Patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer and residual disease after neoadjuvant therapy are at high risk for recurrence. In a phase 3, open-label, international, randomized trial, we investigated postneoadjuvant trastuzumab deruxtecan (T-DXd; 5.4 mg per kilogram of body weight) as compared with trastuzumab emtansine (T-DM1; 3.6 mg per kilogram), the current standard treatment, in patients with HER2-positive breast cancer with residual invasive disease and node-positive disease at surgery or inoperable disease at diagnosis. The primary end point was invasive disease-free survival, and the key secondary end point was disease-free survival (including survival free from noninvasive breast cancers and second primary nonbreast cancers). Other end points included overall survival, distant recurrence-free interval, brain metastasis-free interval, and safety. A total of 1635 patients were randomly assigned (in a 1:1 ratio) to receive T-DXd (818 patients) or T-DM1 (817 patients). At the data-cutoff date, the median duration of follow-up was approximately 30 months in each group. Invasive-disease events or deaths were reported in 51 patients (6.2%) in the T-DXd group and 102 patients (12.5%) in the T-DM1 group (hazard ratio, 0.47; 95% confidence interval [CI], 0.34 to 0.66; P<0.001); 3-year invasive disease-free survival was 92.4% and 83.7%, respectively. Invasive-disease events, noninvasive-disease events, or deaths were reported in 52 patients (6.4%) in the T-DXd group and 103 patients (12.6%) in the T-DM1 group (hazard ratio, 0.47; 95% CI, 0.34 to 0.66; P<0.001); 3-year disease-free survival was 92.3% and 83.5%, respectively. The most common adverse events were nausea (71.3% of patients), constipation (32.0%), decreased neutrophil count (31.6%), and vomiting (31.0%) with T-DXd and increased liver-enzyme levels (aspartate aminotransferase [50.2%] and alanine aminotransferase [45.3%]) and decreased platelet count (49.8%) with T-DM1. The incidence of adjudicated drug-related interstitial lung disease was higher with T-DXd than with T-DM1 (9.6% vs. 1.6%). Two patients with interstitial lung disease in the T-DXd group died. In patients with high-risk, residual invasive HER2-positive breast cancer, postneoadjuvant T-DXd resulted in a significantly higher likelihood of invasive disease-free survival than T-DM1; toxic effects were mainly gastrointestinal and hematologic. An important identified risk of T-DXd is interstitial lung disease, which requires appropriate monitoring and management. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast05 ClinicalTrials.gov number, NCT04622319.).

Trastuzumab deruxtecan has shown efficacy in patients with previously treated human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer. The efficacy and safety of trastuzumab deruxtecan in patients with no previous therapy for HER2-positive advanced or metastatic breast cancer are unclear. We conducted a phase 3 trial involving patients with HER2-positive advanced or metastatic breast cancer and no previous chemotherapy or HER2-directed therapy for metastatic disease. Patients were randomly assigned in a 1:1:1 ratio to receive trastuzumab deruxtecan plus pertuzumab; trastuzumab deruxtecan plus placebo; or a taxane, trastuzumab, and pertuzumab (THP). The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included objective response, duration of response, and safety. For this prespecified interim analysis, data for trastuzumab deruxtecan plus pertuzumab and for THP are reported; data for trastuzumab deruxtecan plus placebo remain blinded until the final analysis of progression-free survival. At the data-cutoff date (February 26, 2025), the median progression-free survival was 40.7 months with trastuzumab deruxtecan plus pertuzumab (383 patients) and 26.9 months with THP (387 patients) (hazard ratio for progression or death, 0.56; 95% confidence interval [CI], 0.44 to 0.71; P<0.00001 [P-value boundary for superiority, 0.00043]). The incidence of a confirmed response was 85.1% with trastuzumab deruxtecan plus pertuzumab and 78.6% with THP (complete responses in 15.1% and 8.5%, respectively), with a median duration of response of 39.2 months and 26.4 months. Safety was consistent with the known profiles of the individual treatments. The incidence of grade 3 or higher adverse events was 63.5% with trastuzumab deruxtecan plus pertuzumab and 62.3% with THP; the most common were neutropenia, hypokalemia, and anemia with trastuzumab deruxtecan plus pertuzumab and neutropenia, leukopenia, and diarrhea with THP. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 12.1% of patients receiving trastuzumab deruxtecan plus pertuzumab (grade 1 or 2 in 44 patients and grade 5 [death] in 2 patients) and in 1.0% of those receiving THP (all grade 1 or 2). Trastuzumab deruxtecan plus pertuzumab led to a significantly lower risk of progression or death than THP when used as first-line treatment for HER2-positive advanced or metastatic breast cancer, with no new safety signals. (Funded by AstraZeneca and Daiichi Sankyo; DESTINY-Breast09 ClinicalTrials.gov number, NCT04784715.).

Abstract Disclosure: K. Ozaki: None. Y. Nishioka: Novo Nordisk, Sanofi, Daiichi Sankyo, Daiichi Sankyo, DeSC Healthcare. H. Nakajima: None. F. Kamitani: None. Y. Kurematsu: None. S. Okada: ONO-Pharma, Mitsubishi Tanabe, Dainippon Sumitomo, Eli Lilly &amp; Company, Takeda, AstraZeneca, Novartis Pharmaceuticals, Novo Nordisk, Mochida Pharmaceutical, Kyowa Kirin, Terumo. T. Myojin: None. T. Noda: None. T. Imamura: None. Y. Takahashi: Novo Nordisk, Otsuka, Recordati, Dainippon Sumitomo, Eli Lilly &amp; Company, ONO-Pharma, Novartis Pharmaceuticals, Boehringer Ingelheim, AstraZeneca, Kyowa Kirin. Background: Virus infection including COVID-19 causes inflammation and sometimes cytokine storm, resulting in a disturbance of immune system and increased possibility of autoimmune diseases. Conflicting results have been reported regarding the development of thyroid diseases after COVID-19 and influenza infection in the previous studies. SARS-CoV-2 infects target cells through ACE2 as the virus receptor. Purpose: The aim of this study is to clarify the incidence rates and characteristics of thyroid diseases following COVID-19 and influenza infection. Methods: We used the DeSC database, an insurance claims database comprising 14.5 million individuals, targeting adults diagnosed with COVID-19 or influenza infection between 2015 and 2023. COVID-19 was defined by ICD-10 codes. Influenza infection was defined by ICD-10 codes and antiviral drug codes. Graves disease (GD) development was defined by the disease name and prescriptions for antithyroid drugs and hypothyroidism development was defined by prescriptions for levothyroxine, within 1-year post-infection. Results: During the observation period, 486,979 COVID-19 cases and 530,772 influenza cases were diagnosed. Compared with the age- and sex-matched control group, the incidence of GD significantly increased in the COVID-19 group (RR 1.42, P &amp;lt; 0.01), while no significant difference was observed in the influenza group (RR 1.01, P = 0.93). In contrast, the incidence of hypothyroidism increased in both groups as compared with the control group (COVID-19: RR 1.70, P &amp;lt; 0.01; influenza: RR 1.57, P &amp;lt; 0.01). In multivariate analysis, the use of angiotensin II receptor blockers and mineralocorticoid receptor antagonists were associated with an increased risk of GD in men in the COVID-19 group (OR 2.67, P = 0.04; OR 3.56, P = 0.05, respectively), but no association was found in the influenza group (OR 0.63, P = 0.09; OR 1.445, P = 0.48, respectively). Discussion: In this study, we demonstrated the impact of COVID-19 and influenza infection on the risk of thyroid diseases by using a large cohort of the insurance claims database. The incidence of GD was increased specifically after COVID-19, while no increase was observed after influenza infection. In contrast, the risk of hypothyroidism increased in both groups. It has been suggested that viral infections may increase the risk of developing hypothyroidism, possibly through activation of the innate immune system, by increasing the expression of Toll-like receptor 3 and this may be common between COVID-19 and influenza. Interestingly, the development of GD was associated with the use of renin-angiotensin system inhibitors (RASi) in men after COVID-19, but not after influenza, suggesting distinct pathophysiological mechanisms for each infection. RASi reportedly increased ACE2 expression in several organs, which may explain such difference. Presentation: Monday, July 14, 2025

