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Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

BACKGROUND: While health systems have implemented resources to improve lipid management in people with atherosclerotic cardiovascular disease, the population-level effectiveness is unclear. METHODS: Electronic health record data from patients with atherosclerotic cardiovascular disease between January 1, 2021, and December 31, 2023, across 16 US academic health systems were analyzed. Atherosclerotic cardiovascular disease (defined by diagnosis and procedure codes) was established on or before the index date defined as the date of the most recent LDL-C (low-density lipoprotein-cholesterol) or the last day of the study period for those without an LDL-C available. Systems were surveyed to identify lipid management programs (eg, prevention/lipid clinic, electronic health record–based tools, and lipid management algorithms). Sequential multilevel multivariable logistic regression modeling was used to (1) assess the system-level association between an LDL-C <70 mg/dL and the presence of lipid management programs, adjusting for patient-level demographic and clinical characteristics, and (2) whether system-level uptake of statin or nonstatin lipid-lowering therapy was associated with an LDL-C <70 mg/dL. RESULTS: We included 1 738 042 patients with atherosclerotic cardiovascular disease (median, 88 365 per system; range, 17 086–2 48 371). About 81% of the health systems had prevention or lipid clinics. The proportion of those on statins ranged from 31.0% to 60.4% across health systems (median, 46.3%). Lower proportions were observed in the use of high-intensity statins (16.2%–33.1%), nonstatins (2.6%–8.1%), and combination lipid-lowering therapy (1.7%–6.3%). Among those with an LDL-C level available (n=890 521), 42.5% had an LDL-C <70 mg/dL, ranging 35.8% to 49.4% across systems. There was no association between the odds of achieving LDL-C <70 mg/dL and health system lipid management algorithm, prevention clinics/lipid clinics, or electronic health record–based tools. Neither system-level high-intensity statin utilization nor nonstatin use was associated with an LDL-C <70 mg/dL. CONCLUSIONS: Despite variability in lipid management resources and lipid-lowering therapy use across systems, many did not reach an LDL-C <70 mg/dL, and there was low uptake of lipid-lowering therapy. Innovative implementation strategies are needed for system-level lipid management.

Background: Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure hospitalizations; yet, tools for individualized 1-year mortality risk stratification remain limited. We conducted a retrospective study to develop and validate a machine learning model using genetic programming and automated model search to predict 1-year all-cause mortality in HFpEF patients admitted for decompensated HF. Methods: Electronic medical records from Mayo Clinic (2010-2020) were queried to identify 7,840 adult patients hospitalized with HF exacerbation and a left ventricular ejection fraction>50% on echocardiograms performed between six months pre-admission and seven days post-discharge. Demographic, clinical, laboratory, medication, comorbidity, and imaging data available at the time of index hospitalization were extracted. The cohort was split into 80% training (n=6,272) and 20% held-out test (n=1,568) sets. After standard preprocessing, we performed an evolutionary AutoML search. The final pipeline applied a RobustScaler, two sequential feature-union blocks, and an XGBoost classifier. Model performance on the test set was assessed by area under the receiver operating characteristic curve (AUC), Brier score, accuracy, precision, recall, and F1 score, each with bootstrap-derived 95% confidence intervals (CIs). For interpretability, SHAP (SHapley Additive exPlanations) values were computed using the full scaled training set as background. Results: On the held-out test set, the XGBoost-based model achieved an AUC of 0.7595 (95% CI: 0.7307-0.7870) and a Brier score of 0.1764 (95% CI: 0.1652-0.1890). Accuracy was 0.7406 (95% CI: 0.7143-0.7645), precision 0.6349 (95% CI: 0.5759-0.6942), recall 0.4135 (95% CI: 0.3636-0.4609), and F1 score 0.5008 (95% CI: 0.4529-0.5444). The global SHAP summary plot (Figure 1) ranked age, serum albumin, blood urea nitrogen (BUN), presence of renal failure, and NT-proBNP as the top 5 predictors. Conclusions: In this large HFpEF cohort, an AutoML-derived XGBoost pipeline achieved robust discrimination (AUC≈0.76) and calibration (Brier≈0.18) for 1-year mortality prediction. SHAP-based explanations highlighted the importance of age, nutritional status (albumin), renal biomarkers (BUN, renal failure), and natriuretic peptides (NT-proBNP) as principal drivers of risk. These interpretable machine learning findings may guide personalized risk stratification and identify therapeutic targets in HFpEF.

