGROUND:Hypertension is a modifiable risk factor for dementia, yet the comparative effectiveness of angiotensin receptor blockers (ARBs) versus angiotensin converting enzyme inhibitors (ACEIs) on dementia risk remains uncertain. OBJECTIVE:To compare the risk of dementia and dementia-free death of ARB versus ACEI initiation among US Veterans with incident hypertension. METHODS:We conducted a retrospective target trial emulation using a new-user, active-comparator design among Veterans with incident hypertension. We analyzed longitudinal electronic health records from 2,577,000 individuals who initiated ARBs or ACEIs between 1/1/2000-12/31/2017, with up to five years of follow-up. The exposure was initiation of an ARB-based versus ACEI-based antihypertensive regimen. Co-primary outcomes were dementia, identified using natural language processing of clinical notes, and dementia-free death. We used inverse probability of treatment weights based on 66 pretreatment covariates to estimate the cumulative incidence of the outcomes for each treatment group. Weighted risk ratios and absolute risk differences through five years were computed with bootstrapped 95% CIs. Secondary outcomes included all-cause death and a composite of dementia or death, evaluated using a weighted Kaplan-Meier approach. RESULTS:Among 2,577,000 Veterans (mean age, 63 years; 4.5% female; 65% White; 15% Black), 10% initiated ARBs and 90% initiated ACEIs. Over five years of follow up, 6% developed dementia, 12% died without dementia, and 13% died overall. ARB initiation yielded consistently lower risk of dementia (risk ratio, 0.88; 95% CI, 0.83-0.93 at 6 months to 0.92; 95% CI, 0.90-0.94 at 5 years) and dementia-free death (risk ratio, 0.90; 95% CI, 0.86-0.96 at 6 months to 1.00; 95% CI, 0.98-1.01 at 5 years) than ACEI initiation. Effects on secondary outcomes were similar to those for primary outcomes. Greater protective dementia effects were observed in older and male Veterans and non-statin users, with similar effects on dementia-free death. DISCUSSION:Among US Veterans with incident treated hypertension, initiation of ARB versus ACEI antihypertensive regimen conveyed a modestly lower risk of dementia. Given the high prevalence of hypertension, these modest effects may confer meaningful population-level benefits on brain health. Future research estimating per-protocol effects using a more generalizable population is needed to confirm our findings. KEY WORDS:antihypertensive medication, dementia, natural language processing, target trial emulation, Veteran.

Introduction In patients newly diagnosed with heart failure with reduced ejection fraction (HFrEF), rapid initiation of quadruple guideline-directed medical therapy (GDMT) improves morbidity and mortality. However, contemporary estimates of time-to-quadruple therapy (TTQ) and associated factors remain unclear. Methods This retrospective cohort study using Veterans Health Administration data assessed patients with incident HFrEF from 1/1/2020-12/31/2023. The index date was defined as later of diagnosis between ICD-10 and EF ≤40%. Quadruple therapy was defined as concurrent use of evidence-based β-blocker, renin-angiotensin system inhibitor, mineralocorticoid receptor antagonist, and sodium-glucose cotransporter-2 inhibitor at any dose. The primary outcome TTQ was determined as the first date all four classes overlapped, based on dispense date and days’ supply. Sex, race, ethnicity, prescription co-pay status (priority group), and clinical factors were evaluated for their association with TTQ. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for factors associated with TTQ were estimated using Cox proportional hazards models, accounting for clustering at the facility-level. Results A total of 52,850 patients with incident HFrEF were included, with a median age of 71.8 years; 2.6% were female, 67.9% were White, and 20.4% were Black. Quadruple therapy was achieved in 11,217 (21.2%) veterans over a median follow-up of 2.9 years, with a median TTQ of 197 days (IQR 49, 528) among those who achieved it (Figure 1). After adjustment, TTQ did not differ significantly between males and females (HR 0.97; 95% CI, 0.86-1.09). Black (HR 1.22; 95% CI, 1.15-1.30), Hispanic (HR 1.21; 95% CI, 1.09-1.33), and Other racial or ethnic individuals (HR 1.11; 95% CI, 1.02-1.20) had higher rates of quadruple therapy initiation compared to White individuals. Prescription co-pays (priority groups 2-8) were associated with an 8% lower rate of achieving quadruple therapy (HR 0.92; 95% CI, 0.87-0.96) compared to no co-pay (priority group 1). Factors associated with delayed (≥6 months from HF diagnosis) TTQ included older age, diabetes, chronic kidney disease, peripheral artery disease, and inpatient HF diagnosis. Conclusions Less than a quarter of patients with HFrEF achieved quadruple therapy by a median of 2.9 years, with a median TTQ of 6 months. Small medication co-pays charged to veterans could represent a modifiable barrier, suggesting that interventions targeting this issue could improve TTQ.

