Citations

Abstract Disclosure: M. Bassiony: None. P. Dogra: None. L. Šambula: None. J. Saini: None. U. Ambroziak: None. D. Kastelan: None. I. Bancos: None. Background: Frailty is characterized by a multi-system decline and increased vulnerability to adverse health outcomes. We have recently shown that patients with mild autonomous cortisol secretion (MACS) demonstrate a higher prevalence of frailty compared to patients with nonfunctioning adrenal adenomas (NFA). Objective: To determine the impact of adrenalectomy versus conservative management in patients with MACS, as compared to patients with NFA. Design: Multi-center, prospective cohort study (2019-2023). Methods: Adults with NFA and MACS were assessed for frailty at baseline and 1-year post-adrenalectomy, or conservative follow up. Frailty was assessed by frailty index (FI) that encompasses 47 health variables (comorbidities, symptoms, daily living activities). Patients with FI >0.25 were classified as frail. MACS was defined as post-dexamethasone cortisol>1.8 mcg/dL. Results: Paired frailty assessments were performed in 226 patients (MACS:117 and NFA:109). At baseline, patients’ median age was 63 years (interquartile range, IQR 55-78) and 113 (50%) were women, without differences between patients with MACS vs NFA. In conservatively treated patients with NFA (n=106) and MACS (n=61), baseline FI (median 0.15 vs 0.16, p=0.190) and frailty prevalence (18% vs 20%, p=0.846) were similar between groups. At follow up, patients with MACS demonstrated an increase in FI (mean of 0.013 vs -0.018 in patients with NFA, p=0.009). In conservatively treated patients, and after excluding outliers, post-dexamethasone cortisol positively correlated with a higher delta FI at follow up (estimate 0.015, p=0.01). Compared to conservatively treated, patients with MACS treated with adrenalectomy (n=56) were younger (median age of 58 vs 67 years, p=0.0002), had a similar post-dexamethasone cortisol (median 3.4 vs 2.8 mcg/dL, p=0.853), a higher FI (median 0.26 vs 0.15, p value <0.0001) and frailty prevalence (52% vs 20% P=0.0003) at baseline. At follow up, patients with MACS treated with adrenalectomy showed improved FI when compared to conservatively treated (mean delta FI of -0.025 vs 0.014, p=0.017). Conclusions: Patients with MACS treated conservatively demonstrate an accelerated frailty when compared to patients with NFA. In contrast, frailty improves in patients with MACS treated with adrenalectomy. Presentation: 6/2/2024

Abstract Disclosure: E.Y. Ferreira: None. J. Saini: None. J. Larson: None. E. Atkinson: None. C. Powell: None. S. Nevin: None. V. Fell: None. I. Bancos: Grant Recipient; Self; HRA Pharmaceuticals. Research Investigator; Self; HRA Pharmaceuticals. Context: Mild autonomous cortisol secretion (MACS) is the most prevalent hormonal abnormality demonstrated in 20-45% of patients with adrenal adenomas. MACS is associated with increased prevalence and incidence of cardiovascular morbidity, frailty, fragility fractures, psychiatric and sleep disorders, as well as increased mortality. Bilateral MACS due to bilateral adrenal adenomas or macronodular adrenal hyperplasia is seen in around 20% of patients with MACS. Management of patients with unilateral MACS who are not surgical candidates or do not desire adrenalectomy, and management of patients with bilateral MACS is challenging. Safe and effective medical therapy is urgently needed in these patients. Objective: 1) assess safety and tolerability of overnight metyrapone therapy in patients with MACS, 2) evaluate the impact of overnight metyrapone on steroid profiling and circadian cortisol secretion and 3) determine the efficacy of overnight metyrapone on metabolic and bone parameters, mood, sleep, cognition, quality of life, frailty and senescence biomarkers. Methods: This open-label, phase 2 interventional single-center study using overnight metyrapone opened for enrollment in December 2023 (NTC06106295) and plans to enroll 30 patients with MACS. Eligible participants include adults with adrenal adenoma or macronodular adrenal hyperplasia and MACS, and at least one comorbidity attributed to