Salehi, Mahdi

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.

Abstract Context Most of the patients included in the clinical trials and real-world studies with osilodrostat only include patients with adrenocorticotropic hormone dependent Cushing syndrome (CS), while data on the efficacy and safety of osilodrostat in patients with adrenal CS is scarce. Objective To assess the efficacy and safety of osilodrostat in adrenal CS. Methods International study of patients with adrenal CS: patients treated with osilodrostat at any time were enrolled in the safety evaluation and those treated for longer than 4 weeks, in the efficacy evaluation. Patients were classified as responders if they experienced a reduction in urinary free cortisol (UFC) >50% (complete responders when UFC levels were below the upper limit of normal [ULN] and partial responders if there was a reduction >50% but not normalization). Results Twenty-eight patients with adrenal CS were enrolled: 16 with adrenocortical carcinoma and 12 with benign disease. Osilodrostat was used in monotherapy in 22 patients and in combination with metyrapone in 6 cases. In those patients treated for longer than 4 weeks (n = 21), 66.7% were classified as responders (28.6% with complete response and 38.1% with partial response), and for those treated for longer than 12 weeks, the rate of response increased to 87.5% The use of osilodrostat as a nonfirst-line therapy (odds ratio 15.0, P = .010) was a predictor of response. Osilodrostat led to a significant decrease in systolic blood pressure and body weight (P < .05). Nine patients developed one or more adverse events and in 56% (n = 5) led to osilodrostat discontinuation. Conclusion Osilodrostat controls hypercortisolism in 66.7% of patients with adrenal CS treated for longer than 4 weeks and in 87.5% of cases treated for longer than 12 weeks, with a positive impact on blood pressure and body weight. Patients who received osilodrostat after other previous steroidogenesis inhibitors have a higher probability of response.

Abstract Disclosure: M. Salehi: None. K. Yu: None. C.A. Villavicencio Torres: None. V. Fell: None. I. Bancos: None. Context: The use of the 1 mg overnight dexamethasone suppression test (1 mg-DST) is considered the standard-of-care test for the assessment of hypercortisolism. Scarce data are available on the utility of 8 mg-DST in distinguishing adrenal from pituitary hypercortisolism. Objective: To determine the value of 8 mg-DST in diagnosing hypercortisolism subtype. Methods: We conducted a single-center retrospective cohort study (2005-2024) of consecutive adults who underwent both the 1 mg-DST and the 8 mg-DST within a 6-month period. Only patients with optimal reference standard confirming the type of hypercortisolism were included. Patients were excluded if they had an abnormal DST and dexamethasone concentration <100 ng/dL or were receiving oral estrogen therapy. Delta cortisol [(post 1 mg-DST cortisol- post 8 mg-DST cortisol) x100/post 1 mg-DST cortisol)] was calculated for each patient. Results: A total of 61 patients (50, 82% women, median age 60 years, interquartile range, IQR 47-67) underwent both 1- and 8 mg-DST at least once, with 8 (13%) patients undergoing the 1 mg-DST and 8 mg-DST twice, and 1 (1.6%) patient undergoing both tests thrice. Adrenal hypercortisolism was diagnosed in 44 (72%) patients and pituitary hypercortisolism in 17 (28%) patients. Median post 1 mg-DST cortisol was 4.6 mcg/dL (IQR 2.8-7.2) in adrenal and 13.7 mcg/dL (IQR 7.3-21.7) in pituitary hypercortisolism. Median post 8 mg-DST cortisol was 3.2 mcg/dL (IQR 2.5-6.3) in adrenal and 3.6 mcg/dL (IQR 2.2-7.5) in pituitary hypercortisolism. Median delta cortisol was higher in pituitary hypercortisolism when compared to adrenal hypercortisolism (69%, IQR 25-83 vs 5 %, IQR -20-16, P<0.001). Delta cortisol demonstrated a good discrimination in distinguishing adrenal from pituitary hypercortisolism with a median area under receiver operator of 82% (95%CI 69-92). A cut-off of 25% provided a specificity of > 85%, while a cut-off of -1% yielded a sensitivity of > 85% in diagnosing adrenal hypercortisolism. Conclusion: In this study, we show that performing 8 mg-DST in addition to 1 mg-DST in selected patients with hypercortisolism and calculating delta cortisol is a valuable in distinguishing hypercortisolism subtype. Presentation: Sunday, July 13, 2025