Zealand Pharma Research Articles

1058-P: Diabetic Ketoacidosis during Pregnancy: Maternal Characteristics and Pregnancy Outcomes

Diabetic ketoacidosis (DKA) during pregnancy is an obstetric emergency associated with morbidity and mortality. As this condition is rare (affecting 1-3% pregnant women with preexisting diabetes) , available data are limited. The aim of this retrospective cohort study is to present comprehensive data on maternal characteristics and pregnancy outcomes for women with DKA who attended our center for prenatal care from 2001-21. In total 71 DKA episodes were identified in 58 women, of whom 86% (n=50) had type 1 diabetes mellitus and 83% (n=48) were White. The mean (±SD) maternal age was 28 (±7) years and diabetes duration was (±7) years. Pregnancy loss during or within 1 week of the DKA episode occurred in 17% (6 miscarriages and 4 stillbirths) . There were no maternal deaths. Women were poorly prepared for pregnancy [mean 1st trimester HbA1c 9.3 (±2.5) %]. Social stressors were present in 52% (n=30) and 24% (n=14) reported smoking. The mean gestational age at DKA was 25.4 weeks (16.3 weeks for pregnancies with fetal demise vs. 27.5 weeks for livebirths, p<0.001) . Insulin non-adherence was the most common precipitating factor (40%) , followed by infection (23%) , and a new diagnosis of type 1 diabetes (10%) . Pre-existing hyperemesis was associated with fetal demise (31%, n=4 vs. 3%, n=2 among livebirths; p=0.004) . The mean plasma glucose at presentation was 362 mg/dL and the β-hydroxybutyrate was 4.2 mmol/L, with 28 (39%) women requiring intensive care unit (ICU) admission. Among livebirths, the mean gestational age at delivery was 32.7 weeks with 41% (n=21) requiring emergency cesarean. Large for gestational age occurred in 29% (n=17) and 8% (n=4) had shoulder dystocia. Congenital anomaly was present in 10% (n=5) . Neonatal hypoglycemia occurred in 60% (n=29) and neonatal ICU admission was required in 52% (n=25) . In summary, pregnancies affected by DKA continue to be associated with numerous adverse pregnancy outcomes. Future work should focus on optimizing prevention strategies in high-risk women. Disclosure M.Dhanasekaran: None. S.Mohan: None. D.Erickson: None. P.Shah: None. L.M.Szymanski: None. A.Vella: Advisory Panel; Crinetics Pharmaceuticals, Inc., Rezolute, Inc., vTv Therapeutics, Zealand Pharma A/S, Other Relationship; Novo Nordisk. A.M.Egan: None. Funding National Institutes of Health (K12 HD065987/HD/NICHD)

652-P: Gaps Remain in Achieving Target T1D Glycemic Goals Despite Advanced Technologies

Continuous glucose monitoring (CGM) metrics and self-reported disease characteristics (severe hypoglycemic events [SHEs], HbA1c) warrant further description in people with T1D using CGM and pumps, including hybrid closed-loop systems (HCLS) . We conducted a one-time online survey of adults with T1D in the T1D Exchange Registry or online communities, where ∼50% of participants contributed up to 1 year of CGM data. Patients were asked about their medical history (SHEs, HbA1c) , while glucose management indicator (GMI) , prolonged hypoglycemic events (<54 mg/dL) , time in and below range (TIR/TBR) , and coefficient of variation (CV) were derived from CGM data. Patients who completed the survey and contributed CGM data (N=926) had a mean age of 42 y and T1D duration of 25 y; 73% were female; 96% were white; 94% had ≥1 year of CGM use. Mean HbA1c was 6.6% (69.0% had HbA1c <7%) . While most patients met consensus glycemic targets (HbA1c, GMI, TIR, TBR, and CV) , with higher proportions observed in those using HCLS pumps than in those using pump + CGM (not HCLS) and MDI + CGM (Table) , patients continued to have significant hypoglycemia based on CGM data and an average of 1.1 SHEs in the prior year. Despite improvements in glycemic control (TIR, TBR, and self-reported HbA1c) with advanced technologies, many patients still cannot achieve clinical targets and experience significant hypoglycemia, highlighting the unmet need for novel T1D treatments. Disclosure L.M.Laffel: Advisory Panel; Medtronic, Roche Diabetes Care, Consultant; Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompé, Insulet Corporation, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk, Provention Bio, Inc. K.S.M.Chapman: None. D.Finan: None. R.M.Bergenstal: Advisory Panel; Hygieia, Medtronic, Roche Diabetes Care, Zealand Pharma A/S, Consultant; Abbott Diabetes, Ascensia Diabetes Care, Bigfoot Biomedical, Inc., CeQur SA, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, Onduo LLC, Sanofi, United HealthCare Services, Inc., Research Support; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi. J.Liu: None. L.Titievsky: Employee; Intercept Pharmaceuticals, Inc., Pfizer Inc., Vertex Pharmaceuticals Incorporated, Stock/Shareholder; Intercept Pharmaceuticals, Inc., Pfizer Inc., Vertex Pharmaceuticals Incorporated. K.Hagan: Employee; Vertex Pharmaceuticals Incorporated. T.Liu: Employee; Takeda Pharmaceutical Company Limited, Vertex Pharmaceuticals Incorporated, Stock/Shareholder; Seattle Genetics, Inc. K.Chandarana: Employee; Vertex Pharmaceuticals Incorporated. J.L.Gaglia: Advisory Panel; Dompé, Regeneron Pharmaceuticals Inc., Consultant; Vertex Pharmaceuticals Incorporated, Research Support; Avotres Inc., Dompé, Janssen Research & Development, LLC, Provention Bio, Inc., Stock/Shareholder; Vertex Pharmaceuticals Incorporated. W.Wolf: None. J.Bispham: Employee; PPD Inc., T1D Exchange.

233-OR: Impact of Nocturnal Hypoglycemia on Daily Sleep Quality, Mood, and Alertness among Adults with Type 1 Diabetes: The Hypo-METRICS (Hypoglycaemia Measurement, Thresholds, and Impacts) Study