Disclosure: F. Kamitani: Dainippon Sumitomo, Sanofi, Kyowa Kirin. Y. Nishioka: Novo Nordisk, Sanofi, Daiichi Sankyo, DeSC Healthcare. H. Nakajima: None. Y. Kurematsu: None. S. Okada: Mitsubishi Tanabe, ONO-Pharma, Eli Lilly & Company, Dainippon Sumitomo, Takeda, AstraZeneca, Novo Nordisk, Novo Nordisk, Mochida Pharmaceutical, Kyowa Kirin, Terumo. T. Myojin: None. T. Noda: None. T. Imamura: None. Y. Takahashi: Novo Nordisk, Recordati, Dainippon Sumitomo, Eli Lilly & Company, ONO-Pharma, Novartis Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Kyowa Kirin.Context: Although multiple endocrine abnormalities have been observed in patients treated with immune checkpoint inhibitors (ICIs), their pathophysiology has not been fully elucidated. Objective: To clarify the incidence, risk factors, and effect of multiple endocrine abnormalities on the overall survival (OS) in patients treated with ICI. Methods: We analyzed 12,978 patients treated with ICI using a Japanese administrative claims database including 12.4 million patients. Endocrine abnormalities were defined by hormone replacement therapy of levothyroxine and hydrocortisone for thyroiditis and hypophysitis/adrenalitis, respectively. More than 90% of ICI-related adrenal insufficiency has reportedly been associated with hypophysitis; therefore, most adrenal insufficiency was considered to represent hypophysitis. ICI-related type 1 diabetes (T1DM) was defined by insulin administration and a specific self-injection fee for T1DM. Kaplan-Meier analysis and Cox regression analysis adjusting for the number of ICI administrations and duration were performed to assess the effect of endocrine abnormalities on OS. Results: Hypothyroidism, adrenal insufficiency, and T1DM were observed in 10.5%, 4.6%, and 0.6% of patients, respectively. Multiple endocrine abnormalities were observed in 1.4%, and the most common combination was hypothyroidism and adrenal insufficiency (1.3%), followed by hypothyroidism and T1DM (0.07%), adrenal insufficiency and T1DM (0.02%), and triple hypothyroidism, adrenal insufficiency, and T1DM (0.02%), respectively. Among 12,978 patients treated with ICIs, 4,738 patients (36.5%) died during the observation period. In single abnormality, we found better survival in the order of patients with hypothyroidism and adrenal insufficiency than those without (P < .01). However, these analyses cannot exclude immortal time bias; therefore, we performed multivariable analysis. Convincingly, it still showed that the development of adrenal insufficiency and hypothyroidism was associated with lower mortality than none (adjusted hazard ratio [aHR] 0.60 and 0.65, respectively). Next, we compared patients with single and multiple endocrine abnormalities. Kaplan-Meier analysis showed better survival in patients with single and multiple endocrine abnormalities than in those without them (P < .01). Multivariable analysis also showed lower mortality in patients with single and multiple endocrine abnormalities groups (aHR 0.65; 95%CI, 0.58-0.72, P < .01; aHR 0.39; 95% CI, 0.28-0.54, P < .01, respectively) than in those without them. In addition, mortality was significantly lower in patients with multiple group than in single group (aHR 0.56; 95% CI, 0.39-0.79, P < .01). Conclusion: The development of multiple endocrine abnormalities was associated with superior survival compared with that of a single abnormality in patients treated with ICI.Presentation: Sunday, July 13, 2025

Introduction and Objective: In SOUL (NCT03914326), oral semaglutide (sema) 14 mg QD, a GLP-1 receptor agonist, reduced major adverse cardiovascular (CV) event (MACE) risk by 14%. GLP-1RAs are routinely prescribed to reduce A1c and BMI in type 2 diabetes (T2D). Whether the CV benefits of oral sema are influenced by baseline A1c or BMI is not fully known. Methods: SOUL’s primary outcome was time to first MACE, assessed for this post hoc analysis by baseline A1c, BMI and body weight using Cox regression. Results: People with T2D (n=9650; A1c 6.5–10%) and known atherosclerotic CV disease (ASCVD) or chronic kidney disease (CKD) were randomized to oral sema or placebo and followed for a mean of 47.5 months. We found significant differences in MACE outcomes associated with oral sema use by baseline A1c, with greater effects apparent with A1c &amp;gt;8.0% (Fig.). When the data were further analyzed across four A1c strata, the MACE benefit from oral sema appeared to apply to those with A1c &amp;gt;7%. The effects of oral sema on MACE were the same in those with BMI above / below 30 kg/m2, as well as across all four BMI strata, and above / below the mean body weight (87.9 kg) (Fig.). Conclusion: In SOUL, the CV benefits of oral sema appeared more pronounced with higher A1c levels at baseline but were consistent across various BMI categories. These data may help inform the individualized use of oral sema in people with T2D and ASCVD and/or CKD. Disclosure S.E. Inzucchi: Consultant; Novo Nordisk, AstraZeneca, Boehringer-Ingelheim, Merck &amp; Co., Inc, Pfizer Inc, Bayer Pharmaceuticals, Inc. R. Abdul Ghani: None. J. Deanfield: Other Relationship; Aegerion Pharmaceuticals, Amgen Inc, AstraZeneca, Bayer Pharmaceuticals, Inc, Boehringer-Ingelheim, Merck &amp; Co., Inc, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Novo Nordisk A/S, Pfizer Inc. M.D.M. Engelmann: Employee; Novo Nordisk. G. Hovingh: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. O.K. Jeppesen: None. M. Kellerer: Advisory Panel; Abbott, Bayer Pharmaceuticals, Inc. Speaker's Bureau; Boehringer-Ingelheim, Johnson &amp; Johnson Medical Devices Companies. Advisory Panel; Lilly Diabetes. Speaker's Bureau; Lilly Diabetes. Advisory Panel; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Advisory Panel; Sanofi. K. Mandavya: Employee; Novo Nordisk. J.F. Mann: Other Relationship; AstraZeneca, Bayer Pharmaceuticals, Inc. Advisory Panel; Novo Nordisk. Board Member; AstraZeneca, Bayer Pharmaceuticals, Inc, Boehringer-Ingelheim, Novo Nordisk. Other Relationship; Sanofi. Consultant; AstraZeneca, Bayer Pharmaceuticals, Inc, Novo Nordisk. Research Support; AstraZeneca. Other Relationship; Boehringer-Ingelheim. Research Support; Novo Nordisk, Sanofi. Speaker's Bureau; AstraZeneca, Bayer Pharmaceuticals, Inc, Novo Nordisk, Novartis AG. Other Relationship; UpToDate Inc / KDIGO. N. Marx: Speaker's Bureau; Abbott, Amgen Inc, AstraZeneca. Advisory Panel; AstraZeneca. Speaker's Bureau; Bayer Pharmaceuticals, Inc. Advisory Panel; Bayer Pharmaceuticals, Inc. Speaker's Bureau; Boehringer-Ingelheim. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Daiichi Sankyo. Advisory Panel; Merck Sharp &amp; Dohme Corp. Speaker's Bureau; Novo Nordisk. Advisory Panel; Novo Nordisk. Speaker's Bureau; Sanofi. Advisory Panel; Sanofi. Speaker's Bureau; Lilly Diabetes. C. Mathieu: Advisory Panel; Novo Nordisk, Sanofi, Eli Lilly and Company, Abbott, Medtronic, SAB Biotherapeutics, Inc, Roche Diabetes Care, Vertex Pharmaceuticals Incorporated, Biomea Fusion, Bayer Pharmaceuticals, Inc. D.K. McGuire: Consultant; Novo Nordisk. Advisory Panel; Novo Nordisk. Consultant; Lilly USA LLC. Advisory Panel; Lilly USA LLC. Consultant; Boehringer-Ingelheim. Advisory Panel; Boehringer-Ingelheim, AstraZeneca, ESPERION Therapeutics, Inc., NewAmsterdam Pharma, Pfizer Inc. Consultant; Applied Therapeutics, Lexicon Pharmaceuticals, Inc, Bayer Pharmaceuticals, Inc, Amgen Inc, Kailera, Idorsia, Alveus, Metsera. V. Mohan: Speaker's Bureau; Novo Nordisk. Advisory Panel; Abbott. Research Support; Servier Laboratories. Speaker's Bureau; USV Private Limited, Sanofi, Medtronic, Eli Lilly and Company. S.L. Mulvagh: Advisory Panel; Novo Nordisk, Merck &amp; Co., Inc. R. Pop-Busui: Board Member; American Diabetes Association. Consultant; Averitas Pharma, Inc. Research Support; Bayer Pharmaceuticals, Inc. Other Relationship; Biogen. Research Support; Juvenile Diabetes Research Foundation (JDRF). Advisory Panel; Lexicon Pharmaceuticals, Inc, Novo Nordisk. Research Support; Novo Nordisk, National Institute of Diabetes and Digestive and Kidney Diseases. Consultant; Roche Diagnostics. N.R. Poulter: Consultant; Servier Laboratories, Alnylam Pharmaceuticals, Inc. Research Support; Servier Laboratories. Speaker's Bureau; AstraZeneca. Consultant; Aktiia. M. Ripa: Employee; Novo Nordisk. G. Roman: Advisory Panel; AstraZeneca. Consultant; Berlin-Chemie AG. Research Support; AstraZeneca. Advisory Panel; Boehringer-Ingelheim, Medtronic, Lilly Diabetes, Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; Roche Diabetes Care, Sanofi, Viatris Inc. R. Sánchez García: None. M. Shechter: None. J.B. Buse: Other Relationship; Corcept Therapeutics, Dexcom, Inc., Novo Nordisk. Consultant; Altimmune Inc, Amgen Inc, ApStem, Aqua Medical, AstraZeneca, Boehringer-Ingelheim, CeQur, Eli Lilly and Company, embecta, GentiBio. Other Relationship; Glyscend Therapeutics. Consultant; Insulet Corporation, Medtronic. Other Relationship; Mellitus Health. Consultant; Metsera. Other Relationship; Pendulum Therapeutics, Praetego, Stability Health. Consultant; Tandem Diabetes Care, Inc, TERNS Pharmaceuticals, Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S. Funding Novo Nordisk A/S