The use of surrogate endpoints can improve feasibility of clinical trials. The results of trial-level analyses are a key factor affecting regulatory policy regarding the uptake of a surrogate endpoint. Trial-level analyses aim to quantify the strength of association between treatment effects on an established clinical endpoint and treatment effects on the surrogate. Unfortunately, there is a well-documented lack of standardization in the meta-regression models used for these analyses. Common models differ in how they account for estimation errors, leading to variation in surrogacy estimands across approaches. This has caused confusion regarding surrogate quality. Moreover, the most used modeling approaches can lead to pessimistic inferences of surrogate quality. We overview common meta-regression models and their corresponding estimands for evaluating trial-level surrogacy, focusing on how each modeling approach accounts for sampling errors. Two broad classes of models can be differentiated. The models in the first class quantify the association between observed, estimated treatment effects, based on unweighted (least squares) or weighted linear regression (weighted least squares with weights proportional to trial sample size). The second class consists of hierarchical meta-regression models, which quantify the association between latent, true treatment effects. We target the trial-level coefficient of determination (R2) in our inferences. We use patient-level meta-analysis of 66 previously conducted chronic kidney disease clinical trials and a small statistical simulation to characterize differences in results between modeling approaches. Across our analyses, use of simple and weighted linear regression produced R2 estimates which were lower than those produced by the hierarchical models. In simulation analyses, use of simple and weighted linear regression resulted in downward bias in R2 when the estimand is defined as the R2 representing the trial-level association of true treatment effects on the clinical and surrogate endpoints. Commonly used methods for evaluating surrogate endpoints can produce unduly pessimistic conclusions of surrogate quality depending on the target of inference. This is because these methods partially or completely ignore estimation error in the analysis. Hierarchical models can be used to overcome such limitations.

Abstract Background: The comparative long-term effects of initiation of an angiotensin receptor blocker (ARB) and angiotensin-converting enzyme inhibitor (ACEI) on cancer risk remain uncertain. The objective of this study was to compare risks of cancer and non-cancer mortality between ARB and ACEI initiators among US veterans. Methods: This prospective cohort included 2,658,758 veterans with hypertension and no history of cancer who initiated either an ARB or an ACEI within the Veterans Health Administration between January 1, 2000, and December 31, 2017. Participants were followed from treatment initiation until the first occurrence of an outcome, death, loss to follow-up, or December 31, 2022 (the end of study). Initiation of ARB or ACEI treatment was determined from pharmacy dispensing records, excluding those with a history of cancer or who filled ARB or ACEI before the study period. The index date (baseline) was defined as the date of initiating either treatment. Inverse probability (IP) of treatment weighting was applied to adjust for 27 baseline covariates and estimate the intent-to-treat effect of ARB versus ACEI initiation. The co-primary outcomes were time to any cancer (ascertained from the VA Cancer Registry) and non-cancer mortality. Secondary outcomes included all-cause mortality, the composite of any cancer or death, incidence of specific cancers, and non-cancer-specific mortality. Cumulative incidence functions and risk ratios (RRs) with 95% confidence intervals (95% CI) were calculated using IP-weighted Aalen-Johansen estimator in the competing risks setting. Results: Among 2,658,758 veterans (median follow-up, 10 years; mean age, 63 years; 5% women; 76% non-Hispanic White; 15% Black), 90% initiated ACEIs and 10% initiated ARBs. ARB initiation was associated with a lower 10-year risk of any cancer (RR, 0.79; 95% CI, 