Aim: To examine how hypoglycemia while asleep impacts self-reported daily functioning among adults with type 1 diabetes (T1D) . Methods: On 70 consecutive mornings, 250 people with T1D wearing a continuous glucose monitor reported sleep quality, mood, and alertness via the Hypo-METRICS smartphone app. Each night was categorized based on presence (+) or absence (-) of person-reported hypoglycemia (PRH) and sensor-detected hypoglycemia (SDH) into one of four types (see Figure 1, Type A-D) . Multilevel regression assessed associations between hypoglycemia and daily functioning (unstandardized coefficients (β) on original 0-scale) , adjusted for baseline demographic, clinical and psychological factors. Results: In the first 54 adults (52% women, age[M±SD]: 45±15 years) , nighttime PRH (Type C & D, Figure 1) was associated with reduced subjective sleep quality (C: β=-0.67; D: β=-0.58) , mood (C: β=-0.43; D: β=-0.58) and alertness (C: β=-0.34, p=0.015; D: β=-0.46) (all p<0.0unless specified) compared to nights without hypoglycemia (Type A) . Nights with SDH only (Type B) showed no significant reductions in sleep, mood or alertness (p>0.05) . Conclusion: These novel data show the potentially pivotal role of the subjective experience of hypoglycemia for sleep quality, mood and alertness. Disclosure U.Soeholm: Research Support; Novo Nordisk A/S. E.Renard: Consultant; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Insulet Corporation, LifeScan, Lilly, Novo Nordisk, Roche Diabetes Care, Sanofi, Tandem Diabetes Care, Inc. E.J.Abbink: None. P.M.Baumann: None. S.R.Heller: Advisory Panel; Eli Lilly and Company, Medtronic, Mylan N.V., Zealand Pharma A/S, Zucara Therapeutics, Other Relationship; Eli Lilly and Company, Research Support; Dexcom, Inc., Speaker's Bureau; Novo Nordisk A/S. B.E.De galan: Research Support; Novo Nordisk. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. M.Evans: Advisory Panel; Pila Pharma, Zucara Therapeutics, Other Relationship; Abbott Diabetes, Dexcom, Inc., Medtronic, Novo Nordisk, Research Support; AstraZeneca, Sanofi, Speaker's Bureau; Lilly Diabetes. D.Pollard: Other Relationship; Novo Nordisk. R.J.Mccrimmon: Advisory Panel; Novo Nordisk, Sanofi, Research Support; Diabetes UK, European Union, MedImmune. S.A.Amiel: Advisory Panel; Medtronic, Novo Nordisk, Other Relationship; Sanofi. M.M.Broadley: None. C.Hendrieckx: None. J.Speight: Advisory Panel; Insulet Corporation, Research Support; Novo Nordisk, Sanofi. P.Choudhary: Advisory Panel; Abbott Diabetes, Lilly Diabetes, Medtronic, Research Support; Novo Nordisk, Speaker's Bureau; Dexcom, Inc., Glooko, Inc., Insulet Corporation, Sanofi. F.Pouwer: Research Support; Eli Lilly and Company, Novo Nordisk, Sanofi. N.Zaremba: None. P.Divilly: None. G.Martine-edith: Other Relationship; Novo Nordisk. G.Nefs: None. Z.Mahmoudi: Employee; Novo Nordisk A/S. J.K.Mader: Advisory Panel; Abbott Diabetes, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Abbott Diabetes, Eli Lilly and Company, Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Servier Laboratories, Stock/Shareholder; decide Clinical Software GmbH. M.Cigler: None. Funding This work was supported by the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement 777460

358-OR: The Effect of Glucagon-Like Peptide-1 Receptor Blockade on Glucagon-Induced Stimulation of Insulin Secretion

Data from transgenic rodent models suggest that glucagon acts as an insulin secretagogue by signalling through the Glucagon-Like Peptide-1 Receptor (GLP1R) present on β-cells. This occurs at high concentrations as are present within the islet. However, its net contribution to physiologic insulin secretion is unknown. To address this question, we studied 12 non-diabetic, weight-stable individuals (26±1 years,25±1 kg/m2) on 2 occasions. During a hyperglycemic clamp (∼8.9mmol/l) where glucose was labeled with [3-3H] glucose, glucagon was infused at 0.4ng/kg/min, for 1 hour, increasing by 0.2ng/kg/min every hour for a total of 5 hours. Subjects were studied on two occasions in random order. On one occasion Exendin-9,39 (300pmol/kg/min) was infused to block the GLP1R, while on the control day saline was infused. The insulin secretion rate (ISR) was calculated by nonparametric deconvolution from plasma concentrations of C-peptide. Endogenous glucose production (EGP) and glucose disappearance (Rd) were measured using the tracer-dilution technique. Glucagon concentrations rose from baseline (6.6±2.1 vs. 5.4±1.5 pmol/l, saline vs. exendin-9,39 respectively, p=0.22) to values that, by design, did not differ between study days (17.8±1.8 vs. 17.1±1.1 pmol/l, p>0.1) . This was accompanied by a rise in C-peptide from fasting concentrations. Integrated C-peptide concentrations were slightly, but significantly, decreased during exendin-9,39 infusion (721±65 vs. 648±55 nmol per 5hr, p=0.02) . In addition, integrated insulin secretion rate was lower during exendin-9,39 infusion (213±26 vs. 191±22 nmol per 5 hr, saline vs. exendin-9,39 respectively, p = 0.03) . Both EGP and Rd did not differ significantly on either experimental day. These data show that in non-diabetic humans, during hyperglycemia as seen in the postprandial period, glucagon partially stimulates the β-cell through GLP1R. It remains to be ascertained if this also applies to individuals with type 2 diabetes. Disclosure R.A. Farahani: None. A.A. Welch: None. M.C. Laurenti: None. C. Cobelli: None. C. Dalla Man: Research Support; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. A. Vella: Advisory Panel; Crinetics Pharmaceuticals, Inc., Rezolute, Inc., vTv Therapeutics, Zealand Pharma A/S. Other Relationship; Novo Nordisk. Funding National Institutes of Health (DK126206)

833-P: Impact of Hypoglycemia on Insulin Titration and Fasting Plasma Glucose in Basal Insulin–Treated Type 2 Diabetes: A Subanalysis of the SoliMix Trial

Introduction: The SoliMix trial (EudraCT: 2017-003370-13) found better HbA1c with weight benefit and lower hypoglycemia risk for iGlarLixi vs. premix BIAsp 30 in people with type 2 diabetes advancing from basal insulin plus oral antihyperglycemic drugs. This exploratory analysis investigated whether hypoglycemia influenced insulin titration and achievement of fasting plasma glucose (FPG) targets with each therapeutic option. Methods: Total insulin dose changes from baseline to Week 12 were stratified by hypoglycemia (yes/no) in each treatment arm and ADA Level 2 hypoglycemia (<54 mg/dL [<3.0 mmol/L]) event rates during Weeks 0-12 were modeled according to FPG at Week 12 (when most insulin titration occurred) . Results: Lesser insulin dose increases occurred in both treatment groups for those who experienced hypoglycemia (mean ± SD iGlarLixi: 3.9 ± 12.5 U; BIAsp 30: 11.0 ± 18.8 U) vs. those who did not (mean ± SD iGlarLixi: 11.2 ± 9.9 U; BIAsp 30: 19.4 ± 19.3 U) . While higher FPG at Week 12 correlated with greater event rates of hypoglycemia in both treatment arms, event rates were higher for BIAsp 30 than for iGlarLixi irrespective of FPG (Figure) . Conclusions: More frequent hypoglycemia with premix BIAsp 30 than with iGlarLixi may result in lower insulin doses, thus hampering insulin titration and resulting in higher FPG. Disclosure F.Giorgino: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Consultant; Lilly Diabetes, Sanofi, Research Support; Lilly Diabetes, Roche Diabetes Care, Takeda Pharmaceutical Company Limited. J.Rosenstock: Consultant; AstraZeneca, Other Relationship; Applied Therapeutics, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Sanofi, Zealand Pharma A/S, Research Support; Genentech, Inc., Merck & Co., Inc., Metacrine, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., vTv Therapeutics. R.Ritzel: Consultant; Novo Nordisk, Sanofi, Speaker's Bureau; AstraZeneca, Lilly, Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Sanofi. O.Deyneli: Advisory Panel; Abbott Diabetes, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Novo Nordisk, Roche Diagnostics, Sanofi, Speaker's Bureau; Abbott, AstraZeneca, Berlin-Chemie AG, Bilim Ilaç, Boehringer Ingelheim International GmbH, Medtronic, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk, Roche Diabetes Care, Sanofi. A.Alvarez: Employee; Sanofi. E.Souhami: Employee; Sanofi, Stock/Shareholder; Sanofi. L.Melas-melt: None. R.J.Mccrimmon: Advisory Panel; Novo Nordisk, Sanofi, Research Support; Diabetes UK, European Union, MedImmune. Funding Sanofi

