Zealand Pharma Research Articles

1195-P: Metformin and Growth Differentiation Factor 15 (GDF-15) in Youth with Type 2 Diabetes

Metformin is the only approved oral therapy in youth with type 2 diabetes (T2D-Y) but its molecular mechanisms remain controversial. Recent data links metformin-induced weight loss with increased levels of a peptide hormone, growth differentiation factor 15 (GDF15). Yet high GDF15 is linked to high stress and lipolysis and its value in T2D-Y is known. We compared fasting GDF15 in 32 T2D-Y not on metformin to 15 matched peers without diabetes and determined the change in GDF15 in 19 T2D-Y after 3 months of metformin (metformin only, n=13 and metformin + liraglutide, n=6). Youth were 15.5 ± 2.6 years (mean ± SD), 64% female, 78% African American with similar BMI 39 ± 7 kg/m2). T2D-Y had higher HbA1c (6.9 ± 1.1 vs. 5.6 ± 0.3%, P 0.2). GDF15 increased ≥2-fold in 6 of 18 T2D-Y (Figure). Overall, GDF15 correlated with age (r=0.4, P=0.01) but the change in GDF15 did not correlate with changes in glucose, weight, blood pressure, inflammatory markers, sex or treatment group. GDF15 was highly variable and not associated with cardiometabolic markers in youth. GDF15 markedly increased in a small subset of youth, but the determinants and implications of this change remain to be elucidated. Changes in GDF15 may have no association with metformin action. Disclosure S. Matta: None. M. W. Haymond: Advisory Panel; Self; Daiichi Sankyo, Zealand Pharma A/S, Other Relationship; Self; AstraZeneca, Stock/Shareholder; Self; Xeris Pharmaceuticals, Inc. S. T. Chung: None. C. K. Cravalho: None. A. Villalobos-perez: None. L. Mabundo: None. V. R. Sharma: None. M. Walter: None. J. M. Dawson: None. A. Zenno: None. A. B. Courville: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases

49-LB: Navigating Barriers to Affording and Obtaining Diabetes Treatment

The financial and personal sacrifices made in response to the high cost of insulin and diabetes supplies may jeopardize the health of people with diabetes (PWD). Yet, little is known about the accommodations PWD make to afford and obtain basic diabetes treatments. PWD (type 1 or type 2) between the ages of 1 and 41 were recruited from a large academic center and through social media. Surveys consisted of 87 questions and were completed by the primary person obtaining/paying for diabetes medications and supplies. Of 2004 surveys sent, we received 97 (5%) responses from predominantly white (87%), non-Hispanic (84%) individuals with private health insurance (79%). In the past year, 41% reported coming within 2-3 days of running out of insulin, and 47% reported running out of diabetes supplies prior to being able to obtain a refill. Additionally, 35% indicated rationing or obtaining insulin from clinics, friends, strangers, or other countries and 41% reported making other financial sacrifices due to issues affording insulin. Sixty-one percent reported receiving unconventional support for obtaining diabetes medications or supplies (Table). In our survey, the burden of obtaining medications and supplies was widely prevalent, even among those with private insurance. Most respondents experienced at least one barrier to access. Improved access to basic diabetes treatment is needed to prevent adverse outcomes among PWD. Disclosure A. Wilcox: None. L. Kerandi: None. K. J. Lipska: None. S. A. Weinzimer: Advisory Panel; Self; Dompe, Zealand Pharma A/S, Speaker’s Bureau; Self; Medtronic. L. M. Nally: None. Funding National Institutes of Health (5K12DK094714-10)

96-LB: Glycemic Management over 6 Months with the Omnipod 5 Automated Insulin Delivery System

Safe and effective use of the Omnipod 5 System was demonstrated in adults and children with type 1 diabetes (T1D) during a 3-month pivotal study. Longer studies are needed to evaluate durability of glycemic benefit. Those completing the pivotal study were invited to continue system use for an additional 12 months, with 95% enrolling in the extension. We present results from the first 3-month follow-up. Participants aged 6-70y with T1D≥6 months and A1C<10% used the system in Automated Mode at home. Following the pivotal study, A1C was measured again after 3 months (6 months of total use). Safety and efficacy endpoints were occurrence of severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) and change in A1C, respectively. Participants (n=217) were aged (mean±SD) 24±17y with T1D duration 11±11y. A1C was lower after 6 months of system use than at baseline for children and adults (p<0.001, Table). For children, A1C was not significantly different between end of pivotal and the 3-month extension, while adults had an additional -0.1% decrease (p<0.01). There was 1 episode of DKA and no episodes of SH during the 3-month extension phase. The safety and improved glycemic outcomes from the pivotal study persisted for an additional 3 months of system use in this large cohort of participants, with 99% continuing into the next extension phase. Sustained reduction of A1C indicates the potential long-term benefit of the Omnipod 5 System.View largeDownload slideView largeDownload slide DisclosureA. L. Carlson: Board Member; Self; JDRF, Other Relationship; Self; Medtronic, Research Support; Self; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, Omnipod, Sanofi, UnitedHealth Group. J. Sherr: Advisory Panel; Self; Cecelia Health, Insulet Corporation, Medtronic, Consultant; Self; Insulet Corporation, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Research Support; Self; Dexcom, Inc., Insulet Corporation, Medtronic, Speaker’s Bureau; Self; Lilly Diabetes. S. N. Mehta: None. L. M. Laffel: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompe, Insulogic LLC, Janssen Pharmaceuticals, Inc., Laxmi Therapeutic Devices, LifeScan, Lilly Diabetes, Medtronic, Provention Bio, Inc. V. Shah: Advisory Panel; Self; Medscape, Sanofi, Research Support; Self; Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Novo Nordisk, Sanofi, vTv Therapeutics. A. Bhargava: Research Support; Self; Abbott, AbbVie Inc., Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Boston Therapeutics, Inc., Covance Inc., Dexcom, Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Insulet Corporation, Janssen Research & Development, LLC, Kowa Pharmaceuticals America, Inc., Madrigal Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Mylan N. V., Novo Nordisk, Poxel SA, Quintiles, Sanofi, Senseonics, Tolerion, Inc., Viking Therapeutics. R. S. Weinstock: Research Support; Self; Boehringer Ingelheim International GmbH, Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Insulet Corporation, Kowa Research Institute, Inc., Medtronic, Tolerion, Inc. S. A. Macleish: Advisory Panel; Self; Insulet Corporation. D. Desalvo: Consultant; Self; Insulet Corporation, Research Support; Self; Insulet Corporation, Speaker’s Bureau; Self; Dexcom, Inc. T. C. Jones: None. G. Aleppo: Consultant; Self; Dexcom, Inc., Insulet Corporation, Research Support; Self; Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Novo Nordisk. A. B. Criego: Consultant; Self; Bigfoot Biomedical, Inc., Other Relationship; Self; Sanofi, Research Support; Self; Abbott Diabetes, Eli Lilly and Company, Insulet Corporation, Medtronic. B. A. Buckingham: Advisory Panel; Self; Medtronic, Tolerion, Inc., Research Support; Self; Beta Bionics, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care. T. T. Ly: Employee; Self; Insulet Corporation. Omnipod 5 research group: n/a. G. P. Forlenza: Advisory Panel; Self; Medtronic, Consultant; Self; Beta Bionics, Inc., Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care, Research Support; Self; Abbott Diabetes, Dexcom, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care. B. W. Bode: Advisory Panel; Self; Eli Lilly and Company, Consultant; Self; Bigfoot Biomedical, Inc., Companion Medical, Lexicon Pharmaceuticals, Inc., Medtronic, Novo Nordisk Inc., Zealand Pharma A/S, Research Support; Self; Abvance Therapeutics, Dexcom, Inc., Diasome Pharmaceuticals, Inc., Dompe, Eli Lilly and Company, Eyenuk, Inc., Insulet Corporation, Jaeb Center for Health Research, MedtroFundingInsulet Corporation