hypercortisolism. Metyrapone is administered overnight at 250 mg to 1000 mg. Duration of the study is 6 months (main study) and up to 42 months for extension study. Primary endpoint is incidence of treatment related adverse events. Key secondary endpoints include: glucocorticoid/androgen ratio, morning/evening cortisol curve, metabolic parameters (change in blood pressure, hyperglycemia, weight), frailty index and senescence biomarkers. Results: Between December 15th 2023 and April 6th, 7 patients with MACS (4, 57% women) enrolled at a median age of 62 years (IQR 56-68). Median BMI was 29 kg/m2(IQR 25-34). Post-dexamethasone cortisol was 3.1 mcg/dL (IQR 2.4-6.2), corticotropin (ACTH) was 7.3 pg/mL (IQR 5-20), and dehydroepiandrosterone-sulfate (DHEAS) was 73 mcg/dL (IQR 59-86). Median hypercortisolism clinical severity score was 9 (IQR 2-11) and biochemical severity score was 3.5 (IQR 2-5). Prevalence of hypertension (57%), dysglycemia (67%), dyslipidemia (86%), depression (57%), anxiety (43%), and bone disease (70%) was high. In 7 participants, median frailty index was 0.2 (IQR 0.2-0.4), and 3 (43%) were considered frail (frailty index >0.25). As of April 6th, 2024, no major treatment-related adverse events were reported, and no patient discontinued therapy. Conclusion: Results of this study will characterize safety and tolerability of overnight metyrapone in patients with MACS and evaluate the impact of overnight metyrapone on MACS-associated comorbidities. Presentation: 6/1/2024

Abstract Disclosure: B. Vekony: None. G. Nyiro: None. Z. Herold: None. J. Fekete: None. F. Ceccato: None. S. Gruber: None. L. Kurzinger: None. M. Parasiliti-Caprino: None. B. Szeredas: None. S. Syed Mohammed Nazri: None. V. Fell: None. M. Bassiony: None. E.A. Azizan: None. I. Bancos: None. F. Beuschlein: None. P. Igaz: None. Background: The differentiation of uni- and bilateral forms of primary aldosteronism (PA) is of pivotal clinical relevance. Whereas unilateral PA warrants surgical treatment, bilateral PA is treated by aldosterone antagonists. The most reliable way to differentiate these two entities is adrenal venous sampling (AVS) that is an invasive method with limited availability and requiring great expertise. Aim: To develop a circulating blood-borne microRNA-based approach using machine learning for the differentiation of uni- and bilateral PA. Methods: Circulating microRNA profiling on an Illumina MiSeq platform was performed on total RNA samples isolated from EDTA-anticoagulated blood specimens taken by AVS from 18 pairs of right and left suprarenal veins (10 uni-, 8 bilateral PA). Significantly differentially expressed microRNAs were analyzed by a neural network (90-10% learner-tester cross-validation simulation). From the top 29 significantly differentially expressed microRNAs, 9 were selected for validation by Taqman RT-qPCR on a separate cohort of 30 AVS-confirmed samples (15-15 uni- and bilateral forms) both on plasma samples from adrenal as well as from peripheral veins. The method was finally tested on another independent cohort of peripheral blood samples from 80 patients (40 uni- and 40 bilateral PA). Results: Regarding the 9 microRNAs selected for validation, microRNA abundance was non-significantly lower in peripheral samples compared to AVS samples. By analyzing peripheral plasma samples, ten combinations of 4-8 microRNAs from the pool of 9 microRNAs turned out to have maximal sensitivity and specificity values over 85 %. The best combination included 6 microRNAs with a sensitivity of 86.3 % and a specificity of 87.91 % (AUC = 0.871). The inclusion of further parameters such as imaging, potassium and renin levels did not improve the model’s performance. Conclusion: The analysis of circulating blood-borne microRNAs represents a minimally invasive and potentially reliable way of differentiating uni- and bilateral PA. If bilateral PA is confirmed by the model, no more localization efforts would be necessary thus simplifying the management of PA patients. This would be relevant both from the patient’s and a public health perspective. Presentation: 6/3/2024