765-P: Glycemic Outcomes across Total Daily Insulin Doses with the Omnipod 5 Automated Insulin Delivery System (AID) among People with Type 1 Diabetes (T1D) Ages 2 to 70 Years

AID systems must accommodate a wide range of insulin requirements safely and effectively to apply to a broad population. We evaluated glycemic outcomes among people ages 2 to 70y with T1D and baseline A1C<10% during a 3-mo home trial with the Omnipod 5 AID System, stratified by their baseline total daily insulin dose (TDD) during a 14-day standard therapy phase (ST, multiple daily injections or pump therapy) before AID use. No minimum TDD or weight was required to enter the study. Glycemic outcomes (time in range (TIR) 70-180 mg/dL, time below range (TBR) <70 mg/dL, time above range (TAR) >180 mg/dL) and change in TDD were evaluated across 6 ST TDD ranges, from <10U to ≥65U, during AID compared with ST. Participants (N=320) had a ST TDD of (mean ± SD) 34.8±21.7U (range 5.3-166.0U) . TDD during AID ranged from 5.0 to 110.7U; TDD increased slightly for those using <30U per day. TIR increased during AID across all TDD ranges (p<0.05, Table) . TAR and TBR were reduced in groups with TDD ≥10U and TDD ≥20U, respectively. Multiple linear regression indicated that older age and higher TIR during ST (both p<0.05) were associated with higher TIR during AID, while no relationship was found between ST TDD and TIR during AID (p=0.29, r2=0.57) . The Omnipod 5 System was safe and effective for a large cohort of people with T1D ages 2 to 70y across a wide range of insulin needs. Disclosure M.Schoelwer: Other Relationship; Dexcom, Inc., Research Support; Insulet Corporation, Medtronic, Tandem Diabetes Care, Inc. L.M.Laffel: Advisory Panel; Medtronic, Roche Diabetes Care, Consultant; Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompé, Insulet Corporation, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk, Provention Bio, Inc. J.Sherr: Advisory Panel; Bigfoot Biomedical, Inc., Cecelia Health, Insulet Corporation, Medtronic, Vertex Pharmaceuticals Incorporated, Consultant; Insulet Corporation, Lexicon Pharmaceuticals, Inc., Research Support; Dexcom, Inc., Insulet Corporation, Jaeb Center for Health Research, JDRF, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases, Speaker's Bureau; Lilly Diabetes. C.J.Levy: Advisory Panel; Dexcom, Inc., Eli Lilly and Company, Research Support; Abbott Diabetes, Dexcom, Inc., Insulet Corporation, T1D Exchange, Tandem Diabetes Care, Inc. I.B.Hirsch: Consultant; Abbott Diabetes, Bigfoot Biomedical, Inc., GWave, Roche Diabetes Care, Research Support; Beta Bionics, Inc., Insulet Corporation, Medtronic. S.A.Macleish: Advisory Panel; Insulet Corporation. D.Desalvo: Consultant; Dexcom, Inc., Insulet Corporation, Research Support; Insulet Corporation. V.Shah: Advisory Panel; Medscape, Sanofi, Consultant; Dexcom, Inc., Research Support; Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Novo Nordisk. A.Bhargava: Research Support; Abbott Diabetes, AbbVie Inc., Boehringer Ingelheim International GmbH, Boston Therapeutics, Inc., Covance, Dexcom, Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Insulet Corporation, Kowa Pharmaceuticals America, Inc., Lexicon Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Medtronic, Novo Nordisk, Poxel SA, Quintiles, Sanofi, Senseonics, Tolerion, Inc., Viking Therapeutics, vTv Therapeutics. T.C.Jones: None. G.Aleppo: Consultant; Insulet Corporation, Research Support; AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Fractyl Health, Inc., Insulet Corporation, Novo Nordisk, Speaker's Bureau; Dexcom, Inc. B.W.Bode: Advisory Panel; CeQur SA, MannKind Corporation, Medtronic, Novo Nordisk, Zealand Pharma A/S, Consultant; Bigfoot Biomedical, Inc., Research Support; Abbott, Beta Bionics, Inc., Dexcom, Inc., Diasome, Dompé, Eli Lilly and Company, Insulet Corporation, IQVIA Inc., Jaeb Center for Health Research, Medtronic, Novo Nordisk, Provention Bio, Inc., REMD Biotherapeutics, Sanvita Medical, Senseonics, ViaCyte, Inc., Speaker's Bureau; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Insulet Corporation, MannKind Corporation, Novo Nordisk, Sanofi, Xeris Pharmaceuticals, Inc., Stock/Shareholder; AgaMatrix, Glytec, LLC. R.E.Gurlin: Employee; Insulet Corporation. T.T.Ly: Employee; Insulet Corporation, Stock/Shareholder; Insulet Corporation. Omnipod 5 research group: n/a. A.L.Carlson: Advisory Panel; MannKind Corporation, Employee; Bright Health Group, Other Relationship; Medtronic, Research Support; Funding This study was funded by Insulet Corporation.

291-OR: Using the Performance in Exercise and Knowledge (PEAK) Guidelines Incorporated in a Smartphone-Based Decision Support System Improves Glucose Outcomes during Free-Living Exercise

DailyDose is a smart-phone decision support system developed at Oregon Health & Science University that uses Dexcom G6 CGM and Medtonic’s InPen. The app calculates insulin doses using CGM value and trend, insulin-on-board, carbohydrate amount, and exercise information. Insulin dosing and carbohydrate intake recommendations before and after exercise are adjusted according to the 2017 consensus statement by Riddell et al. known as the PEAK Guidelines. Twenty-four adults with T1D, using multiple daily injections of insulin at baseline, completed a two-week run-in period then used the DailyDose intervention for 8 weeks. Participants completed 3 at-home exercise sessions per week, one aerobic exercise video and two other sessions of their choice. We examined the impact of the use of PEAK guidelines on glucose outcomes during exercise comparing 176 exercise sessions done during run-in and 471 sessions done during the intervention period. Glucose outcomes were assessed from start of exercise to 4 hours after the start or until either a meal was consumed, insulin dosed or new exercise session initiated. Mixed effects analysis was used to determine significance of the intervention on glucose outcomes. The nadir of the glucose was lower for the run-in compared with the intervention (120.6 vs. 130.9 mg/dL, P=.012) . Change in glucose from the start of exercise to the nadir was 58.0 for the run-in versus 46.9 for the intervention period (P=.016) . Time in hyperglycemia (>180mg/dL) during the exercise periods trended toward being lower during the intervention (43.8% run-in, 35.0% intervention, P=.059) , as did time in range of 70-180 mg/dL, (54.2% run-in, 62.2% intervention, P=.081) . There was no difference in time in hypoglycemia. Data suggest that use of PEAK within a decision support app can help prevent more severe glucose drops during and after exercise with a trend toward improving time in range. Disclosure L.M.Wilson: n/a. S.M.Oganessian: None. D.Branigan: None. V.Gabo: None. J.H.Eom: None. J.El youssef: None. K.Winters-stone: None. J.R.Castle: Advisory Panel; Insulet Corporation, Novo Nordisk, Zealand Pharma A/S, Stock/Shareholder; Pacific Diabetes Technologies. P.G.Jacobs: Other Relationship; Pacific Diabetes Technologies, Research Support; Dexcom, Inc. F.H.Guillot: Stock/Shareholder; Pacific Diabetes Technologies. N.S.Tyler: None. T.Kushner: Consultant; Tandem Diabetes Care, Inc. A.Z.Espinoza: None. C.M.Mosquera-lopez: None. J.Pinsonault: None. R.Dodier: None. Funding The Leona M. and Harry B. Helmsley Charitable Trust (Grant 2018PG-T1D001) , OHSU Medical Research Foundation, Supplies provided by Dexcom