726-P: Glucose Control Using Fast-Acting Insulin Aspart in a Real-World Setting: A One-Year Multicenter Study in People with Type 1 Diabetes Using Continuous Glucose Monitoring

Objective: Data on switching from traditional mealtime insulin analogs to fast-acting insulin aspart (Fiasp) in routine clinical practice are sparse. The aim was to evaluate the efficacy and safety of this switch in a “real-world” clinical practice setting in adult people with type 1 diabetes (PWD1) who were using intermittent or real-time continuous glucose monitoring (iCGM or rtCGM) in Belgium. Research Design and Methods: Data from 438 adult PWD1 (60% men, age 44.6±16.1 y, duration of diabetes 21.5±14.0 y, iCGM/rtCGM: 391/47, multiple daily injections/pump: 409/29), who initiated Fiasp between January 2018 and May 2020 were retrospectively analyzed. The primary endpoint was the evolution of time in range (TIR, 70-180 mg/dl) at 6 (n=416) and 12 months (n=380). Secondary endpoints included change in HbA1c, BMI, insulin doses, time below range (T&amp;lt;70 and T&amp;lt;54 mg/dl) and time above range (T&amp;gt;180 and T&amp;gt;250 mg/dl). Results: TIR improved from 50.3±15.6% to 54.3±15.1% at 6 months and 55.5±15.2% at 12 months (p&amp;lt;0.0001), corresponding to an increase of 75 minutes/day at 12 months. T&amp;lt;70 mg/dl evolved from 7.4±5.5% to 7.6±5.8% and to 6.8±5.5% (p=0.037), and T&amp;lt;54 mg/dl evolved from 3.1±3.3% to 3.1±3.7% and 2.5±3.0% (p=0.003) at 6 and 12 months, respectively. Also, T&amp;gt;180 mg/dl decreased from 42.3±16.7% to 38.1±16.5% and to 37.7±16.9% (p&amp;lt;0.0001), and T&amp;gt;250 mg/dl evolved from 16.5±12.8% to 13.8±11.8% and to 13.1±12.5% (p&amp;lt;0.0001) at 6 and 12 months. At 12 months HbA1c (from 7.8±1.1% to 7.7±1.0%), insulin doses (0.66±0.24 to 0.62±0.21 units/kg body weight/day and ratio bolus/basal from 1.28 to 1.30) and BMI (from 25.8±4.0 to 26.2±4.1 kg/m2) did not change significantly. Conclusions: In a Belgian real-world setting of adult PWD1, switching to Fiasp resulted in a 5% increased TIR, corresponding to 75 min/day, in combination with less time spent below and above range. Disclosure L. Billion: None. F. W. Peiffer: None. K. P. Van dessel: None. C. Mathieu: Advisory Panel; Self; Novo Nordisk, Sanofi, Merck Sharp and Dohme Ltd., Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Insulet and Zealand Pharma, Research Support; Self; Medtronic, Novo Nordisk, Sanofi and ActoBio Therapeutics, Speaker’s Bureau; Self; Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, AstraZeneca and Novartis. P. Gillard: None. C. De block: Advisory Panel; Self; A. Menarini Diagnostics, Abbott Diagnostics, AstraZeneca, Boehringer Ingelheim , Eli Lilly and Company, MSD, Novartis AG, Novo Nordisk, Roche Diagnostics, Sanofi, Research Support; Self; AstraZeneca, Novo Nordisk, Speaker’s Bureau; Self; A. Menarini Diagnostics, Abbott Diagnostics, Boehringer Ingelheim , Eli Lilly and Company, Novo Nordisk, Sanofi. S. Charleer: None. L. Verbraeken: None. M. Sterckx: None. K. Vangelabbeek: None. N. De block: None. C. Janssen: None. N. Bolsens: Advisory Panel; Self; Medtronic. E. L. Dirinck: None.

738-P: Proposed Biosimilar Gan &amp; Lee Insulin Aspart (GL-ASP) Shows Pharmacokinetic (PK) and Pharmacodynamic (PD) Bioequivalence (BE) to U.S.- and EU-Licensed Insulin Aspart (ASP)

This randomized, double-blind, three-way crossover trial (NCT04237129) investigated the PK and PD properties of GL-ASP, a proposed biosimilar ASP by Gan & Lee, US licensed Novolog® and EU authorized NovoRapid® (US-ASP and EU-ASP) in 36 healthy male subjects (mean±SD age 36±12 years, BMI 24.3±2.7 kg/m²). Each subject received a single 0.2 U/kg dose of either GL-ASP, US-ASP or EU-ASP in each of the 3 euglycemic glucose clamp periods (ClampArt, clamp level 81 mg/dl, clamp duration 12h post-dose). GL-ASP and comparator insulins showed superimposable ASP concentration- and glucose infusion rate (GIR) profiles (Figure). PK BE was demonstrated between GL-ASP and the two comparator insulins as serum ASP concentration point estimates (using log-transformed data) were close to 100% and 90% CIs were well contained within the pre-defined similarity margins of 80-125% (Figure). Likewise, the primary PD endpoints met BE-criteria as did the secondary PK/PD-endpoints AUCASP.0-2h and AUCGIR.0-2h. Sensitivity analyses with untransformed data or exclusion of profiles with C-peptide increases confirmed PD BE. Adverse events were rare with all insulins (7-14 events per insulin, only 1 injection site reaction [mild erythema] with GL-ASP). In conclusion, GL-ASP demonstrated both PK- and PD-bioequivalence to US- and EU-licensed ASP formulations. Disclosure L. Plum-moerschel: None. E. H. Uhrmacher: None. E. Zijlstra: Speaker’s Bureau; Self; Novo Nordisk A/S. J. Lu: Employee; Self; Gan & Lee Pharmaceuticals. M. G. Wilson: Consultant; Self; Gan & Lee Pharmaceuticals, Employee; Spouse/Partner; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company, Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. M. E. Barton: Employee; Self; Gan & Lee Pharmaceuticals. T. Heise: Advisory Panel; Self; Novo Nordisk A/S, Valbiotis, Research Support; Self; ADOCIA, Afon Technology Ltd., AstraZeneca, Biocon, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Gan & Lee Pharmaceuticals, Johnson & Johnson, Julphar, Mylan N. V., Nestle, Neuraly, Nordic Bioscience, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker’s Bureau; Self; Novo Nordisk A/S. Funding Gan & Lee Pharmaceuticals

