Menarini Diagnostics Research Articles

Evaluation of a New Multiparametric Microdot Array-Based Immunoassay Panel for Systemic Autoimmune Disease Diagnosis.

The early reliable detection and quantification of autoantibodies play an important role in autoimmune disease diagnosis and in disease-course monitoring. New technologies, such as the multiplexed determination of autoantibodies, have recently been introduced and are being adopted more frequently. The aim of this study was to evaluate the ability of a new microdot array-based multiparametric assay (ZENIT AMiDot CTD panel, A. Menarini Diagnostics, Firenze, Italy) to correctly classify patients with autoimmune rheumatic diseases (ARDs) and compare it to a fluorescence enzyme immunoassay (FEIA) for the detection of anti-ENAs. The study included 69 consecutive samples from patients with ARDs that were analyzed using two different methods (FEIA and AMiDot) to detect anti-CENP B and six anti-ENA antibodies: anti-Scl-70, anti-SSB/La, anti-Jo-1, anti-U1-RNP, anti-Ro52, and anti-Ro60. The control group sera came from sixty-eight blood donors. Tests were run on the automated slide processor ZENIT FLOW, and then the slides were imaged and analyzed using ZENIT fast. Since the samples were selected for at least one antibody positivity with an ARD diagnosis, we did not calculate clinical sensitivity but only specificity, which was 98.53%, ranging from 90% for anti-SSB/La antibodies to 100% for anti-CENP B ones. Mean agreement among the methods assessed by Cohen's kappa was 0.816 ± 0.240. The assay demonstrated good clinical performance and may be considered a valuable aid in detecting ARD patients, offering an alternative to methods such as FEIA which are largely in use today.

Protection of Rights of Undertakings and the Criminal Nature of Proceedings of the Antimonopoly Committee of Ukraine: Practice of the Constitutional Court of Ukraine and the Supreme Court

The article is devoted to examination of the practice of the Constitutional Court of Ukraine (the "CCU") and the Supreme Court (the "SC") regarding their perception and application of the practice of the European Court of Human Rights (the "ECHR") on autonomous interpretation of the term "criminal charge" for the purpose of protecting human rights under the Convention for the Protection of Human Rightsand Fundamental Freedoms (the "Convention"), to which Ukraine is a party, and equating the decisions of competition authorities to "criminal charges", in part of equating administrative proceedings of the Antimonopoly Committee of Ukraine (the "AMCU") on holding undertakings liable for infringements of Ukrainian antimonopoly legislation to criminal proceedings in part of requirements for protection of rights of undertakings.
 Analysis of the CCU's practice shows that it generally accepts and applies the ECHR's practice on equating certain administrative proceedings to "criminal" ones within the meaning of the Convention and extending criminal law guarantees to these proceedings. The CCU has not yet formed a position specifically with respect to criminal character of the AMCU's proceedings. At the same time, the CCU's positions developed considering the ECHR's practice, stating that criminal law principles and guarantees should apply to administrative proceedings concerning violations of customs rules, and the references made by the CCU to one of the most well-known ECHR's decisions on extending "criminal charge" to a decision of competition authority on imposition of a fine for violation of competition laws - A. Menarini Diagnostics S.R.L. v. Italy, when substantiating these positions, allow to assert the likelihood of the CCU equating the AMCU's administrative proceedings to criminal ones in part of requirements for protection of rights of undertakings, when this issue arises before it.
 As for the Supreme Court, questions about application of the Engel criteria to the AMCU's proceedings on enforcement of antimonopoly legislation increasingly arise before it. Undertakings seek the SC's conclusions on application of these criteria to the AMCU's proceedings. The SC has been reluctant to form such conclusions and has denied their formation thus far. The SC's practice, where it recognized the AMCU's proceedings as criminal ones for the purpose of protecting rights of undertakings, is currently absent. Therefore, one can only wait to see how the SC's practice on this issue will develop in the future.

THU066 An 8-year Interim Report Of The B2412 Study, An Open-label, Multicenter Pasireotide Rollover Study For Patients Who Continued To Receive Benefit From Pasireotide At Completion Of An Earlier Trial

Abstract Disclosure: M. Gadelha: Advisory Board Member; Self; Novo Nordisk, Recordati, Crinetics Pharmaceuticals. Speaker; Self; Recordati, Novo Nordisk, Ipsen, Crinetics Pharmaceuticals. M.D. Bronstein: None. E. Grineva: Advisory Board Member; Self; Ipsen, Merck, Pfizer, Inc. Speaker; Self; Recordati, Ipsen, Pfizer Berlin Chemie, Teva Pharmaceutical Industries Ltd., A. Menarini, Siemens Healthineers. N. Kapoor: None. C. De Block: Consulting Fee; Self; Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, A Menarini Diagnostics, Eli Lilly & Company, Insulet Corporation, Medtronic, Novo Nordisk, Roche Pharmaceuticals. Research Investigator; Self; AstraZeneca, Boehringer Ingelheim, Indigo Diabetes, Novo Nordisk. Speaker; Self; Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, A Menarini Diagnostics, Eli Lilly & Company, Insulet Corporation, Medtronic, Novo Nordisk, Roche Pharmaceuticals. J.M. Escalante Pulido: None. G. Rollin: Advisory Board Member; Self; Merck Serono. Speaker; Self; Novo Nordisk, Abbott Laboratories, AstraZeneca, Merck Serono. R. Baggenstoss: None. A. Piacentini: Employee; Self; Recordati. A.M. Pedroncelli: Employee; Self; Recordati. W. Gallardo: Speaker; Self; Pfizer, Inc., Merck, Ipsen, Novartis Pharmaceuticals. Introduction: A robust clinical development program of 14 trials demonstrated that the second-generation somatostatin receptor ligand, pasireotide, is an effective treatment for patients (pts) with rare endocrine disorders, including acromegaly and Cushing’s disease (CD). Pts with acromegaly or CD have significant morbidity, reduced quality of life and, if inadequately treated, a higher mortality risk than the general population. This 8-year interim analysis evaluated the long-term safety of pasireotide treatment in pts with acromegaly, CD or other endocrine disorders. Methods: This ongoing, open-label, multicenter study allows continued treatment for pts who completed a previous pasireotide parent trial (NCT01794793). Pts who continued to receive clinical benefit, as determined by the investigator in the parent study, entered the rollover study and remained on pasireotide. Depending on the route of administration in the parent study, pts received pasireotide long-acting release (LAR; n=303) or subcutaneous (sc; n=38) as monotherapy (n=36), or sc in combination with cabergoline (n=2). The primary objective was to evaluate long-term safety, determined by frequency of adverse events (AEs)/serious adverse events (SAEs). Results: Overall, 341 pts from 29 countries have entered the study from 14 parent studies; 228 pts had acromegaly, 64 CD and 49 other endocrine disorders, including melanoma, dumping syndrome and neuroendocrine tumors. Median (min−max) exposure to all pasireotide formulations from rollover baseline to data cut-off and across all indications was 45.3 months (0.9−100.8). Median (min−max) dose from rollover baseline was 45.4 mg/month (5.3−128.3) with pasireotide LAR and 1200 µg/day (300−1800) with pasireotide sc. In total, 89 (26.1%) pts discontinued treatment; the most common reason was consent withdrawal (n=21, 6.2%). Most common AEs during rollover (≥10% in all pts) were nasopharyngitis (acromegaly n=13, 5.7%; CD n=14, 21.9%; other diseases n=14, 28.6%), hyperglycemia (acromegaly n=29, 12.7%; CD n=2, 3.1%; other diseases n=7, 14.3%), back pain (acromegaly n=20, 8.8%; CD n=7, 10.9%; other diseases n=8, 16.3%) and headache (acromegaly n=21, 9.2%; CD n=6, 9.4%; other diseases n=7, 14.3%). SAEs were reported in 87 (25.5%) pts; the most common were cholelithiasis and COVID-19 (both n=9, 2.6%). Overall, 18 (5.3%) pts discontinued treatment because of AEs. Incidence of new hyperglycemia-related AEs during rollover was low. No new safety signals were identified. Conclusions: Hyperglycemia is an expected AE during pasireotide treatment, often occurring in the first 3 months of therapy. These data in pts with acromegaly, CD or other endocrine disorders support pasireotide as a well-tolerated long-term treatment and affirm that pts continue to receive long-term benefit, with a low discontinuation rate over 8 years. Presentation: Thursday, June 15, 2023