88-OR: Discordance between Glucose Management Indicator (GMI) and A1C in Well-Controlled Type 1 Diabetes (T1D) and Nondiabetic Population

Glucose management indicator (GMI) was developed using a linear regression formula to estimate A1C from mean glucose. The study population that was used to develop and validate GMI had a mean A1C of 7.3 ± 0.8%. Therefore, we hypothesize that GMI may overestimate A1C in those with A1C <6.5%. Non-pregnant adults (≥18 years) with T1D for ≥2 years and using Dexcom G6 for ≥6 months from Barbara Davis Center for Diabetes (n=93, 40.6 ± 12.6 years, female 58.4%, A1C 5.9 ± 0.4%) and subjects from “Glucose Sensor Profile in Healthy Non-diabetic Subjects” study (N=153, 31.2± 21.0 years, female 66.0%, A1C 5.1 ± 0.3%) were included. All participants used Dexcom G6 continuous glucose monitor (CGM) . Up to days (healthy participants) and 15 days (T1D patients) of CGM data was compared with laboratory A1C. Discordance in GMI and A1C is presented by A1C <5.7% (healthy participants) and A1C between 5.7-6.4% (T1D patients) . The degree of discordance between GMI and A1C was higher in those with A1C<6.5% compared to original GMI development cohort [Figure 1A]. The differences between A1C and GMI were largely negative in both A1C categories (A1C <5.7% and A1C of 5.7-6.4%) . On average, GMI was 0.59% higher in the A1C < 5.7% group and 0.49% higher in the A1C 5.7 - 6.4% group (both p < 0.0001) [Figure 1B and 1C]. The current GMI formula may overestimate A1C and may need to be re-assessed for those with A1C <6.5%. Disclosure V.Shah: Advisory Panel; Medscape, Sanofi, Consultant; Dexcom, Inc., Research Support; Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Novo Nordisk. T.B.Vigers: None. L.Pyle: None. S.Dubose: None. P.Calhoun: None. R.M.Bergenstal: Advisory Panel; Hygieia, Medtronic, Roche Diabetes Care, Zealand Pharma A/S, Consultant; Abbott Diabetes, Ascensia Diabetes Care, Bigfoot Biomedical, Inc., CeQur SA, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, Onduo LLC, Sanofi, United HealthCare Services, Inc., Research Support; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi.

1413-P: Semaglutide 2.4 mg Improved Glucose Metabolism and Reverted Prediabetes to Normoglycemia in Adults with Overweight/Obesity vs. Liraglutide 3.0 mg (STEP 8)

The STEP 8 trial randomized 338 adults with overweight/obesity to weekly semaglutide 2.4 mg or placebo (PBO) , or daily liraglutide 3.0 mg or PBO, plus lifestyle intervention for 68 wks (3:1:3:1) ; PBO data not shown. Body weight (BW) change was greater with semaglutide vs. liraglutide (-15.8% vs. -6.4%, respectively; p<0.0001) . This exploratory analysis assessed effects on glucose metabolism and glycemic status (normoglycemia; prediabetes; T2D) at wk 68 in participants (pts) with prediabetes at baseline (BL; 43 semaglutide/45 liraglutide; mean HbA1c 5.9/5.8%; fasting plasma glucose [FPG] 102/100 mg/dL; HOMA-IR 4.9/3.7; BW 104/1kg) . Analyses were not adjusted for multiplicity. At wk 68, 89.5% of pts were normoglycemic with semaglutide vs. 64.9% with liraglutide (p=0.01) (Figure) ; in these pts, 76.5% had weight loss ≥10% with semaglutide vs. 33.3% with liraglutide. One pt in each group developed T2D (Figure) . From BL to wk 68, semaglutide led to greater reductions vs. liraglutide in HbA1c (difference: -0.22 %; p=0.0002) , FPG (difference: -6.2 mg/dL; p=0.02) , and HOMA-IR (relative % difference: -28%; p=0.02) . In conclusion, both semaglutide 2.4 mg and liraglutide 3.0 mg had clinically beneficial effects on glucose metabolism and glycemic status in pts with overweight/obesity and prediabetes, though the effect of semaglutide was greater vs. liraglutide. Disclosure J.Rosenstock: Consultant; AstraZeneca, Other Relationship; Applied Therapeutics, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Sanofi, Zealand Pharma A/S, Research Support; Genentech, Inc., Merck & Co., Inc., Metacrine, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., vTv Therapeutics. W.Garvey: Other Relationship; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Epitomee, JAZZ Pharmaceuticals, Novo Nordisk, Novo Nordisk, Pfizer Inc., Pfizer Inc. B.Goldman: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. U.Khalid: None. R.Sørrig: Employee; Novo Nordisk A/S. D.Rubino: Advisory Panel; Novo Nordisk, Other Relationship; Endocrine Society, PeerView, WebMD LLC, Research Support; Boehringer Ingelheim International GmbH, Novo Nordisk, Obesinov, SARL, Speaker's Bureau; Novo Nordisk, Stock/Shareholder; Novo Nordisk. Funding Funded by Novo Nordisk A/S

32-OR: The Advancing Care for T1D Obesity Network (ACT1ON) Sequential Multiple Assignment Randomized Trial Pilot Re-randomization Results

Background: Sequential Multiple Assignment Randomized Trials (SMARTs) efficiently address practical treatment comparison questions and adapt dynamically based on response. They may be useful for development of approaches to co-manage weight and glycemia T1D, which is critical yet challenging. Methods: Our SMART pilot with three diet periods enrolled young adults with T1D (BMI 27-39.9 kg/m²) . Participants were re-randomized after ∼3 months on the hypocaloric Look AHEAD (Low Fat) or Low Carbohydrate (Low Carb) ; or Mediterranean (Med, not calorie restricted) diet if <2% weight was lost, HbA1c increased ≥0.5%, diet was unacceptable, or hypoglycemia increased. We present descriptive statistics for weight, HbA1c, and re-randomization for diet period 1 pre-COVID before shifting to a virtual protocol. Results: The proportion re-randomized was 57.9% and did not vary by diet. Weight was lost overall but insufficient weight loss was the most common reason for re-randomization for Low Fat and Med. An HbA1c increase ≥0.5% was most common on Med. Low diet acceptability was the most common reason for re-randomization on Low Carb. Conclusions: We achieved safe weight loss among young adults with T1D but observed heterogeneity in reasons for re-randomization by diet, although differences were not statistically significant. A fully-powered efficacy trial may confirm our findings. Disclosure D.Igudesman: None. R.E.Pratley: Other Relationship; Bayer AG, Corcept Therapeutics, Dexcom, Inc., Hanmi Pharm. Co., Ltd., Merck & Co., Inc., Metavention, Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. M.R.Kosorok: n/a. D.M.Maahs: Advisory Panel; Abbott Diabetes, Eli Lilly and Company, Medtronic, Novo Nordisk, Sanofi, Consultant; Aditx Therapeutics, Inc., Biospex. E.J.Mayer-davis: None. J.Crandell: n/a. T.Pokaprakarn: None. K.Corbin: None. D.P.Zaharieva: Research Support; Insulet Corporation, International Society for Pediatric and Adolescent Diabetes, Leona M. and Harry B. Helmsley Charitable Trust. A.Addala: None. J.Thomas: None. A.Casu: None. M.Riddell: Advisory Panel; Zealand Pharma A/S, Zucara Therapeutics, Consultant; Eli Lilly and Company, Jaeb Center for Health Research, Speaker's Bureau; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk. Funding National Institutes of Health 1DP3DK113358