1197-P: Effect of Somatostatin Receptor 2 Antagonist (SSTR2a) on Glycemia and Glucagon Levels in a Rat Model of Type 2 Diabetes (T2D)

Background: Defective glucagon counterregulation to hypoglycemia in T1D involves elevated somatostatin signalling on the α cell. In rats, SSTR2a treatment (ZT-01 Methods: High fat fed, low dose streptozotocin (T2D) and healthy rats were treated with subcutaneous ZT-01 or vehicle (N=7-8/group). Glycemia, glucagon and C-peptide were measured for 4 h post-dose. Results: SSTR2a treatment promoted a significant rise in basal glucagon in both T2D and control rats, up to 3 hours post-dose. Basal C-peptide was lower in T2D versus healthy rats (1.9 vs. 2.5 ng/ml) increasing in both groups 30 min after SSTR2a dosing (2.7 vs. 4.1 ng/mL). Both diabetes (p=0.03) and treatment (p=0.01) were significant effects (2-way ANOVA). Post-dose glucose was elevated from baseline in T2D but not in healthy rats. Conclusion: High dose SSTR2a transiently increased glucagon. C-peptide was increased to a lesser extent in T2D. Consequently, glucose levels were affected in T2D but not healthy rats. Insulin production and sensitivity in T2D may play an important role in responses to SSTR2a in this model. Disclosure N. C. D9souza: None. E. G. Hoffman: None. S. C. Atherley: None. S. Champsi: None. M. Popkov: None. R. Liggins: Employee; Self; Zucara Therapeutics Inc. M. Riddell: Advisory Panel; Self; Zealand Pharma A/S, Consultant; Self; Lilly Diabetes, Research Support; Self; Dexcom, Inc., Insulet Corporation, Speaker9s Bureau; Self; Novo Nordisk Inc., Sanofi, Stock/Shareholder; Self; Zucara Therapeutics Inc. Funding GlycoNet

225-OR: Cardiovascular Autonomic Neuropathy and Risk of Heart Failure in Participants with Type 2 Diabetes Enrolled in DEVOTE Trial

Aims: We assessed whether cardiovascular autonomic neuropathy (CAN), as assessed by heart rate variability (HRV), is associated with an increased risk of heart failure (HF) in 6347 patients with type 2 diabetes (T2D) enrolled in the DEVOTE trial with HRV data available. Methods: DEVOTE was a randomized, double-blind trial comparing the impact of insulin degludec to glargine 100 units/mL on cardiovascular outcomes. Indices of HRV were derived from 10-sec standard electrocardiogram at enrollment, with values below the 5th percentile of the cohort defined as abnormal. Time to first hospitalization due to HF was analyzed using Kaplan-Meier survival curves and the log-rank test. Results: A total of 369 (5.8%) had CAN. Participants with and without CAN had significant different [mean(standard deviation)] age [63.4(7.3) and 64.9(7.3) years], A1C [8.9(1.9) and 8.4(1.6)%], body mass index [33.0(7.4) and 33.6(6.8) kg/m2] and number of subjects from minority ethnicity [19.5 and 15.2%], respectively (P Conclusion: These data suggest that CAN may be used for risk stratifying in patients with T2D at risk for developing symptomatic HF. Disclosure R. Pop-busui: Advisory Panel; Self; Novo Nordisk, Consultant; Self; Averitas Pharma, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Nevro Corp., Regenacy. L. Ang: None. S. Hayek: Advisory Panel; Self; Walden Biosciences. K. R. Mizokami-stout: None. E. Parvaresh rizi: Employee; Self; Novo Nordisk. I. Lingvay: Advisory Panel; Self; Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Consultant; Self; TARGET PharmaSolutions, Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk, Pfizer Inc., Zealand Pharma A/S, Research Support; Self; Mylan N. V., Sanofi. On behalf of the devote study group: n/a. Funding Novo Nordisk

342-P: Effects of Sitagliptin on Hypoglycemic Episodes and Counterregulation in Type 2 Diabetic Patients Tightly Titrated with Insulin Glargine

DPP-4 inhibitors may prevent hypoglycemic episodes in insulin-treated type 2 diabetes (T2D), but mechanisms are unclear. 20 T2D patients treated with basal insulin and metformin (± other agents) were recruited for two randomized treatments (placebo or 100 mg/d sitagliptin) in addition to insulin glargine/metformin; 17 completed (3 women, 14 men; age 57 ± 7 yrs.; BMI 28.8 ± 3.9 kg/m2; HbA1c 7.4 ± 0.7 %). After titrating fasting plasma glucose (PG) to 90-110 mg/dl, patients were observed during a 3-day (d) inpatient period with exposure to oral glucose or lipid loads, strenuous exercise and fasting, while increasing insulin doses to 110, and 120 % of the titrated dose before d 2 and 3, respectively. Hypoglycemic episodes (PG &amp;lt; 70 mg/dl) were identified by measuring venous plasma glucose or symptoms, and prompted the determination of counter-regulatory hormones at the glucose nadir and 30 and 60 min later. After titrating insulin glargine, fasting PG was 112 ± 5 and 107 ± 5 mg/dl with placebo and sitagliptin treatment, respectively. Concentrations of insulin, C-peptide and counterregulatory hormones were similar during both treatments. Hypoglycemic episodes were mainly nocturnal (10 p.m. to 7 a.m.), with a similar PG nadir (65 ± 4 mg/dl) and incidence with placebo and sitagliptin (4.5 ± 3.2 vs. 4.6 ± 3.6 episodes per patient, respectively, p = 0.96). With a similar incidence of daytime (7 a.m. to 10 p.m.) chemical hypoglycemia, the incidence of symptomatic episodes was higher with sitagliptin (0.2 ± 0.4 vs. 0.0 ± 0.0, p = 0.028). Counter-regulatory responses were suppressed by sitagliptin for cortisol (p = 0.022), unchanged for glucagon, HGH, noradrenaline and prolactin, and accentuated for adrenaline (p = 0.022). Our results suggest that sitagliptin treatment augments counter-regulatory responses of adrenaline at minimal degrees of hypoglycemia. This may increase symptoms, in particular during daytime, and may offer opportunities for earlier treatment. Disclosure M. A. Nauck: Advisory Panel; Self; Berlin-Chemie AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk, Consultant; Self; Eli Lilly and Company, Novo Nordisk, Research Support; Self; Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk, Speaker’s Bureau; Self; Berlin-Chemie AG, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk. A. Feldmann: None. J. J. Meier: Advisory Panel; Self; AstraZeneca, MSD Corporation, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, MSD Corporation, Novo Nordisk, Sanofi. M. Nauck: None. C. Kapitza: Research Support; Self; ADOCIA, Afon Technology, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gan &amp; Lee Pharmaceuticals, Johnson &amp; Johnson, Julphar, Mylan N. V., Nestlé, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Funding Merck Sharp &amp; Dohme Corp