Introduction and Objective: The STRIDE trial (NCT04560998) demonstrated that once weekly semaglutide 1.0 mg significantly improved maximum walking distance (MWD) in people with type 2 diabetes (T2D) and symptomatic peripheral artery disease (PAD) vs. placebo. Whether the benefits are consistent across T2D characteristics has not been described. Methods: The primary outcome in STRIDE, MWD measured on a constant load treadmill at 52 weeks, was analyzed by T2D duration (≥10 vs. &amp;lt;10 years), obesity status (BMI (≥30 vs. &amp;lt;30 kg/m2)), glycemic control (HbA1c (≥7% vs. &amp;lt;7%)), and concomitant T2D medications (SGLT2i or insulin). A mixed model for repeated measurements was employed, incorporating treatment, region, and subgroup as fixed factors, along with the treatment-by-subgroup interaction. Baseline values were used as covariates, all nested within each visit. Results: Among 792 randomized STRIDE participants at baseline, median T2D duration was 12.2 years, BMI 28.7 kg/m2, HbA1c 7.1%, with 35.1% on SGLT2i and 31.7% on insulin. Semaglutide significantly improved MWD regardless of T2D duration, BMI, HbA1c and concomitant SGLT2i or insulin use (Figure). Conclusion: These findings support the efficacy of semaglutide in patients with symptomatic PAD across the spectrum of T2D including non-obese participants and those with HbA1c &amp;lt;7%. Disclosure N. Rasouli: Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; Eli Lilly and Company. Research Support; Eli Lilly and Company. E. Guder Arslan: Employee; Novo Nordisk A/S, Sanofi. A. Catarig: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. K. Houlind: Consultant; LeMaitre, Novo Nordisk. B. Ludvik: Research Support; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Advisory Panel; Novo Nordisk, Boehringer-Ingelheim. Speaker's Bureau; Boehringer-Ingelheim. Research Support; Amgen Inc. Speaker's Bureau; AstraZeneca. Research Support; Eli Lilly and Company. Advisory Panel; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. J. Nordanstig: Advisory Panel; AstraZeneca, Novo Nordisk. Other Relationship; Novo Nordisk. H. Sourij: Advisory Panel; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Research Support; Eli Lilly and Company. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Daiichi Sankyo. Advisory Panel; Novo Nordisk A/S. Speaker's Bureau; Novo Nordisk A/S. Advisory Panel; Novartis AG, Amarin Corporation, Amgen Inc. S. Thomas: None. S. Verma: Other Relationship; Various. M.P. Bonaca: Other Relationship; CPC Clinical Research. Funding The STRIDE trial was funded by Novo Nordisk A/S

Introduction and Objective: Despite the very high risk for macrovascular complications, there are scant data on the benefit of lipid-lowering in type 1 diabetes (T1D). We examined the clinical efficacy of intensive LDL-C lowering with the PCSK9 inhibitor evolocumab in T1D. Methods: FOURIER enrolled pts w/ stable atherosclerotic cardiovascular disease (ASCVD) on statin randomized to evolocumab or placebo (median FU 2.2y). The primary endpoint (PEP) was CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary endpoint (SEP) was CV death, MI, or stroke. Hazard ratios (HR) and absolute risk reductions (ARR) with evolocumab vs. placebo were compared among pts w/o diabetes (no DM), with type 2 diabetes (T2D), and with T1D. Results: Of 27,564 pts, 197 (0.7%) had T1D. Their median (IQR) age was 58 (53-64) yrs and duration of diabetes 28 yrs. In the placebo arm, there was a stepwise increase in the 2.5-y KM rate of the PEP, going from 11.0% to 15.2% to 20.4% in pts w/ no DM, T2D, and T1D, respectively (p&amp;lt;0.0001; Fig). Evolocumab reduced the risk of the PEP by 13% (HR 0.87; 95% CI 0.73-0.96), 16% (HR 0.84 [0.75-0.93]), and 34% (HR 0.66 [0.32-1.38]), respectively. Corresponding ARRs were 1.3%, 2.5%, and 7.3%. Similar trends were seen for the key SEP. Conclusion: T1D pts with ASCVD face elevated MACE risk, and intensive LDL-C lowering with evolocumab appears to provide substantial clinical benefit in this high-risk group. Disclosure Y. Kang: None. R.P. Giugliano: Research Support; Amgen Inc, Anthos Therapeutics, Daiichi Sankyo, Ionis Pharmaceuticals. Other Relationship; Amgen Inc, CADECI, Centrix, Daiichi Sankyo, Dr. Reddy's Laboratories, Korean Heart Rhythm Society, Medical Education Resources (MER), Menarini, Pfizer Inc, SHAKEHEART, SUMMEET. Consultant; Amgen Inc, AstraZeneca, Beckman Coulter, Daiichi Sankyo, Gilead Sciences, Inc, Inventiva Pharma, Novartis Pharmaceuticals Corporation, Perosphere, Samsung, Syneos Health. X. Ran: None. P. Deedwania: None. G.M. De Ferrari: Advisory Panel; Daiichi Sankyo. Board Member; Amgen Inc, Merck &amp; Co., Inc, Novartis AG. J.T. George: Employee; Amgen Inc. I. Gouni-Berthold: Speaker's Bureau; Amgen Inc, Sanofi-Aventis Deutschland GmbH. Advisory Panel; Daiichi Sankyo. Speaker's Bureau; Novartis AG. Advisory Panel; Novartis AG. Speaker's Bureau; Ultragenyx, Daiichi Sankyo. G. Paiva da Silva Lima: Employee; Amgen Inc. Stock/Shareholder; Amgen Inc. Y. Handelsman: Research Support; Amgen Inc. Consultant; Amgen Inc. Research Support; Applied Therapeutics. Consultant; Applied Therapeutics. Research Support; Corcept Therapeutics. Consultant; Corcept Therapeutics. Research Support; Ionis Pharmaceuticals, Lilly Diabetes, Merck Sharp &amp; Dohme Corp, Regeneron Pharmaceuticals. B.S. Lewis: Consultant; Janssen Pharmaceuticals, Inc. E. Ohman: Employee; Amgen Inc. A.C. Keech: Research Support; Abbott, Amgen Inc, ASPEN Australia, Mylan. Speaker's Bureau; Novartis AG, Pfizer Inc. Research Support; Kowa Company, Ltd. Speaker's Bureau; Sanofi. Research Support; AbbVie Inc, Viatris Inc. H. Wang: Employee; Amgen Inc. M.S. Sabatine: Research Support; Amgen Inc. Consultant; Amgen Inc. Research Support; AstraZeneca. Consultant; AstraZeneca. Research Support; Ionis Pharmaceuticals, Marea, Merck &amp; Co., Inc, Novartis Pharmaceuticals Corporation, Verve Therapeutics. L.A. Leiter: Other Relationship; Amgen Inc. Advisory Panel; Amgen Inc. Speaker's Bureau; Amgen Inc. Other Relationship; Eli Lilly and Company. Advisory Panel; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Advisory Panel; HLS Therapeutics. Speaker's Bureau; HLS Therapeutics. Advisory Panel; Merck &amp; Co., Inc, Novartis Pharmaceuticals Corporation. Speaker's Bureau; Novartis Pharmaceuticals Corporation. Advisory Panel; Regeneron Pharmaceuticals. Funding Dr Kang is funded by a T32 postdoctoral training grant from the National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK007529).