278-OR: ADA Presidents' Select Abstract: Impact of Overnight Blood Glucose on Next-Day Functioning in T1D

Introduction: While people with T1D report that blood glucose (BG) fluctuations affect their day-to-day functioning, these relationships are poorly understood. Using continuous glucose monitoring (CGM) , accelerometry, and momentary surveys and cognitive tasks, we sought to understand how various BG metrics during sleeping hours impact functioning the following day. Methods: Participants wore a blinded CGM and accelerometer for 10-14 days, during which they completed surveys and cognitive tasks 5-6 times per day. Using dynamic structural equation modeling, we evaluated the within-person impact of overnight BG on the following day’s functioning, while controlling for the prior day’s functioning. BG variables included % time <70 mg/dL, % time >250 mg/dL, and coefficient of variation (CV) . Functioning variables included cognitive measures of sustained attention and perceptual speed; daily step count; and self-reported fatigue, task performance, and net activity demand. Results: Among 127 adults with T1D (41±15 yrs, 46% male, 39% Latinx, 35% White, 10% Black, 4% Asian, 12% multiethnic/other) , all three BG variables predicted changes in next day functioning. More time <70 predicted poorer sustained attention (standardized b= -0.06) , while more time >250 predicted more fatigue (0.09) and lower step count (-0.12) (all p<0.05) . Higher CV had the broadest impact, predicting poorer sustained attention (-0.06) , more fatigue (0.05) , and less engagement in demanding activities (-0.05) (all p<0.05) . Conclusion: Our findings indicate that overnight BG impacts cognition, physical activity, fatigue, and activity engagement the following day. While effect sizes are small, the cumulative impact of these decrements in function should be considered in the context of a life-long disorder. The consistent findings among diverse outcomes, including both objective and self-report measures, strengthen confidence in the overall conclusion that overnight BG has wide-ranging implications for functioning in adults with T1D. Disclosure E. Pyatak: Research Support; Abbott Diabetes. D. Spruijt-Metz: None. S. Schneider: None. J.P. Crandall: Research Support; Abbott Diabetes. A.L. Peters: Advisory Panel; Abbott Diabetes, AstraZeneca, Eli Lilly and Company, Novo Nordisk, Shouti, Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S. Research Support; Abbott Diabetes, Dexcom, Inc., Insulet Corporation, Leona M. and Harry B. Helmsley Charitable Trust. Stock/Shareholder; Teladoc Health. Other Relationship; Omada Health, Inc. H. Jin: None. S. Agarwal: Advisory Panel; Medtronic. Consultant; Beta Bionics, Inc. L.T. Pham: None. A. Ali: None. C.J. Hoogendoorn: None. G. Crespo-Ramos: None. R. Basile: None. J.S. Gonzalez: Consultant; Virta Health Corp. Funding National Institutes of Health (1R01DK121298-01)

181-OR: Sympathetic Activity in Patients with Type 2 Diabetes Mellitus Treated with Empagliflozin or Hydrochlorothiazide

Changes in sympathetic nervous system activity may contribute to beneficial effects of sodium glucose transporter (SGLT2) inhibition on cardiovascular outcomes. We hypothesized that SGLT inhibition with empagliflozin lowers sympathetic activity compared with hydrochlorothiazide (HCT) to discern SGLT2-specific actions from non-specific responses to increased natriuresis. In this double-blind, randomized study patients with type 2 diabetes mellitus on metformin monotherapy received either 25 mg/day empagliflozin (n=20) or 25 mg/day HCT (n=21) for 6 weeks. Muscle sympathetic nerve activity (MSNA) , blood pressure, cardiovascular, and metabolic biomarkers were assessed at baseline and end of treatment. Empagliflozin significantly increased urinary glucose excretion (difference in change from baseline 47.4 mmol/l vs. HCT) , reduced fasting plasma glucose (-1.91 mmol/l) , HbA1c (-0.58%) , and body weight (-1.23 kg, all p<0.05) . Office systolic blood pressure decreased with both treatments. MSNA (burst frequency -1.95 [95% confidence interval -8.67; 4.78] bursts/min) , baroreflex heart rate control (0.84 [-1.18; 2.87] ms/mmHg) and plasma catecholamines did not change significantly with either treatment. MSNA increased with higher body weight loss with both treatments, but more pronounced and significant only with HCT (p=0.0015) . In conclusion, neither empagliflozin nor HCT treatment led to clinically relevant changes in sympathetic activity. Given the important role of the sympathetic nervous system in the progression of cardiovascular disease, mechanisms attenuating sympathetic activity in the face of increased sodium excretion deserve further attention. Disclosure K.Heusser: None. J.Tank: None. A.Fischer: None. T.Heise: Advisory Panel; Novo Nordisk A/S, Research Support; ADOCIA, AstraZeneca, Biocon, Boehringer Ingelheim International GmbH, Crinetics Pharmaceuticals, Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Genova, Nestlé, Neuraly Inc., Novo Nordisk A/S, Sanofi, Zealand Pharma A/S, Speaker's Bureau; Eli Lilly and Company, Gan & Lee Pharmaceuticals, Novo Nordisk A/S. J.Jordan: Consultant; Novo Nordisk, Other Relationship; Eternygen, Research Support; Boehringer Ingelheim International GmbH.

96-LB: Safety of Glucose Regulation by the Bionic Pancreas without Continuous Glucose Monitoring Input

The bionic pancreas (BP) continues to make all insulin dosing decisions autonomously when continuous glucose monitoring (CGM) data is not available. Basal insulin is given based on a profile determined autonomously by the BP when CGM data was available. Meals are announced as Breakfast, Lunch, or Dinner and by relative size (Usual, Less, More) ; insulin dosing is based on adaptation that occurred when CGM data was available. Insulin may be delivered, or temporarily suspended, autonomously by the BP in response to entered blood glucose (BG) values. At the end of the 13-week Pivotal RCT of the BP in type 1 diabetes, participants in the BP group could participate in a study testing the BP without CGM input. Unblinded CGM was replaced by blinded CGM not connected to the BP for ∼49.5 hours. Participants were to enter fingerstick BG values every ∼2 hours during the day and once overnight. Adherence with BG entry requirements by the 54 participants (aged 7-70) was high. There was no severe hypoglycemia or DKA. The frequency of CGM-measured hypoglycemia was similar during the BG Period to the RCT and Pre-Randomization periods. Hyperglycemia metrics were nominally higher during the BG Period than the RCT, but nominally lower than the Pre-randomization Baseline period. The BP can autonomously determine all insulin doses and achieve safe glucose control without CGM input when intermittent BG values are provided by the user. Disclosure C. A. Balliro: Consultant; Beta Bionics, Inc., Zealand Pharma A/S. Funding Funding from National Institute of Diabetes and Digestive and Kidney Diseases (#1UC4DK108612-01) . Funding and bionic pancreas devices from Beta Bionics, Inc. Fast-acting insulin aspart and insulin aspart provided by Novo Nordisk Insulin lispro by Eli LillyBlood glucose meters and test strips (Contour Next One Blood Glucose Monitoring System) provided by Ascensia Diabetes Care, Basel, CH. Continuous glucose monitor sensors and transmitters were purchased from Dexcom, Inc. at a discounted price.

