Citations

Abstract Disclosure: R. Castaneda: None. D. Bechenati: None. R.D. Rivera Gutierrez: None. M.A. Espinosa: None. J.L. Villamarin: None. E. Tama: None. J.L. Meek: None. P. Bennett: None. A. Acosta: Novo Nordisk, Gila Therapeutics, Amgen Inc, Regeneron Pharmaceuticals, Boehringer Ingelheim, Rhythm Pharmaceuticals, General Mills, Currax, Nestle, Phenomix Sciences, Busch Health, RareDiseases, National Institute of Health, Vivus Pharmaceuticals, Apollo Endosurgery, Satiogen Pharmaceuticals, Spatz Medical. S. Faubion: Era Women’s Health Platform, PriMed, MedAll, AiCME, Medscape, Weight Watchers. C. Shufelt: Bayer Advisory Board. M.D. Hurtado: Novo Nordisk, National Institute of Health, Phenomix. Introduction: Tirzepatide, a dual GIP and GLP-1 receptor agonist, is an FDA-approved medication demonstrating the highest efficacy for weight loss among currently available treatments. However, the influence of sex and age on weight loss outcomes with tirzepatide remains unclear. Objective: To investigate the influence of sex and age on weight loss outcomes in patients treated with tirzepatide. Methods: This retrospective study evaluated weight loss outcomes associated with tirzepatide across sex and age groups. Patients with active malignancy, prior bariatric surgery, or concurrent anti-obesity medication were excluded. The primary endpoint was total body weight loss percentage (TBWL%) at 15 months by sex and age. The influence of age was analyzed as a categorical (≤45, 46-59, ≥60 years) and continuous variable. Secondary outcomes included TBWL% at 3, 6, 9, and 12 months by sex and age. Data were analyzed using independent t-tests, one-way ANOVA, and multivariate regression; results are reported as mean ± standard deviation. Results: The study included 1033 patients (57.1% female; mean age 56 ± 11 years; mean BMI, 37.7 ± 8 kg/m2). By age category, 18.8% (196) were ≤45 years (35.7% males, 64.3% females), 45.9% (473) were 46-59 years (42.7% males, 57.3% females), and 35.3% (364) were ≥60 years (54.7% males, 45.3% females). At all timepoints, TBWL was significantly greater in females compared to males at all timepoints. At 15 months females had a higher TBWL than males: 15.3% ± 10, n=340, vs. 10.2% ± 8, n=244, (p < 0.001). Among females, premenopausal women achieved a higher TBWL than postmenopausal women: 16.9% ± 10 vs 14.4% ± 9, p = 0.04. Analysis by age groups revealed a trend toward higher TBWL in younger patients that did not reach statistical significance (p = 0.152): ≤45 years (14.7% ± 10%), 46-59 years (12.9% ± 10%), and ≥60 years (12.7% ± 9%). After adjusting for baseline age, BMI, and diabetes status, sex remained a strong predictor for weight loss outcomes (PE= 4.5, 95% CI [2.96, 5.97], p < 0.001), following type 2 diabetes status (PE= 4.8, 95% CI [3.0, 6.7], p < 0.001). Conclusion: Sex but not age was a strong predictor of weight loss with tirzepatide. Female sex was associated with greater weight loss than male sex. These results emphasize the importance of considering sex-specific factors in weight loss strategies and warrant further investigation into the underlying biological mechanisms. Differential weight loss by menopause, underscores the role of sex hormones. Presentation: Monday, July 14, 2025

Abstract Disclosure: E.M. Lewiecki: Amgen Inc, Kyowa Kirin, Ultragenyx, Angitia, Radius Health, Inc, Ascendis. E. Kapoor: Fresenius Kabi USA Inc., Astellas Pharma, Estetra SRL, WellFound Inc., Exeltis. S. Hurtado: None. V.M. Navarro: Bayer, Inc. M. Torres: Bayer, Inc. J. Beau: Bayer, Inc. I. Gkioni: Syneos Health LLC (providing service to Bayer), AstraZeneca. K. Genga: Bayer, Inc.. Background: The neuropeptide substance-P and its receptor neurokinin-1 (SP-NK1R pathway) play a role in bone metabolism and remodelling. Pre-clinical evidence also points to a role of this pathway in energy homeostasis. NK-1R antagonists have been proposed as potential therapies in obesity and