Introduction and Objective: Sleep duration is associated with glycemic control, but causality is unclear. Our mHealth intervention promoted earlier bedtime to assess impact on sleep duration and glycemic control. Methods: We conducted a 12 week single-blind, two-arm RCT with 70 short-sleeping T2D patients in Japan using actigraphs and sleep diaries. The key eligible criteria included short sleep duration (≤ 6 h), elevated HbA1c levels (≥ 7.5 %), and no sleep disorders. The Intervention group received Theory of Planned Behavior-based interventions targeting earlier bedtimes using achievable bedtime goal setting and feedback. Results: The arms were well matched, except for BMI (Intervention 24.7 vs. Control 26.6 kg/m2). The Intervention demonstrated a significant 32.8 minute improvement in mean sleep duration (p = 0.004) and suggestive but not significant improvements in BMI (0.24, p = 0.17]) and HbA1c (0.11, p = 0.51). The pooled SD of HbA1c change, at 0.70, exceeded our prior estimate of 0.41. Conclusion: The intervention improved sleep duration, piloting effective methods. The improvements in BMI and HbA1c, while not statistically significant, are suggestive of a causal link. High pooled SD of change in BMI and HbA1c suggests the need for follow up with larger sample sizes. Disclosure R. Nakada: None. K. Waki: Consultant; Astellas Pharma Inc. Other Relationship; Astellas Pharma Inc, Sumitomo Dainippon Pharma Co., Ltd. Consultant; Terumo Corporation. Other Relationship; Terumo Corporation. Speaker's Bureau; Sanofi. D. Lane: None. S. Iwata: None. A. Isogawa: None. K. Miyoshi: Research Support; The Descente and Ishimoto Memorial Foundation for the Promotion of Sports Science. H. Waki: Speaker's Bureau; LifeScan Diabetes Institute, MSD Life Science Foundation, Astellas Pharma Inc, AstraZeneca, Abbott, Eisai, Sanofi, Novartis AG, Novo Nordisk, Bayer Pharmaceuticals, Inc, Kyowa Kirin Co., Ltd, Kowa Company, Ltd. Research Support; Kowa Company, Ltd. Speaker's Bureau; Sumitomo Dainippon Pharma Co., Ltd, Ono Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co. Ltd, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Eli Lilly and Company, Boehringer-Ingelheim. S. Kato: None. H. Sawaki: None. T. Murata: Research Support; Medtronic. Speaker's Bureau; Abbott Japan Co., Ltd, Dexcom, Inc. Y. Hirota: Speaker's Bureau; Novo Nordisk, Sanofi, Eli Lilly and Company, Terumo Corporation, Sumitomo Dainippon Pharma Co., Ltd. Research Support; Medtronic, Kyowa Kirin Co., Ltd, Abbott Japan Co., Ltd. S. Saito: None. S. Nishikage: None. A. Tone: Speaker's Bureau; Johnson &amp; Johnson Medical Devices Companies, Medtronic, Eli Lilly and Company, Sanofi, Kowa Company, Ltd, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Sanwa Kagaku Kenkyusho Co., Ltd, Sumitomo Dainippon Pharma Co., Ltd, Novartis Pharmaceuticals Corporation, Taiho Pharmaceutical Co. Ltd, Kyowa Kirin Co., Ltd, Abbott Japan Co., Ltd, Boehringer-Ingelheim, Terumo Corporation, Roche Diagnostics, ARKRAY, Inc., Dexcom, Inc. M. Toyoda: None. S. Kajino: None. K. Yokota: None. Y. Tsurutani: None. T. Yamauchi: Research Support; Asahi Mutual Life Insurance Company. Other Relationship; Astellas Pharma Inc, AstraZeneca, Abbott Japan Co., Ltd, ARKRAY Marketing, Inc., Amgen Inc. Research Support; Boehringer-Ingelheim. Other Relationship; Boehringer-Ingelheim, Bayer Pharmaceuticals, Inc, Covidien Japan Inc., Daiichi Sankyo, Eli Lilly and Company. Research Support; EA Pharma Co.,Ltd. Other Relationship; GlaxoSmithKline K.K. Research Support; Kowa Company, Ltd. Other Relationship; Kowa Company, Ltd, Kyowa Kirin Co., Ltd, Medtronic, Merck Sharp &amp; Dohme Corp, Mitsubishi Tanabe Pharma Corporation. Research Support; Novo Nordisk. Other Relationship; Novo Nordisk, Ono Pharmaceutical Co., Ltd, Sumitomo Pharma Co., Sanofi K.K., SANWA KAGAKU KENKYUSHO CO.,LTD., Taiho Pharmaceutical Co. Ltd, Teijin Pharma Limited, Nipro Corporation. Research Support; NITTO BOSEKI CO.,LTD. Other Relationship; ViewSendICT Inc. M. Nangaku: Other Relationship; Astellas Pharma Inc, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline plc, Daiichi Sankyo, Kyowa Kirin Co., Ltd, Boehringer-Ingelheim. Consultant; Novo Nordisk. Research Support; Bayer Pharmaceuticals, Inc. Other Relationship; Mitsubishi Tanabe Pharma Corporation. K. Ohe: None. T. Kawaguchi: Other Relationship; Nitto Boseki Co., Ltd.

Introduction and Objective: Diet interventions to treat diabetes have poor adherence due in part to burdensome food logging. Assessing photos of meals may make food logging easier, and we investigated the accuracy of AI for this task. Methods: We assessed 1363 Japanese meals with photographs and nutritional data: 364 real world with weighed food records (WFR), 470 laboratory with WFR, and 529 real world with dietician estimates. Using one shot prompting implementing chain-of-thought logic, we used 988/247/128 train/validate/evaluate splits to fine-tune gpt-4o-2024-08-06, assessing nutrient estimates against estimates from non-fine-tuned baseline models. Results: Performance against the evaluation set was good for the baseline models. The finetuned GPT-4o model had mixed improvement results, with comparable performance or small improvements in most factors but a decrease in performance against protein. The finetuned model was comparable to or better than the performance of human dieticians in a previous study, with particular strengths (mean ICC, [95% CI]) in fat (0.57 [0.55-0.58]), energy (0.79 [0.78-0.79]), and fiber (0.67 [0.65-0.68]). Conclusion: For our data, fine tuning improved some measures but degraded others. Overall, current AI provides useful levels of accuracy for nutritional estimates based on photos of meals, with or without fine tuning. Disclosure Y. Ji: None. K. Waki: Consultant; Astellas Pharma Inc. Other Relationship; Astellas Pharma Inc, Sumitomo Dainippon Pharma Co., Ltd. Consultant; Terumo Corporation. Other Relationship; Terumo Corporation. Speaker's Bureau; Sanofi. D. Lane: None. T. Yamauchi: Research Support; Asahi Mutual Life Insurance Company. Other Relationship; Astellas Pharma Inc, AstraZeneca, Abbott Japan Co., Ltd, ARKRAY Marketing, Inc., Amgen Inc. Research Support; Boehringer-Ingelheim. Other Relationship; Boehringer-Ingelheim, Bayer Pharmaceuticals, Inc, Covidien Japan Inc., Daiichi Sankyo, Eli Lilly and Company. Research Support; EA Pharma Co.,Ltd. Other Relationship; GlaxoSmithKline K.K. Research Support; Kowa Company, Ltd. Other Relationship; Kowa Company, Ltd, Kyowa Kirin Co., Ltd, Medtronic, Merck Sharp &amp; Dohme Corp, Mitsubishi Tanabe Pharma Corporation. Research Support; Novo Nordisk. Other Relationship; Novo Nordisk, Ono Pharmaceutical Co., Ltd, Sumitomo Pharma Co., Sanofi K.K., SANWA KAGAKU KENKYUSHO CO.,LTD., Taiho Pharmaceutical Co. Ltd, Teijin Pharma Limited, Nipro Corporation. Research Support; NITTO BOSEKI CO.,LTD. Other Relationship; ViewSendICT Inc. M. Nangaku: Other Relationship; Astellas Pharma Inc, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline plc, Daiichi Sankyo, Kyowa Kirin Co., Ltd, Boehringer-Ingelheim. Consultant; Novo Nordisk. Research Support; Bayer Pharmaceuticals, Inc. Other Relationship; Mitsubishi Tanabe Pharma Corporation. K. Ohe: None.