689-P: Comparing the Rates of Sensor-Detected Hypoglycaemia and Patient-Reported Hypoglycaemia by Awareness of Hypoglycaemia Using Continuous Glucose Monitoring: The Hypo-METRICS Trial

Impaired awareness of hypoglycemia (IAH) is attributed to hypoglycemia exposure. Continuous glucose monitoring (CGM) detects more hypoglycemia particularly during sleep. We compared rates and duration of sensor detected hypoglycemia (SDH) and patient reported hypoglycemia (PRH) in people with type 1 diabetes (T1D) using CGM or flash monitoring.We recruited 92 participants with T1D using CGM/Flash reporting >1 hypoglycemic episode in the last month. Participants were defined as normal awareness of hypoglycemia (NAH) (Gold score <4; n=70) and IAH (Gold score >4; n=22) . All wore an additional blinded CGM and recorded episodes of PRH (symptomatic episodes that resolved on carbohydrate ingestion, or a measured glucose <72mg/dl) in real time on a smartphone app for weeks. Sleep status was obtained using an actigraphy monitor. Time in range (59.4 vs. 62.4%; p=0.18) and time < 70 mg/dl (4.6 vs. 6.0%; p=0.44) were not different between groups. Rates and duration of SDH < 70 mg/dl, < 55 mg/dl and < 40 mg/dl during sleep and awake were not different (table 1) . Rates of PRH were also not different (table 1) . While CGM has benefits, it cannot be used to define IAH. CGM allows people with IAH to self-detect hypoglycemia similar to those with NAH, providing a technology supported awareness. Disclosure P.Divilly: None. S.R.Heller: Advisory Panel; Eli Lilly and Company, Medtronic, Mylan N.V., Zealand Pharma A/S, Zucara Therapeutics, Other Relationship; Eli Lilly and Company, Research Support; Dexcom, Inc., Speaker’s Bureau; Novo Nordisk A/S. M.Evans: Advisory Panel; Pila Pharma, Zucara Therapeutics, Other Relationship; Abbott Diabetes, Dexcom, Inc., Medtronic, Novo Nordisk, Research Support; AstraZeneca, Sanofi, Speaker’s Bureau; Lilly Diabetes. J.K.Mader: Advisory Panel; Abbott Diabetes, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Speaker’s Bureau; Abbott Diabetes, Eli Lilly and Company, Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Servier Laboratories, Stock/Shareholder; decide Clinical Software GmbH. S.A.Amiel: Advisory Panel; Medtronic, Novo Nordisk, Other Relationship; Sanofi. P.Choudhary: Advisory Panel; Abbott Diabetes, Lilly Diabetes, Medtronic, Research Support; Novo Nordisk, Speaker’s Bureau; Dexcom, Inc., Glooko, Inc., Insulet Corporation, Sanofi. A.Seibold: Employee; Abbott Diabetes, Stock/Shareholder; Abbott. G.Martine-edith: Other Relationship; Novo Nordisk. Z.Mahmoudi: Employee; Novo Nordisk A/S. N.Zaremba: None. U.Soeholm: Research Support; Novo Nordisk A/S. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. R.J.Mccrimmon: Advisory Panel; Novo Nordisk, Sanofi, Research Support; Diabetes UK, European Union, MedImmune. B.E.De galan: Research Support; Novo Nordisk. E.Renard: Consultant; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Insulet Corporation, LifeScan, Lilly, Novo Nordisk, Roche Diabetes Care, Sanofi, Tandem Diabetes Care, Inc. Funding Innovative Medicines Initiative (777460)

766-P: Glycemic Outcomes with the Omnipod 5 Automated Insulin Delivery (AID) System Stratified by Baseline Hypoglycemia Risk among People with Type 1 Diabetes (T1D) Ages 2 to 70 Years

Hypoglycemia remains a major concern for persons with T1D using injections or “open loop” insulin pump delivery. Risk avoidance strategies are required, but often at the expense of increased hyperglycemia and elevated A1C levels. AID systems may reduce the need for human intervention by minimizing out-of-range glucose levels. We evaluated glycemic outcomes of people with T1D using the Omnipod 5 AID System, stratified by each user's time below range (TBR, % <70 mg/dL) with their prior standard therapy (ST) . Participants of 3 age groups: 2-5.9, 6-13.9, and 14-70 years, with A1C<10% used AID for 3 months at home after a 14-day ST phase. TBR and time in range (TIR, % 70-180 mg/dL) were evaluated across 3 ST TBR groups: ≤1%, >1% to <4%, and ≥4%. Trends were similar across all age groups. Overall, those with high ST TBR (≥4%) had a higher ST TIR (64.9%) ; AID substantially decreased TBR (-3.4%, -49 min/d) and increased TIR (73.9%) (Table) . Those with low ST TBR (≤1%) had lower ST TIR (50.8%) ; AID increased TIR substantially (to 67.9%) , while TBR was low (0.7%) . AID was associated with significant reductions in time below range in cohorts with high hypoglycemia risk (≥4% TBR) at baseline. In the lowest hypoglycemia risk at baseline cohort (≤1% TBR) , the median TBR remained ≤1%, although TBR was modestly higher, but this group had the largest increase in TIR. Disclosure G.P.Forlenza: Advisory Panel; Lilly, Medtronic, Consultant; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care, Inc., Research Support; Dexcom, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care, Inc. L.M.Laffel: Advisory Panel; Medtronic, Roche Diabetes Care, Consultant; Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompé, Insulet Corporation, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk, Provention Bio, Inc. J.Sherr: Advisory Panel; Bigfoot Biomedical, Inc., Cecelia Health, Insulet Corporation, Medtronic, Vertex Pharmaceuticals Incorporated, Consultant; Insulet Corporation, Lexicon Pharmaceuticals, Inc., Research Support; Dexcom, Inc., Insulet Corporation, Jaeb Center for Health Research, JDRF, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases, Speaker's Bureau; Lilly Diabetes. C.J.Levy: Advisory Panel; Dexcom, Inc., Eli Lilly and Company, Research Support; Abbott Diabetes, Dexcom, Inc., Insulet Corporation, T1D Exchange, Tandem Diabetes Care, Inc. I.B.Hirsch: Consultant; Abbott Diabetes, Bigfoot Biomedical, Inc., GWave, Roche Diabetes Care, Research Support; Beta Bionics, Inc., Insulet Corporation, Medtronic. S.A.Macleish: Advisory Panel; Insulet Corporation. D.Desalvo: Consultant; Dexcom, Inc., Insulet Corporation, Research Support; Insulet Corporation. V.Shah: Advisory Panel; Medscape, Sanofi, Consultant; Dexcom, Inc., Research Support; Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Novo Nordisk. A.Bhargava: Research Support; Abbott Diabetes, AbbVie Inc., Boehringer Ingelheim International GmbH, Boston Therapeutics, Inc., Covance, Dexcom, Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Insulet Corporation, Kowa Pharmaceuticals America, Inc., Lexicon Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Medtronic, Novo Nordisk, Poxel SA, Quintiles, Sanofi, Senseonics, Tolerion, Inc., Viking Therapeutics, vTv Therapeutics. T.C.Jones: None. G.Aleppo: Consultant; Insulet Corporation, Research Support; AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Fractyl Health, Inc., Insulet Corporation, Novo Nordisk, Speaker's Bureau; Dexcom, Inc. B.W.Bode: Advisory Panel; CeQur SA, MannKind Corporation, Medtronic, Novo Nordisk, Zealand Pharma A/S, Consultant; Bigfoot Biomedical, Inc., Research Support; Abbott, Beta Bionics, Inc., Dexcom, Inc., Diasome, Dompé, Eli Lilly and Company, Insulet Corporation, IQVIA Inc., Jaeb Center for Health Research, Medtronic, Novo Nordisk, Provention Bio, Inc., REMD Biotherapeutics, Sanvita Medical, Senseonics, ViaCyte, Inc., Speaker's Bureau; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Insulet Corporation, MannKind Corporation, Novo Nordisk, Sanofi, Xeris Pharmaceuticals, Inc., Stock/Shareholder; AgaMatrix, Glytec, LLC. L.M.Huyett: Employee; Insulet Corporation, Stock/Shareholder; Insulet Corporation. T.T.Ly: Employee; Insulet Corporation, Stock/Shareholder; Insulet Corporation. Omnipod 5 research group: n/a. A.L.Carlson: Advisory Panel; MannKind Corporation; Employee; Bright Health Group; Other Relationship; Medtronic; Research Support; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Novo Nordisk, Sanofi, UnitedHealth Group. Funding This study was funded by Insulet Corporation.