740-P: Proposed Biosimilar Gan &amp; Lee Insulin Glargine (GL-GLA) Shows Pharmacokinetic (PK) and Pharmacodynamic (PD) Bioequivalence (BE) to U.S.- and EU-Licensed Insulin Glargine (IG)

This randomized, double-blind, three-way crossover trial (NCT04236895) compared the PK and PD properties of GL-GLA, a proposed biosimilar IG by Gan & Lee, US- and EU-licensed Lantus® (US-IG and EU-IG) in 114 male subjects with type 1 diabetes (mean±SD age 42±8 years, BMI 25.8±2.0 kg/m²). Each subject received a single 0.5 U/kg dose of either GL-GLA, EU-IG, or US-IG in each of the 3 euglycemic glucose clamp periods (ClampArt, clamp level 100 mg/dl, clamp duration 30h post-dose). PK is presented as concentrations of the mainly absorbed IG metabolite M1. GL-GLA and comparator insulins showed superimposable profiles for PK and glucose infusion rates (GIR, Figure). PK BE was demonstrated between GL-GLA and the comparator insulins as the point estimates for measured metabolite M1 were close to 100% and 90% CIs were well contained within the pre-defined similarity margins of 80-125% (Figure). Likewise, the primary PD endpoints met BE-criteria as did secondary PK/PD-endpoints including AUCM1.0-12h, AUCM1.12-24h, AUCGIR.0-12h, and AUCGIR.12‑24h. All insulins were well tolerated with similar adverse event rates (19% [GL-GLA]; 26% [US-IG]; 21% [EU-IG]) and only few events of injection site reactions per insulin. In conclusion, GL-GLA demonstrated both PK- and PD-bioequivalence to US- and EU-licensed insulin glargine formulations. Disclosure T. Heise: Advisory Panel; Self; Novo Nordisk A/S, Valbiotis, Research Support; Self; ADOCIA, Afon Technology Ltd., AstraZeneca, Biocon, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Gan & Lee Pharmaceuticals, Johnson & Johnson, Julphar, Mylan N. V., Nestle, Neuraly, Nordic Bioscience, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker’s Bureau; Self; Novo Nordisk A/S. L. Plum-moerschel: None. G. Andersen: None. J. Lu: Employee; Self; Gan & Lee Pharmaceuticals. M. G. Wilson: Consultant; Self; Gan & Lee Pharmaceuticals, Employee; Spouse/Partner; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company, Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. E. Zijlstra: Speaker’s Bureau; Self; Novo Nordisk A/S. Funding Gan & Lee Pharmaceuticals

65-LB: Real-World Continuous Glucose Monitoring Data on Time-in-Range from a U.S. Population, 2015–2019

Aims: Improvements in technology and access have led to growing adoption of continuous glucose monitoring (CGM). Targets for glucose metrics including time in range (TIR) have been published. We aimed to investigate i) the proportion of people with ≥70% TIR and ii) the proportion with ≥70% TIR and Methods: Data were collected from 2015 to 2019 from the Cornerstone4Care (C4C) database, a freely available patient support program for people with both type 1 diabetes (T1D) and type 2 diabetes (T2D) on any treatment type. CGM traces were divided into 14-day periods according to the ambulatory glucose profile (AGP)-reporting system. Only profiles with data aligned with these standards were included. Patient data are presented using the first or the mean of all AGP profiles. Results: In total, 484 persons uploaded CGM-data to the database (4727 AGPs); 242 had T1D and 74 had T2D (self-reported), the rest were unknown (Table). People uploaded between 1 and 75 AGPs (mean=10). Average TIR (70-180 mg/dL) based on mean profiles was 63%, 68% and 64% for T1D, T2D and all, respectively. Conclusions: Less than half of the population achieved ≥70% TIR, ~30% with ≥70% TIR and Disclosure R. M. Bergenstal: Advisory Panel; Self; Abbott Diabetes, Eli Lilly and Company, Novo Nordisk, Onduo LLC., Roche, Sanofi, United Healthcare, Consultant; Self; Abbott Diabetes, Ascensia, Dexcom, Inc., Eli Lilly and Company, Hygieia, Johnson & Johnson, Medtronic, Novo Nordisk, Onduo LLC., Roche, Sanofi, United Healthcare, Other Relationship; Self; HealthPartners Institute, Research Support; Self; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Helmsley Charitable Trust, Hygieia, Johnson & Johnson, Medtronic, NIDDK, Novo Nordisk, Onduo LLC., Roche, Sanofi, United Healthcare. E. Hachmann-nielsen: Employee; Self; Novo Nordisk A/S. J. Tarp: Employee; Self; Novo Nordisk. K. Kvist: Employee; Self; Novo Nordisk A/S. J. B. Buse: Consultant; Self; Cirius Therapeutics, CSL Behring, Fortress Biotch, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego Inc., Stability Health, Zealand Pharma A/S, Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk, vTv Therapeutics, Research Support; Self; NovaTarg Therapeutics, Novo Nordisk, Sanofi, Tolerion, Inc., vTv Therapeutics, Stock/Shareholder; Self; Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Stability Health. Funding Novo Nordisk A/S

215-OR: Performance of a Dual Hormone Closed-Loop System vs. an Insulin-Only Closed-Loop System during Challenging Inpatient Conditions: A Single-Blinded Randomized Controlled Crossover Trial

Objective: To assess the efficacy and safety of an insulin-glucagon dual-hormone (DH) compared with an insulin-only single-hormone (SH) closed-loop system. Methods: In a 33-h, randomized, crossover, inpatient study, 13 participants with type 1 diabetes used two modes of the DiaCon Artificial Pancreas system: DH and SH closed-loop control. During each study period, participants had two overnight stays, received an underbolus (50%) for their breakfast, normal bolus (100%) for lunch, overbolus (130%) for dinner and performed unannounced exercise for 45 min (bicycled at estimated 50% V02max). The co-primary endpoints were sensor-based percentage of time in hypoglycemia (&amp;lt;3.9 mmol/L) and the number of 15 g carbohydrate rescues whenever plasma glucose &amp;lt;3.0 mmol/L from 0 to 33 h after initiation of the systems. Results: Overall, the average number of carbohydrate rescues was significantly lower during DH compared with SH (mean±SD: 0.8±1.3 vs. 1.4±1.4 per 33 h, p = 0.04). The percentages of time in hypoglycemia (3.6±2.1% vs. 3.8±3.3%, p = 0.46), target range (3.9-10.0 mmol/L: 67.2±15.4% vs. 65.3±12.4%, p = 0.41) and hyperglycemia (&amp;gt;10.0 mmol/L: 26.8±16.0% vs. 28.7±12.7%, p = 0.41) were similar between study arms. Mean glucose was lower for DH than SH (8.3±1.2 vs. 8.6±1.0 mmol/L, p = 0.04) with similar coefficient of variation (40±8.3 vs. 38±5.0%, p = 0.30). From exercise start and 4 h onwards, DH achieved more time in range (86.7±11.7 vs. 74.7±16.5%, p = 0.01), but similar time in hypoglycemia (10.5±18.7 vs. 12.6±24.3%, p = 0.32) and numbers of carbohydrate rescues (5±0.7 vs. 6±0. 7, p = 0.38). No differences were observed on visual analog scale-measured nausea (p = 0.47), headache (p = 0.77), hunger (p = 0.66), and palpitation (p = 0.11). Conclusions: During challenging inpatient conditions, the DH system achieved similar glucose control but significantly reduced need for carbohydrate rescue compared with SH. Disclosure A. G. Ranjan: None. D. Boiroux: Consultant; Self; Novo Nordisk A/S, Employee; Spouse/Partner; Novo Nordisk A/S. C. Laugesen: None. S. Schmidt: None. A. T. Reenberg: None. J. B. Jørgensen: None. K. Nørgaard: Advisory Panel; Self; Medtronic, Other Relationship; Self; Novo Nordisk Inc., Zealand Pharma A/S, Speaker’s Bureau; Self; Medtronic. Funding Danish Diabetes Association; Danish Diabetes Academy (PD002-19)