musculoskeletal disorders like osteoporosis. Elinzanetant (EZN) is a dual neurokinin-1 and -3 receptor antagonist in late-stage development for vasomotor symptoms (hot flashes) associated with menopause. This post hoc analysis evaluates potential benefits of EZN on the skeleton, body weight, and body composition in postmenopausal women. Methods: Data were gathered from exploratory endpoints of the 52-week (wk), placebo (PL)-controlled, OASIS-3 Phase 3 EZN efficacy and safety trial. Mean percentage (%) change in total bone mass (kg) (measured indirectly by bioelectrical impedance analysis at baseline (BL), wks 4, 8, 12, 18, 24, 36, 52); mean % change in bone mineral density (BMD, measured directly by dual-energy X-ray absorptiometry at BL, wks 24 and 52) in femoral neck, total hip, and lumbar spine; and mean % change in key bone turnover markers osteocalcin (OC) and procollagen 1N-terminal propeptide (P1NP) at BL, wks 4, 8, 12, 18, 24, 36, 52 were evaluated. Weight, body mass index (BMI: weight/height2), waist circumference (WC), fat mass index (FMI; fat mass/height2), lean mass index (LMI; lean mass/height2) and body water were measured to monitor body composition at BL and wks 4, 8, 12, 18, 24, 36, 52. A sub-analysis was performed based on FMI at baseline (FMI ≤9 normal fat mass; >9 excess fat mass). Descriptive statistics were used to evaluate all parameters and trends. Results: From BL to wk 52, increasing trends in bone mass were observed with EZN (mean [SD]: 2.81 [1.02] to 2.95 [1.96]) but not PL (mean [SD]: 2.87 [1.09] to 2.87 [1.13]). In parallel, lower BMD reductions were seen in EZN vs PL at all skeletal sites [EZN vs PL, mean % change from BL: femoral neck (0.00% vs -1.22%), total hip (-0.70% vs -1.37%), and lumbar spine (-0.57% vs -1.22%), with considerable variability in both groups (SD range 3.01 - 4.70)]. Lower levels of circulating OC and P1NP were consistently observed over 52 wks of EZN treatment, suggesting a lower rate of bone resorption with EZN vs PL. Trending reductions in weight, BMI, and WC, along with increases in LMI and body water were observed with EZN vs PL. Trends of higher LMI in patients with excess fat, or lower FMI in patients with normal fat at BL were observed with EZN, suggestive of a positive body re-composition with EZN. Conclusions: These data expand on EZN safety profile and further point to novel potential benefits for the skeleton and body composition of postmenopausal women. Further research is warranted to provide conclusive evidence of the benefits of EZN specifically in post-menopausal women with obesity/overweight status or osteoporosis. Sponsorship: Bayer U.S., Whippany, NJ, USA Presentation: Monday, July 14, 2025

Abstract Disclosure: R.D. Rivera Gutierrez: None. D. Bechenati: None. R. Castaneda: None. M.A. Espinosa: None. J.L. Villamarin: None. E. Tama: None. J.L. Meek: None. T.M. Taaffe: None. P.K. Bennett: None. A.J. Acosta: Novo Nordisk, Gila Therapeutics, Rhythm Pharmaceuticals, Amgen Inc, General Mills, Regeneron Pharmaceuticals, Boehringer Ingelheim, Currax, Nestle, Phenomix Sciences, Busch Health, RareDiseases, National Institute of Health, Vivus Pharmaceuticals, Apollo Endosurgery, Satiogen Pharmaceuticals, Spatz Medical. S. Faubion: Era Women’s Health Platform, PriMed, AiCME, MedAll, Medscape, Weight Watchers. C. Shufelt: Bayer Advisory Board. M.D. Hurtado: Novo Nordisk, National Institute of Health, Phenomix Sciences. Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular (CV) benefits. Tirzepatide (TZP), a dual GLP-1 and gastric inhibitory polypeptide (GIP) receptor agonist approved for weight management and glycemic control, currently lacks evidence on CV outcomes. This study evaluates TZP’s impact on cardiometabolic parameters and atherosclerotic cardiovascular disease (ASCVD) risk scores. Methods: We conducted a multicenter retrospective study of adults prescribed TZP from June 1, 2022, to November 1, 2024. Inclusion criteria included 12 months of TZP use and age >18 years. Exclusion criteria were pregnancy, active malignancy, concurrent FDA-approved antiobesity medications, and prior bariatric surgery. Endpoints included changes in blood pressure, lipid profiles, liver enzymes, glucose control parameters, medication use (statins, aspirin, antihypertensives), and ASCVD risk scores from baseline to 12 months, stratified by sex. Data were obtained from electronic medical records. We present data as mean differences [95% CI]. We used T-tests and multivariate regression analyses for analyses. Results: Among 831 participants (59.4% female; 91.2% White; mean age: 58 ± 12 years), 12-month weight loss was -12% [-13, -11], p<0.001. We observed significant improvement in systolic blood pressure (SBP) (-4 [-5, -3] mmHg, p<0.001), triglycerides (TG) (-38 [-52, -23] mg/dL, p<0.001), total cholesterol (TC) (-7 [-10, -4] mg/dL, p<0.001), LDL cholesterol (LDL) (-6 [-9, -4] mg/dL, p<0.001), fasting glucose (FG) (-39 [-48, -29] mg/dL, p<0.001), ALT (-10 [-15, -5] U/L, p<0.001), HbA1c (-1.3% [-1.5, -1.2], p<0.001), and HDL cholesterol (HDL) (+4 [+3, +5] mg/dL, p<0.001). The Lifetime and 10-year ASCVD scores did not significantly change after 12 months (p>0.05), underscoring TZP’s potential in mitigating the aging-associated increase in CV risk. Considering sex, females had greater weight loss (-13% [-14, -12] vs. -10% [-11, -9], p<0.001), and greater improvements in TC (-5% [-8, -2] vs -3% [-6, 0.1], p<0.001) and LDL (-10% [-14, -6] vs -4% [-8, 1], p<0.001). Males had a greater reduction in DBP (-2% [-4, -1] vs (-1% [-6, 3], p=0.006). Both males and females demonstrated similar improvements in FG and HbA1c. Conclusion: TZP significantly improved CV and metabolic parameters after 12 months, with greater benefits observed in females. These improvements effectively mitigated the age-related rise in ASCVD risk scores. Larger, prospective studies are warranted to confirm these findings and further investigate TZP’s long-term CV effects. Presentation: Monday, July 14, 2025

OBJECTIVE In many individuals, type 2 diabetes (T2D) remains poorly controlled despite taking multiple glucose-lowering therapies. Several studies have demonstrated that endogenous hypercortisolism is prevalent among these individuals. We tested whether cortisol-directed therapy improves their glycemic control. RESEARCH DESIGN AND METHODS In this prospective, multicenter, double-blind study, 136 individuals with T2D (hemoglobin A1c [HbA1c] 7.5%–11.5% [58–102 mmol/mol] on multiple medications) and hypercortisolism (by dexamethasone suppression test) were randomized 2:1 to the glucocorticoid receptor antagonist mifepristone (300–900 mg once daily; n = 91) or placebo (n = 45) for 24 weeks, with stratification by presence/absence of an adrenal imaging abnormality. The primary end point was the change in HbA1c. Secondary end points included changes in glucose-lowering medications, weight, and waist circumference and safety. RESULTS Mean baseline HbA1c in the study cohort was 8.55% (69.9 mmol/mol). At 24 weeks, the least squares mean (LSM) difference from placebo in HbA1c was −1.32% (95% CI −1.81 to −0.83; P < 0.001). Participants receiving mifepristone experienced reductions in body weight and waist circumference (placebo-adjusted LSM differences of −5.12 kg [95% CI −8.20 to −2.03] and −5.1 cm [−8.23 to −1.99], respectively). Of participants on mifepristone, 46% discontinued therapy, compared with 18% on placebo. Adverse events with mifepristone (>10% of participants) included hypokalemia, fatigue, nausea, vomiting, headache, peripheral edema, diarrhea, and dizziness, consistent with mifepristone’s known tolerability profile. Increases in blood pressure also occurred. CONCLUSIONS In individuals with inadequately controlled T2D and hypercortisolism, cortisol-directed medical therapy with mifepristone reduced HbA1c, with a manageable tolerability profile.