Abstract Disclosure: H. Ahmad: None. M. Kakakhel: None. A. Ullah: None. M. Saeed: None. J. Ikram: None. A. Qadeer: None. M. Khawar: None. H. Jawad: None. S. Haider: None. R. Haider: None. F. Ahmed: None. R.W. Kirchoff: None. Background: Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the destruction of insulin-producing cells in the pancreas. It is a global health concern with regional variation in incidence and prevalence. This study aims to analyze the regional incidence and prevalence of T1DM among adolescents and young adults (15-39 years) from 1990 to 2021 in 26 regions. Methods: Global Burden of Disease (GBD) data for 2021 were analyzed to assess regional incidence and prevalence of T1DM among adolescents and young adults. The Annual Average Percentage Change (AAPC) was calculated to evaluate trends from 1990 to 2021, with statistical significance determined using p-values. Results: In 2021, middle socio-demographic index (SDI) has the highest incidence (54541) as well as prevalence (1.86 million), followed by Low-middle SDI (I: 48416, P: 1.80 million) and South Asia (I: 46310, P: 1.73 million). Oceania has the lowest incidence (356) as well as prevalence (12885), followed by Andean Latin America (I: 911, P: 31954) and Caribbean regions (I: 1214, P: 54610), respectively. The largest increase in AAPC of incidence was showed by Southern Latin America (2.23, CI: 2.11-2.30), High-income Asia Pacific (2.22, CI: 2.18-2.26), and Western Europe (1.80, CI: 1.73-1.84) regions, while Western Europe (1.72, CI: 1.66-1.75), Eastern Europe (1.64, CI: 1.63-1.66), and Australasia (1.38, CI: 1.36-1.40) showed largest increase in AAPC of prevalence. The Caribbean region had the greatest decline in AAPC of prevalence (-0.11, CI: -0.08 to -0.12) followed by Eastern Sub-Saharan Africa (-0.07, CI: -0.06 to -0.09) and Central Latin America (-0.04, CI: -0.02 to -0.07). There was no region with decline in incidence. All AAPC values were statistically significant (p &lt; 0.000001). Conclusion: Middle SDI region exhibited the highest incidence and prevalence, highlighting the vulnerability of these populations, while Oceania and Andean Latin America bore the least burden. Notably, several regions, particularly in Europe, experienced substantial increases in both incidence and prevalence, emphasizing the need for targeted interventions. Conversely, some regions, such as the Caribbean, showed encouraging declines in prevalence, suggesting that effective prevention and control strategies can be implemented. These findings underscore the importance of tailored approaches to address the evolving burden of T1DM. Presentation: Saturday, July 12, 2025

Abstract Disclosure: M. Kakakhel: None. S. Cheema: None. R. Haider: None. R. Noor: None. S. N.l: None. S.M. Irshad: None. A. Ullah: None. H. Jawad: None. A. Nawaz: None. M. Khawar: None. A. Qadeer: None. H. Ahmad: None. R. Alcaraz: None. F. Ahmed: None. Background: Bone density and structure-related disorders, such as osteoporosis and related fractures, significantly contribute to morbidity and mortality, particularly among aging populations. Monitoring temporal trends and geographic variations in mortality is essential to inform targeted public health interventions. In this study, we aimed to examine temporal and geographic variations in mortality associated with bone density and structure-related disorders in the United States from 1999 to 2022. Methods: Using ICD-10 codes M80-M85, this retrospective ecological study utilized mortality data extracted from the CDC WONDER database for the years 1999-2022. Age-adjusted mortality rates (AAMRs) were calculated and stratified by demographic variables (age, sex, and race/ethnicity) and geographic regions. Temporal trends were analyzed using Joinpoint regression to estimate annual percent changes (APCs). Geographic variations were visualized using choropleth maps, and subgroup analyses were performed to explore disparities. Statistical significance was set at p &lt; 0.05. Results: Age-adjusted mortality rates (AAMRs) for bone density and structure-related disorders decreased overall from 1999 to 2019, with a subsequent rise observed in 2020 and 2022. Joinpoint regression revealed a significant negative trend from 2007-2016 (APC = -7.46%, p &lt; 0.000001), followed by a positive reversal from 2019-2022 (APC = 3.78%, p = 0.013). Both males and females experienced declines in mortality, but females had a slightly higher APC of -3.10% compared to -2.82% for males. Asian/Pacific Islander groups exhibited the most pronounced decrease in mortality (APC = -11.92%, p &lt; 0.000001) from 2009-2015, with a positive rebound in recent years. Black or African American populations had the smallest decline (APC = -1.35%). The Southern U.S. experienced the steepest decline in mortality from 2010-2016 (APC = -10.92%, p &lt; 0.000001), followed by a strong positive trend from 2019-2022 (APC = 6.61%, p &lt; 0.000001). Conversely, the West and Northeast regions showed milder trends with less pronounced reversals. Older age groups (65-74, 75-84) showed significant decreases in mortality, particularly the 65-74 group, which reversed to a positive trend (APC = 6.97%) from 2019-2022. The highest number of deaths occurred at the decedent’s home (3,330 in 2022). Subgroup analyses indicated significant temporal shifts in the mortality patterns across different racial/ethnic groups and geographic regions. Hispanic/Latino and Asian/Pacific Islander populations exhibited an increase in mortality rates post-2019, particularly in 2020. Conclusion: From 1999 to 2022, mortality from bone density and structure-related disorders in the U.S. exhibited significant temporal and geographic variations. These findings highlight the need for targeted public health strategies. Presentation: Monday, July 14, 2025