Introduction and Objective: Several drugs reduce the risk of chronic kidney disease (CKD) progression and cardiovascular events in people with CKD and type 2 diabetes (T2D), including the selective non-steroidal mineralocorticoid receptor antagonist, finerenone, and sodium-glucose cotransporter 2 inhibitors (SGLT2is). However, it remains unclear if these drugs should be sequentially or simultaneously initiated in individuals with CKD and T2D. Methods: CONFIDENCE is a randomized, controlled, double-blind, double-dummy, global, multicenter, clinical trial in adults with CKD, defined as having an estimated glomerular filtration rate (eGFR) of 30 to 90 mL/min/1.73 m2 and 100 ≤UACR &amp;lt;5000 mg/g, and T2D. Participants were randomized 1:1:1 to once daily 10 or 20 mg finerenone plus placebo, 10 mg empagliflozin plus placebo, or 10 or 20 mg finerenone plus 10 mg empagliflozin. The primary efficacy endpoint is the relative change in UACR from baseline at Day 180. Secondary endpoints include the proportion of individuals achieving a reduction in UACR &amp;gt;30% from baseline to Day 180, the incidence of hyperkalemia and acute kidney injury, and the assessment of initial and longer-term changes in eGFR. Results: There were 818 participants randomized across 14 countries between July 2022 and August 2024. Mean eGFR (ml/min/1.73 m2 [SD]) was 54.2 (17.1). Median UACR (mg/g [IQR]) was 583 (292, 1140). Mean HbA1c (% [SD]) was 7.3 (1.2). Mean systolic/diastolic BP (mmHg) was 135.2/77.3. GLP-1 RAs and insulin were used by 182 (23%) and 313 (39%) participants, respectively. Conclusion: CONFIDENCE will determine the efficacy and safety of finerenone and empagliflozin combination therapy compared with either agent alone in people with CKD and T2D. Data will be available and we intend to present the primary results at ERA, we will present additional endpoints and subgroups of interest. Disclosure R. Agarwal: Consultant; Bayer Pharmaceuticals, Inc, Boehringer-Ingelheim, Novartis Pharmaceuticals Corporation. Other Relationship; Vertex Pharmaceuticals Incorporated, Chinook Therapeutics, Inc, UpToDate. Consultant; Vera Therapeutics, Akebia. J.B. Green: Consultant; BI Lilly NovoNordisk Bayer Anji Vertex Valo Mineralys AstraZeneca. Research Support; BI Lilly Merck Bluedrop Roche. H.L. Heerspink: Consultant; Alnylam Pharmaceuticals, Inc, Alexion Pharmaceuticals, Inc, AstraZeneca, Bayer Pharmaceuticals, Inc, Boehringer-Ingelheim, Eli Lilly and Company, Janssen Pharmaceuticals, Inc, Novartis AG, Novo Nordisk A/S, Roche Pharmaceuticals, Traveere Pharmaceuticals, Menarini. J.F. Mann: Other Relationship; AstraZeneca, Bayer Pharmaceuticals, Inc. Advisory Panel; Novo Nordisk. Board Member; AstraZeneca, Bayer Pharmaceuticals, Inc, Boehringer-Ingelheim, Novo Nordisk. Other Relationship; Sanofi. Consultant; AstraZeneca, Bayer Pharmaceuticals, Inc, Novo Nordisk. Research Support; AstraZeneca. Other Relationship; Boehringer-Ingelheim. Research Support; Novo Nordisk, Sanofi. Speaker's Bureau; AstraZeneca, Bayer Pharmaceuticals, Inc, Novo Nordisk, Novartis AG. Other Relationship; UpToDate Inc / KDIGO. J.B. McGill: Advisory Panel; Bayer Pharmaceuticals, Inc. Consultant; Jaeb Center for Health Research. Advisory Panel; Boehringer-Ingelheim, Lilly Diabetes, Novo Nordisk, MannKind Corporation. Research Support; Diagnode, Lexicon Pharmaceuticals, Inc, Biomea Fusion. A.K. Mottl: Research Support; Alexion Pharmaceuticals, Inc, Bayer Pharmaceuticals, Inc. Advisory Panel; Bayer Pharmaceuticals, Inc, Vera Therapeutics. Research Support; Novartis Pharmaceuticals Corporation. Advisory Panel; Novartis Pharmaceuticals Corporation. Other Relationship; Novo Nordisk, UpToDate. J. Rosenstock: Advisory Panel; Amgen Inc. Research Support; Amgen Inc. Advisory Panel; Applied Therapeutics. Research Support; Applied Therapeutics, AstraZeneca. Advisory Panel; Bayer Pharmaceuticals, Inc, Biomea Fusion, Corcept Therapeutics, Eli Lilly and Company. Research Support; Eli Lilly and Company. Advisory Panel; Hanmi Pharm. Co., Ltd. Research Support; Merck &amp; Co., Inc, Novartis AG. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk, Pfizer Inc. Advisory Panel; Regeneron Pharmaceuticals. Research Support; Regeneron Pharmaceuticals, Regeneron Pharmaceuticals. Advisory Panel; Regor Therapeutics, Roche Pharmaceuticals, Sanofi. Research Support; Sanofi. Advisory Panel; Structure Therapeutics, Inc, Zealand Pharma A/S. P. Rossing: Speaker's Bureau; Abbott. Advisory Panel; AstraZeneca, Bayer Pharmaceuticals, Inc, Boehringer-Ingelheim, Gilead Sciences, Inc, Novo Nordisk. Other Relationship; Lexicon Pharmaceuticals, Inc. Speaker's Bureau; Daiichi Sankyo. M. Vaduganathan: Advisory Panel; American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Fresenius Medical Care, Idorsia Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Mile, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health. Research Support; AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. M. Brinker: Employee; Bayer AG. Stock/Shareholder; Bayer AG. C. Scott: Employee; Bayer Pharmaceuticals, Inc. L. Li: Employee; Bayer Pharmaceuticals, Inc. K. Rohwedder: Employee; Bayer Pharmaceuticals, Inc. M. Nangaku: Other Relationship; Astellas Pharma Inc, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline plc, Daiichi Sankyo, Kyowa Kirin Co., Ltd, Boehringer-Ingelheim. Consultant; Novo Nordisk. Research Support; Bayer Pharmaceuticals, Inc. Other Relationship; Mitsubishi Tanabe Pharma Corporation. Funding This work was supported by Bayer AG, who funded the CONFIDENCE study.

Introduction and Objective: SGLT2 inhibitors, primarily used for type 2 diabetes, exhibit cardioprotective effects by improving myocardial metabolism, reducing oxidative stress, and modulating inflammation and fibrosis—key factors in acute myocardial infarction (AMI). This study explores the molecular mechanisms of SGLT2 inhibitors, focusing on non-coding RNAs and sirtuin pathways, to identify biomarkers and strategies for preventing heart failure post-AMI. Methods: We analyzed microRNAs (miRNAs) involved in sirtuin pathways and validated miRNA and sirtuin gene expressions (SIRT1-7) in 243 patients at baseline and after 26 weeks of treatment (486 samples) using qRT-PCR. We also conducted SHAP analysis, miRNA target predictions, and enrichment analyses. Results: Bioinformatics identified interaction networks for SGLT2 (5225 nodes) and SIRT1-7 (top 100 interactors), annotated for oxidative stress, inflammation, fibrosis, and hypoxia-ischemia. Combining miRNA predictions with these networks identified 13 key miRNAs, including hsa-miR-34a-5p, miR-182-5p, and hsa-miR-302a-3p, targeting SIRT and SGLT2-related pathways. Empagliflozin treatment significantly increased SIRT6, SIRT7, and miR-34a while reducing SIRT4 (p&amp;lt;0.05). Baseline SIRT2 and SIRT4 levels independently predicted unfavorable LVEF outcomes (AUC: 0.655, p=0.002), with improved prediction using a panel including miR-182-5p (AUC: 0.786, p=0.0003). NT-proBNP levels were higher in the unfavorable group after 26 weeks, but no baseline differences were observed. Conclusion: Empagliflozin modulates sirtuin and miRNA expression, suggesting cardioprotective effects in AMI. Baseline SIRT2, SIRT4, and miR-182-5p levels predict unfavorable LVEF outcomes, with a combined biomarker panel offering high accuracy. These findings highlight the potential of integrating sirtuins, miRNAs, and clinical biomarkers for improved cardiac outcome management post-AMI. Disclosure A. Nowak-Szwed: Speaker's Bureau; Novo Nordisk. C. Eyileten: None. Z. Wicik: None. S. Ahmadova: None. J. Siller-Matula: None. D. von Lewinski: Speaker's Bureau; Daiichi Sankyo, Novo Nordisk. Research Support; Merck Sharp &amp; Dohme Corp. H. Sourij: Advisory Panel; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Research Support; Eli Lilly and Company. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Daiichi Sankyo. Advisory Panel; Novo Nordisk A/S. Speaker's Bureau; Novo Nordisk A/S. Advisory Panel; Novartis AG, Amarin Corporation, Amgen Inc. M. Postula: None. Funding EMPATHYtrial 2019/ABM/01/00037NCN 2022/45/N/NZ7/0246