1111-P: Integrating Longitudinal Clinical and Baseline Multiomics Data for Predicting C-Peptide Progression in Newly Diagnosed Type 1 Diabetes

Background: Development of disease-modifying therapy for type 1 diabetes (T1D) is hampered by the limited understanding of pathogenesis, heterogeneity, lack of disease biomarkers and stratifiers. Using the INNODIA consortium pan-European infrastructure to collect prospective clinical data from newly diagnosed subjects combined with multi-omics data, we mined integrated datasets using deep learning to identify novel relationships that could transform the disease monitoring landscape. Method: Samples collected &amp;lt;6 weeks from diagnosis from 100 islet autoantibody positive participants were prioritised for omics analysis and the data integrated with clinical parameters and C-peptide (CP) from mixed meal tolerance tests (at 3, 6 and 12 months). SNP array data, plasma metabolomics, lipidomics and miRNAs, serum proteomics, whole blood RNA-sequencing and multiFACS immunomics from PBMCs were collected. We applied a variational autoencoder (VAE) to simultaneously integrate the data and learn CP progression over 12 months. The latent (lower dimensional) representation of the VAE integrated data was clustered to identify clinically meaningful subgroups. Results: Clustering identified five age-independent subgroups with significantly different progression patterns (p&amp;lt;0.05). Cluster 1 and 3 associated with lower fasted and stimulated CP. Cluster 2 and 5 associated with higher fasted CP, while cluster 4 most strongly associated with higher stimulated CP. Cluster 1 had the lowest stimulated CP at baseline, cluster 5 the lowest fasted CP and cluster 4 the highest fasted and stimulated CP at baseline. Investigation of the most predictive signals from the omics data is ongoing. Discussion: The preliminary results suggest that the VAE can learn meaningful progression patterns from integrated clinical and multi-omics data, which holds great promise to uncover important data structures not readily discovered when analyzing single data types. Disclosure C. Brorsson: Employee; Spouse/Partner; Novo Nordisk A/S. J. Almagro armenteros: None. G. Mazzoni: Employee; Self; Novo Nordisk A/S. S. Kaur: None. A. M. Schulte: None. C. Mathieu: Advisory Panel; Self; Novo Nordisk, Sanofi, Merck Sharp and Dohme Ltd., Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Insulet and Zealand Pharma, Research Support; Self; Medtronic, Novo Nordisk, Sanofi and ActoBio Therapeutics, Speaker’s Bureau; Self; Novo Nordisk, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, AstraZeneca and Novartis. S. Brunak: Board Member; Self; Intomics A/S, Proscion A/S, Stock/Shareholder; Self; Hoba Therapeutics Aps, Novo Nordisk A/S. On behalf of the innodia consortium: n/a. Funding INNODIA (115797)

131-OR: ADA Presidents’ Select Abstract: Effect of Insulin Degludec vs. Insulin Glargine U100 on Occurrence of Nocturnal Hypoglycemia Assessed by Nocturnal Plasma Glucose Profiles in People with Type 1 Diabetes Prone to Nocturnal Severe Hypoglycemia

Background and Aims: The risk of nocturnal hypoglycemia (NH) is a limiting factor for achieving good glycemic control in people with type 1 diabetes (T1D). Insulin degludec (IDeg) is proven to lower the risk of self-reported NH. As most episodes of NH are asymptomatic, we assessed differences in occurrence of NH by hourly plasma glucose (PG) measurements at treatments with IDeg or insulin glargine U100 (IGlar) in people with T1D suffering from recurrent nocturnal severe hypoglycemia. Materials and Methods: Pre-defined optional substudy of the HypoDeg trial, a 2-year investigator-initiated, randomized, cross-over trial where 149 participants with T1D were randomized to treatment with IDeg or IGlar. Fifty-one participants (mean (SD) age 58 (13) years, diabetes duration 28 (14) years and HbA1c 7.8 (1) %) were admitted for two nights for hourly blinded plasma glucose measurements for a minimum of one night (23:00h to 07:00h) during each 1-year treatment period. The primary endpoints were NH at level 1 (PG ≤ 3.9 mmol/L) and level 2 (PG &amp;lt; 3.0 mmol/L). Results: We collected data from 196 nights. A total of 57 nights (regardless of level) in 33 participants were hypoglycemic, including 20 nights with symptomatic hypoglycemia. The incidence of NH at level 1 was lower when treated with IDeg [17 events in 97 nights (18%)] as compared to IGlar [36 events in 99 nights (36%)], corresponding to a hazard ratio (HR) of 0.39 (95% CI: 0.22-0.71; p=0.002) during treatment with IDeg. At level 2, the incidence of NH was also lower during treatment with IDeg [8 events in 97 nights (8%)] as compared to IGlar [20 events in 99 nights (20%)], corresponding to an HR of 0.36 [95% CI: 0.16-0.80; p=0.013] during treatment with IDeg. Conclusion: In people with T1D and recurrent nocturnal severe hypoglycemia, treatment with IDeg as compared to IGlar results in a clinically significant lower rate of NH at both levels of hypoglycemia. Disclosure J. M. Brøsen: None. S. Lerche: None. K. Nørgaard: Advisory Panel; Self; Medtronic, Other Relationship; Self; Novo Nordisk Inc., Zealand Pharma A/S, Speaker’s Bureau; Self; Medtronic. H. D. Parving: None. L. Tarnow: None. B. Thorsteinsson: None. U. Pedersen-bjergaard: Advisory Panel; Self; Novo Nordisk A/S, Sanofi-Aventis, Consultant; Self; Abbott, Speaker’s Bureau; Self; Novo Nordisk A/S. R. Agesen: Employee; Self; Novo Nordisk. P. L. Kristensen: Speaker’s Bureau; Self; AstraZeneca, Eli Lilly and Company. A. Alibegovic: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. H. U. Andersen: Stock/Shareholder; Self; Novo Nordisk A/S. P. Gustenhoff: None. C. Hedetoft: None. T. Jensen: Stock/Shareholder; Self; Novo Nordisk A/S. C. B. Juhl: None. Funding Novo Nordisk