OBJECTIVE Despite the use of multiple glucose-lowering medications, glycemic targets are not met in a significant fraction of people with type 2 diabetes. In this prospective, observational study we assessed the prevalence of hypercortisolism, a potential contributing factor to inadequate glucose control. RESEARCH DESIGN AND METHODS Individuals with type 2 diabetes and HbA1c 7.5%–11.5% (58–102 mmol/mol) on two or more glucose-lowering medications with or without micro-/macrovascular complications or taking multiple blood pressure–lowering medications were screened with a 1-mg dexamethasone suppression test. Common causes of false-positive DSTs were excluded. The primary end point was the prevalence of hypercortisolism, defined as post-DST cortisol >1.8 μg/dL (50 nmol/L). Characteristics associated with hypercortisolism were assessed with multiple logistic regression. The percentage and characteristics of participants with hypercortisolism and adrenal imaging abnormalities were also assessed. RESULTS Post-DST cortisol was unsuppressed in 252 of 1,057 participants (prevalence 23.8%; 95% CI 21.3, 26.5). Hypercortisolism prevalence was 33.3% among participants with cardiac disorders and 36.6% among those taking three or more blood pressure–lowering medications. Adrenal imaging abnormalities were reported in 34.7% of participants with hypercortisolism. Use of sodium–glucose cotransporter 2 inhibitors (odds ratio 1.558), maximum-dose glucagon-like peptide 1 receptor agonists (1.544), tirzepatide (1.981), or a higher number of blood pressure–lowering medications (1.390); older age (1.316); BMI <30 kg/m2 (1.639); non-Latino/Hispanic ethnicity (3.718); and use of fibrates (2.676) or analgesics (1.457) were associated with higher prevalence (all P < 0.03). CONCLUSIONS Hypercortisolism was associated with hyperglycemia in approximately one-quarter of individuals with inadequately controlled type 2 diabetes despite multiple medications.

Introduction: Light-chain amyloidosis (ALA) is a rare plasma cell disorder characterized by multiorgan involvement. Patients often present with non-specific symptoms, which can lead to a delay in diagnosis. This is associated with progressive organ involvement and shorter survival. Reducing the time from symptom onset to diagnosis is a critical step in improving outcomes. This study was designed to evaluate the clinical prodrome and challenges associated with the diagnosis of ALA from the patient perspective. Methods: This retrospective study surveyed patients with ALA through the online HealthTree® Cure Hub platform, which helps patients navigate their disease in a holistic way. The survey consisted of 32 questions, including 23 multiple-choice, 7 date-entry, and two free-response questions. Data on diagnosis and demographics were extracted from the electronic health record and self-reported data linked to HealthTree® Cure Hub. Results were reported as numbers and percentages, and comparisons were made by age (≥70 vs. <70 years) and sex. The following statistical methods were used: Fisher's exact test for categorical data, two-sample t-test and F-test for normally distributed continuous data, Wilcoxon rank-sum test for skewed data and Spearman correlation coefficient. Results: We surveyed 248 patients. Of those, a total of 87 patients with a self-reported diagnosis of ALA completed the questionnaire between March 12, 2023, and May 8, 2024. The median age was 66 years; 55% were female, and 91% were white. The most common initial symptoms prompting patients to seek medical evaluation were fatigue/weakness (47%), swelling (38%), shortness of breath (28%), chest pain (23%), and foamy urine (22%). Pain in hands/feet, carpal tunnel syndrome, loss of appetite, hoarseness, macroglossia, diarrhea, periorbital puffiness, nail changes, and erectile dysfunction each accounted for <10% of cases. Signs and symptoms were first detected by patients themselves in 58% of cases, by a physician in 33% and by a family member or friend for the rest. The median number of symptoms per individual was 2; 31% reported only one symptom, 37% 2-3, 18% 4-6, and 14% >6; with chest pain being the most common (39%), followed by swelling (22%), shortness of breath (13%), and foamy urine (13%); one patient reported erectile dysfunction and another reported arrhythmias as their only symptom. There was a correlation between hoarseness and nail changes (ρ=0.71), and carpal tunnel syndrome and orthostatic hypotension (ρ=0.63). Only 16% were aware of ALA as a condition prior to symptom onset. Thirty six percent presented to a general practitioner for initial evaluation; about 50% sought a specialist, including a myeloma/amyloid specialist (21%), and 14% were first evaluated in the emergency department. While most patients (45%) were diagnosed by a hematologist/oncologist, patients reported seeing a median of 3 physicians (range: 1-10) before the diagnosis was established. Among responders, 61% reported having myeloma at the time of testing. After diagnosis, about 50% were referred to a center specialized in ALA, and 72% met with a stem cell transplant specialist. Most patients reported receiving multidisciplinary care, with a median of 3 additional specialists participating in ALA care (range: 0-16). More than half of patients (59%) felt the diagnosis was delayed; among those, 42%, 24%, 24%, and 11% reported a delay of 1-6, 7-12, 13-24, and >24 months, respectively. The proportion of patients reporting >12-month delay was higher among older patients (54% vs. 27%, P=0.02). A quarter of responders felt their treatment was delayed. Half of patients felt the diagnostic delay contributed to a decrease in treatment efficacy and 48% did not feel that all medical professionals were knowledgeable about ALA. Only 38% felt the diagnostic process was simple and easy within their healthcare system. Conclusion: Most patients with AL amyloidosis initially present with non-specific symptoms, with fatigue/weakness being the most common. Over a third were evaluated first by a general practitioner, and about a third reported a diagnostic delay of >12 months. The diagnostic process is associated with high healthcare utilization, even among patients with concurrent multiple myeloma. Increasing disease awareness among patients and medical providers may shorten the time to diagnosis and contribute to improved outcomes.