151-LB: Postprandial Glucose Metabolism Differs between Early Adolescents and Adults with Type 1 Diabetes

Postprandial glucose turnover in adolescents with type 1 diabetes (T1D) has not been investigated. To do so, we studied adolescents (n=15, age 11.5±0.5 yrs, BMI 19±2.3 kg/m2, HbA1c 7.5±1%, diabetes duration 4.6±3 yrs) and adults (n=15, age 36.3±9.4 yrs, BMI 27.1±2.1 kg/m2, HbA1c 6.9±1.1%, diabetes duration 18.1±9.6 yrs) with T1D after a mixed meal. Healthy adults (n=14, age 26.9 ± 7 yrs, BMI 24.9±2.5 kg/m2, HbA1c 5.0±0.3%) served as controls. T1D subjects administered their customary insulin bolus dose at meal onset. Rates of endogenous glucose production (EGP) , meal glucose appearance (MRa) and glucose disappearance (Rd) were calculated by the triple tracer method with stable isotopes ([1-13C] glucose, [2-13C] glucose and [6, 6-2H2] glucose) . Integrated glucose excursions did not differ between adolescents and adults with T1D during early (0-120 min) and total (0-300 min) postprandial periods. While basal EGP at start of the meal was higher (p<0.01) , integrated rates of EGP, MRa, Rd and glucose clearance were all lower (p<0.03) in adolescents than in adults with T1D during the early postprandial period and were numerically lower (p=0.08) during the total postprandial period (Figure1) . Taken together, the data demonstrates significant differences in postprandial glucose metabolism between adolescents and adults with T1D. Additional studies are ongoing to determine the causes of these differences. Disclosure F. Ruchi: None. D. Romeres: None. S. Gururaj: None. M. D. Deboer: Research Support; Dexcom, Inc., Tandem Diabetes Care, Inc. R. Basu: Consultant; Sparrow Pharmaceuticals Inc, Research Support; Abbott Diabetes, AstraZeneca. A. Basu: Speaker's Bureau; Zealand Pharma A/S. Funding DK 124886, DK 085516, DK 029953

727-P: Glycemic Effect of Tirzepatide by Duration of Diabetes

Results of SURPASS-1 through -5 trials have shown robust efficacy of novel dual GIP/GLP-1 receptor agonist tirzepatide (TZP) in people with type 2 diabetes. To understand whether glucose-lowering effect of tirzepatide depends on the duration of diabetes we conducted a subgroup analysis within each of the 5 Phase 3 trials. The primary endpoint of the 5 SURPASS clinical trials was mean change from baseline in HbA1c for 5mg, 10mg, and 15mg to 40 or 52 weeks against various comparators in adults with type 2 diabetes. This subgroup analysis of the 5 trials assessed whether mean change of HbA1c from baseline in the overall population were consistent when assessed by baseline duration of diabetes category (≤5 years, 5 to years, >years) in patients while they were on-treatment and without rescue medication (efficacy estimand) . For all 5 studies, analysis of change from baseline in HbA1c at 40 or 52 weeks for all 3 duration of diabetes subgroups were consistent with primary study results, with the treatment differences favoring all 3 doses of TZP compared with placebo or active comparator (Figure) . The most frequent adverse events were mild-to-moderate, gastrointestinal-related and occurred during the dose-escalation period. In conclusion, these results suggest that TZP was effective for mean change from baseline Hba1c for patients regardless of baseline duration of diabetes consistent with the overall patient population across the 5 SURPASS studies. Disclosure C.De block: Advisory Panel; Abbott Diagnostics, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk, Research Support; Indigo Diabetes, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk. C.Mathieu: Advisory Panel; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Imcyse, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca. H.Sapin: Employee; Eli Lilly and Company. J.I.Kiljanski: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.Peleshok: Employee; Eli Lilly and Company, Eli Lilly and Company.

394-P: Baseline Risk Markers and Visit-to-Visit Variability in Relation to Kidney Outcomes: A Post Hoc Analysis of the PERL Study