0.75-0.83) and a similar 10-year risk of non-cancer mortality (RR, 1.03; 95% CI, 0.88-1.07) compared with ACEI initiation. Associations were consistent across most cancer types, except for inconclusive findings for breast and renal cancers. In subgroup analyses, a stronger inverse association between ARB initiation compared to ACEI initiation and cancer risk was observed among older patients (≥70 years). Conclusions and Relevance: ARB initiators had a lower risk of developing any cancer compared with initiation of ACEIs, with no observed difference in non-cancer or all-cause mortality. We also reported stronger inverse association for ARBs in older adults in subgroup analyses. Further research should clarify underlying biological mechanisms, confirm causality in randomized trials, and evaluate personalized antihypertensive strategies that incorporate cancer risk considerations. Citation Format: Caroline Himbert, Daniel K. Addo, Yizhe Xu, Tao He, Catherine G. Derington, Tom Greene, Jordana B. Cohen, Adam Bress, Sheetal Hardikar. Cancer risk with initiation of angiotensin receptor blockers (ARBs) vs. angiotensin converting enzyme inhibitors (ACEIs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1304.

Importance:Apolipoprotein E ( APOE ) ε4 is the strongest genetic risk factor for sporadic dementia, yet whether the benefits of intensive systolic blood pressure (SBP) control differ by APOE ε4 carrier status remains unknown. This is among the first randomized evaluations of intensive SBP control on all-cause dementia by APOE ε4 status in US adults without diabetes. Objective:To compare effects of intensive vs standard SBP control on incident all-cause probable dementia between APOE ε4 carriers and non-carriers. Design Setting and Participants:Secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), a multicenter randomized trial of adults >50 years with hypertension and increased cardiovascular risk, but without diabetes, prior stroke, or dementia. Primary cognitive follow-up ended July 2018. Participants were further followed with telephone-based outcome assessment from 2019 through 2023. Interventions:Intensive SBP control (goal <120 mm Hg) vs standard SBP control (goal <140 mm Hg). Main Outcomes and Measures:The primary outcome was all-cause probable dementia. Secondary outcomes were mild cognitive impairment (MCI); MCI or dementia; MCI, dementia, or death; and all-cause mortality. APOE ε4 status was the primary effect modifier. Results:Of 9,361 randomized participants, 8,390 (89.6%) had APOE genotyping (29% ε4 carriers); 7,733 (82.6%) had both genotype and outcome data (mean age, 68 years; 36% female; 28% Non-Hispanic Black). Over a median follow-up of 5.1 years, dementia rates (intensive vs standard) were 9.7 vs 13.2 per 1,000 person-years among ε4 carriers (hazard ratio [HR], 0.73; 95% CI, 0.51-1.04) and 6.1 vs 6.7 among non-carriers (HR, 0.91; 95% CI, 0.67-1.23; P-interaction = .35). Four-year risk differences were -1.7% (95% CI, -3.4% to 0%; number needed to treat, 59) among carriers and 0.2% (95% CI, -0.6% to 1%) among non-carriers (P-interaction = .045). Patterns were similar for the composite of MCI or dementia; effects on MCI were similar between APOE ε4 subgroups. Conclusions and Relevance:Among US adults at high cardiovascular risk, intensive SBP control yielded larger absolute risk reduction in dementia among APOE ε4 carriers than non-carriers; relative effects were similar. These findings may inform APOE ε4-stratified blood pressure management for dementia prevention. KEY POINTS:Question: What is the effect of intensive vs standard systolic blood pressure (SBP) control on incident dementia by APOE ε4 status? Findings: In SPRINT, intensive vs standard SBP control yielded a significantly larger 4-year absolute risk reduction in dementia among APOE ε4 carriers (-1.7%) than non-carriers (0.2%; P-interaction = .045); the relative-scale interactions were directionally consistent but not significant. Meaning: Among US adults at high cardiovascular risk, intensive SBP control yielded larger absolute benefit among APOE ε4 carriers than non-carriers; relative benefits were similar. APOE ε4 status may inform risk-stratified blood pressure management for dementia prevention.

