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Background and aims: Regular physical activity and exercise represent a corner stone in the treatment of type 1 diabetes (T1D) , however, exercise-induced hypoglycemia remains the major barrier to a physically active lifestyle. Therefore, the ULTRAFLEXI-1 study compared two basal insulin analogues, Glargine 300U/ml (IGlar U300) and Degludec (IDeg) , in two different doses (100% and 75% of the regular dose) when used around spontaneous exercise sessions in adults with T1D. Methods: We performed a randomized, single-center, four-period, cross-over trial (EudraCT: 2019-003209-89) and included adults with T1D treated with multiple daily insulin injections and an HbA1c ≤10% (≤86 mmol/mol) . In each of the four 2-weeks-periods, participants attended six spontaneous evening cycling sessions (60 minutes, moderate intensity) . The days of exercising were randomized and announced at 8 A.M. to the participants. The basal insulin used on the exercise days during the four periods were: IGlar U300 100% or 75% of the regular dose or IDeg 100% or 75%, respectively. 100% of the regular basal insulin dose was used at all non-exercise days. CGM was performed using a blinded Dexcom G6 device. The primary outcome was TBR ( Results: 25 people were enrolled (14 male) , aged 41.4±11.9 years, with a mean diabetes duration of 16.8±10.4 years and a mean HbA1c of 7.5±0.8%. (59±9 mmol/mol) . Mean TBR during the 24-hour periods following the exercise sessions was 2.71±2.56% for IGlar U300 (100%) and 4.37%±3.43% for IDeg (100%) (p=0.025) as well as 2.28±2.67% for IGlar U300 compared to 2.55 ±2.87% with IDeg when using the 75% dose on exercise days (p=0.720) . Conclusion: Time spent in hypoglycemia after spontaneous exercise sessions was significantly lower in people with type 1 diabetes receiving IGlar U300 as compared to IDeg when the 100% dose was used. Disclosure O. Moser: Research Support; Dexcom, Inc., Sanofi, Speaker’s Bureau; Medtronic. M. L. Eckstein: None. L. Hönger: None. J. Lenz: None. I. Mursic: None. C. Sternad: None. M. Zanker: None. H. Ziko: None. P. N. Pferschy: None. N. J. Tripolt: None. H. Sourij: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Research Support; Boehringer Ingelheim International GmbH, Sanofi, Speaker’s Bureau; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk. A. Mueller: None. F. Aberer: Other Relationship; Amgen Inc., Boehringer Ingelheim International GmbH, Sanofi. F. Aziz: None. H. Kojzar: None. C. Sourij: None. A. M. Obermayer: None. F. M. Abbas: None. P. Birnbaumer: None. Funding Sanofi-aventis (DCV-2018-12349)

Insulin icodec is a basal insulin in development for once-weekly (OW) dosing. The aim of this study was to compare the hypoglycemia frequency and response after icodec vs. insulin glargine U100 (IGlar) overdosing. In a randomized, open-label, two-period crossover trial, 43 individuals with T2D on basal insulin±metformin (mean±SD age 56±9 yrs, HbA1c 7.2±0.7%) received OW icodec for 6 weeks and once-daily IGlar for 12 days at equimolar total weekly doses based on the individual daily run-in IGlar dose (mean 30±14 U) titrated to a fasting SMPG target of 80-130 mg/dL. Once at steady state, double (DD) and triple (TD) doses of icodec and IGlar were followed by hypoglycemia induction 44 h (icodec) or 7 h (IGlar) post-dose (expected time of maximum glucose-lowering effect) : First, euglycemia was maintained at 100 mg/dL by variable i.v. glucose. Then, PG was allowed to decrease to a nadir of no less than 45 mg/dL maintained for 15 min. Euglycemia was restored by constant i.v. glucose. Hypoglycemic symptom score (HSS) and counterregulatory hormones were assessed at PG 100 mg/dL and at predefined PG levels until nadir PG. For DD, clinically significant hypoglycemia (PG In conclusion, a DD or TD of once-weekly insulin icodec does not lead to increased risk of hypoglycemia compared to once-daily IGlar. During hypoglycemia, a comparable symptomatic response and a moderately greater endocrine response were seen for icodec vs. IGlar. Disclosure E.Svehlikova: n/a. K.Niss arfelt: Employee; Novo Nordisk. R.Cailleteau: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. S.Deller: None. K.Thomsen: Employee; Novo Nordisk. M.Hart: None. I.Mursic: None. T.Pieber: Advisory Panel; Arecor, Novo Nordisk A/S, Research Support; AstraZeneca, European Union, JDRF, Novo Nordisk Foundation, Sanofi, Speaker's Bureau; Novo Nordisk A/S, Roche Diagnostics. H.Haahr: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. Funding Novo Nordisk

Objectives: To evaluate the effect of SGLT2i on the development of DKA during insulin depletion in T1DM. Methods: Sixteen male, C-peptide negative T1DM subjects were enrolled in this open, randomized, crossover, bicentric trial with two 7-day treatment periods (with/without SGLT2i). At the end of each treatment period, insulin was withdrawn for a maximum of 12h, followed by recovery phase (12h). Results: SGLT2i led to significantly lower plasma glucose (PG) values during insulin depletion (PGmax with/without SGLT2i: 174±40 (mean±SD) vs. 302±48 mg/dL; 95% CI for ratio: 0.51-0.60), but to higher beta-hydroxybutyrate (BHB) values (Figure) and a steeper BHB increase (delta BHB: 8.1±2.0 vs. 6.0±1.7 µmol/L/min; 95% CI for ratio: 1.22-1.49). pH, bicarbonate and base excess during insulin depletion were comparable. Baseline glucagon (7.8±2.5 vs. 5.0±1.6 pmol/L; 95% CI for ratio: 1.26-1.95) and FFA levels (0.65±0.27 vs. 0.43±0.31 mmol/L; 95% CI for ratio: 1.08-2.28) were higher with SGLT2i, but data indicate that after increase during insulin depletion comparable concentrations were reached for both. Conclusions: SGLT2i keeps PG in near normal ranges during DKA development and recovery, potentially impeding DKA diagnosis. While SGLT2i leads to higher ketone levels, increased baseline glucagon and FFA, an effect on pH and acidosis was not demonstrated. Disclosure I. Mursic: None. E. Svehlikova: None. W. Regittnig: None. T. Augustin: None. C. Magnes: None. A. Eberl: None. T. Heise: Advisory Panel; Self; Mylan, Novo Nordisk A/S. Research Support; Self; ADOCIA, Aerami, Becton, Dickinson and Company, Biocon, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Gan & Lee Pharmaceuticals, MedImmune, Merck KGaA, Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Sanofi, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. O. Klein: None. M. Wolf: None. M. Urschitz: None. M. Brunner: None. H. Sourij: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. T. Pieber: Advisory Panel; Self; ADOCIA, Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S, Roche Diagnostics K.K.