Abstract Disclosure: B. Vekony: None. G. Nyiro: None. Z. Herold: None. J. Fekete: None. F. Ceccato: None. S. Gruber: None. L. Kurzinger: None. M. Parasiliti-Caprino: None. B. Szeredas: None. S.K. Nazri: None. V. Fell: None. M. Bassiony: None. E.A. Azizan: None. I. Bancos: None. F. Beuschlein: None. P. Igaz: None. Background: The differentiation of uni- and bilateral forms of primary aldosteronism (PA) is of pivotal clinical relevance. Whereas unilateral PA warrants surgical treatment, bilateral PA is treated by aldosterone antagonists. The most reliable way to differentiate these two entities is adrenal venous sampling (AVS) that is an invasive method with limited availability and requiring great expertise. Aim: To develop a circulating blood-borne microRNA-based approach using machine learning for the differentiation of uni- and bilateral PA. Methods: Circulating microRNA profiling on an Illumina MiSeq platform was performed on total RNA samples isolated from EDTA-anticoagulated blood specimens taken by AVS from 18 pairs of right and left suprarenal veins (10 uni-, 8 bilateral PA). Significantly differentially expressed microRNAs were analyzed by a neural network (90-10% learner-tester cross-validation simulation). From the top 29 significantly differentially expressed microRNAs, 9 were selected for validation by Taqman RT-qPCR on a separate cohort of 30 AVS-confirmed samples (15-15 uni- and bilateral forms) both on plasma samples from adrenal as well as from peripheral veins. The method was finally tested on another independent cohort of peripheral blood samples from 80 patients (40 uni- and 40 bilateral PA). Results: Regarding the 9 microRNAs selected for validation, microRNA abundance was non-significantly lower in peripheral samples compared to AVS samples. By analyzing peripheral plasma samples, ten combinations of 4-8 microRNAs from the pool of 9 microRNAs turned out to have maximal sensitivity and specificity values over 85 %. The best combination included 6 microRNAs with a sensitivity of 86.3 % and a specificity of 87.91 % (AUC = 0.871). The inclusion of further parameters such as imaging, potassium and renin levels did not improve the model’s performance. Conclusion: The analysis of circulating blood-borne microRNAs represents a minimally invasive and potentially reliable way of differentiating uni- and bilateral PA. If bilateral PA is confirmed by the model, no more localization efforts would be necessary thus simplifying the management of PA patients. This would be relevant both from the patient’s and a public health perspective. Presentation: 6/3/2024

Abstract Disclosure: K. Yu: None. S. Athimulam: None. J. Saini: None. R. Kaur: None. R.J. Singh: None. S.K. Grebe: None. Q. Xue: None. I. Bancos: Advisory Board Member; Self; AstraZeneca, Corcept, Novo Nordisk, HRA Pharmaceuticals, Neurocrine, Diurnal, Recordati, Sparrow, Xeris, Spruce, Adrenas. Research Investigator; Self; HRA Pharmaceuticals, Recordati. Context: Early diagnosis is essential to assure a better prognosis in patients with adrenocortical carcinoma (ACC). Guidelines suggested performing urine steroid profiling in patients with indeterminate adrenal tumors to make a noninvasive diagnosis of ACC. However, urine steroid profiling is not widely available. Accuracy of clinically available serum steroids in diagnosing ACC has not been established. Objective: To determine the accuracy of 11-deoxycortisol, 17OH-progesterone, and 17OH-pregnenolone in diagnosing ACC. Design: Prospective single-center cohort study. Participants: Between 2015 and 2023, consecutive patients with adrenal mass were prospectively enrolled in the prospective registry and biobank study. Patients who agreed to contribute a fasting serum sample were included in the study. Exclusion criteria were congenital adrenal hyperplasia, exogenous glucocorticoid use, absence of unenhanced Hounsfield unit measurements (HU), and lack of established reference standard (histopathology, imaging characteristics, 2-year imaging follow up, or 5-year clinical follow up). Measures and Outcomes: measurements included 11-deoxycortisol, 17OH-progesterone, and 17OH-pregnenolone by liquid chromatography–mass spectrometry. Localized