251-OR: The Impact of Identifying Sleep with a Fitbit on Calculated Rates of Nocturnal Hypoglycemia—The Hypo-Metrics Study

Consensus defines nocturnal hypoglycemia as occurring between 00:00 and 06:00 hrs. However, this may introduce bias, as for many, these hours only partially match real sleeping hours. Therefore, we compared rates of hypoglycemia while asleep (defined by Fitbit Charge 4) to rates of conventionally-defined nocturnal hypoglycemia. Hypo-METRICS study participants wore a Fitbit charge 4 and blinded FreeStyle Libre glucose monitor for up to 70 days. Every hypoglycemia episode (≤70mg/dL or ≤54mg/dL for ≥15 min) was classified as ‘asleep’ or ‘awake’ based on Fitbit sleep intervals and ‘nocturnal’ (00:00-06:00 hrs) or ‘day-time’. We compared weekly sensor-detected hypoglycemia (SDH) rates whilst asleep to nocturnal SDH rates using a paired sample Wilcoxon test. We included 542 participants (269 with type 1 diabetes, median (IQR) age 56 (44-66) years, HbA1c 7.3%(6.7-7.9), with 69 (65-70) nights with sleep data/participant). Sleep duration was 6.1 (5.2-6.8) hours. Median weekly rates of SDH while asleep were higher than rates of nocturnal SDH both ≤70mg/dL (1.3 (0.6-2.5) vs 0.9 (0.4-1.8), p<0.001) and ≤54mg/dL (0.4 (0.2-0.9) vs 0.3 (0.1-0.7), p<0.001). Stratifying by type of diabetes did not change the direction or magnitude of the differences in SDH rates. Using clock time to estimate nocturnal hypoglycemia underestimates hypoglycemia whilst asleep by up to a third. Using activity trackers such as Fitbit to identify sleep offers a novel way to estimate hypoglycemia whilst asleep to better reflect lived experience of nocturnal hypoglycemia. Disclosure G.Martine-edith: Other Relationship; Novo Nordisk A/S. R.J.Mccrimmon: Advisory Panel; Sanofi, Speaker's Bureau; Novo Nordisk A/S. E.Renard: Consultant; Abbott Diabetes, Dexcom, Inc., AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Insulet Corporation, MannKind Corporation, Novo Nordisk, Sanofi, Roche Diabetes Care. S.R.Heller: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Other Relationship; Eli Lilly and Company, Research Support; Dexcom, Inc., Speaker's Bureau; Novo Nordisk, Medtronic. M.Evans: Advisory Panel; Zucara Therapeutics, Pila Pharma, Dexcom, Inc., Other Relationship; Novo Nordisk, AstraZeneca, Abbott Diabetes, Speaker's Bureau; Eli Lilly and Company. J.K.Mader: Advisory Panel; Novo Nordisk A/S, Abbott Diabetes, Roche Diabetes Care, Eli Lilly and Company, Sanofi, Medtronic, Becton, Dickinson and Company, Pharmasense, embecta, Research Support; A. Menarini Diagnostics, Abbott Diabetes, Roche Diabetes Care, Dexcom, Inc., Profusa, Inc., Speaker's Bureau; Novo Nordisk A/S, A. Menarini Diagnostics, Abbott Diabetes, Roche Diabetes Care, Eli Lilly and Company, Sanofi, Boehringer Ingelheim Inc., Becton, Dickinson and Company, Ypsomed AG, Viatris Inc., Servier Laboratories, Medtrust, Stock/Shareholder; Decide Clinical Software GmbH. S.A.Amiel: Advisory Panel; Medtronic, Other Relationship; Sanofi, Novo Nordisk. P.Choudhary: Advisory Panel; Medtronic, Novo Nordisk, Dexcom, Inc., MannKind Corporation, Insulet Corporation, Research Support; Abbott Diabetes, Speaker's Bureau; Sanofi, Lilly. Hypo-resolve consortium: n/a. P.Divilly: None. N.Zaremba: None. U.Soeholm: Employee; Novo Nordisk A/S. A.Kingsnorth: None. Z.Mahmoudi: Employee; Novo Nordisk. M.Gomes: Employee; Novo Nordisk A/S. B.E.De galan: Research Support; Novo Nordisk. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi, Vertex Pharmaceuticals Incorporated. Funding Innovative Medicines Initiative 2 Joint Undertaking (777460)

392-P: Optimizing Duration and Threshold of Sensor Glucose for Identifying Symptomatic Hypoglycemia in Insulin-Treated Diabetes—Hypo-METRICS Study

Many episodes of hypoglycemia defined by the ATTD consensus are asymptomatic. We investigated if optimizing the glucose threshold and duration for sensor detected hypoglycemia (SDH) improves precision and sensitivity for identifying symptomatic hypoglycaemia from continuous glucose monitoring (CGM) data. We analysed 10 weeks of blinded CGM (Libre 2) and FitBit data from 435 participants [217 type 1, 218 type 2] with intact hypoglycemic awareness (Gold score <4). They self-reported symptomatic hypoglycemia on the Hypo-METRICS smartphone app. We used particle Markov chain Monte Carlo optimisation to generate the threshold and duration of SDH that maximizes detection of symptomatic hypoglycemia across our population and assessed impact of sleep status and diabetes type. The optimized threshold and duration were 70mg/dl for 27 min, with 2% gain of precision but 8% loss of sensitivity vs level 1 SDH (70mg/dl >15 min). Both level 1 SDH and our optimized definition had 3-fold increased sensitivity vs level 2 SDH (54mg/dl >15 min), with minimal loss of precision (Table). Our data validate ATTD level 1 hypoglycemia. Overall precision for detection of symptomatic hypoglycemia remains low despite optimization. Disclosure P.Divilly: None. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi, Vertex Pharmaceuticals Incorporated. R.J.Mccrimmon: Advisory Panel; Sanofi, Speaker's Bureau; Novo Nordisk A/S. J.K.Mader: Advisory Panel; Novo Nordisk A/S, Abbott Diabetes, Roche Diabetes Care, Eli Lilly and Company, Sanofi, Medtronic, Becton, Dickinson and Company, Pharmasense, embecta, Research Support; A. Menarini Diagnostics, Abbott Diabetes, Roche Diabetes Care, Dexcom, Inc., Profusa, Inc., Speaker's Bureau; Novo Nordisk A/S, A. Menarini Diagnostics, Abbott Diabetes, Roche Diabetes Care, Eli Lilly and Company, Sanofi, Boehringer Ingelheim Inc., Becton, Dickinson and Company, Ypsomed AG, Viatris Inc., Servier Laboratories, Medtrust, Stock/Shareholder; Decide Clinical Software GmbH. M.Evans: Advisory Panel; Zucara Therapeutics, Pila Pharma, Dexcom, Inc., Other Relationship; Novo Nordisk, AstraZeneca, Abbott Diabetes, Speaker's Bureau; Eli Lilly and Company. S.A.Amiel: Advisory Panel; Medtronic, Other Relationship; Sanofi, Novo Nordisk. P.Choudhary: Advisory Panel; Medtronic, Novo Nordisk, Dexcom, Inc., MannKind Corporation, Insulet Corporation, Research Support; Abbott Diabetes, Speaker's Bureau; Sanofi, Lilly. Hypo-resolve consortium: n/a. Z.Mahmoudi: Employee; Novo Nordisk. G.Martine-edith: Other Relationship; Novo Nordisk A/S. D.Boiroux: Employee; Novo Nordisk A/S. N.Zaremba: None. U.Soeholm: Employee; Novo Nordisk A/S. M.Gomes: Employee; Novo Nordisk A/S. A.A.Vaag: None. B.E.De galan: Research Support; Novo Nordisk. Funding Innovative Medicines Initiative 2 Joint Undertaking (777460)