606-P: Higher Derived Time-in-Range with IDegLira vs. Insulin Glargine U100 in Patients with T2D

Aims: To compare derived time in range (dTIR) with insulin degludec/liraglutide (IDegLira) and insulin glargine 100 units/mL (IGlar U100) in patients with type 2 diabetes (T2D). Methods: Data from DUAL V, a trial of patients with T2D uncontrolled on IGlar U100 randomized to switch to IDegLira or up-titration of IGlar U100 (+metformin; n=557), and DUAL VIII, a durability trial of insulin-naive patients with T2D randomized to either IDegLira or IGlar U100 (+ oral antidiabetic drugs; n=1012), were evaluated post hoc. Self-monitored blood glucose profiles (weeks 0, 12, and 26 [DUAL V] or weeks 0, 26, and 104 [DUAL VIII]) were used to derive the proportion of available readings within (dTIR: 70-180 mg/dL [3.9-10 mmol/L]), below (dTBR: 180 mg/dL [>10 mmol/L]) target range. Results: Estimated treatment differences (IDegLira− IGlar U100) for change from baseline to end of treatment (EOT) in dTIR were significantly greater with IDegLira vs. IGlar U100 (Figure). The proportion of patients achieving ≥70% dTIR at EOT with IDegLira and IGlar U100, respectively, was 62% and 60% in DUAL V, and 50% and 26% in DUAL VIII; the proportion achieving a ≥5% increase in dTIR from baseline to EOT was 63% in both groups in DUAL V, and 44% and 25%, respectively, in DUAL VIII. Conclusion: IDegLira was associated with significantly greater dTIR vs. IGlar U100 in insulin-experienced and insulin-naive patients with T2D. Disclosure A. Philis-tsimikas: Advisory Panel; Self; Bayer Inc., Lilly Diabetes, Medtronic, Novo Nordisk, Consultant; Self; Sanofi-Aventis, Employee; Spouse/Partner; Ionis, Other Relationship; Self; Merck & Co., Inc., Research Support; Self; Dexcom, Inc., Lilly Diabetes, Medtronic, Novo Nordisk, Sanofi-Aventis. V. R. Aroda: Consultant; Self; Applied Therapeutics, Duke, Novo Nordisk, Pfizer Inc., Sanofi, Employee; Spouse/Partner; Janssen , Merck , Research Support; Self; Applied Therapeutics, Eli Lilly and Company, Fractyl , Medpace, Medpace, Novo Nordisk, Premier , Sanofi, Stock/Shareholder; Spouse/Partner; Janssen, Merck. C. De block: Advisory Panel; Self; A. Menarini Diagnostics, Abbott Diagnostics, AstraZeneca, Boehringer Ingelheim , Eli Lilly and Company, MSD, Novartis AG, Novo Nordisk, Roche Diagnostics, Sanofi, Research Support; Self; AstraZeneca, Novo Nordisk, Speaker9s Bureau; Self; A. Menarini Diagnostics, Abbott Diagnostics, Boehringer Ingelheim , Eli Lilly and Company, Novo Nordisk, Sanofi. L. K. Billings: Advisory Panel; Self; Bayer Inc., Lilly Diabetes, Novo Nordisk, Sanofi. E. Hachmann-nielsen: Employee; Self; Novo Nordisk A/S. A. Liebl: Advisory Panel; Self; AstraZeneca, Becton, Dickinson and Company, Boehringer Ingelheim International GmbH, Eli Lilly and Company, MSD, Novo Nordisk, Roche, Speaker9s Bureau; Self; AstraZeneca, Bayer, Becton, Dickinson and Company, Boehringer Ingelheim International GmbH, Bristol Myers Squibb , Dexcom, Inc., Eli Lilly and Company, Medtronic, MSD, Novo Nordisk, OmniaMed, Roche, Sanofi. R. Sivarathinasami: Employee; Self; Novo Nordisk Service Centre India Private Ltd. J. M. D9cruz: Employee; Self; NovoNordisk GBS. I. Lingvay: Advisory Panel; Self; Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Consultant; Self; TARGET PharmaSolutions, Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk, Pfizer Inc., Zealand Pharma A/S, Research Support; Self; Mylan N. V., Sanofi. Funding Novo Nordisk A/S

83-OR: Influence of Baseline Characteristics on Weight Loss with Semaglutide 2.4 mg in Adults with Overweight/Obesity and Type 2 Diabetes (STEP 2)

Weight loss (WL) with semaglutide 2.4 mg vs. placebo (PBO) in the STEP 2 trial was analyzed according to baseline characteristics. STEP 2 was a 68-week RCT (NCT03552757). Adults (N=1210) with BMI ≥27 kg/m2 and type 2 diabetes (T2D; HbA1c 7-10% [53-86 mmol/mol]) were randomized to once‑weekly s.c. semaglutide 2.4 mg, 1.0 mg (data not shown) or PBO. Categorical WL was evaluated at week 68 by baseline age, sex, race, body weight (BW), HbA1c, and diabetes therapy. The odds of achieving WL ≥5% or ≥10% for these parameters were compared using post-hoc logistic regression analyses (not controlled for multiplicity). At week 68, the proportions of patients (pts) with WL ≥5% and ≥10% were 73.2% and 49.9% for semaglutide 2.4 mg vs. 27.6% and 7.1% for PBO. Pts were significantly more likely to achieve WL ≥5% or ≥10% with semaglutide 2.4 mg vs. PBO in most subgroups (Table). There were no significant interactions for any subgroups, except sex; the odds ratios for achieving WL ≥5% or ≥10% with semaglutide 2.4 mg vs. PBO were more than double for females vs. males (p Disclosure I. Lingvay: Advisory Panel; Self; Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Consultant; Self; TARGET PharmaSolutions, Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk, Pfizer Inc., Zealand Pharma A/S, Research Support; Self; Mylan N. V., Sanofi. W. Garvey: None. L. Faerch: Employee; Self; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S. A. Koroleva: Employee; Self; Novo Nordisk A/S. R. F. Kushner: Advisory Panel; Self; Novo Nordisk A/S. C. Le roux: Advisory Panel; Self; Boehringer Ingelheim International GmbH, GI Dynamics, Herbalife International of America, Inc., Johnson & Johnson, Medtronic, Novo Nordisk A/S. S. Lim: None. O. Mosenzon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., BOL Pharma, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi, Research Support; Self; AstraZeneca, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. T. A. Wadden: Advisory Panel; Self; Novo Nordisk, Weight Watchers International, Inc. S. O. R. Wallenstein: Employee; Self; Novo Nordisk. Funding Novo Nordisk A/S