Generalized Matrix Learning Vector Quantization (LGMLVQ) analysis was used to develop serum steroid score and assessed with area under receiver operating curve (AUROC). Results: Of 263 patients with adrenal masses, 44 (17%) were diagnosed with ACC, 161 (61%) with adrenocortical adenomas (ACAs), 27 (10%) with other adrenal malignancies, and 31 (12%) with other. HU ≥ 20 were demonstrated in all ACCs, in all but one other adrenal malignancy, and only in 58 (31%) ACAs. All 3 steroids were higher in patients with ACCs vs nonACCs, including when comparing ACCs with functioning ACAs, and with ACAs with HU ≥ 20 (P<0.0001 for all). LGMLVQ analysis yielded a serum steroid score that discriminated between ACC and non-ACC groups with a mean threshold fixed AUROC of 0.823. Serum steroid score of 0.29 demonstrated a mean false negative rate of 0% and a score of 0.61 demonstrated a mean false positive rate of 0%. Conclusions: We showed that measurements of 11-deoxycortisol, 17OH-progesterone, and 17OH-pregnenolone could be valuable in diagnosing ACC. After appropriate validation, serum steroid score could be integrated in clinical practice. Presentation: 6/2/2024

Abstract Disclosure: J. Saini: None. S. Singh: None. A.L. Ebbehøj: None. C.D. Zhang: None. R. Nathani: None. V. Fell: None. E. Atkinson: None. S. Achenbach: None. A. Rivard: None. R.J. Singh: None. S.K. Grebe: None. I. Bancos: None. Abstract Context: Mild autonomous cortisol secretion (MACS) is diagnosed based on post-dexamethasone cortisol>1.8 mcg/dL. Scarce evidence exists on steroid circadian secretion and steroid metabolome in MACS. Objective: To characterize 24-hour urine steroid metabolome in patients with MACS and determine circadian differences in urine steroid profiling and cortisol concentrations in patients with MACS versus referent subjects. Design: Cross-sectional study, 2018-2023. Setting: Referral center Participants: 72 patients with MACS and 72 age-, sex-, BMI-, and menopausal status-matched referent subjects. Measurements: Urine was collected over a 24-hour (h) period in separate day- and night-time collections. High-resolution mass spectrometry assay was used to measure 25 steroids. A subgroup of patients and referent subjects were admitted for every 2-hour serum measurement of free and total cortisol. Outcomes: Steroids, sums, and ratios Results: Patients with MACS had lower mcg/24h median androgens (2084 vs 3283, P<0.001), higher glucocorticoids (15754 vs 12936, P<0.001), and higher glucocorticoid/androgen ratio (8.7 vs 3.9, P<0.001). Steroid day/night ratios were lower in patients when compared to referent subjects, reflecting a higher relative nocturnal steroid production in MACS. In a subgroup of 12 patients with MACS and 10 referent subjects, the 24-hour area under the curves for total and free cortisol were similar. However, nocturnal mean total (5.3 vs 4.0 mcg/dL, P=0.056) and free (0.2 vs 0.1 mcg/dL, P=0.035) cortisol were higher in patients vs referent subjects. Conclusion: Patients with MACS demonstrate an abnormal urine steroid metabolome, with a high glucocorticoid to androgen ratio, and a higher nocturnal steroid production. Presentation: 6/3/2024

Abstract Disclosure: J. Saini: None. B. Salama: None. S.R. Chacko: None. K. Yu: None. I. Bancos: None. Objective: Measurement of baseline dehydroepiandrosterone sulfate (DHEAS) is suggested by the guidelines in support of diagnosing mild autonomous cortisol secretion (MACS). However, evidence on the diagnostic accuracy of DHEAS in MACS is difficult to interpret due to differences in the diagnostic cutoffs, small sample size, and heterogeneous reference standards. We aimed to conduct a systematic review and meta-analysis of published literature to assess the performance of DHEAS in diagnosing MACS, as defined in the 2023 guidelines. Methods: A comprehensive search was conducted using several databases from each database’s inception to January 8th, 2024. Databases include Ovid MEDLINE (R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Databases of Systematic Reviews, and Scopus. Only original studies of at least 20 participants were included. MACS was defined as post-dexamethasone