Abstract Disclosure: M. Kakakhel: None. S. Fatima: None. H. Ahmad: None. A. Ibrahim: None. W. Rahman: None. R. Haider: None. H. Jawad: None. A. Qadeer: None. M. Khawar: None. F. Ahmed: None. J. Ikram: None. R. Kirchoff: None. Background: Across the world, type 1 diabetes mellitus (T1DM) is a major health problem for teenagers and young people. This study aims to examine the incidence and prevalence of T1DM by gender in the 15-39 age range between 1990 and 2021. Methods: We analyzed data from the Global Burden of Disease (GBD) to evaluate incidence and prevalence rates of T1DM in each gender from 1990 to 2021. The Annual Percentage Change (APC) and The Annual Average Percentage Change (AAPC) was used to assess trends, with p-values determining the statistical significance. Results: From 1990 to 2021, the global prevalence of T1DM was found to be increased steadily for both genders, with the highest rates recorded in 2021: 247.32 per 100,000 for females and 246.47 per 100,000 for males. Incidence rates in 2021 showed a contrasting pattern, with males exhibiting higher rates (7.18 per 100,000) compared to females (5.98 per 100,000). AAPC analysis showed that males exhibit a faster rise in both prevalence and incidence compared to females over the study period. The difference in AAPC between males and females is more pronounced for prevalence (+0.3748%) compared to incidence (+0.1956%), with all AAPC values being statistically significant (p &lt; 0.000001). Following the APC analysis, other significant trends were revealed. Male incidence experienced the greatest increase during 2015-2021, with an APC of +1.9033% (p &lt; 0.000001), whereas female incidence increased most between 2011 and 2014 (APC = +1.3050%; p &lt; 0.000001). In contrast, the most significant decline in incidence was observed in females during 1990-1992, with an APC of +0.1665% (p = 0.006799), which was the lowest increase in the dataset. For prevalence, males exhibited the highest increase during 2015-2021, with an APC of +1.3938% (p &lt; 0.000001), whereas females had their peak increase during 2006-2009, with an APC of +0.8957% (p &lt; 0.000001). The slowest increase in prevalence for females occurred during 2014-2019, with an APC of +0.4591% (p &lt; 0.000001). Conclusion: The prevalence and incidence of T1DM among people aged 15-39 increased significantly between 1990 and 2021, with a greater increase in males. This highlights the need for gender-specific strategies in T1DM prevention and management, and research into the factors driving these disparities. Presentation: Sunday, July 13, 2025