391-P: Individualized Optimization of Duration and Threshold of Sensor Hypoglycemia Improves Identification of Symptomatic Hypoglycemia Episodes—Hypo-METRICS Study

Current definitions of sensor detected hypoglycemia (SDH) give high levels of asymptomatic hypoglycemia on continuous glucose monitoring (CGM). We defined individually optimised thresholds and durations for sensor detected hypoglycemia (SDH) that better identify symptomatic hypoglycemia experienced by people with insulin treated diabetes. We analysed 10 weeks of blinded CGM (Libre 2) and FitBit data from 435 participants [217 type 1, 218 type 2]. They self reported symptomatic hypoglycemia on the Hypo-METRICS smartphone app. We used particle Markov chain Monte Carlo optimization to generate the threshold and duration of SDH that maximizes detection of symptomatic hypoglycemia for each individual (and by Fitbit sleep status). When using individual definitions of SDH, precision for detection of symptomatic hypoglycemia increased by 23% with 2% loss of sensitivity vs the consensus definition of Level 1 SDH (70mg/dl > 15 mins). Precision and sensitivity increased by 41% and 20% respectively vs level 2 SDH (54 mg/dl > 15 mins). Increased precision, with minimal change of sensitivity, were greatest during sleep, and irrespective of diabetes types and sleep status (Table). Optimizing SDH definitions at the individual level and by sleep status could minimize false alarms without increasing missed clinically important hypoglycemia episodes. Disclosure Z.Mahmoudi: Employee; Novo Nordisk. B.E.De galan: Research Support; Novo Nordisk. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi, Vertex Pharmaceuticals Incorporated. R.J.Mccrimmon: Advisory Panel; Sanofi, Speaker's Bureau; Novo Nordisk A/S. E.Renard: Consultant; Abbott Diabetes, Dexcom, Inc., AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Insulet Corporation, MannKind Corporation, Novo Nordisk, Sanofi, Roche Diabetes Care. S.R.Heller: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Other Relationship; Eli Lilly and Company, Research Support; Dexcom, Inc., Speaker's Bureau; Novo Nordisk, Medtronic. M.Evans: Advisory Panel; Zucara Therapeutics, Pila Pharma, Dexcom, Inc., Other Relationship; Novo Nordisk, AstraZeneca, Abbott Diabetes, Speaker's Bureau; Eli Lilly and Company. J.K.Mader: Advisory Panel; Novo Nordisk A/S, Abbott Diabetes, Roche Diabetes Care, Eli Lilly and Company, Sanofi, Medtronic, Becton, Dickinson and Company, Pharmasense, embecta, Research Support; A. Menarini Diagnostics, Abbott Diabetes, Roche Diabetes Care, Dexcom, Inc., Profusa, Inc., Speaker's Bureau; Novo Nordisk A/S, A. Menarini Diagnostics, Abbott Diabetes, Roche Diabetes Care, Eli Lilly and Company, Sanofi, Boehringer Ingelheim Inc., Becton, Dickinson and Company, Ypsomed AG, Viatris Inc., Servier Laboratories, Medtrust, Stock/Shareholder; Decide Clinical Software GmbH. S.A.Amiel: Advisory Panel; Medtronic, Other Relationship; Sanofi, Novo Nordisk. P.Choudhary: Advisory Panel; Medtronic, Novo Nordisk, Dexcom, Inc., MannKind Corporation, Insulet Corporation, Research Support; Abbott Diabetes, Speaker's Bureau; Sanofi, Lilly. Hypo-resolve consortium: n/a. P.Divilly: None. G.Martine-edith: Other Relationship; Novo Nordisk A/S. D.Boiroux: Employee; Novo Nordisk A/S. N.Zaremba: None. U.Soeholm: Employee; Novo Nordisk A/S. M.Gomes: Employee; Novo Nordisk A/S. A.A.Vaag: None. J.Speight: Research Support; Sanofi, Medtronic, Abbott Diabetes, Lilly, Novo Nordisk A/S, Speaker's Bureau; Sanofi. Funding Innovative Medicines Initiative 2 Joint Undertaking (777460)

250-OR: Majority of Sensor Hypoglycemia Is Not Detected by People Living with Diabetes—Hypo-METRICS Study

The multicentre prospective observational Hypo-METRICS study assessed rates of sensor detected hypoglycemia (SDH) and person reported hypoglycemia-PRH (symptoms resolved by carbohydrates or measured glucose <72 mg/dl), in people with type 1 (T1D) and insulin treated type 2 (T2D) diabetes. We report overall rates of hypoglycemia and the proportion and rates of undetected SDH. All 602 participants (277 T1D vs 325 T2D) had ≥1 PRH in the 3 months prior to the study. They wore a blinded continuous glucose monitor and recorded PRH on the Hypo-METRICS smartphone app for 10 weeks. SDH was defined by ATTD consensus. PRH without SDH ± 1 hour was consider undetected. The median (IQR) weekly rate of PRH was 3.4 (1.9-5.3) vs 0.8 (0.3-1.7) episodes/week in T1D vs T2D respectively (p<0.01), SDH <70mg/dl was 6.7 (3.9-10.8) vs 2.1 (0.9-4.3) episodes/week respectively (p<0.01) and SDH <54mg/dl was 1.3 (0.5-2.8) vs 0.3 (0-0.6) episodes/weeks respectively (p<0.01). The proportion of undetected episodes at SDH <70mg/dl was higher in T2D, 68 vs 78% (p<0.01) and at SDH <54mg/dl, 62 vs 82% (p<0.01). The weekly rates of undetected episodes were higher in T1D for SDH <70mg/dl (4.6 vs 1.8 episodes/week, p<0.01) and for SDH <54mg/dl (0.8 vs 0.2 episodes /week, p<0.01). Baseline characteristics are in table 1. Most sensor hypoglycemia goes undetected by people with diabetes. Further work will assess the impact of undetected episodes. Disclosure P.Divilly: None. S.R.Heller: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Other Relationship; Eli Lilly and Company, Research Support; Dexcom, Inc., Speaker's Bureau; Novo Nordisk, Medtronic. M.Evans: Advisory Panel; Zucara Therapeutics, Pila Pharma, Dexcom, Inc., Other Relationship; Novo Nordisk, AstraZeneca, Abbott Diabetes, Speaker's Bureau; Eli Lilly and Company. J.K.Mader: Advisory Panel; Novo Nordisk A/S, Abbott Diabetes, Roche Diabetes Care, Eli Lilly and Company, Sanofi, Medtronic, Becton, Dickinson and Company, Pharmasense, embecta, Research Support; A. Menarini Diagnostics, Abbott Diabetes, Roche Diabetes Care, Dexcom, Inc., Profusa, Inc., Speaker's Bureau; Novo Nordisk A/S, A. Menarini Diagnostics, Abbott Diabetes, Roche Diabetes Care, Eli Lilly and Company, Sanofi, Boehringer Ingelheim Inc., Becton, Dickinson and Company, Ypsomed AG, Viatris Inc., Servier Laboratories, Medtrust, Stock/Shareholder; Decide Clinical Software GmbH. S.A.Amiel: Advisory Panel; Medtronic, Other Relationship; Sanofi, Novo Nordisk. P.Choudhary: Advisory Panel; Medtronic, Novo Nordisk, Dexcom, Inc., MannKind Corporation, Insulet Corporation, Research Support; Abbott Diabetes, Speaker's Bureau; Sanofi, Lilly. Hypo-resolve consortium: n/a. G.Martine-edith: Other Relationship; Novo Nordisk A/S. Z.Mahmoudi: Employee; Novo Nordisk. N.Zaremba: None. U.Soeholm: Employee; Novo Nordisk A/S. B.E.De galan: Research Support; Novo Nordisk. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi, Vertex Pharmaceuticals Incorporated. R.J.Mccrimmon: Advisory Panel; Sanofi, Speaker's Bureau; Novo Nordisk A/S. E.Renard: Consultant; Abbott Diabetes, Dexcom, Inc., AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Insulet Corporation, MannKind Corporation, Novo Nordisk, Sanofi, Roche Diabetes Care. Funding Innovative Medicines Initiative 2 Joint Undertaking (777460)