Introduction and Objective: Imeglimin is an oral antidiabetic agent with beneficial effects on mitochondrial function. Studies have shown that imeglimin reduces gluconeogenesis and stimulates muscle glucose uptake, thereby improving insulin resistance. Additionally, it promotes insulin secretion by increasing NAD+ levels in pancreatic β-cells. Studies have also demonstrated that imeglimin reduces mitochondrial oxidative stress and the activity of mitochondrial complex I in hepatic mitochondria of mice fed high-fat or high-sucrose diets. However, the effects of imeglimin on diabetic neuropathy remain unclear. Therefore, we investigated the effects of imeglimin on diabetic neuropathy in streptozotocin (STZ)-induced diabetic rats. Methods: Male Wistar rats were injected intraperitoneally with vehicle or STZ to induce diabetes. Four weeks after STZ injection, rats were orally gavaged with vehicle or imeglimin (200 mg/kg) twice daily for four weeks. Subsequently, assessments of mortor nerve conduction velocity (MNCV), sciatic nerve conduction velocity (SNCV), sciatic nerve blood flow (SNBF) were performed. Results: Imeglimin did not significantly affect body weight or blood glucose levels. Compared to controls, diabetic rats exhibited a trend toward decreased MNCV, which was attenuated by imeglimin. Diabetic rats also showed significant reductions in SNCV, and SNBF compared to controls. Imeglimin treatment significantly ameliorated the reduction in SNCV and SNBF. Conclusion: These findings from STZ-induced diabetic rats indicate the therapeutic potential of imeglimin for diabetic neuropathy. Disclosure W. Nihei: None. A. Kato: None. T. Sato: None. T. Himeno: None. N. Nakamura: None. K. Sango: None. K. Naruse: None. J. Nakamura: Speaker's Bureau; Daiichi Sankyo, Novo Nordisk. H. Kamiya: Research Support; Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Sumitomo Dainippon Pharma Co., Ltd. K. Kato: Speaker's Bureau; Daiichi Sankyo. Funding JSPS KAKENHI (24K09971)

Introduction and Objective: Pancreatic α cells have attracted attention for their plasticity, which enables transdifferentiation into β cells and holds potential for curing diabetes. However the molecular mechanisms underlying the development and differentiation of pancreatic α cells remain unclear. Methods: We have generated a reporter mouse, “Gcg-Timer”, in which newly generated α (early α) cells can be sorted by FACS separately from more differentiated α (late α) cells with high temporal resolution. To investigate α-cell transcriptomics at the single-cell level, we sorted early and late α cells from Gcg-Timer embryos at E17.5 using FACS and performed single-cell RNA sequencing (scRNA-seq). Results: Pseudotime analysis demonstrated that the clusters of early α cells overlapped with those of late α cells, suggesting that fluorescent reporter-based α-cell maturation does not reflect transcriptional maturation. This contrasts with our recent finding that fluorescent reporter-based β-cell maturation reflects transcriptional maturation based on scRNA-seq in “Ins1-eGFP;Timer” embryos. To further investigate the distinct features of α-cell and β-cell differentiation, we comprehensively analyzed scRNA-seq data from Neurog3-Cre; ROSA-mTmG mouse embryos, human fetal pancreata, and the two mouse lines described above. Pseudotime analysis using Neurog3-Cre; ROSA-mTmG mouse embryonic and human fetal pancreata revealed that Ins1 mRNA expression levels gradually increased in the β-cell lineage, consistent with the data from Ins1-eGFP;Timer embryos, whereas Gcg mRNA levels peaked midway through the differentiation process and then decreased in the α-cell lineage. Conclusion: Single-cell transcriptome data from different mouse lines and human fetal pancreata demonstrated distinct mRNA expression profiles between α-cell and β-cell differentiation, suggesting the complex transcriptional regulation of the Gcg gene during differentiation. Disclosure N. Shimizu: None. T. Taguchi: None. M. Himuro: None. A. Suzuki: None. R. Fujishima: None. I. Shimomura: Advisory Panel; Novo Nordisk Pharma Ltd., Eli Lilly Japan K.K., Amgen Inc, Shionogi &amp; Co., Ltd, Sumitomo Pharma Co., Ltd., Nissin Foods Holdings Co., Ltd. Research Support; Novo Nordisk Pharma Ltd., Teijin Pharma Limited, Mochida Pharmaceutical Co., Ltd., Kowa Company, Ltd, Kyowa Kirin Co., Ltd, Sumitomo Pharma Co., Ltd., Rohto Pharmaceutical Co., Ltd., Kobayashi Pharmaceutical Co., Ltd., Nissin Foods Holdings Co., Ltd., Kubara Honke Group Co., Ltd., Cancerscan Inc. Speaker's Bureau; Arkray, Inc., MSD K.K., Astellas Pharma Inc, AstraZeneca, Abbott Japan Co., Ltd, Ono Pharmaceutical Co., Ltd, Otsuka Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Johnson &amp; Johnson K.K., Kyowa Kirin Co., Ltd, Kowa Company, Ltd, Sanofi, Sumitomo Pharma Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Teijin Pharma Limited, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical Co., Ltd., Nipro Corporation, Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Mochida Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., Pfizer Japan Inc., Lotte Co., Ltd. H. Watada: Speaker's Bureau; Novo Nordisk, Boehringer-Ingelheim, Sumitomo Pharma, Eli Lilly and Company, Roche Diabetes Care, Merck Sharp &amp; Dohme Corp, Sanwa Kagaku, Daiichi Sankyo. Research Support; Sumitomo Pharma, SBI Pharma, Kowa Company, Ltd, Sanwa Kagaku, Boehringer-Ingelheim. Speaker's Bureau; Kyowa Kirin Co., Ltd, Bayer Pharmaceuticals, Inc, Abbott Japan Co., Ltd, Mitsubishi Tanabe Pharma Corporation. F.C. Lynn: None. S. Sasaki: Speaker's Bureau; Kowa Company, Ltd. T. Miyatsuka: Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd, Kowa Company, Ltd, Mitsubishi Tanabe Pharma Corporation, Abbott Japan Co., Ltd, Novartis Pharmaceuticals Corporation, Ono Pharmaceutical Co., Ltd. Funding the Japan Society for the Promotion of Science (JSPS) KAKENHI (22K08633 to TM); the Japan Diabetes Society Carrier Development Award supported by Sanofi (to TM); Japan Insulin-Dependent Diabetes Mellitus (IDDM) Network (to TM)

Introduction and Objective: Epidemiological and genetic studies have shown an inverse association between hypercholesterolemia and type 2 diabetes (T2DM), particularly in Familial Hypercholesterolemia (FH). Defects in LDL receptor gene (LDLR) may lead to beta-cell apoptosis, and statin therapy might complicate it. The study evaluated biomarkers related to T2DM severe hypercholesterolemic patients in a genetic FH cascade screening program. Methods: Cross-sectional study, 1,431 patients with severe hypercholesterolemia, with FH-causing genes or not. T2DM was diagnosed by ADA criteria or by the use of antidiabetic medications. Results: A total of 797 patients with genetically confirmed FH (96.6% with variations in the LDLR, 47.7 ± 15.0 years; 56.7% female; baseline LDL-C 199 ± 74 mg/dL, body mass index (BMI) 27.55 ± 4.85 kg/m², 27.1% with previous cardiovascular disease, (CVD)) and 634 patients without FH variants (56.04 ± 12.6 years; 67.4% female; baseline LDL-C 191 ± 66 mg/dL, BMI: 26.91 ± 5.05 kg/m², 25.1% CVD were analyzed. FH patients were younger (p&amp;lt;0.001), leaner (p=0.004), and had a higher proportion of males (p&amp;lt; 0.001). At baseline, 67.8% of FH received statin therapy, compared to 87.4% of non-FH patients (p&amp;lt;0.001). The prevalence of T2DM at baseline was 13.4% in the FH group vs. 21.8% (odds ratio-OR 0.555, 95%CI 0.420-0.732, p&amp;lt;0.001). However, this association lost significance after multivariate analysis. Factors independently associated with T2DM included age (OR: 1.049, 95% CI: 1.032-1.066, p &amp;lt; 0.001), BMI (OR: 1.111, 95% CI: 1.073-1.151, p &amp;lt; 0.001), triglycerides (OR: 1.003, 95% CI: 1.001-1.005, p&amp;lt; 0.001), hypertension (OR: 2.845, 95% CI: 1.886-4.292, p &amp;lt; 0.001), and previous CVD (OR: 1.901, 95% CI: 1.324-2.729, p &amp;lt; 0.001). No association was observed with genetic defects or statin therapy. Conclusion: Among this group of hypercholesterolemic individuals, T2DM was not less prevalent in those with molecularly confirmed FH. Disclosure F.C.P. Maia: Other Relationship; Eli Lilly and Company. Speaker's Bureau; Amgen Inc, Novo Nordisk. M.H. Miname: Speaker's Bureau; Novartis Pharmaceuticals Corporation, Ache, Novo Nordisk. K.A.P. Maia: Research Support; Lilly USA LLC. Speaker's Bureau; Novo Nordisk, Novartis Pharmaceuticals Corporation, Servier Laboratories. H. Takematsu: None. P.G. Lorente: None. M.H. Mizuta: None. R. Santos: Research Support; Amgen Inc, Sanofi. Consultant; ESPERION Therapeutics, Inc., Daiichi Sankyo. Speaker's Bureau; Daiichi Sankyo. Research Support; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Research Support; Kowa Company, Ltd, Novartis Pharmaceuticals Corporation. Speaker's Bureau; Novo Nordisk. Research Support; Ionis Pharmaceuticals. Speaker's Bureau; Novartis Pharmaceuticals Corporation.