cortisol >1.8 mcg/dL. QUADAS-2 was used to assess the risk of bias. Bivariate and random effects meta-analysis was used to generate pooled diagnostic accuracy estimates. Results: The initial search yielded 285 articles, and only 7 studies met the inclusion criteria. In 7 studies (1 from North America, 3 from Asia, and 3 from Europe), a total of 574 patients with MACS and 830 referent subjects (patients with adrenal tumors without MACS) were included. The mean age was specified only in 5 studies and was similar in patients with MACS (55.5 years) and referent group (53.3 years). Patients with MACS had a higher number of women (323/472, 68.4%) as compared to the referent group (352/658, 53.4%). DHEAS cutoffs studied included: lower cutoff of age-and sex-specific ranges (3 studies), 40 mcg/dL (3 studies), 60 mcg/dL (1 study), and 67.5 mcg/dL (1 study). With increasing DHEAS cutoff, sensitivity for MACS diagnosis increased, and specificity decreased. Most studies (4 studies) used the chemiluminescent immunoassay to measure DHEAS. A meta-analysis of studies using DHEAS cut-off between 40-70 mcg/dL was performed, with a pooled sensitivity of 68% (95% CI: 51-81) and a pooled specificity of 85% (78-89). The positive likelihood ratio was 4 (95% CI: 3-6; I2=36.94, P=0.175) and the negative likelihood ratio was 0.4 (0.3-0.6; I2=49.97, P=0.092). Most studies were at a high risk of bias for selection of patients, index, or reference standard. Conclusion: Based on limited heterogeneous evidence, measurement of DHEAS provides additional value in diagnosing MACS. Further larger diagnostic accuracy studies should explore various DHEAS cutoffs and consider assay variability. Presentation: 6/3/2024

Abstract Disclosure: J. Saini: None. V. Fell: None. B. Atkinson: None. S. Achenbach: None. I. Bancos: None. Background: Patients with mild autonomous cortisol secretion (MACS) have a higher prevalence of frailty and reduced muscle strength as compared to patients with nonfunctioning adrenal adenomas or subjects without adrenal disorders. Objective: To determine the impact of adrenalectomy on frailty and parameters of functional strength in patients with MACS. Methods: We conducted a single-center prospective longitudinal study of adults with MACS scheduled for adrenalectomy and referent subjects evaluated between 2018 and 2023. MACS was defined as serum cortisol>1.8 mcg/dL after 1 mg dexamethasone suppression test in patients with adrenal adenomas and no features of overt hypercortisolism. Referent subjects were included if they had abdominal imaging and had no adrenal disorders. Patients and referent subjects had a baseline and a follow-up evaluation at least 10 months later. Differences were assessed using paired t-tests for (1) Frailty Index (FI)--calculated using a questionnaire containing 47 variables on comorbidities, symptoms, and daily living activities (frailty defined as FI>0.25) (2) physical function assessed using handgrip strength (Jamar Plus digital hand dynamometer), timed up-and-go test (time taken to rise from a chair, walk to and from 3 m, and sit down), gait speed, 6-minute walk test, and (3) Advanced Glycation End (AGE) Product (using AGE reader). Results: We evaluated 41 patients before and after adrenalectomy, and 31 referent subjects at baseline and follow-up visit, at a similar interval (median 1.6, IQR 1.2-2.0 vs 1.5 years, IQR 1.0-2.2, P=0.759). While sex distributions were no different between the 2 groups (women, 66% vs 84%, P=0.086), patients with MACS were older than the referent group (median age 57.3, IQR 48.8-66.9 vs 49.0, IQR 41.7-57.9 years, P=0.005). Post-adrenalectomy, FI decreased by a mean of 0.057 (SD 0.08), P<0.001 in patients, and remained unchanged in the referent group. AGE decreased in patients by 0.148 (SD 0.45), P=0.04 but not in referent subjects (-0.047, SD 0.242, P=0.5). Patients demonstrated no improvement in parameters of muscle strength: gait speed (mean change 0.305 m/s, P=0.453), 6-minute walk test (mean change 16.4 meters, P=0.201), dominant (mean Z score change -0.055, P=0.72) and nondominant (mean Z score change -0.199, P=0.192) hand grip muscle strength. At follow-up, both patients (mean change 1.897 seconds, P<0.001) and referent subjects (mean change=1.475 seconds, P<0.001) demonstrated a deterioration on the timed up-and-go test. Conclusions: While no improvement was seen in the parameters of muscle strength, adrenalectomy improved the frailty index in patients with MACS. In addition, AGE, a biomarker associated with cardiovascular morbidity, decreased after adrenalectomy, suggesting a beneficial cardiovascular impact of MACS reversal. Presentation: 6/1/2024