85-LB: CGM Outcomes and Hypoglycemia Duration with Once-Weekly Insulin Icodec vs. Once-Daily Insulin Glargine U100 in Insulin-Naïve T2D—ONWARDS 1 Exploratory Analysis

In ONWARDS 1, a phase 3a, treat-to-target trial (NCT04460885) in insulin-naïve T2D randomized 1:1 to once-weekly icodec or once-daily glargine U100, time in, above and below range (TIR, TAR, TBR) and hypoglycemia duration were assessed with double-blinded CGM at pre-specified periods throughout the trial. TIR (70-180 mg/dL), TAR (>180 mg/dL), TBR (<70 and <54 mg/dL), median duration of hypoglycemia <70 mg/dL and the proportion of an episode spent <54 mg/dL were assessed at weeks (wks) 0-4, 22-26, 48-52, and 74-78. At wks 22-26, 48-52, and 74-78, mean TIR with icodec met the recommended target of >70%, and TIR and TAR were significantly improved with icodec vs glargine, with no significant difference between arms in TBR <54 mg/dL (table). There was a difference in favor of glargine in TBR <70 mg/dL at wks 48-52 and 74-78, but mean TBR <70 mg/dL and TBR <54 mg/dL were below recommended targets (4% and 1%, respectively) at all time periods for both arms. TIR, TBR and TAR did not differ significantly between arms at wks 0-4. Median duration of hypoglycemia <70 mg/dL and proportion of time <54 mg/dL were similar between arms at all time periods. In summary, TIR and TAR at wks 22-26, 48-52, and 74-78 were significantly improved with icodec vs glargine U100, with no significant difference in TBR <54 mg/dL and a similar duration of hypoglycemia <70 mg/dL between arms. Disclosure R. M. Bergenstal: Advisory Panel; Abbott Diabetes. Research Support; Abbott Diabetes. Consultant; Ascensia Diabetes Care, Bigfoot Biomedical, Inc., CeQur SA, Dexcom, Inc. Research Support; Dexcom, Inc. Advisory Panel; Eli Lilly and Company. Research Support; Eli Lilly and Company. Consultant; Hygieia. Research Support; Insulet Corporation, Medtronic. Advisory Panel; Medtronic, Novo Nordisk. Research Support; Novo Nordisk. Consultant; Onduo LLC. Advisory Panel; Roche Diabetes Care. Research Support; Sanofi. Consultant; Sanofi. Research Support; UnitedHealth Group. Consultant; Vertex Pharmaceuticals Incorporated. Advisory Panel; Zealand Pharma A/S. S. K. Watt: Employee; Novo Nordisk. A. S. A. Matos: Employee; Novo Nordisk A/S. I. Lingvay: Advisory Panel; Novo Nordisk A/S. Research Support; Novo Nordisk A/S. Advisory Panel; Lilly Diabetes, Boehringer-Ingelheim. Research Support; Boehringer-Ingelheim. Consultant; Carmot Therapeutics, Inc., Merck Sharp & Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc. Advisory Panel; Sanofi. Consultant; Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer. J. K. Mader: Advisory Panel; Novo Nordisk A/S. Speaker's Bureau; Novo Nordisk A/S, A. Menarini Diagnostics. Research Support; A. Menarini Diagnostics, Abbott Diabetes. Advisory Panel; Abbott Diabetes. Speaker's Bureau; Abbott Diabetes. Advisory Panel; Roche Diabetes Care. Speaker's Bureau; Roche Diabetes Care. Research Support; Roche Diabetes Care. Advisory Panel; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Advisory Panel; Sanofi. Speaker's Bureau; Sanofi. Advisory Panel; Medtronic. Speaker's Bureau; Boehringer Ingelheim Inc., Becton, Dickinson and Company. Advisory Panel; Becton, Dickinson and Company. Speaker's Bureau; Ypsomed AG, Viatris Inc., Servier Laboratories. Research Support; Dexcom, Inc., Profusa, Inc. Stock/Shareholder; Decide Clinical Software GmbH. Advisory Panel; Pharmasense, embecta. Speaker's Bureau; Medtrust. T. Nishida: Employee; Novo Nordisk Pharma Ltd. Stock/Shareholder; Novo Nordisk A/S. J. Rosenstock: Advisory Panel; Applied Therapeutics Inc. Research Support; Applied Therapeutics Inc. Advisory Panel; Boehringer Ingelheim Inc. Research Support; Boehringer Ingelheim Inc. Advisory Panel; Eli Lilly and Company. Research Support; Eli Lilly and Company, Merck & Co., Inc., Novartis. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; Oramed Pharmaceuticals. Research Support; Pfizer Inc. Advisory Panel; Sanofi. Research Support; Sanofi. Advisory Panel; Zealand Pharma A/S, Intarcia Therapeutics, Inc. Research Support; Intarcia Therapeutics, Inc. Advisory Panel; Hanmi Pharm. Co., Ltd. Funding Novo Nordisk A/S

275-OR: Association between Treatment Adherence and CGM Outcomes in People with T1D Using Smart Insulin Pens in a Real-World Setting

Adherence to insulin therapy can be challenging for individuals with T1D. This analysis explored how adherence to basal and bolus insulin injections influences glycemic outcomes. Data were collected from adults (≥18 years) administering basal insulin (degludec) and bolus insulin (aspart or faster aspart) using smart insulin pens with CGM; data were aggregated in 14-day periods. Treatment adherence was defined as the number of missed basal insulin doses (>40 hrs between doses), flex basal insulin doses (dosing time deviated >±6 hrs from previous day) and missed bolus insulin doses (meals with no bolus dose within -15 to +60 mins from meal onset). Glycemic outcomes included time in range (TIR), time below range, glucose management index (GMI), and coefficient of variation. Multinational data from 403 adults who had 3588 14-day periods with ≥70% CGM coverage were analyzed. Individuals with one missed basal dose per 14-days had a lower TIR (-4.04% [95% CI: -6.83; -1.26]) and higher GMI (0.20% [95% CI: 0.02; 0.38]) than individuals without missed basal doses; flex basal doses were not associated with TIR changes. Missed bolus insulin doses were also associated with lower TIR (Table). These real-world data confirm associations between missed basal and bolus insulin doses and impaired TIR, highlighting a need for digital tools such as smart insulin pens to help individuals manage their diabetes. Disclosure T.Danne: Research Support; Abbott Diabetes, AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Medtronic, Stock/Shareholder; DreaMed Diabetes, Ltd. N.V.Hartvig: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. A.Kaas: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. N.N.Knudsen: Employee; Novo Nordisk. J.K.Mader: Advisory Panel; Novo Nordisk A/S, Abbott Diabetes, Roche Diabetes Care, Eli Lilly and Company, Sanofi, Medtronic, Becton, Dickinson and Company, Pharmasense, embecta, Research Support; A. Menarini Diagnostics, Abbott Diabetes, Roche Diabetes Care, Dexcom, Inc., Profusa, Inc., Speaker's Bureau; Novo Nordisk A/S, A. Menarini Diagnostics, Abbott Diabetes, Roche Diabetes Care, Eli Lilly and Company, Sanofi, Boehringer Ingelheim Inc., Becton, Dickinson and Company, Ypsomed AG, Viatris Inc., Servier Laboratories, Medtrust, Stock/Shareholder; Decide Clinical Software GmbH. Funding Novo Nordisk A/S

388-P: The Impact of Routine CGM on Hypoglycemia Rates and Psychological Outcomes in the Hypo-METRICS Study