Introduction and Objective: Coronary artery calcification (CAC), a proxy of atherosclerosis, has increased incidence and prevalence in individuals with diabetes. It is also known that CAC predicts future coronary heart disease, along with mortality in this population. We aimed to evaluate whether the association between diabetes and CAC incidence holds in individuals with diabetes and BMI &amp;lt; 30 kg/m2. Methods: We analyzed data of 2,105 asymptomatic individuals with BMI &amp;lt; 30 kg/m2 and no prior cardiovascular disease from the ELSA-Brasil cohort. The association between diabetes at baseline and CAC incidence was examined by multivariable logistic regression adjusted for age, sex, race, tobacco use, hypertension, triglycerides, LDL-c, and HDL. CAC incidence was defined by initial CAC = 0 and repeated CAC &amp;gt; 0. The mean interscan period was 5.2 years. Results: At baseline, the mean age was 48 ± 7.5 years, 60.7% of individuals were female, and 58.9% were White, with a mean BMI of 25 ± 2.8 kg/m2, diabetes prevalence of 10.7% and hypertension prevalence of 18.3%. Diabetes was associated with CAC incidence, odds ratio (OR) 1.82 (95% CI 1.3-2.55, p&amp;lt;0.001) in the crude model and in the model adjusted for age, sex, race, and tobacco, OR 1.79 (95% CI 1.26 -2.52, p: 0.001). In the fully adjusted model, the OR was 1.4 (95% CI 0.97-2.02, p:0.07). The overall CAC incidence was 15.1%, 14.1% in individuals without diabetes and 23% in individuals with diabetes (chi square p&amp;lt; 0.001). Conclusion: Individuals with BMI &amp;lt; 30 kg/m2 and diabetes have increased incidence of CAC, a proxy of coronary atherosclerosis. Diabetes is associated with increased odds of incident coronary calcification even after adjustment for several confounders. In the fully adjusted model, there was a trend towards significance that did not reach the classic statistical significance as the OR was attenuated by other factors, such as hypertension and dyslipidemia. Disclosure T.B. Mendes: None. C.C. Janovsky: None. G. Generoso: None. B. Halpern: Other Relationship; Eli Lilly and Company, AstraZeneca, Novo Nordisk, Merck &amp; Co., Inc, Boehringer-Ingelheim. Advisory Panel; Currax. R. Correa Fabiano: None. R. Santos: Research Support; Amgen Inc, Sanofi. Consultant; ESPERION Therapeutics, Inc., Daiichi Sankyo. Speaker's Bureau; Daiichi Sankyo. Research Support; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Research Support; Kowa Company, Ltd, Novartis Pharmaceuticals Corporation. Speaker's Bureau; Novo Nordisk. Research Support; Ionis Pharmaceuticals. Speaker's Bureau; Novartis Pharmaceuticals Corporation. I.M. Bensenor: None. P.A. Lotufo: None. M.S. Bittencourt: Speaker's Bureau; Cleerly. Board Member; Elucid.

Introduction and Objective: Several clinical trials have demonstrated the importance of strict glycemic control in minimizing the risk of diabetic complications. Although frequent blood glucose measurement using the invasive finger-prick method is effective for achieving strict glycemic control, it is burdensome and uncomfortable for patients. Glycated albumin (GA) is a biomarker that reflects glycemic control over the preceding two weeks. Previously, we demonstrated that GA levels in tears correlate with those in blood. We hypothesized that regular GA testing in tears could promote behavior changes and improve glycemic control. Methods: Participants with type 2 diabetes were recruited and randomly divided into two groups. The intervention group underwent tear GA testing every two weeks and reported the results online, while the control group did not receive this intervention. After an 8-week intervention period, outcomes were compared between the two groups. GA levels in tears were measured using liquid chromatography-mass spectrometry. Results: A total of 56 participants were enrolled in the study. The intervention group showed significant improvements in fasting blood glucose, HbA1c, GA, and non-HDL cholesterol levels compared with the control group. Conclusion: GA levels in tears, a diabetes-related biomarker, can be measured noninvasively. Regular measurement of tear GA levels has the potential to enhance digital health education and telehealth practices, providing a noninvasive approach to improving glycemic control. Disclosure M. Aihara: None. N. Kubota: None. T. Yamauchi: Research Support; Asahi Mutual Life Insurance Company. Other Relationship; Astellas Pharma Inc, AstraZeneca, Abbott Japan Co., Ltd, ARKRAY Marketing, Inc., Amgen Inc. Research Support; Boehringer-Ingelheim. Other Relationship; Boehringer-Ingelheim, Bayer Pharmaceuticals, Inc, Covidien Japan Inc., Daiichi Sankyo, Eli Lilly and Company. Research Support; EA Pharma Co.,Ltd. Other Relationship; GlaxoSmithKline K.K. Research Support; Kowa Company, Ltd. Other Relationship; Kowa Company, Ltd, Kyowa Kirin Co., Ltd, Medtronic, Merck Sharp &amp; Dohme Corp, Mitsubishi Tanabe Pharma Corporation. Research Support; Novo Nordisk. Other Relationship; Novo Nordisk, Ono Pharmaceutical Co., Ltd, Sumitomo Pharma Co., Sanofi K.K., SANWA KAGAKU KENKYUSHO CO.,LTD., Taiho Pharmaceutical Co. Ltd, Teijin Pharma Limited, Nipro Corporation. Research Support; NITTO BOSEKI CO.,LTD. Other Relationship; ViewSendICT Inc.

Introduction and Objective: Medisafe WITH is a unique patch pump that allows the insulin reservoir to be removed, and has been used since 2018 (Terumo, Tokyo, Japan). The aim of this study is to evaluate the safety and the effectiveness of this novel device. Methods: We conducted a single-arm, multicenter, retrospective observational study of 26 weeks. Inclusion criteria were individuals with type 1 diabetes who initiated to use Medisafe WITH between June 1, 2019 and June 30, 2023. Exclusion criteria were individuals considered to be unsuitable as subjects by the decision of the investigators. Date of introduction, treatment before and after initiation, and at 26 weeks, information of medical events, and the reasons of discontinuation. The primary outcomes were the incidence of diabetic ketoacidosis (DKA) and severe hypoglycemia (SH) for 26 weeks, and the secondary outcomes included changes in HbA1c, BMI, insulin dose, and information of discontinuation. Results: A total of 135 individuals treated at 20 study facilities in Japan were registered. They were aged 32 ± 15 years with diabetes duration of 10 [4-18] (median [IQR]) years. During the 22,865 person-days of observation, the incidence of DKA was 0.22/1000 person-days [95% CI: 0.08-0.44], and that of SH was 0.13/1000 person-days [0.03-0.34]. The HbA1c levels at 26 weeks were 7.5 ± 1.3%, which was significantly lower than those at baseline (7.8 ± 1.4%) (p = 0.014). Sixteen individuals (11.9%) discontinued during the 26 weeks, and the continuation rate was 88.1%. After discontinuation, 63% switched to insulin pump from other manufactures, and the rest switched to multiple daily insulin injections. Conclusion: When using Medisafe WITH, it is necessary to provide thorough education on carrying insulin pens in case of emergency, real-time CGM or frequent blood glucose measurements, and contacting the manufacturer's call center or medical institution as necessary. (UMIN-CTR: UMIN000055106) Disclosure J. Miura: Speaker's Bureau; Abbott, Dexcom, Inc., Medtronic. Research Support; Terumo Corporation. Speaker's Bureau; Novo Nordisk. T. Murata: Research Support; Medtronic. Speaker's Bureau; Abbott Japan Co., Ltd, Dexcom, Inc. Y. Hirota: Speaker's Bureau; Novo Nordisk, Sanofi, Eli Lilly and Company, Terumo Corporation, Sumitomo Dainippon Pharma Co., Ltd. Research Support; Medtronic, Kyowa Kirin Co., Ltd, Abbott Japan Co., Ltd. M. Toyoda: None. T. Omura: None. T. Kawamura: Speaker's Bureau; Terumo Corporation, Novo Nordisk, Eli Lilly and Company, Medtronic. M. Hirose: None. Y. Tsurutani: None. T. Urakami: Speaker's Bureau; Novo Nordisk, Abbott Japan Co., Ltd, Terumo Corporation. Y. Ishigaki: None. T. Murakami: None. S. Meguro: Speaker's Bureau; Abbott Japan Co., Ltd, Asahi Kasei Pharma Corp., AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Kaken Pharmaceutical Co., Ltd,, Kowa Company, Ltd, Kyowa Kirin Co., Ltd, LifeScan Diabetes Institute, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co. Ltd,, MSD K.K.,, Boehringer-Ingelheim, Nipro Corporation,, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd, Sanofi, Sanwa Kagaku Kenkyusho Co. Ltd,, Sumitomo Dainippon Pharma Co., Ltd, Teijin Pharma Limited. Research Support; Asahi Kasei Pharma Corp. M. Sone: None. Y. Aso: None. S. Kamei: None. K. Shiga: None. T. Murakami: None. M. Ogura: Research Support; LifeScan Diabetes Institute. H. Sawaki: None. K. Hara: None. R. Hattori: None. N. Kodani: Speaker's Bureau; Abbott Japan Co., Ltd, Dexcom, Inc., Medtronic. N. Sakane: None. Funding Terumo Company

