First-Line β-Blocker Use for Hypertension in the Veterans Health Administration.

Importance: Starting in 2014, US guidelines have not recommended β-blockers for first-line treatment of hypertension in the absence of compelling indications due to their tolerability profile and inferior protection against stroke and mortality compared with other first-line agents. The prevalence and factors associated with this guideline-discordant practice are unknown.

Objective: To estimate the prevalence of and factors associated with first-line β-blocker use among those without compelling indications for a β-blocker.

Modeling the genomic architecture of adiposity and anthropometrics across the lifespan.

Obesity-related conditions are among the leading causes of preventable death and are increasing in prevalence worldwide. Body size and composition are complex traits that are challenging to characterize due to environmental and genetic influences, longitudinal variation, heterogeneity between sexes, and differing health risks based on adipose distribution. Here, we construct a 4-factor genomic structural equation model using 18 measures, unveiling shared and distinct genetic architectures underlying birth size, abdominal size, adipose distribution, and adiposity.

Enabling reproducible type 1 diabetes polygenic risk scoring for clinical and translational applications.

Objective: Type 1 diabetes polygenic risk scores (PRS) offer a promising tool for identifying diabetes subtypes in adults with new-onset disease. We aimed to develop a pipeline for the clinical translation of type 1 diabetes PRS to support clinical decision-making within a large health system and to provide publicly available code for applying these methods to future PRS models.

Research Design And Methods: We adapted two established type 1 diabetes PRS models: a 67-SNP (GRS2) and a 7-SNP (AA7) score for a clinical genotyping platform and applied them to 73,346 participants in the biobank at the Colorado Center for Personalized Medicine (CCPM).

Sodium-Glucose Cotransporter 2 Inhibitor Use for Heart Failure in US Ambulatory Cardiovascular Care.

Importance: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy reduces risk of heart failure (HF) events and cardiovascular death among individuals with HF. Trends of SGLT2i use in cardiovascular ambulatory care in the US remain unknown.

Objective: To evaluate the rate of SGLT2i use among patients with HF in the cardiovascular ambulatory care setting.

Ancestry Calibration of Polygenic Risk Scores Improves Risk Stratification and Effect Estimation in African American Adults.

Polygenic risk score (PRS) distributions vary across populations, complicating PRS risk assessment. We evaluated the impact of PRS calibration according to individualized genetic ancestry estimates on PRS performance using two large multi-ethnic PRS for type 2 diabetes (T2D) (PRS) and height (PRS), in 8,841 African American (AA) individuals from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. We calibrated each participant's score as a function of estimated genetic similarity to the Yoruba (GSYRI) cohort in the 1000 Genomes Project.

Diet quality, unprocessed plant-based foods, and vascular function in adults with CKD: Secondary analysis of a pilot randomized clinical trial.

Objective: Chronic kidney disease (CKD) is prevalent among Veterans and is strongly associated with cardiovascular disease (CVD) and mortality. Fruit and vegetable intake may help manage CKD and CVD. However, the relationships of dietary intake of kidney-impacting nutrients from plant-based foods with vascular function, oxidation, and inflammation in CKD is uncertain.

Real-world cardiovascular effects of liraglutide: transportability analysis of the LEADER trial.

Objective: To evaluate generalizability of the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) randomized clinical trial (RCT) - a cardiovascular outcomes study of the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide - to US Veterans Affairs Healthcare System (VA) patients with diabetes, a population at high cardiovascular disease risk lacking direct RCT evidence of GLP-1RA efficacy.

Design: Transportability analysis that integrates real-world and RCT data to estimate the average treatment effect of liraglutide versus placebo had LEADER enrolled VA diabetes patients.

Setting: Multi-national RCT and US VA.

Type 2 Diabetes Polygenic Risk Score Interactions with Lifestyle Risk Factors in Black Americans.

Introduction: Prior work in predominantly European ancestry populations has explained how the risk associated with demographic, lifestyle, and health factors differs with underlying genetic susceptibility to type 2 diabetes (T2D), but less is known about these relationships in Black Americans.

Methods: We used covariate-adjusted logistic regression models of T2D to examine interactions between a published trans-ancestry derived T2D polygenic risk score (PRS) and various demographic, lifestyle, and health-related factors among 28,251 self-identified Black Americans from six cohort studies.

Results: The results are generally consistent with prior work in White populations.

Long-term effects and effect heterogeneity of lifestyle and metformin interventions on type 2 diabetes incidence over 21 years in the US Diabetes Prevention Program randomised clinical trial.

Background: In the US Diabetes Prevention Program (DPP), a 3-year randomised clinical trial in 3234 adults with prediabetes, type 2 diabetes incidence was reduced by 58% with intensive lifestyle intervention (ILS) and by 31% with metformin, compared with placebo. We sought to assess the long-term effects and potential heterogeneity of treatment effects over approximately 21 years of follow-up.

Methods: The DPP trial was continued with protocol modifications as the DPP Outcomes Study (DPPOS).

Evidence-based SGLT2 inhibitor and GLP-1 receptor agonist use by race in the VA healthcare system.