We aimed to compare weekly rates of sensor detected hypoglycemia (SDH), person reported hypoglycemia (PRH) and psychological outcomes in people with type 1 (T1D) and insulin treated type 2 diabetes (T2D) using routine continuous glucose monitoring (CGM) or capillary blood glucose monitoring (BGM) in the prospective observational Hypo-METRICS study. Participants (T1D/CBG=67, T1D/CGM=210, T2D/CBG=192, T2D/CGM=133, 55% men, median (IQR) age 56 (45-66) years) completed person reported outcomes measures, wore a blinded study CGM and reported PRH in real time on the Hypo-METRICS app for 10 weeks. We used the Wilcoxon rank sum test. Median weekly PRH rates were higher in CGM vs BGM users in both T1D (4.5 (2.4-6.3) vs 2.6 (1-3.9) Z=-5.1, p<0.005) and T2D (1.7 (0.6-2.3) vs 1.0 (0.2-1.2), Z=-5.8 p<0.005). There were no differences in SDH rates at 70 or 54mg/dl for CGM or BGM users with T1D or T2D (Table 1). Diabetes distress (Problem Areas In Diabetes) was higher in CGM vs BGM users with T1D (25 (10-36) vs 19 (5-26), Z=-3.2, p=0.008), but not T2D. There were no significant differences between CGM and BGM users in Hypoglycaemia Fear Survey Behaviour or Worry subscales, depression (PHQ-9) or anxiety (GAD-7) in either group. Despite similar SDH rates, T1D CGM users have higher PRH and diabetes distress scores; this may reflect populations with greater access to CGM. Further research is needed to investigate these findings. Disclosure N.Zaremba: None. M.Evans: Advisory Panel; Zucara Therapeutics, Pila Pharma, Dexcom, Inc., Other Relationship; Novo Nordisk, AstraZeneca, Abbott Diabetes, Speaker's Bureau; Eli Lilly and Company. E.Renard: Consultant; Abbott Diabetes, Dexcom, Inc., AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Insulet Corporation, MannKind Corporation, Novo Nordisk, Sanofi, Roche Diabetes Care. S.R.Heller: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Other Relationship; Eli Lilly and Company, Research Support; Dexcom, Inc., Speaker's Bureau; Novo Nordisk, Medtronic. J.Speight: Research Support; Sanofi, Medtronic, Abbott Diabetes, Lilly, Novo Nordisk A/S, Speaker's Bureau; Sanofi. S.A.Amiel: Advisory Panel; Medtronic, Other Relationship; Sanofi, Novo Nordisk. P.Choudhary: Advisory Panel; Medtronic, Novo Nordisk, Dexcom, Inc., MannKind Corporation, Insulet Corporation, Research Support; Abbott Diabetes, Speaker's Bureau; Sanofi, Lilly. P.Divilly: None. G.Martine-edith: Other Relationship; Novo Nordisk A/S. Z.Mahmoudi: Employee; Novo Nordisk. U.Soeholm: Employee; Novo Nordisk A/S. B.E.De galan: Research Support; Novo Nordisk. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi, Vertex Pharmaceuticals Incorporated. R.J.Mccrimmon: Advisory Panel; Sanofi, Speaker's Bureau; Novo Nordisk A/S. J.K.Mader: Advisory Panel; Novo Nordisk A/S, Abbott Diabetes, Roche Diabetes Care, Eli Lilly and Company, Sanofi, Medtronic, Becton, Dickinson and Company, Pharmasense, embecta, Research Support; A. Menarini Diagnostics, Abbott Diabetes, Roche Diabetes Care, Dexcom, Inc., Profusa, Inc., Speaker's Bureau; Novo Nordisk A/S, A. Menarini Diagnostics, Abbott Diabetes, Roche Diabetes Care, Eli Lilly and Company, Sanofi, Boehringer Ingelheim Inc., Becton, Dickinson and Company, Ypsomed AG, Viatris Inc., Servier Laboratories, Medtrust, Stock/Shareholder; Decide Clinical Software GmbH. Funding Innovative Medicines Initiative 2 Joint Undertaking (777460)

1661-P: The Myokine Irisin Is Endocytosed and Signals through an αV Integrin-Independent Mechanism in Pancreatic ß-Cells

Irisin is a hormone secreted by skeletal muscle, able to improve metabolic homeostasis and promote energy expenditure. We have previously demonstrated that irisin protects human and rodent β-cells and pancreatic islets from lipotoxicity-induced apoptosis, increases insulin biosynthesis and glucose-stimulated insulin secretion (GSIS), and promotes β-cell proliferation, both in vitro and in vivo in mice. Irisin may also restore the defects that are characteristic of islets from T2D patients. Although it has been demonstrated that irisin mediates its effects on bone and fat via αV integrin receptors, the presence of an irisin receptor in β-cells has not been reported. In INS-1E cells, we found that irisin activates its intracellular signalling and enhances GSIS in the presence of a specific αV integrin knockdown or a chemical inhibitor of cellular integrins (RGDS), thus excluding the involvement of integrin receptors in irisin effects. Through a pull-down assay/mass spectrometry approach, we identified 102 irisin interactors in human pancreatic islets, mostly belonging to intracellular compartments (i.e., vesicles and membrane rafts), and not including canonical membrane receptors. We therefore hypothesized that irisin could be endocytosed in pancreatic β-cells and confirmed this by immunoblotting and immunofluorescence techniques. In addition, nystatin, an inhibitor of lipid-raft dependent endocytosis, reduced irisin entry into β-cells. These results suggest for the first time that irisin effects on pancreatic β-cells are independent of engaging the αV integrin receptor and may instead depend on its endocytosis. These results are important beyond irisin, as they propose a potential new mechanism of action for peptide hormones. In addition, we highlight the possibility that the same hormone, i.e. irisin, may signal through different receptors in different target tissues. Disclosure N.Marrano: None. A.Borrelli: None. G.Biondi: None. M.Rella: None. A.Cignarelli: Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi. S.Perrini: None. L.Laviola: Advisory Panel; A. Menarini Diagnostics, Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Roche Diabetes Care, Sanofi, Other Relationship; Medtronic, Speaker's Bureau; Abbott, Terumo Corporation. F.Giorgino: Advisory Panel; Boehringer-Ingelheim, Amarin Corporation, Medtronic, Roche Diabetes Care, Sanofi, Bayer Inc., Novo Nordisk, Consultant; Novo Nordisk, Lilly, Research Support; Lilly, Roche Diabetes Care, AlfaSigma, Speaker's Bureau; Abbott, Boehringer-Ingelheim, Lilly, Sanofi, Medscape. A.Natalicchio: Other Relationship; AstraZeneca, Novo Nordisk, Sanofi, Boehringer-Ingelheim, Lilly.

591-P: Elite Cyclists with Type 1 Diabetes (T1D) Show Acceptable Glycemic Excursions during a Time-Trial Performance under High-Definition Transcranial Direct-Current Stimulation (HD-tDCS)

Patients with T1D are typically challenged by glycemic fluctuations during exercise. We recently applied HD-tDCS - a neuromodulation enhancer - both in healthy and T1D elite cyclists to improve endurance performance. Here, in a double-blind, counterbalanced, randomized order, nine elite cyclists (28 ± 3.5 years; BMI: 20.8 ± 1.3 kg/m2; VO2peak: 65.3 ± 1.7 mL/min/kg) with T1D (no complications) underwent either HD-tDCS (F3, F4) or control (SHAM) and completed a constant-load trial (CLT) at 75% of the 2nd ventilatory threshold plus a 15-km cycling time-trial (TT). Comparing the two conditions by real-time continuous glucose monitoring (CGM), subjects showed similar glycemic variability in any part of the session (Figure: bold line = mean; dotted lines = min & max), with a significant effect of time (F=26.32; P<0.0001), but no interaction stimulation x time (F=0.08; P>0.99) nor effect of stimulation (F=0.077; P=0.79). Further, CGM data were stable for the 3 days preceding and following the tests. Given that glycemic control becomes of critical interest not only for health but also for performance goals, these findings suggest that HD-tDCS can be safely used as a performance improvement device in athletes with T1D, and possibly in a wider population of active T1D-subjects. Disclosure R.Codella: None. G.Gallo: None. A.Meloni: None. L.Luzi: Advisory Panel; Eli Lilly and Company, Medtronic, Research Support; Gelesis, Speaker's Bureau; A. Menarini Diagnostics, Amgen Inc., Boehringer Ingelheim and Eli Lilly Alliance, Eli Lilly and Company, Novo Nordisk, Novartis. L.Filipas: None.