Introduction and Objective: We showed that genetic variability in the PPARA region influences the effectiveness of the PPAR-α agonist fenofibrate on CVD and diabetic retinopathy (DR) progression, even in subjects without atherogenic dyslipidemia. Evidence suggests that higher genetically determined PPARA expression (Genetic Score (eQtGS) of PPARA retinal expression) may contribute to greater fenofibrate benefit. Here, we tested, in a pharmacogenetic trial, whether PPARA eQtGS influences fenofibrate’s effect on lipid and apolipoprotein profiles in statin-treated subjects with on-target lipid levels. Methods: We enrolled adult patients with type 2 diabetes, stable statin treatment, LDL-C &amp;lt;100 mg/dL, triglycerides &amp;lt;200 mg/dl, HbA1c &amp;lt;8%, and eGFR &amp;gt;60 mL/min, to be randomized to 12 weeks of fenofibrate or placebo. Lipid profile, apolipoproteins, transaminases, creatinine, CPK, and CRP were assessed. The eQtGS was derived from the EyeGEx database. Results: A total of 180 subjects (mean age: 66 years, 23% female, 33% obese, 23% with prior CAD, HbA1c: 6.6%) completed the study. All were on statins, mean LDLc was 62 mg/dl and triglycerides 102 mg/dl. Fenofibrate significantly reduced triglycerides (-20.7 mg/dL) and ApoCIII (-1.56 mg/dL) while increasing LDL-C (+4.62 mg/dL), ApoAII (+8.5 mg/dL), and creatinine (+0.14 mg/dL, all p&amp;lt;0.05). PPARA eQtGS significantly modulated fenofibrate’s effects on total and LDL-C, ApoB (higher PPARA eQtGS being associated with lower levels of LDL-C and ApoB after fenofibrate treatment). A significant positive eQtGS by fenofibrate interaction was found on fenofibrate-induced transaminase elevations. Conclusion: These precision medicine finding supports the concept that genetically determined PPARA expression affects fenofibrate response. Nonetheless the observed differences are unlikely to fully explain the large CVD and DR effect seen in previous studies. Further research is needed to dissect additional mechanisms and tissue-specific eQtGS effects. Disclosure M. Morieri: Advisory Panel; Amgen Inc. Speaker's Bureau; AstraZeneca, Novo Nordisk, Daiichi Sankyo, Merck Sharp &amp; Dohme Corp, Servier Laboratories, Novartis Pharmaceuticals Corporation, Lilly Diabetes. M. Giordano: None. C. Fagarazzi: None. C. Boscaro: None. M. Marassi: None. E. Iori: None. F. Amendolagine: None. A. Rodella: None. L. Migliozzi: None. C. Pipino: None. C. Zambon: None. A. Doria: Research Support; Abbott, Lexicon Pharmaceuticals, Inc, Dexcom, Inc. M. Albiero: None. G. Fadini: Speaker's Bureau; AstraZeneca. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Menarini. Advisory Panel; Lilly Diabetes. Consultant; Lilly Diabetes. Speaker's Bureau; Lilly Diabetes. Advisory Panel; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Advisory Panel; Sanofi. Speaker's Bureau; Sanofi. Funding Italian Ministry of Health Grant “Ricerca Finalizzata 2019” (GR-2019-12369702)

Introduction and Objective: This study evaluates a non-invasive method for diabetes prediction using retinal imaging features—Reti-DR (probability of diabetic retinopathy) and Reti-HbA1c (probability of HbA1c &amp;gt; 6.5)—alongside demographic and clinical data. The objective was to determine the predictive accuracy of this approach without blood-based tests. Methods: Cross-sectional data from 1,191 CMERC-HI participants (732 non-diabetic, 459 diabetic), a cohort at high risk of cardiovascular events, were analyzed. Independent variables included Reti-DR, Reti-HbA1c, age, gender, and BMI. Scores were averaged across fundus images. Reti-DR and Reti-HbA1c models were pre-trained on ~0.2M and 325,177 fundus images, respectively, from a health screening dataset. Data were split into training (80%, n=952) and testing (20%, n=239) sets. Features were standardized, and logistic regression was evaluated using AUC and positive predictive value (PPV)/sensitivity at the optimal threshold. Results: The model achieved an AUC of 0.81. At an optimal threshold of 0.33, PPV was 0.58, and sensitivity was 0.80. Odds ratios showed Reti-HbA1c (2.24) and Reti-DR (1.75) as the strongest predictors. Conclusion: This study demonstrates a feasible, non-invasive method for detecting diabetes, including in individuals on medications. Integrating Reti-DR and Reti-HbA1c into models offers an alternative to blood tests. Disclosure J. Cho: Employee; Mediwhale. T. Rim: Employee; Mediwhale Inc. Stock/Shareholder; Mediwhale Inc. S. Thakur: Employee; Mediwhale Inc. J. Park: Employee; Mediwhale. D. Nam: Employee; Mediwhale. M. Yoon: None. Y. Lee: Other Relationship; Mediwhale Inc. C. Lee: Speaker's Bureau; Novartis Pharmaceuticals Corporation. Advisory Panel; Novo Nordisk. Speaker's Bureau; Bayer Pharmaceuticals, Inc, Daiichi Sankyo. Stock/Shareholder; Mediwhale. S. Park: None. H. Kim: Employee; Mediwhale. Y. Jung: Employee; Mediwhale. H. Ko: Employee; mediwhale.

Introduction and Objective: Although cross-sectional studies link prediabetes (PreDM) and diabetes (DM) to sarcopenia in older adults, longitudinal data are scarce. This study examined whether baseline glucose tolerance status influences five-year changes in muscle mass and strength in community-dwelling older adults. Methods: We analyzed 1,072 participants (446 men, 626 women) from the Bunkyo Health Study, categorized into normal glucose tolerance (NGT), PreDM, or DM. Their mean baseline ages/HbA1c were 71.4y/5.6%, 73.1y/5.8%, and 73.2y/6.5%, respectively. Skeletal muscle index (SMI), grip strength, and knee extension strength were measured at baseline and five-year follow-up. Analysis of covariance, adjusted for age and baseline values, compared changes among groups. Among 968 participants without sarcopenia at baseline, logistic regression evaluated new-onset sarcopenia. Results: Over five years, men’s SMI changed by -8.2%, -6.6%, and -6.0%; women’s SMI changed by +5.0%, +3.1%, and +5.8% across NGT, PreDM, and DM, respectively. Grip strength declined in men by -5.6%, -7.2%, -7.7%, and in women by -4.9%, -6.5%, -5.4%. Knee extension strength decreased in men by -8.2%, -7.9%, -9.3%, and in women by -3.9%, -6.9%, -9.6%. Notably, only women with DM showed a significantly greater decline in knee extension strength versus NGT (p&amp;lt;0.003). No other between-group differences were detected, and there was no significant association with new-onset sarcopenia. Conclusion: In this five-year longitudinal study of older adults, baseline glucose tolerance did not significantly modify overall declines in muscle mass or sarcopenia incidence, although DM women experienced a greater decline in knee extension strength. While aging may be predominant in a relatively well-controlled population, these findings underscore the importance of monitoring and maintaining lower-limb muscle strength—particularly among older women with DM—to prevent functional decline. Disclosure T. Kogai: None. H. Kaga: None. H. Naito: None. T. Tajima: None. H. Tabata: None. S. Kakehi: None. S. Kadowaki: None. H. Watada: Speaker's Bureau; Novo Nordisk, Boehringer-Ingelheim, Sumitomo Pharma, Eli Lilly and Company, Roche Diabetes Care, Merck Sharp &amp; Dohme Corp, Sanwa Kagaku, Daiichi Sankyo. Research Support; Sumitomo Pharma, SBI Pharma, Kowa Company, Ltd, Sanwa Kagaku, Boehringer-Ingelheim. Speaker's Bureau; Kyowa Kirin Co., Ltd, Bayer Pharmaceuticals, Inc, Abbott Japan Co., Ltd, Mitsubishi Tanabe Pharma Corporation. Y. Tamura: None.