Vericiguat is a soluble guanylate cyclase stimulator previously shown to improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, the underlying mechanisms remain incompletely understood. To evaluate the feasibility of assessing the effects of vericiguat on endothelial function, we conducted a pilot, randomized, double-blind, placebo-controlled trial of vericiguat in patients with HFrEF. Feasibility and efficacy outcomes were assessed at baseline and at 12 weeks on treatment. The primary efficacy outcome was brachial artery flow-mediated vasodilation. Secondary efficacy outcomes included N-terminal pro-brain natriuretic peptide, inflammatory markers, functional capacity, and health-related quality of life. An analysis of covariance model was used for continuous and Mantel-Haenszel tests for discretized outcomes. We enrolled 26 participants (median age 67 years, 84% male), with 25 completing 12-week follow-up, 13 in the active and 12 in the control arm. Feasibility objectives were successfully met, including enrollment, retention, drug titration, and completeness of data collection for all endpoints. In exploratory analyses, treatment with vericiguat resulted in flow-mediated dilation mean difference of 0.7%, (95% confidence interval: -1.1% to 2.5%, p = 0.40) and a nominally significant reduction of log NTproBNP of -0.42 (95% confidence interval: -0.81 to -0.04, p = 0.03). No significant differences in inflammatory biomarkers, functional capacity, or health-related quality of life were observed. We demonstrated the feasibility of assessing endothelial function in patients with HFrEF treated with vericiguat. While the pilot study size did not provide sufficient precision to confirm a treatment effect, our findings support future larger and longer studies to evaluate the therapeutic potential of soluble guanylate cyclase stimulation on endothelial function in HFrEF.

Abstract Introduction The goal of this study was to test the effects of an 8-week behavioral sleep extension intervention among adults with elevated blood pressure and objective sleep duration < 7 hours per night. Methods Adults ages 18+ with sleep duration < 7 hours documented using 7 nights of actigraphy and resting clinic blood pressure >120/80-150/90 mmHg, were randomized to an 8 weeks of brief telephone coaching, a Fitbit and sleep-focused educational content versus health education and a brief weekly phone call to confirm receipt of information. The intervention was followed by a 2-month maintenance period of monthly educational materials focused on sleep vs. general health education and monthly phone/email contact. Participants completed assessments as 8 weeks, 6 months and 12 months consisting of actigraphy, 24h ambulatory blood pressure monitoring (ABPM), cardiometabolic testing (BMI, body fat, HbA1c, triglycerides, cholesterol, and high sensitivity CRP (hsCRP). Data were analyzed using mixed models controlling for age, race and ethnicity. Results The study included 120 participants, 60 sleep extension (age m=42.2, sd=11.3, n=25 females) and 60 health education (age m=41.0, sd=10.2, n=23 females). The intervention group demonstrated a greater change in sleep duration at 8 weeks and maintained their sleep duration at 12 months but the difference between groups was not significant. There was not a significance difference between the groups in sleep duration at 6 months or 12 months or for other actigraphy measures. The intervention group demonstrated greater improvement in depression scores but there were no other significant changes in self-reported sleep quality, sleep related impairment or perceived stress. There was a reduction in 24h SBP and DBP at 8 weeks and 6 months in the control group but no change in the intervention group. The intervention group demonstrated decreases in triglycerides and VLDL at 8 weeks and 6 months. No other changes in cardiometabolic outcomes were observed. Conclusion Results demonstrate a behavioral sleep extension led to increased sleep duration and improved mood during the coaching period, but few improvements in cardiometabolic health. Future research is needed to understand variability in sleep outcomes and techniques to maintain changes over time. Support (if any) R01NR018891