Abstract Disclosure: I. Bancos: Advisory Board Member; Self; Adrenas, Diurnal, Neurocrine, Spruce, HRA Pharmaceuticals, Sparrow, Recordati Rare Diseases, Xeris, Novo Nordisk, AstraZeneca, Corcept. Consulting Fee; Self; Adrenas, Diurnal, Neurocrine, Spruce, HRA Pharmaceuticals, Sparrow, Recordati Rare Diseases, Xeris, Novo Nordisk, AstraZeneca, Corcept. Grant Recipient; Self; Recordati, HRA Pharmaceuticals. Other; Self; Adrenas, Diurnal, Neurocrine, Spruce, HRA Pharmaceuticals, Sparrow, Recordati Rare Diseases, Xeris, Novo Nordisk, AstraZeneca, Corcept. E.B. Geer: Advisory Board Member; Self; Recordati Rare Diseases. Consulting Fee; Self; Lundbeck, Crinetics, HRA Pharmaceuticals, Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Grant Recipient; Self; Xeris Pharmaceuticals (Strongbridge), Corcept, Recordati Rare Diseases, Sparrow. F. Castinetti: Consulting Fee; Self; HRA Pharmaceuticals, Recordati. Grant Recipient; Self; HRA Pharmaceuticals, Recordati. R. Feelders: Advisory Board Member; Self; Recordati. Consulting Fee; Self; HRA Pharmaceuticals, Recordati. Grant Recipient; Self; Corcept Therapeutics. M. Fleseriu: Advisory Board Member; Self; Recordati Rare Diseases. Consulting Fee; Self; Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Grant Recipient; Self; Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). R. Pivonello: Consulting Fee; Self; Corcept Therapeutics, Recordati, Crinetics Pharmaceuticals, H Lundbeck. Grant Recipient; Self; Recordati, Corcept Therapeutics, Xeris Pharmaceuticals (Strongbridge), Neurocrine Biosciences. M. Reincke: Advisory Board Member; Self; Recordati Rare Diseases. Consulting Fee; Self; Recordati Rare Diseases, HRA Pharmaceuticals, Lundbeck, Crinetics. Grant Recipient; Self; Recordati Rare Diseases, HRA Pharmaceuticals, Lundbeck, Crinetics. Speaker; Self; Recordati Rare Diseases, HRA Pharmaceuticals, Lundbeck, Crinetics. A. Tabarin: Advisory Board Member; Self; Recordati Rare Diseases. Consulting Fee; Self; H Lundbeck, Crinetics, HRA Pharmaceuticals, Recordati Rare Diseases. J. Le Mouhaër: Employee; Self; Recordati. J. Stermenska: Employee; Self; Recordati. M. Maldonado: Employee; Self; Recordati. B.M. Biller: Advisory Board Member; Self; Recordati Rare Diseases. Consulting Fee; Self; H Lundbeck, Recordati Rare Diseases, Sparrow, Xeris Pharmaceuticals (Strongbridge). Introduction: Osilodrostat, a potent oral 11β-hydroxylase inhibitor, provides control of cortisol production and improves outcomes in patients (pts), as shown by the clinical development program of Cushing’s disease (CD; Fleseriu M et al. Lancet Diabetes Endocrinol 2021;9:847-75) leading to EMA approval for Cushing’s syndrome (CS) and FDA approval for CD. The prospective LINC 6 study (NCT05382156) evaluates long-term safety and efficacy of osilodrostat in routine clinical practice over a 3-­year follow-up of CS pts. Here, we report 1-year interim data. Methods: Pts aged ≥18 years with endogenous CS are being enrolled in countries where osilodrostat is approved and available (including USA and Europe), irrespective of prior osilodrostat use. Treatment decisions and follow-up are at investigator discretion. The primary endpoint is incidence of osilodrostat-related adverse events (AEs) and serious AEs, focusing on AEs related to hypocortisolism, accumulation of adrenal hormone precursors, QT prolongation and pituitary tumor enlargement. Secondary endpoints include change in mean urinary free cortisol (mUFC), serum cortisol and late-night salivary cortisol (LNSC). Evaluation of biochemical parameters is recommended at baseline, months 1 and 3, and every 3 months thereafter, as available. AEs are recorded at baseline and each visit. Analyses are descriptive. We report change for pts with assessments at baseline and every 3 months. Results: Of 106 pts enrolled at the 1-year interim analysis, 94 were included in the safety population: CD, n=78; non-CD CS, n=16 (adrenal adenoma, n=3; adrenal hyperplasia, n=3; ectopic, n=9; other, n=1). Mean (SD) age was 53.2 years (12.7); 70.2% (n=66) were female. Median (min-max) osilodrostat exposure and dose were 5.5 months (0.1-13.9) and 5.0 mg/day (1.0-60.0). 