276-OR: Postprandial Hyper- and Hypoglycemia Are Related to Injection Time—An Insulclock Connected Insulin Cap–Based Real-World Study

Background: Reaching the optimal postprandial glucose dynamics is a daily challenge for people with T1D. The study aimed to analyze postprandial hyperglycemia excursion (PHE) and late postprandial hypoglycemia (LPH) risk according to insulin injection time. Methods: Real-world, retrospective study in T1D using multiple daily injection (MDI) insulin. Five hours of paired CGM and automatically tracked insulin injections were collected with the Insulclock® connected cap. Meal events were identified using the ROC detection methodology. Postprandial glucometrics and LPH (glucose <70 mg/dL 2-5 hours after a meal) were evaluated according to insulin injection time. Results: Meal glycemic excursions (n=2784) were analyzed in 82 people. In 63% insulin was injected after the meal started. The best balance between PHE control and LPH risk is obtained by injecting -15 to 0 minutes before meals. Higher PHE (glucose peak-baseline; mg/dL) was observed in delayed injections (mean±SD): Early (-45-15 min) (n=348) 101.8 ± 34.0; Optimal (-15-0 min)(n=612) 98.3± 29.8; Delayed (0-+45 min) (n=1528) 114.8±40,2 (n=348), (p <0.001). LPH risk also increased with delayed injections, n (%): Early 31 (8.9); Optimal 47 (7.7); Delayed 171 (11.2), (p 0.038). Conclusion: The correct timing of insulin injection is crucial to reduce postprandial hyper- and hypoglycemia. Disclosure F.Gomez-peralta: Advisory Panel; Abbott Diabetes, Insulcloud S.L., Speaker's Bureau; A. Menarini Diagnostics, Boehringer Ingelheim and Eli Lilly Alliance, Lilly Diabetes, Novartis, Novo Nordisk. C.Cerqueira: Employee; Insulcloud S.L. J.Pérez: Employee; Insulcloud S.L. L.Ruiz-valdepeñas: Employee; Insulcloud S.L., Stock/Shareholder; Insulcloud S.L. X.Valledor: Employee; Insulcloud S.L. A.Lopez-picado: Employee; Insulcloud S.L.. C.Abreu: Speaker's Bureau; Lilly, Novo Nordisk. E.Fernández-rubio: Speaker's Bureau; Lilly Diabetes, Novo Nordisk, AstraZeneca. P.Pujante alarcón: None. E.García: Advisory Panel; Airliquide, Speaker's Bureau; Abbott Diabetes, Dexcom, Inc., Boehringer Ingelheim and Eli Lilly Alliance, Novo Nordisk, Sanofi, Airliquide. S.Azriel: Advisory Panel; Boehringer-Ingelheim, Novo Nordisk, Medtronic, Speaker's Bureau; Dexcom, Inc., Lilly Diabetes, AstraZeneca, Sanofi. R.Corcoy: Advisory Panel; Novo Nordisk, Other Relationship; Novo Nordisk, Lilly, Sanofi, Abbott, Speaker's Bureau; Sanofi, Roche Diabetes Care.

424-P: Diabetic Kidney Disease (DKD) Worsens CV Outcomes after First-Ever Major Cardiovascular Event in Type 2 Diabetes (T2D)

Aim: CV prognosis worsens in T2D after a first CV event. We assessed impact of DKD on mortality and subsequent CV events after a first CV event. Methods: Death rate was recorded over a median 14.1 (IQR 13.8-14.5) years follow-up in 961 T2D subjects. Vital status (Italian Health Card Database) was censored on December 31, 2017 (major CV events available for 947 participants). Effect of DKD (ACR <30/≥30 mg/g) and/or CKD-EPI eGFR ≥60/<60 ml/min/1.73 m2) was determined by Kaplan-Meier (K-M) curves and hazard ratios (HR, 95% CI) by unadjusted and adjusted Cox regression models (age, diabetes duration (DD), sex, smoking, retinopathy, hypertension, dyslipidemia, prior CVD; no-DKD as reference). Results: At census, 229 subjects were dead (23.8%) and 298 participants out of 947 (31.5%) had a first CV event during a median 13.8 year pre-event follow-up. Compared with free-CV event subjects, those with CVD were older, more often men, with longer diabetes duration, worse CV risk profile, more microvascular complications and CVD before recruitment. During a median 6 yr post-first CV event follow-up 99 subjects died: 57 (27.4%) no DKD, 42 (46.7%) DKD (K-M, p=0.005). Compared to no DKD the latter had an unadjusted HR of 1.76 (1.18-2.63, p=0.005; adjusted 1.69, 1.13-2.52, p=0.011). Death rate increased with DKD worsening with statistically significant HR (unadjusted 3.31, 1.73-6.31, p<0.0001; adjusted 3.32, 1.65-6.64, p=0.001) for ACR≥30/eGFR<60. During a median 3.1 post-first CV event follow-up, a new CV event occurred in 124 subjects: 82 (39.4%) no DKD and 42 (46.7%) DKD (K-M, p=0.019) with unadjusted HR for a new CV event in DKD of 1.40 (0.96-2.03, p=0.077). Rate of a secondary CV event increased across DKD phenotypes with unadjusted (HR 3.42, 95% CI 1.76-6.65, p<0.0001) and adjusted HR of 3.18 (1.57-6.44; p=0.001) for ACR≥30/eGFR<60, respectively. Conclusions: In T2D subjects, DKD still worsens the risk of mortality and secondary CV events after the occurrence of a first CV event. Disclosure M.Garofolo: Consultant; Novo Nordisk, Employee; Eli Lilly and Company. D.Lucchesi: None. M.Giambalvo: None. M.Capobianco: None. P.Francesconi: None. G.Penno: Advisory Panel; Eli Lilly and Company, Bayer Inc., Consultant; Novo Nordisk, AstraZeneca, Boehringer Ingelheim Inc. S.Del prato: Advisory Panel; Abbott Diagnostics, Altimmune, Amarin Corporation, Applied Therapeutics Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Vertex Pharmaceuticals Incorporated, Novartis, Consultant; A. Menarini Diagnostics, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi.

1400-P: Low Blood Oxygen Saturation Is Associated with Impaired Glucose Control in Diabetes

Low Blood Oxygen Saturation (BOS) is associated with increased overall morbidity / mortality and prevalence of diabetes is known to increase with altitude (lower 02 partial pressure). Individuals with complicated diabetes commonly have low blood oxygen saturation compared with nondiabetic patients. To unravel the link between low BOS and glucose metabolism, we investigated the correlation between BOS and glucose, BOS and HbA1c levels, BOS and VO2 consumption (Resting Energy Expenditure) in a cohort of adults with diabetes mellitus. The study included 1362 adults with diabetes (616 F, 746 M; 66.4 ± 14.2 years, range 18-85 years; BMI 27.6 ± 5.0 kg/m2, range 18-49.6 kg/m2; SpO2 97.2 ± 1.4%, range 88-100%; glucose 137.7 ± 45.0 mg/dl, range 50.0-323.0 mg/dl). A significant inverse correlation (Pearson) between the glucose (glucometer) and the BOS (pulsoximeter) (p<0.0001*; r = -0.1530). An inverse correlation (Pearson correlation) between the HbA1c levels and the BOS (n=1295; 568 F, 727 M; 67.5 ± 13.1 years, range 18-85 years; BMI 27.8 ± 5.2 kg/m2, range 18-49.8 kg/m2; HbA1c 52.9 ± 13.0, range 25-152 mmol/mol; p<0.0001*; r = -0.1351). In summary, we showed an inverse relationship between oxygen saturation and both glucose and glycosylated hemoglobin levels. Although the exact mechanisms behind lower blood oxygen saturation in diabetes are unknown, we speculate that a reduced pulmonary diffusion capacity as a consequence of pulmonary microvascular damage could play an important role. In conclusion, present preliminary data indicate the routine measurement of BOS along with glucose and glycosylated hemoglobin in the outpatient visit setting of diabetic patients as a biomarker of seriousness of disease. Disclosure L. Luzi: Speaker's Bureau; A. Menarini Diagnostics, Amgen Inc., Boehringer Ingelheim and Eli Lilly Alliance. Advisory Panel; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Research Support; Gelesis. Advisory Panel; Medtronic. Speaker's Bureau; Novo Nordisk, Novartis. C. Macrì: None. A. Ferrulli: None. C.C. Berra: None. C. Romano: None. S. Massarini: None. Funding IRCCS MultiMedica (Ricerca Corrente)