23-OR: ADA Presidents’ Select Abstract: Genetic Architecture and Novel Genes Implicated in Youth-Onset Type 2 Diabetes

Youth-onset type 2 diabetes (T2D) has a strong genetic predisposition and is regarded as a phenotypic extreme of adult-onset T2D. In this study, we aimed to investigate the contribution of rare coding variants to the genetic basis of youth-onset T2D by analyzing whole-exome sequences of 3,005 persons with youth-onset T2D (diagnosed before 20 years of age) from the Progress in Diabetes Genetics in Youth (ProDiGY) consortium and 9,777 ancestry matched adult controls. We identified three genes with aggregate rare variant associations reaching exome-wide significance (P&amp;lt;2.6×10-6). In addition, we were able to identify eight genes previously linked to diabetes that were included in the top 20 (P&amp;lt;2.0×10-6) overlapping biologically characterized gene sets. These 11 genes were classified into three groups: 1) monogenic diabetes-related genes (HNF1A, GCK, and RFX6), 2) obesity-related genes (MC4R, ATXN2L, GHRL, and CPQ), and 3) β-cell function related genes (SLC30A8, ABCC8, PAM, and SIX3). A novel exome-wide significant gene burden association was observed for ATXN2L with odds ratio (OR) 1.26, P=1.1×10-6. For known diabetes genes, the effect sizes of gene burden analysis in youth-onset T2D were much larger than that of adult-onset T2D: examples include MC4R (OR 3.5, P=1.7×10-11 vs. OR 2.1, P=2.7×10-10 in adults) and HNF1A (OR 7.5, P=1.2×10-10 vs. OR 1.2, P=0.022). In terms of liability variance explained, both common and rare variants contributed more to youth-onset T2D than they did to adult-onset T2D (3.1-fold enrichment for common variants, 5.3-fold enrichment for rare variants). However, greater enrichment of rare variants in youth-onset T2D caused the liability variance explained by rare variants to approach 28% of that explained by common variants, in contrast to 17% for adult-onset T2D. These data paint a picture of youth-onset T2D as a disease intermediate in extremity between monogenic diabetes and T2D, in which genetic variants in both insulin secretion and insulin response pathways are implicated. Disclosure S. Kwak: None. L. M. Laffel: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompe, Insulogic LLC, Janssen Pharmaceuticals, Inc., Laxmi Therapeutic Devices, LifeScan, Lilly Diabetes, Medtronic, Provention Bio, Inc. E. M. Isganaitis: None. M. W. Haymond: Advisory Panel; Self; Daiichi Sankyo, Zealand Pharma A/S, Other Relationship; Self; AstraZeneca, Stock/Shareholder; Self; Xeris Pharmaceuticals, Inc. L. L. Levitsky: Consultant; Self; Eli Lilly and Company. T. I. Pollin: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. J. Flannick: None. On behalf of the prodigy consortium: n/a. S. Srinivasan: None. L. Chen: None. J. Todd: None. E. T. Jensen: None. J. Divers: None. A. K. Mottl: Advisory Panel; Self; Bayer U. S. C. Pihoker: None. R. Gandica: None. Funding National Institutes of Health (1R01DK125490-01)

712-P: International Consensus on the Ethics of Open-Source Automated Insulin Delivery

Background: Despite observational evidence for the efficacy and safety of open-source automated insulin delivery (OS-AID) there is a lack of guidance for healthcare providers. The ethics of providing care for those using unregulated technology is a concern. Methods: Consensus guidelines are in development, through the OPEN project, by an experienced multi-disciplinary group of endocrinologists, diabetes care and education specialists, exercise physiologists and psychologists. Results: The principles of biomedical ethics - autonomy, justice, beneficence and non-maleficence - provide a framework for analysis. Autonomy requires that the user understands system risks and benefits. OS-AID provides complete transparency and customization, facilitating understanding and control. Algorithms used in commercial systems are proprietary, impeding the ability to discuss and personalize operation. Justice requires burdens and benefits be distributed fairly. Commercial systems are not uniformly accessible. OS-AID provides freely available software and allows the mixing and matching of compatible CGMs and pumps, supporting equity. Beneficence means doing good for the individual. In real-world observational trials both open-source (OpenAPS: n=34, mean TIR 71-&amp;gt;80% at max 2.5 years; Loop: n=558, mean TIR 67-&amp;gt;73% at 6 months) and commercial AID systems (670G: n=3141, mean TIR 66-&amp;gt;73% at 3 months; Control-IQ: n=1659, median TIR: 68-&amp;gt;78% at 1 month) provide a statistically significant and clinically meaningful increase in TIR at the population level. Non-maleficence requires treatment does not harm the individual. AID systems can reduce burden, hypoglycemia and hyperglycemia. Conclusions: The international consensus group concludes OS-AID is ethical, but unregulated. We recommend legal interpretations and frameworks be clarified and updated so that individuals are not deprived of beneficial therapy. Commercial AID systems may benefit from transparency and equity offered by OS-AID systems. Disclosure K. Braune: None. M. Riddell: Advisory Panel; Self; Zealand Pharma A/S, Consultant; Self; Lilly Diabetes, Research Support; Self; Dexcom, Inc., Insulet Corporation, Speaker’s Bureau; Self; Novo Nordisk Inc., Sanofi, Stock/Shareholder; Self; Zucara Therapeutics Inc. T. C. Skinner: Advisory Panel; Self; Liva Health Care, Novo Nordisk. K. Raile: Advisory Panel; Self; Abbott Diabetes, Lilly Diabetes, Research Support; Self; Dexcom, Inc. C. Johnston: None. R. Lal: Consultant; Self; Abbott Diabetes, Biolinq, Capillary Biomedical, Inc., Morgan Stanley, Tidepool. S. Hussain: Speaker’s Bureau; Self; Novo Nordisk. M. Quigley: None. L. Petruzelkova: None. G. Scheiner: Advisory Panel; Self; Capillary Biomedical, Inc., Companion Medical, Eli Lilly and Company, Consultant; Self; ADOCIA, Ascensia Diabetes Care, mySugr, Triple Jump, Ypsomed, Speaker’s Bureau; Self; Dexcom, Inc., Xeris Pharmaceuticals, Inc. P. Winterdijk: None. S. Schmidt: None. L. H. Raimond: None. K. K. Hood: Consultant; Self; Cecelia Health, Cercacor, LifeScan Diabetes Institute. Funding National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007217, 1K12DK122550, 1K23DK122017, P30DK116074); European Commission’s Horizon 2020 Research and Innovation Programme/Marie Sklodowska-Curie Action Research and Innovation Staff Exchange (RISE) grant agreement number 823902

Dasiglucagon: First Approval.