Abstract Disclosure: M. Kakakhel: None. S. Fatima: None. H. Ahmad: None. M. Khan: None. A. Rai: None. A. Qadeer: None. R. Haider: None. M. Khawar: None. U. Habib: None. H. Jawad: None. J. Ikram: None. F. Ahmed: None. R. Kirchoff: None. Introduction: Type 1 Diabetes Mellitus (T1DM) is a disease that affects people all over the world. This condition causes significant morbidity, as measured by Disability-Adjusted Life Years (DALYs) and mortality rates, and its severity varies worldwide. The purpose of this study is to examine trends in T1DM-related death rates and DALYs across 26 geographical areas from 1990 to 2021 in order to provide a current picture of the disease's consequences and identify regional differences. Methods: This study examined DALYs and mortality rates per 100,000 people in individuals aged 15-39 years using data from the Global Burden of Disease Study from 1990 to 2021. Trends were assessed using the Average Annual Percentage Change (AAPC), with p-values used to define statistical significance. The study examined 26 regions with varied socioeconomic development indices (SDI). Using confidence intervals to account for data uncertainty, DALYs and mortality were examined to investigate the disease burden across time. Results: In 1990, the Middle SDI region had the highest DALYs at 298,352 (95% CI: 256,144 -349,670), which reached 382,857 (95% CI: 213,704-317,664) by 2021 (AAPC = 0.15, P-value &lt; 0.000001). The region with the highest DALYs in 2021 was the Low-Middle SDI, with 419,772 (95% CI: 344,307- 495,496) cases (AAPC = -2.93, P-value = &lt;0.000001). From 1990 to 2021, Oceania consistently had the lowest DALYs of 1,895 (95% CI: 1,264-2,577) and 4,210(95% CI: 3,011-5,724), respectively (AAPC= 0.15, P-value = 0.0004). Mortality rates in 1990 were highest in the Middle SDI area with 3,758 deaths (95% CI: 3,343-4,332) (AAPC= -1.23, P-value = &lt;0.000001), but by 2021, South Asia had the highest mortality rate at 5,189(95% CI: 4,272-6,087) (AAPC= -0.49). Oceania had the lowest mortality rate of 25 deaths (95% CI 145-35) (AAPC = 0.193, P-value = &lt;0.0004) in 1990, whereas Australasia had the lowest mortality rate of 28 deaths (95% CI 26-29) in 2021 (AAPC = -0.93, P-value = &lt;0.000001). Conclusion: From 1990 to 2021, the global burden of type 1 diabetes—as indicated by DALYs and death rates—underwent a substantial shift, with significant rises in several regions. DALYs were highest in the Middle SDI region in 1990 but have migrated to the Low-Middle SDI region by 2021, reflecting shifting healthcare issues and demographics. Mortality rates followed a similar pattern, with South Asia and the Low-Middle SDI regions experiencing the highest rates in 2021. Over both time periods, however, Oceania and Australasia consistently had the lowest DALYs and death rates. These findings emphasise the critical need for targeted interventions in high-burden areas. Addressing these differences is crucial for decreasing the global burden of T1DM. Presentation: Sunday, July 13, 2025

Abstract Disclosure: H. Ahmad: None. S. Fatima: None. M. Kakakhel: None. I. khan: None. A. Raza: None. Z. Khan: None. R. Haider: None. A. Qadeer: None. M. Khawar: None. F. Ullah: None. H. Jawad: None. J. Ikram: None. F. Ahmed: None. R.W. Kirchoff: None. Background: Type 1 diabetes mellitus (T1DM) is an autoimmune condition, characterized by the destruction of pancreatic beta cells, resulting in lifelong dependency on insulin. It is a significant health burden in adolescents and young adults, with long-term complications affecting quality of life and survival. We aim to explore sex-stratified trends in mortality and disability-adjusted life years (DALYs) due to T1DM from 1990 to 2021. Methods: We obtained sex-stratified data for adolescents and young adults (15-39 years) with T1DM from the Global Burden of Disease (GBD) from 1990 to 2021. The mortality rates were age-standardized and expressed per 100,000 deaths. Trends were analyzed as annual percentage change (APC) and average APC (AAPC) using Joinpoint Regression. Results: From 1990 to 2021, deaths due to T1DM in adolescent and young adult males increased globally from 7,123 to 9,244 per annum, with age-standardized mortality rates (ASMRs) decreasing from 0.64 to 0.61 and standardized DALYs rising from 49.56 to 51. In females, deaths rose from 6,160 to 6,892, with ASMRs declining from 0.57 to 0.47 and DALYs declining from 47.12 to 43.11. Despite the apparent rise in deaths, ASMRs exhibited a significant decline in both sexes, with an AAPC of -0.16% (95% CI: -0.20 to -0.12) in males and -0.62% (-0.68 to -0.55) in females, four times that of in males. The DALYs showed a significant decline in females with an AAPC of -0.31% (-0.35 to -0.26) but a significant increase in males with an AAPC of 0.09% (0.04 to 0.12). Males showed the greatest APC increase in ASMRs of 1.34% from 1990 to 1994, while females showed the greatest APC increase of 0.45% from 1990 to 2000, three times less and over twice the period seen in males. This was followed by the greatest APC decline of -1.14% in females from 2001 to 2011, and a non-significant decline of -0.14% till 2021. Males experienced the greatest decline of -1.14% from 2000 to 2013. It then increased significantly from 2013 to 2018 (APC: 0.73%), followed by a significant decline of -0.62% till 2021, almost four times that in females. DALYs showed a similar trend in females with the greatest increase of 0.45% from 1990 to 2000, followed by the greatest decrease of -1.14% till 2011, and then a non-significant decline of -0.14 till 2021. Males showed the greatest increase of 1.24% from 1990 to 1994 and the greatest decrease of 0.63% from 2000 to 2013, followed by a much smaller decline. Conclusion: Although ASMRs declined, the recent decline in ASMRs in females is becoming less pronounced highlighting the importance of ongoing monitoring and improvement strategies. The disparity in DALYs between males and females also demands the need for targeted interventions addressing male-specific challenges to reduce the burden of T1DM. Presentation: Sunday, July 13, 2025