38-OR: Insulin Prevents Palmitate-Induced Stress Kinase Activation, Autophagy, and Apoptosis in Human Cardiac Progenitor Cells

Abnormal accumulation of saturated fatty acids in the heart results in insulin resistance, stress kinase activation, and increased cardiovascular risk in humans. The viability of human cardiac progenitor cells (CPC) is essential for myocardium homeostasis. This study investigates the ability of palmitate, a saturated fatty acid, to induce apoptosis, autophagy, and stress kinase activation in human CPC isolated from right auricle biopsies of nondiabetic, non-obese subjects, and the potential protective effects of insulin on palmitate-induced abnormalities. Human CPC expressed both IR-A and IR-B, and IR-A was more expressed than IR-B, as assessed by quantitative RT-PCR and immunoblotting. Exposure of human CPC to 100 nM insulin for 15 minutes resulted in increased Akt (S473) and p44/p42 MAPK (T202/Y204) phosphorylation (p<0.05), as evidenced by immunoblotting. Treatment of human CPC with palmitate 0.25 mM for 16 h induced apoptosis (p<0.05), as assessed by caspase-3 cleavage and ELISA assay, and increased S63-phosphorylation of c-Jun (p<0.05), a downstream transcription factor of JNK 1/2, as assessed by immunoblotting. Exposure of human CPC to 0.25 mM palmitate for 16 h resulted also in increased autophagy, evidenced by light chain 3-II immunoblotting (p<0.05). Pretreatment with 20 µM SP600125, a JNK inhibitor, for 1 h inhibited palmitate-induced apoptosis (p<0.05), but not autophagy. Similarly, pretreatment with 10 mM 3-methyladenine, an autophagy inhibitor, for 1 h decreased palmitate-induced apoptosis (p<0.05). Interestingly, palmitate effects on apoptosis, autophagy, and on stress kinase activation, were prevented when human CPC were pretreated with 100 nM insulin for 1 h (p<0.05). In conclusion, insulin prevents palmitate-induced apoptosis by inhibition of JNK signaling and autophagy in human CPC. Hence, preserving insulin signaling in human CPC might protect from lipotoxicity-induced metabolic alterations in the heart. Disclosure I. Calderoni: None. R. Doria: None. C. Caccioppoli: None. V. Genchi: None. G. Palma: None. G. Santarpino: None. A.D. Milano: None. A. Leonardini: None. A. Natalicchio: Other Relationship; AstraZeneca, Novo Nordisk, Sanofi, Boehringer-Ingelheim, Lilly. S. Perrini: None. A. Cignarelli: Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi. F. Giorgino: Research Support; Lilly, Roche Diabetes Care. Consultant; Novo Nordisk, Lilly. Speaker's Bureau; Abbott, Boehringer-Ingelheim, Lilly. Advisory Panel; Boehringer-Ingelheim, Amarin Corporation, Medtronic, Roche Diabetes Care, Sanofi. Speaker's Bureau; Sanofi. Advisory Panel; Bayer Inc., Novo Nordisk. Research Support; AlfaSigma. Speaker's Bureau; Medscape. L. Laviola: Speaker's Bureau; Abbott. Advisory Panel; A. Menarini Diagnostics, Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Roche Diabetes Care. Speaker's Bureau; Terumo Corporation. Other Relationship; Medtronic. Advisory Panel; Sanofi.

450-P: N-Terminal Pro-B Type Natriuretic Peptide Concentrations in Diabetic Cardiomyopathy—Baseline Data from the ARISE-HF Trial

Background: Diabetic Cardiomyopathy (DbCM) is a form of Stage B heart failure (HF). Concentrations of N-terminal pro-B type natriuretic peptide (NT-proBNP) may predict risk for HF progression in persons with DbCM. The ARISE-HF study (NCT04083339) is evaluating efficacy of AT-001, a highly selective aldose reductase inhibitor (AT-001) to improve exercise tolerance in affected patients. The aim of this analysis was to assess association between baseline NT-proBNP and cardiac status in type 2 diabetes participants with DbCM. Methods: Impaired exercise tolerance and baseline characteristics were evaluated in 679 patients with DbCM as a function of NT-proBNP at enrollment. Results: Median NT-proBNP in the overall study population was 71 ng/L (IQR 35-133). Baseline characteristics were similar across NT-proBNP concentrations, however, participants with higher NT-proBNP had higher left atrial volume (p<0.001) and higher right ventricular systolic pressure (p=0.04) on baseline echocardiogram. Higher NT-proBNP concentrations were associated with reduced physical activity reflected in lower PASE Score and a worse functional capacity reflected in lower peak VO2 (p<0.001) (Table 1). Conclusion: Among patients with DbCM, elevated NT-proBNP is associated with echocardiographic abnormalities and worse cardiac functional capacity and inversely associated with activity. Disclosure J.Butler: Consultant; Abbott,, Amgen, Applied Therapeutics, Array, Astra Zeneca, Bayer,, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharma,, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sequana Medical, Vifor, Speaker's Bureau; Novartis, Boehringer Ingelheim-Lilly, Astra Zeneca, Janssen. F.Zannad: Advisory Panel; BMS, Novo Nordisk, Pfizer Inc., Servier Laboratories, Other Relationship; Applied Therapeutics Inc., Bayer Inc., Boehringer Ingelheim and Eli Lilly Alliance, Merck & Co., Inc., Novartis. J.L.Januzzi: Consultant; Boehringer Ingelheim Inc., Janssen Pharmaceuticals, Inc., AstraZeneca, Research Support; Applied Therapeutics Inc., Abbott, Roche Diagnostics, Novartis, Innolife Co., Ltd. S.Del prato: Advisory Panel; Abbott Diagnostics, Altimmune, Amarin Corporation, Applied Therapeutics Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Vertex Pharmaceuticals Incorporated, Novartis, Consultant; A. Menarini Diagnostics, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. J.Ezekowitz: Advisory Panel; Applied Therapeutics Inc. N.E.Ibrahim: None. C.S.Lam: Other Relationship; Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Boehringer-Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, Us2.ai. R.Perfetti: None. J.Rosenstock: Advisory Panel; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Oramed Pharmaceuticals, Sanofi, Zealand Pharma A/S, Intarcia Therapeutics, Inc., Hanmi Pharm. Co., Ltd., Research Support; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck & Co., Inc., Novartis, Novo Nordisk, Pfizer Inc., Sanofi, Intarcia Therapeutics, Inc. W.Tang: Consultant; Sequana Medical NV, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics LLC, Renovacor, Boston Scientific Corporation, Kiniksa Pharmaceuticals Inc, WhiteSwell Inc, CardiaTec Biosciences Inc, Other Relationship; American Board of Internal Medicine, Springer Nature, Research Support; National Heart, Lung, and Blood Institute. A.Urbinati: None.