Dasiglucagon (Zegalogue®) is an antihypoglycaemic agent being developed by Zealand Pharma for the treatment of hypoglycaemia, type1 diabetes mellitus (T1DM) management and congenital hyperinsulinism. In March 2021, dasiglucagon received its first approval in the USA for the treatment of severe hypoglycaemia in paediatric and adult patients with diabetes aged 6years and above. Dasiglucagon, a glucagon analogue, is available as a single-dose autoinjector or prefilled syringe for subcutaneous injection. This article summarizes the milestones in the development of dasiglucagon leading to this first approval for hypoglycaemia.

1053-P: Dasiglucagon Hypopal Autoinjector as a Fast and Effective Treatment for Severe Hypoglycemia: Results of a Phase 3 Trial

Severe hypoglycemia is a major concern for patients with diabetes on insulin therapy. Rescue requires caregivers to provide effective treatment, including glucagon injections. Dasiglucagon is a stable glucagon analog in development to be administered with the HypoPal® auto-injector for treatment of severe hypoglycemia. This phase 3 trial, ZP4207-17145, assessed the clinical efficacy and safety of 0.6 mg dasiglucagon subcutaneous (SC) administered via the HypoPal® auto-injector compared with placebo. In total, 45 eligible patients with T1D were randomized (3:1) to dasiglucagon or placebo and dosed following induced hypoglycemia. The primary endpoint was time to plasma glucose (PG) recovery, defined as first PG increase ≥20 mg/dL after treatment initiation without rescue glucose. Dasiglucagon injection provided a fast and effective increase in PG. The median time (95% CI) to recovery based on sampling time was 10 (8.0, 12.0) min for dasiglucagon and 35 (20.0, -) min for placebo (p&amp;lt;0.0001). The median (95% CI) estimated true time to recovery (interpolated between sampling times) was 9.3 (7.8, 10.3) min for dasiglucagon and 25.8 (19.2, 34.8) min for placebo. Nausea and vomiting are well-known side effects of glucagon and were reported in 61.8% and 29.8% of patients receiving dasiglucagon, respectively. Nausea was reported in 10% of patients receiving placebo. No safety concerns were raised for dasiglucagon. In conclusion, dasiglucagon 0.6mg SC administered via the HypoPal® auto-injector provided fast and effective recovery from hypoglycemia. The results are consistent with previously reported results from a pivotal phase 3 trial testing dasiglucagon administered via a pre-filled syringe, NCT03378635, where a median time to recovery of 10 min was also observed. Disclosure T.S. Bailey: Consultant; Self; Abbott, LifeScan, Inc., Novo Nordisk A/S, Sanofi US. Research Support; Self; Abbott, Ascensia Diabetes Care, Capillary Biomedical, Inc., Dance Biopharm Holdings, Inc., Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Kowa Pharmaceuticals America, Inc., Lexicon Pharmaceuticals, Inc., Medtronic, Medtrum, Novo Nordisk A/S, REMD Biotherapeutics, Sanofi-Aventis, Senseonics, Viacyte, Inc., vTv Therapeutics, Zealand Pharma A/S. Speaker’s Bureau; Self; Medtronic, Sanofi US. J. Willard: None. L.J. Klaff: Research Support; Self; Abbott, Ascensia Diabetes Care, Dexcom, Inc., Lilly Diabetes, Medtronic, Novo Nordisk A/S, REMD Biotherapeutics, Roche Diabetes Care, Sanofi-Aventis, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. L.S. List: Employee; Spouse/Partner; Novo Nordisk A/S. Employee; Self; Zealand Pharma A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S, Zealand Pharma A/S. A.E. Melgaard: Employee; Self; Zealand Pharma A/S. R. Tehranchi: Employee; Self; Zealand Pharma A/S.

180-OR: Dasiglucagon as a Fast and Effective Treatment for Severe Hypoglycemia in Children with Diabetes

Dasiglucagon is a stable glucagon analog being developed in the HypoPal® auto-injector to address the need for easy-to-use, fast and effective treatment of severe hypoglycemia in individuals with diabetes. In this pediatric Phase 3 trial, ZP4207-17086, the clinical efficacy and safety of 0.6 mg dasiglucagon administered subcutaneously (SC) (same dose as adults) was compared to placebo and with reference to GlucaGen®. In total, 42 eligible children with T1D between 6 and 17 years (6-11 years: 16 children and 12-17 years: 25 children) were randomized (2:1:1) to dasiglucagon, placebo or GlucaGen® and dosed following induced hypoglycemia. The primary endpoint was time to plasma glucose (PG) recovery, defined as first PG increase ≥20 mg/dL after treatment initiation without rescue glucose. The results showed that dasiglucagon 0.6 mg SC induced a fast and effective PG increase. The median time (95% CI) to recovery based on sampling time was 10 (8, 12) min for dasiglucagon vs. 30 (20, -) min for placebo (p&amp;lt;0.001); and 10 (8, 12) min for GlucaGen®. The estimated true time to recovery (interpolated between sampling times) showed that the median (95% CI) time was 8.7 (6.9, 10.6) min for dasiglucagon, 29.3 (18.5, -) min for placebo and 9.8 (7.4, 10.6) min for GlucaGen®. Nausea and vomiting are known side effects following administration of glucagon products and were reported for active treatments only: with dasiglucagon (6-11 years; nausea: 25% and vomiting: 25%; 12-17 years; nausea: 92% and vomiting: 67%) and with GlucaGen® (6-11 years; nausea: 50% and vomiting: 25%; 12-17 years; nausea: 17% and vomiting: 0%). No relationship between exposure (AUC0-5 hr or Cmax) to dasiglucagon and nausea and vomiting was found. No safety concerns were raised for dasiglucagon within the trial. In conclusion, consistent with adult phase 3 trials this study demonstrated a fast, effective treatment response with a median time to recovery of 10 min in children ≥ 6 years, and an overall safety profile similar to glucagon. Disclosure T. Battelino: Advisory Panel; Self; Medtronic, Sanofi. Consultant; Self; Indigo Diabetes. Research Support; Self; Medtronic, Novo Nordisk A/S, Zealand Pharma A/S. Speaker’s Bureau; Self; Abbott, AstraZeneca, Dexcom, Inc., Lilly Diabetes, Medtronic. Stock/Shareholder; Self; DreaMed Diabetes. R. Tehranchi: Employee; Self; Zealand Pharma A/S. A.E. Melgaard: Employee; Self; Zealand Pharma A/S. D. Skydsgaard: Employee; Self; Zealand Pharma A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S, Roche Diabetes Care. T.S. Bailey: Consultant; Self; Abbott, LifeScan, Inc., Novo Nordisk A/S, Sanofi US. Research Support; Self; Abbott, Ascensia Diabetes Care, Capillary Biomedical, Inc., Dance Biopharm Holdings, Inc., Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Kowa Pharmaceuticals America, Inc., Lexicon Pharmaceuticals, Inc., Medtronic, Medtrum, Novo Nordisk A/S, REMD Biotherapeutics, Sanofi-Aventis, Senseonics, Viacyte, Inc., vTv Therapeutics, Zealand Pharma A/S. Speaker’s Bureau; Self; Medtronic, Sanofi US. L. DiMeglio: None. T. Danne: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Sanofi.