Background: Baseline risk variables and visit-to-visit variability (VV) of systolic blood pressure (SBP) , HbA1c, serum creatinine, and uric acid (UA) are potential risk markers of kidney function decline in type 1 diabetes. Methods: Post-hoc analysis of the PERL study (NCT02017171) - a double-blind randomized placebo-controlled clinical trial investigating allopurinol’s effect on iohexol-derived glomerular filtration rate (iGFR) in type 1 diabetes with elevated UA. Primary outcome was iGFR change over three years. Linear regression with backwards selection of baseline clinical variables was performed to identify an optimized model forecasting iGFR change. VV of SBP, HbA1c, serum creatinine, and UA were calculated as standard deviations of the residuals in individual linear regression models (LV) and coefficients of variation (CV) using all available measurements in the run-in period; thereafter assessed by linear regression, with iGFR change as the dependent variable. Adjustment included sex, baseline age, diabetes duration, BMI, HbA1c, SBP, kidney function (iGFR or eGFR, as appropriate) , urine albumin excretion rate (UAER) , smoking, and renin-angiotensin system inhibitor use. Results: 422 participants completed the trial, 4were included in this analysis. In the optimized baseline risk marker model, race other (including but not limited to Hawaiian/Pacific Islander) than White, Black, or Asian, higher HbA1c, UAER, and heart rate, and lower iGFR were associated with faster iGFR decline; Hispanic/Latino ethnicity was not. Assessing VV, higher LV and CV of SBP was associated with faster iGFR decline (adjusted LV β: -0.79, p=0.01; CV β: -0.79, p=0.04) ; VVs of HbA1c, creatinine, and UA were not. Conclusions: We identified several risk markers of faster iGFR decline in a high-risk population of individuals with type 1 diabetes. In addition to previously described associations, higher SBP VV was a risk marker for faster kidney function decline. Disclosure V.Rotbain curovic: None. S.Polsky: Advisory Panel; Medtronic, Other Relationship; diaTribe, Research Support; Dexcom, Inc., Eli Lilly and Company, Leona M. and Harry B. Helmsley Charitable Trust, Medtronic, National Institute of Diabetes and Digestive and Kidney Diseases, Sanofi-Aventis U.S. R.Pop-busui: Advisory Panel; Averitas Pharma, Inc., Boehringer Ingelheim International GmbH, Nevro Corp., Novo Nordisk, Reata Pharmaceuticals, Inc., Regenacy Pharmaceuticals, Inc. R.J.Sigal: Advisory Panel; Novo Nordisk Canada Inc., Research Support; Novo Nordisk Canada Inc. K.R.Tuttle: Advisory Panel; Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Consultant; AstraZeneca, Eli Lilly and Company, Research Support; Bayer AG, Goldfinch Bio, Inc., Novo Nordisk, Travere. G.E.Umpierrez: Research Support; AstraZeneca, Dexcom, Inc., Novo Nordisk. A.Wallia: Advisory Panel; Eli Lilly and Company, Research Support; Novo Nordisk, UnitedHealth Group. S.Rosas: Advisory Panel; AstraZeneca, Teladoc Health, Other Relationship; Bayer AG, Research Support; AstraZeneca, Bayer AG. P.Rossing: Consultant; Astellas Pharma Inc., AstraZeneca, Bayer AG, Gilead Sciences, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Speaker's Bureau; Eli Lilly and Company. The perl study group: n/a. N.Roy: None. T.W.Hansen: Stock/Shareholder; Novo Nordisk A/S. L.Caramori: Advisory Panel; Bayer AG, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Research Support; Bayer AG, Novartis AG. D.Cherney: Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC, Lilly, Maze, BMS, CSL-Behring, Merck, Otsuka, Novartis and Novo-Nordisk , Mitsubishi Tanabe Pharma Corporation, Sanofi, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. I.De boer: Advisory Panel; AstraZeneca, Bayer AG, Cyclerion Therapeutics, Inc., George Clinical, Goldfinch Bio, Inc., Other Relationship; American Society of Nephrology, Research Support; Dexcom, Inc. I.B.Hirsch: Consultant; Abbott Diabetes, Bigfoot Biomedical, Inc., GWave, Roche Diabetes Care, Research Support; Beta Bionics, Inc., Insulet Corporation, Medtronic. I.Lingvay: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Mannkind, TARGET PharmaSolutions; Valeritas;; Altimmune; DataRevive; Click; Medscape Duke CRI; Janssen Pharma; Bayer; Intercept, Novo Nordisk, Sanofi, Zealand Pharma A/S, Consultant; Novo Nordisk, Research Support; NovoNordisk; Mylan; Merck, Sanofi. J.B.Mcgill: Advisory Panel; Gilead Sciences, Inc., Lilly Diabetes, MannKind Corporation, Novo Nordisk A/S, Provention Bio, Inc., Salix Pharmaceuticals, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; Dexcom, Inc., Novo Nordisk. Funding Supported by grants from the NIDDK (R03-DK-094484, R34-DK-097808, UC4-DK-101108, P30-DK-036836, and P30-DK-020572) , the JDRF (17-2012-377) , the National Center for Advancing Translational Sciences (UL1-TR-002494, UL1-TR- 001422, UL1-TR-002556, UL1-TR-002319, and UL1-TR- 001105) , and the National Institute on Aging (Claude Pepper Center grant number, P30-AG-024824)

828-P: Preservation of ß-Cell Function in Pancreatic Insufficient Cystic Fibrosis (CF) with Highly Effective CFTR Modulator Therapy

CF related diabetes is common with pancreatic insufficient CF (PI-CF) . Highly effective modulator therapy enhances aberrant CF transmembrane conductance regulator (CFTR) function and improves pulmonary and nutritional status. Ivacaftor therapy for indicated CFTR mutations enhanced insulin secretion to glucose-potentiated arginine (GPA) testing; however the effects of elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta™) on β-cell function have not been assessed. We retrospectively compared changes in GPA measures performed on two visits in individuals with PI-CF without diabetes and who were 1) initiated on ETI after the baseline visit (ETI group) vs. 2) not treated with CFTR modulator therapy (controls) . ETI participants (mean±SD age 27±9 years) and 8 matched controls were followed up after a median (IQR) 5.8 (3.7-6.7) and 2.7 (1.9-3.0) years, respectively (p=0.001) , with ETI initiation 1.1 (0.2-1.2) years before the follow-up visit. Weight increased in both groups, but by more in the ETI group (p<0.01) . No differences in lung function or HbA1c were observed; however, improvement in oral glucose tolerance test 2-hour glucose was observed in the ETI group (p<0.05) that was different by trend from the change seen in controls (p=0.09) . Acute insulin and C-peptide responses to glucose-potentiated arginine deteriorated in controls (p<0.05) but not in the ETI group, while C-peptide changes differed between groups (p<0.05) . A trend towards lower acute proinsulin response was seen in the ETI group (p=0.07) with the change different between groups (p<0.05) . Deterioration in the proinsulin secretory ratio was observed in the control (p<0.05) but not the ETI group (between group change, p=0.01) . ETI therapy appears to preserve β-cell function in CF through effects on glucose-dependent insulin secretion and proinsulin processing. Further work should determine whether early intervention with ETI can prevent deterioration of glucose tolerance in PI-CF. Disclosure A.Flatt: None. M.R.Rickels: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Consultant; L-Nutra Inc. A.Kelly: Research Support; vTv Therapeutics. S.Sheikh: None. A.J.Peleckis: None. K.Gallagher: None. P.Alvarado: None. D.Hadjiliadis: Advisory Panel; AstraZeneca, Research Support; Mylan N.V. D.Stefanovski: None. R.J.Gallop: None. R.C.Rubenstein: None. Funding Public Health Service research grants (RDK97830; K23 DK107937; UL1 TR001878) and National Institutes of Health (P30 DK19525) .

1202-P: Disparities in Incidence of Diagnosed Diabetes in Rural United States, 2011–2018

US rural, compared to non-rural, populations have diabetes health disparities. However, it is unknown if there are rural disparities in incident diabetes. We used CDC data on incidence of diagnosed diabetes in adults aged ≥20 years, available for 97.5% of US counties (n=3145/3226) . Trends in the annual age-adjusted incident diabetes rate per 1000 adults (AADR) were assessed by weighted least squares regression. Year was fitted nonlinearly with a spline function, and AADR fold-change was tested by a model-based contrast of 20vs. 2018. The average AADR of 8.7 (95% CI 8.6-8.7) ranged from 9.3 (in 2011) to 8.3 (in 2013) and 8.9 (in 2018) , and concealed subnational disparities based on rurality (Figure) . In 2018, compared with 2011, the AADR decreased for large central metro counties (most urban) with AADR fold-change of 0.92 (0.91-0.93) but increased for noncore counties (most rural) with AADR fold-change of 1. (1.01-1.08) (both P<.01) . The AADR declined in counties with intermediate rurality except for micropolitan counties (no change; P=.56) . When stratified by region, the largest rural disparity in AADR was observed in the South, with smaller disparities in other regions. In summary, from 2011-2018, rural counties had the highest overall AADR. The overall disparity in trends based on county rurality and the disparity in incidence in the rural South and rural West highlight areas for diabetes primary prevention interventions. Disclosure K.R. Bailey: None. M.M. Mielke: Consultant; Biogen, LabCorp. A. Vella: Advisory Panel; Crinetics Pharmaceuticals, Inc., Rezolute, Inc., vTv Therapeutics, Zealand Pharma A/S. Other Relationship; Novo Nordisk. Funding National Institute on Minority Health and Health Disparities (NIH K23 MD016230)