Introduction: Understanding patient preferences and decision-making processes is crucial in managing relapsed multiple myeloma (RRMM). Shared decision-making has become a key element of patient-centered care, allowing patients to collaborate with healthcare providers in choosing treatments that align with their health and quality of life goals. This study examines how the perceived severity of treatment side effects influences patient decision-making autonomy and communication patterns, providing insights into decision-making practices in hematology. Methods: A survey was conducted with 784 RRMM patients as of January 1, 2024, using HealthTree Cure Hub (PMID: 35271305). Among the participants, 333 experienced a relapse and responded to the question about how side effect severity affected their treatment choices. Of these, 54% (n=181) considered side effects to be very or extremely influential (VE), whereas 46% (n=152) regarded them as somewhat, slightly, or not influential at all (SSN). Participants evaluated these factors on 5-point Likert scales: 1 (very poor) to 5 (very good); 0 (not at all influential) to 4 (extremely influential). The survey assessed patient involvement in final treatment decisions, discussions with fellow patients, family or caregivers, and the time allocated and used for decision-making. Results: Patients in the VE group reported a better understanding of the likely side effects of treatment options compared to the SSN group (VE: 3.9±1.0; SSN: 3.6±1.0, p<0.05), with a higher proportion reporting a very good understanding (VE: 31%, n=45; SSN: 18%, n=29, p=0.036). A weak relationship confirmed VE patients engaged in additional side effect education before making a change in treatment decisions (r=0.164, p=0.004). VE patients also reported a better understanding of the balance between effectiveness and potential side effects of treatments than SSN patients (VE: 3.8±1.0; SSN: 3.5±1.1, p<0.05), with more VE patients reporting a very good understanding (29%, n=41 vs. 15%, n=24, p=0.006). A weak relationship confirmed that VE patients more closely evaluated the trade-offs of treatment options when choosing a new treatment regimen (r=0.197, p<0.001). Likely to achieve a better understanding, more VE patients talked with fellow patients (VE: 19%, n=24; SSN: 7%, n=11, p = 0.003) and rated these conversations as more influential than SSN (VE: 1.5±1.5; SSN: 1.1±1.4, p<0.05). Additionally, VE patients were more likely to discuss treatment options with family or caregivers before making a final decision (VE: 49%, n=61; SSN: 29%, n=43, p<0.05). Moreover, VE patients reported greater involvement in their doctor-patient communication approach (VE: 3.2±0.8; SSN: 2.8±0.8, p<0.05), with scores ranging from 1 (“...follow the doctor's suggestions”) to 4 (“...we discuss my preferences... and I make the final decision”). Furthermore, VE patients reported more self-determination in the treatment decision-making process than SSN patients, with more VE patients making the final treatment decision themselves rather than having their doctor decide (“I made the final decision” - VE: 66%, n=93; SSN: 52%, n=81; “My doctor made the final decision” - VE: 34%, n=47; SSN: 46%, n=72, p=0.013). VE patients reported being provided 1.5 more weeks of time to make a treatment decision than the SSN (4.8±8.9 v. 3.3±6.0 wks, p<0.05). Subsequently, VE patients reported using 79% more time than SSN patients to arrive at a final decision (VE: 2.5±6.0; SSN: 1.4±1.9 wks, p<0.05), likely attributed to time spent gaining a better understanding, having more conversations with patients and family, more shared decision making and self-determination in their treatment decision. Conclusion: The study highlights that RRMM patients who consider side effects to be very or extremely influential in their treatment decisions report being more proactive in understanding and discussing their treatment options. These patients engage more with healthcare providers, peers, and family members and are granted more time to make informed decisions. This emphasis on understanding and communication underscores the importance of personalized patient education and shared decision-making in the treatment of RRMM, especially for patients who are highly influenced by potential side effects. Together, these findings underscore the ongoing need for patient-centered care and education to optimize treatment choices.