Importance:Timely prescription of quadruple guideline-directed medical therapies (GDMTs) for patients with heart failure with reduced ejection fraction (HFrEF) is associated with improved morbidity and mortality, yet contemporary estimates of time to quadruple therapy (TTQ) and the factors associated with its achievement remain unknown. Objective:To characterize TTQ and factors associated with TTQ in HFrEF. Design, Setting, and Participants:This was a retrospective cohort study including patients with incident HFrEF from the Veterans Health Administration database during the January 1, 2020, to December 31, 2023, period. Study data were analyzed from November 2024 to December 2025. Exposures:Primary factors included race and ethnicity, sex, and copay status (priority group). Secondary factors included clinical characteristics. Main Outcomes and Measures:The main outcome included quadruple therapy according to pharmacy fill data-concurrent use of evidence-based β-blockers, renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors. TTQ was defined as the first date that all 4 medication classes overlapped, based on dispense date and days' supply. Results:Among 52 850 patients with incident HFrEF (median [SD] age, 71.8 [11] years; 51 473 male [97%]; 10 791 Black [20%]; 2528 Hispanic [5%]; 35 867 White [68%]; 3664 other [7%]), 11 217 (21.2%) achieved quadruple therapy over a median (IQR) follow-up of 2.9 (1.9-3.9) years. The median (IQR) TTQ was 197 (49-528) days. After adjustment, Black patients (hazard ratio [HR], 1.22; 95% CI, 1.15-1.30), Hispanic patients (HR, 1.21; 95% CI, 1.09-1.33), and those from other racial or ethnic groups (HR, 1.11; 95% CI, 1.02-1.20) had higher rates of quadruple therapy than White patients. There was no difference in TTQ in females vs males (HR, 0.97; 95% CI, 0.86-1.09). Prescription copays (priority groups 2-8) were associated with an 8% lower rate of achieving quadruple therapy (HR, 0.92; 95% CI, 0.87-0.96) than no prescription copay (priority group 1). Rates of quadruple therapy were higher among veterans with an outpatient HFrEF diagnosis vs inpatient (22.2% vs 14.2%), with diabetes vs without diabetes (23.6% vs 19.3%), and without chronic kidney disease vs with chronic kidney disease (22.5% vs 18.1%). Conclusion and Relevance:Results of this cohort study suggest that opportunities exist to improve both the rate and timeliness of quadruple therapy as only 21.2% of patients with HFrEF achieved it, with a median follow-up of 2.9 years and TTQ of 6 months. Medication copays represent a modifiable barrier, providing a potential target for interventions to enhance TTQ.

Dynamic prediction of future clinical outcomes based on longitudinally measured predictors plays a crucial role in disease management and patient counseling, particularly when conventional static models are inadequate. Joint modeling of longitudinal and time-to-event data provides a useful framework for addressing this challenge. In this paper, we present a comprehensive development of the recently proposed backward joint model (BJM; Shen and Li 2021}, which factorizes the likelihood into the distribution of time-to-event data and the conditional distribution of longitudinal data given the event time. This structure facilitates computation and is well-suited for multivariate longitudinal data. We introduce several novel developments to the BJM, including the extrapolation and two-part specifications, as well as the incorporation of competing risks. We also address an important yet underexplored problem in the literature: predicting future longitudinal trajectories conditional on predicted event times. Additionally, we explore the connection between BJM and existing joint modeling approaches. All these extensions preserve the computational advantages of the basic BJM formulation, including one-dimensional numerical integration, convex optimization via the EM algorithm, and a quick procedure for consistent estimation using standard software. We evaluate the method's performance through simulation studies and illustrate its utility in a chronic kidney disease application.