246-OR: Dapagliflozin Counteracts the Proapoptotic Effects of the Secretome of Visceral Adipose Cells from Obese Subjects in Human Cardiac Progenitor Cells via the SGLT2 Cotransporter

Dapagliflozin (DAPA), an SGLT2 inhibitor, has been shown to counteract heart failure outcomes in subjects with obesity and diabetes. We investigated the mechanisms of the protective action of DAPA in human cardiac progenitor cells (hCPC) exposed to the conditioned medium (CM) from abdominal visceral (AV) and epicardial (E) adipose stem cells (ASC) and from AV mature adipocytes from obese subjects. ASC and mature adipocytes were isolated from AV and E adipose tissue biopsies of 15 obese (Ob) and 13 non-Ob subjects (n-Ob), respectively. hCPC were isolated from right auricle biopsies of healthy non-Ob donors. Exposure of hCPC to the CM of adipose cells from Ob, but not from non-Ob subjects, induced apoptosis, c-Jun phosphorylation, and impairment of actin filaments, as assessed by ELISA assay and immunofluorescence, respectively, while these effects were not observed when the hCPC were pretreated with DAPA. The CM of adipose cells from Ob compared to n-Ob subjects displayed a different pattern of pro-inflammatory and anti-inflammatory cytokines. The levels of pro-inflammatory cytokines such as RANTES and MIP1β were increased in the CM from AV-ASC with higher BMI (p<0.05), while the levels of anti-inflammatory factors such as GCSF in the CM of E-ASC were inversely correlated with BMI (p<0.05). SGLT2 was found to be expressed as both mRNA and protein in the hCPC, and silencing of SGLT2 with a specific siRNA attenuated the capacity of DAPA to counteract the pro-apoptotic effects of the CM. In conclusion, we show that: i) in human obesity, the CM of both AV- and E-ASC and mature adipocytes is characterized by pro-inflammatory cytokines that induce stress kinase activation and apoptosis in the hCPC; ii) hCPC express SGLT2 mRNA and protein; iii) DAPA prevents the hCPC damage induced by the CM through an SGLT2-dependent mechanism. Disclosure G.Palma: None. A.Natalicchio: Other Relationship; AstraZeneca, Novo Nordisk, Sanofi, Boehringer-Ingelheim, Lilly. L.Laviola: Advisory Panel; A. Menarini Diagnostics, Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Roche Diabetes Care, Sanofi, Other Relationship; Medtronic, Speaker's Bureau; Abbott, Terumo Corporation. A.Pezzolla: None. F.Giorgino: Advisory Panel; Boehringer-Ingelheim, Amarin Corporation, Medtronic, Roche Diabetes Care, Sanofi, Bayer Inc., Novo Nordisk, Consultant; Novo Nordisk, Lilly, Research Support; Lilly, Roche Diabetes Care, AlfaSigma, Speaker's Bureau; Abbott, Boehringer-Ingelheim, Lilly, Sanofi, Medscape. S.Perrini: None. C.Caccioppoli: None. R.Doria: None. V.Genchi: None. I.Calderoni: None. A.Braun: None. G.Santarpino: None. A.D.Milano: None. A.Cignarelli: Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi.

613-P: Low Muscle Mass and/or Function Is Common in Type 2 Diabetes

Sarcopenia (low muscle mass/muscle function [MM/MF]) and sarcopenic obesity (sarcopenia+obesity, SO) have relevant clinical implications, but few data are available on pts with type 2 diabetes (T2D), especially in Western populations. We assessed the proportion of Caucasian pts with T2D and sarcopenia/SO and clinical correlates of sarcopenia. During routine follow-up outpatient visits (Jun-Dec 2022), we measured skeletal MM by bioelectrical impedance analysis (BIA) and MF by hand-grip strength in all pts except those with contraindications to BIA. Low MM and low MF were diagnosed using validated sex- and sex-/age-specific cut-offs, respectively, as recommended by ESPEN & EASO. Anthropometrics, glycemic control (HbA1c) and type/number of complications were recorded for all pts. A total of 116 pts with T2D were included (64.7% F, median [25°; 75° percentile] age 70.0 [62.3; 78.0] years, 35.3% with obesity). Sarcopenia was diagnosed in 12.9% of pts. Of these, 40% (5.2% of the total) had SO. Low MM with normal MF (LMM) and low MF with normal MM (LMF) were found in 16.4% and 21.6% of pts. There were no significant differences in sex, age, HbA1c, or number of complications between patients with or without sarcopenia nor among subgroups, but the proportion of elderly pts (age ≥65y) was lower among those with vs those without sarcopenia (26.7% vs 57.4%, p=0.026). Median BMI was greater (p<0.05) in pts with LMM or sarcopenia vs those with normal MM/MF or LMF (31.6 [30.5; 34.6], 29.2 [26.1; 34.8], 26.7 [23.4; 30.4] and 24.5 [21.3; 29.8] kg/m2, respectively). At logistic regression adjusted by sex and age, the likelihood of sarcopenia increased by 11.4% for each unit increase in BMI (odds ratio 1.114, [95%CI 1.01; 1.23] p=0.037). In conclusion, the majority of Caucasian pts with T2D has low MM, MF or both (sarcopenia), the risk of sarcopenia increasing with greater BMI. The lower proportion of elderly suggests reduced life expectancy in T2D pts with sarcopenia. The assessment of sarcopenia in T2D should be implemented in routine clinical practice. Disclosure C.Conte: None. S.Boussetta: None. F.Leva: None. P.Moro: None. C.C.Berra: None. L.Luzi: Advisory Panel; Eli Lilly and Company, Medtronic, Research Support; Gelesis, Speaker's Bureau; A. Menarini Diagnostics, Amgen Inc., Boehringer Ingelheim and Eli Lilly Alliance, Eli Lilly and Company, Novo Nordisk, Novartis.

373-OR: Repetitive Transcranial Magnetic Stimulation—A Potential Antiobesity Approach for Long-Term Maintenance of Weight Loss

Current anti-obesity interventions result in early rapid weight loss, but long-term maintenance of lost weight is much more challenging. Initial weight loss is typically followed by a weight plateau and progressive regain. We demonstrated the efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) in inducing long-term weight loss (up to 1 year) in individuals with obesity by modulating the brain dopaminergic system and the prefrontal cortex. In a post-hoc analysis, we re-evaluated body weight loss up to 3 years after, in 44 individuals treated with a 5-week high frequency rTMS or sham stimulation, for obesity. Out of 44 subjects, 30 individuals (21 F/9 M, BMI 35.3±2.8, age 49.9±9.3) did not undergo any further weight loss treatments (except diet), 9 subjects (5 F/4 M, BMI 40.4±4.7, age 44.7±.6.1) underwent bariatric surgery, and 5 patients were treated for persistent obesity with a GLP-1 receptor agonist (GLP1-RA) (5 F/0 M, BMI 36.8±6.5, age 53.2±13.9). Out of 30 subject who did not undergo any further weight loss intervention, the 16 patients who received real rTMS (10 F/6 M, BMI 34.6±3.2, age 49.2±7.5) reported a significant body weight loss compared to the Sham group (11 F/3M, BMI 36.1±2.0, age 50.7±2.0) at the end of the 5-week intervention (BMI:-4.5±1.7% vs -1.6±1.8%, p=0.0001). Crucially, they continued to lose body weight compared to the Sham even 3 years after the end of intervention (BMI: -9.5±7.6% vs -3.6±8.4%, p=0.056). As expected, during the 3-year follow-up, bariatric surgery was more effective in promoting weight loss compared to the rTMS and the GLP1-RA (p=0.0001), but rTMS has not been shown to be less effective than GLP1-RA in maintaining lost weight (p=0.621). This preliminary evidence of efficacy of rTMS in promoting long-term weight loss (over one year) may be explained via neuronal neuroplasticity. TMS alone or in combination with other anti-obesity approaches may open new ways to sustain the efficacy of weight control interventions. Disclosure A.Ferrulli: None. S.Massarini: None. C.Macrì: None. P.Senesi: None. I.Terruzzi: None. D.Cannavaro: None. L.Luzi: Advisory Panel; Eli Lilly and Company, Medtronic, Research Support; Gelesis, Speaker's Bureau; A. Menarini Diagnostics, Amgen Inc., Boehringer Ingelheim and Eli Lilly Alliance, Eli Lilly and Company, Novo Nordisk, Novartis. Funding IRCCS MultiMedica (Ricerca Corrente)