29 pts reported 109 AEs; 12 pts reported 44 AEs that were considered treatment related. Overall, the most common (≥5%) AEs were asthenia and vomiting (both n=6/109; 5.5%); treatment-related AEs with highest frequency were vomiting and dizziness (both n=4/44; 9.1%). 7 AEs led to discontinuation in 4 pts; 5 AEs were considered osilodrostat related (nausea and vomiting in 1 pt; worsening hypertension, uncontrolled blood pressure and dizziness in another) and 2 were not (pituitary tumor surgery and right adrenalectomy). AEs related to hypocortisolism, accumulation of adrenal hormone precursors, QT prolongation and pituitary tumor enlargement occurred in 7 (7.4%), 4 (4.3%), 2 (2.1%) and 0 pts, respectively. At month 3, mUFC, serum cortisol and LNSC were normalized in 71.4% (n=10/14), 69.2% (n=18/26) and 50.0% (n=7/14) of pts. Conclusions: Results from this real-world clinical setting show that osilodrostat is generally well tolerated and provides early improvements in mUFC and LNSC in pts with endogenous CS, building on evidence from the previous randomized, controlled trials LINC 3 and LINC 4. Presentation: 6/3/2024

Abstract Disclosure: L. Rahimi: None. J. Saini: None. E. Atkinson: None. S. Achenbach: None. A. Kattah: None. I. Bancos: None. Introduction: Patients with mild autonomous cortisol secretion (MACS) have higher prevalence of cardiovascular comorbidities including chronic kidney disease. However, considering that patients with MACS may have relative skeletal muscle atrophy, it is unclear whether the creatine-based assessment of kidney function is accurate in this population. Objective: To characterize the differences in assessing estimated glomerular filtration rate using cystatin (eGFRcys) versus creatinine (eGFRcre) in patients with MACS versus referent subjects. Methods: Cross-sectional single-center study, 2019-2022. MACS was defined as serum cortisol concentration >1.8 mcg/dL after the 1 mg overnight dexamethasone suppression test (DST). For each patient, eGFRcre, eGFRcys and eGFRcre/eGFRcys ratio were measured and compared between the two groups. Body composition was measured by DXA scan. The Kruskal-Wallis test was used to compare measurements between groups. Result: A total of 37 patients with MACS (median age 59 years (interquartile range, IQR 47-67), 25 (68%) women) and 45 referent subjects (median age 57 years (IQR 51-66), 30 (67%) women) were included. The distribution of BMI, total body fat mass and total body lean mass were similar between the two groups. In the MACS cohort, the median cortisol following 1-mg DST was 3.0 ug/dL (IQR, 2.2-4.0). While assessment of kidney function with eGFRcre showed no differences between patients with MACS and referent subjects (median 85.1 vs 87.0 ml/min/1.73m2, P=0.431), kidney function using eGFRcys was lower in MACS (median 78.0 vs 89.3 ml/min/1.73m2 in referents, P<0.014), resulting also in a higher eGFRcre/eGFRcys ratio (median 1.07 vs 0.97 in MACS vs referents, P=0.053). After adjusting for age, sex, and BMI, a higher 1 mg DST cortisol level in the MACS cohort was associated with a higher eGFRcre/eGFRcys ratio (Spearman correlation coefficient of 0.35, P = 0.042). Lower eGFRcys was associated with higher fat mass (Spearman correlation of -0.26, P = 0.023), and a higher eGFRcre/eGFRcys ratio showed a trend towards lower lean mass (Spearman correlation of -0.20, P = 0.081). Conclusion: Creatinine-based eGFR assessment in patients with MACS underestimates the degree of kidney dysfunction, likely due to underlying skeletal muscle atrophy. eGFRcys is a more accurate indicator of kidney function in patients with hypercortisolism. Presentation: 6/1/2024