KEY POINTS:In veterans with type 2 diabetes and low kidney failure risk, sodium-glucose cotransporter 2 inhibitors (SGLT2is) were more kidney protective while glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were more cardioprotective. For cardiovascular-kidney-metabolic outcomes, GLP-1 RAs were more protective at moderate kidney failure risk and SGLT2is were more protective at high kidney failure risk. The kidney failure risk equation might be a clinically useful tool to guide therapy in type 2 diabetes. BACKGROUND:Head-to-head comparisons of non-exendin glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) on kidney failure or cardiovascular-kidney-metabolic (CKM) composite end points are lacking. Whether kidney failure risk modifies the comparative effectiveness of GLP-1 RA versus SGLT2i is clinically relevant. METHODS:We defined a national veterans cohort with type 2 diabetes who initiated an SGLT2i, non-exendin GLP-1 RA, or insulin glargine between January 1, 2018, and December 31, 2021. After applying inverse probability of treatment weighting to balance baseline characteristics, outcomes were compared across new-user groups through March 31, 2023. Outcomes included kidney failure (stage 5 CKD or long-term KRT), major adverse cardiovascular events (MACEs: heart failure, myocardial infarction, or stroke), CKM composite (kidney failure or MACE), all-cause death, and composites of outcomes with death. We tested for effect modification by the kidney failure risk equation (KFRE) score on comparative pairwise drug effectiveness. RESULTS:Out of 160,428 veterans, 53%, 14%, and 34% were new users of SGLT2i, GLP-1 RA, and insulin glargine, respectively. Relative to GLP-1 RA new-users, SGLT2i new-users had similar mortality risk, a trend toward lower kidney failure risk (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.74 to 1.06), but higher risk of MACE (HR, 1.14; 95% CI, 1.09 to 1.20) and CKM composite (HR, 1.13; 95% CI, 1.08 to 1.19). The effect of SGLT2i versus GLP-1 RA differed significantly between moderate-risk (2%-6%) and high-risk (≥6%) KFRE subgroups for all outcomes except all-cause death. In those with moderate-risk KFRE, GLP-1 RA seemed more protective for kidney failure, MACE, and CKM composite, while SGLT2i appeared more protective in those with high-risk KFRE. CONCLUSIONS:Compared with GLP-1 RA, SGLT2i had comparable risks of mortality, perhaps a lower risk of kidney failure, but modestly higher risk of cardiovascular events in the entire cohort. However, GLP-1 RA were more beneficial in those with moderate kidney failure risk and SGLT2i more beneficial in those with high kidney failure risk. PODCAST:This article contains a podcast at https://dts.podtrac.com/redirect.mp3//www.asn-online.org/media/podcast/JASN/2026_07_29_KTS_July2026.mp3.

In randomized trials, the primary analysis often estimates the average treatment effect on a clinical endpoint. Some treatments also lead to early changes in a biomarker that is prognostic for the clinical endpoint, prompting investigators to explore how these acute biomarker changes might inform the treatment's effect on long-term clinical outcomes. A naive analysis that directly examines treatment-by-biomarker-change interactions may lead to biased estimates because it fails to account for the fact that biomarker changes are influenced by the treatment and post-randomization factors. A key statistical challenge is that we do not know whether the observed biomarker change in an individual patient truly reflects a treatment-induced effect or whether the change would have occurred under placebo as well. This uncertainty makes it difficult to disentangle the causal effect of the treatment from natural biomarker variability. We apply principal stratification with a normal copula governed by the correlation [Formula: see text] between the potential acute biomarker changes under treatment and placebo. A flexible model for the conditional distribution of the clinical endpoint given the biomarker change enables estimation of the conditional average treatment effect on the clinical endpoint, given the acute biomarker change under treatment, as a function of [Formula: see text]. We illustrate the method by determining how knowledge of acute change in estimated glomerular filtration rate modifies the expected effect of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on clinical endpoints in patients with chronic kidney disease.