Importance: Adoption of novel therapeutics often lags for Black versus non-Hispanic White patients. Seminal clinical trials established the cardiovascular efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) in patients with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease. However, it is uncertain whether race influences the evidence-based prescription of these agents.

Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes.

Elevated fasting insulin levels (FI), indicative of altered insulin secretion and sensitivity, may precede type 2 diabetes (T2D) and cardiovascular disease onset. In this study, we group FI-associated genetic variants based on their genetic and phenotypic similarities and identify seven clusters with distinct mechanisms contributing to elevated FI levels. Clusters fall into two types: "non-diabetogenic hyperinsulinemia," where clusters are not associated with increased T2D risk, and "diabetogenic hyperinsulinemia," where T2D associations are driven by body fat distribution, liver function, circulating lipids, or inflammation.

Type 2 diabetes polygenic risk score demonstrates context-dependent effects and associations with type 2 diabetes-related risk factors and complications across diverse populations.

Polygenic risk scores (PRS) hold prognostic value for identifying individuals at higher risk of type 2 diabetes (T2D). However, further characterization is needed to understand the generalizability of T2D PRS in diverse populations across various contexts. We characterized a multi-ancestry T2D PRS among 244,637 cases and 637,891 controls across eight populations from the Population Architecture Genomics and Epidemiology (PAGE) Study and 13 additional biobanks and cohorts.

Epigenome-wide association study meta-analysis of BMI in African American Adults.

Despite considerable advances in identifying risk factors for obesity development, there remains substantial gaps in our knowledge about its etiology. Variation in obesity (defined by BMI) is thought to be due in part to heritable factors; however, obesity-associated genetic variants only account for a small portion of heritability. Epigenetic regulation defined by genetic and/or environmental factors with changes in gene expression, may account for some of this "missing heritability".

Cardiovascular Health Score and Atherosclerotic Cardiovascular Disease in the Million Veteran Program.

Importance: The American Heart Association proposed Life's Essential 8 (LE8) as an enhanced measurement tool for cardiovascular health.

Objective: To examine the association of LE8 with risk of atherosclerotic cardiovascular disease (ASCVD) incidence and prognosis in veterans.

Design, Setting, And Participants: This was a prospective cohort study of US veterans enrolled in the Department of Veterans Affairs (VA) Million Veteran Program (MVP) between 2011 and 2022.

Increased Genetic Risk for β-Cell Failure Is Associated With β-Cell Function Decline in People With Prediabetes.

Partitioned polygenic scores (pPS) have been developed to capture pathophysiologic processes underlying type 2 diabetes (T2D). We investigated the association of T2D pPS with diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (β-cell, proinsulin, liver/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin, or placebo arms.

Type 1 Diabetes Genetic Risk in 109,954 Veterans With Adult-Onset Diabetes: The Million Veteran Program (MVP).

Objective: To characterize high type 1 diabetes (T1D) genetic risk in a population where type 2 diabetes (T2D) predominates.

Research Design And Methods: Characteristics typically associated with T1D were assessed in 109,594 Million Veteran Program participants with adult-onset diabetes, 2011-2021, who had T1D genetic risk scores (GRS) defined as low (0 to <45%), medium (45 to <90%), high (90 to <95%), or highest (≥95%).

Results: T1D characteristics increased progressively with higher genetic risk (P < 0.

Primary care providers' preferences for the communication and management of actionable genomic findings from a research biobank.

Purpose: Little is known about non-genetics health care specialists' attitudes toward the return and utilization of actionable genomic results from a research biobank. We surveyed primary care providers (PCPs) to explore their perspectives on these results and their preferences for return.

Methods: We administered a paper and web-based 27-question survey to PCPs residing locally and caring for adult patients.

Association between Timing of Clinical Evaluation by a Physician or Advanced Practitioner and Risk of Rehospitalization in Older Adults Admitted to a Skilled Nursing Facility Following Hospitalization: A Cohort Study.

Objectives: How transitional care services are provided to patients receiving post-acute care in skilled nursing facilities (SNFs) is not well understood. We aimed to determine the association of timing of physician or advanced practice provider (APP) visit after SNF admission with rehospitalization risk in a national cohort of older adults.

Design: Retrospective cohort study.

Heterogeneous effects on type 2 diabetes and cardiovascular outcomes of genetic variants and traits associated with fasting insulin.

Hyperinsulinemia is a complex and heterogeneous phenotype that characterizes molecular alterations that precede the development of type 2 diabetes (T2D). It results from a complex combination of molecular processes, including insulin secretion and insulin sensitivity, that differ between individuals. To better understand the physiology of hyperinsulinemia and ultimately T2D, we implemented a genetic approach grouping fasting insulin (FI)-associated genetic variants based on their molecular and phenotypic similarities.

Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Incident Type 2 Diabetes Risk.

Objective: Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D.

Mendelian randomization study of diabetes and dementia in the Million Veteran Program.

Introduction: Diabetes and dementia are diseases of high health-care burden worldwide. Individuals with diabetes have 1.4 to 2.