Vertex Pharmaceuticals Incorporated Research Articles

213-OR: ADA Presidents' Select Abstract: EMBARK—A Randomized, Controlled Trial Comparing Three Approaches to Reducing Diabetes Distress in Adults with Type 1 Diabetes

Diabetes distress (DD) refers to the fears, worries and burdens associated with the diabetes experience. DD is common, distinct from depression, and associated with glycemic and disease management. EMBARK is a randomized, controlled clinical trial comparing three interventions to reduce DD among adults with type 1 diabetes (T1D). Following baseline assessment, participants were randomly assigned to either: (1) Streamline, an educator-led education and management program, (2) TunedIn, a psychologist-led program focused exclusively on reducing DD, or (3) FixIt, an integration of StreamLine and TunedIn. All interventions were group-based (8 to 12 members) and virtual, including initial workshop(s), 1:1 phone calls, and follow-up meetings over a 4-month period. Recruitment occurred through clinics and community organizations in the U.S. Inclusion criteria were: T1D diagnosis, elevated DD (≥ 2.0 T1-DDS score), age ≥ 21 years, HbA1c ≥ 7.5% (58 mmol/mol), and English speaking. Regression analyses recorded change in DD from baseline to immediate post-intervention. A total of 300 adults with T1D participated (M±SD 46±15 years of age, 79% female, HbA1c 8.3%±0.9 (67 mmol/mol), T1-DDS score 2.8±0.8). Large and clinically meaningful reductions in total DD score occurred for each of the three study arms at follow-up (p < .001). The greatest DD reductions occurred in the FixIt intervention (Δ .88±.80), followed by TunedIn (Δ .59±.70), and then Streamline (Δ .48±.71); with DD reductions significantly greater in FixIt compared to Streamline (p = .005). The same pattern of results was evident in comparisons for the DD sources of Powerlessness (p < .001), Management (p = .06), Hypoglycemia (p = .009), and Physician Distress (p = .01). These preliminary findings highlight the benefit of focusing directly on the emotional side of diabetes to reduce DD and indicate that DD reductions are greatest when education and emotional DD-targeted interventions are integrated. Disclosure D.M.Hessler: Consultant; Lilly. A.Ahmann: Advisory Panel; Medtronic. U.Masharani: Research Support; Clementia Pharmaceuticals. L.Fisher: Consultant; Abbott Diabetes, Eli Lilly and Company, Research Support; Ascensia Diabetes Care. L.A.Strycker: None. W.H.Polonsky: Consultant; Abbott Diabetes, Boehringer Ingelheim and Eli Lilly Alliance, Eli Lilly and Company, Insulet Corporation, Intuity Medical, Inc., MannKind Corporation, Provention Bio, Inc., Sanofi-Aventis U.S., Vertex Pharmaceuticals Incorporated. S.Guzman: Consultant; Abbott Diabetes. G.Aleppo: Advisory Panel; Medscape, Consultant; Bayer Inc., Insulet Corporation, Research Support; Dexcom, Inc., Eli Lilly and Company, Emmes, Insulet Corporation, Fractyl Health, Inc., WellDoc, Speaker's Bureau; Dexcom, Inc. E.Stephens: None. S.Kim: None. N.B.Argento: Advisory Panel; Dexcom, Inc., Eli Lilly and Company, ConvaTec Inc., Diabeloop SA, Senseonics, Speaker's Bureau; Dexcom, Inc., Boehringer Ingelheim and Eli Lilly Alliance, Novo Nordisk, MannKind Corporation, Zealand Pharma A/S, Xeris Pharmaceuticals, Inc., Eli Lilly and Company. Funding National Institutes of Health (5R01DK121241)

836-P: Glucose-Dependent Insulin Production and Insulin-Independence in Type 1 Diabetes from Stem Cell–Derived, Fully Differentiated Islet Cells—Updated Data from the VX-880 Clinical Trial

VX-880 is an investigational allogeneic stem cell-derived, fully differentiated, pancreatic islet cell replacement therapy being evaluated in a phase 1/2 clinical trial in patients with T1D and impaired hypoglycemic awareness and severe hypoglycemia. The phase 1/2 trial has three parts: Part A in which 2 patients are enrolled sequentially and receive half the target dose (presented at ADA 2022), Part B in which 5 patients are enrolled sequentially and receive the target (full) dose, and Part C where 10 patients are enrolled concurrently and receive the target (full) dose. The first two patients infused with VX-880 at half the target dose (in Part A) had restored insulin production and glucose control. One of these patients achieved and has maintained insulin independence, defined as at least one week off exogenous insulin, HbA1C ≤7%, post-prandial serum glucose at 90 minutes ≤180 mg/dL, fasting serum glucose ≤126 mg/dL, and fasting or stimulated C-peptide ≥166 pmol/L (latter 3 measured during mixed-meal tolerance test). The safety profile was consistent with the immunosuppressive regimen used in the study and the perioperative period. Part B is now fully enrolled and multiple patients have been dosed with the full (target) dose. Longer-term data on both patients in Part A and new data on patients who received the full (target) dose in Part B will be provided in the presentation. These results are the first from a clinical trial of allogeneic, fully differentiated, insulin producing, stem cell-derived islets which has demonstrated the potential to restore insulin production and glycemic control and provide insulin independence in patients with T1D. Disclosure T.W.Reichman: Consultant; Sernova, Corp., Research Support; Vertex Pharmaceuticals Incorporated. J.L.Shih: Employee; Vertex Pharmaceuticals Incorporated. C.Wang: Employee; Vertex Pharmaceuticals Incorporated. D.Melton: None. F.Pagliuca: Employee; Vertex Pharmaceuticals Incorporated, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. B.Sanna: Employee; Vertex Pharmaceuticals Incorporated. L.S.Kean: Advisory Panel; HiFiBio, Mammoth Biosciences, Consultant; Vertex Pharmaceuticals Incorporated, Other Relationship; Bristol-Myers Squibb Company, Research Support; Bristol-Myers Squibb Company, Adaptive Biotechnologies, Merck & Co., Inc., Tessera, Novartis. A.L.Peters: Advisory Panel; Abbott Diabetes, Medscape, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Research Support; Abbott Diabetes, Dexcom, Inc., Insulet Corporation, Stock/Shareholder; Omada Health, Inc., Livongo. P.Witkowski: Advisory Panel; Vertex Pharmaceuticals Incorporated, Novartis. M.R.Rickels: Consultant; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Research Support; Dompé. C.Ricordi: Advisory Panel; Vertex Pharmaceuticals Incorporated. A.Naji: None. J.F.Markmann: None. B.A.Perkins: Advisory Panel; Dexcom, Inc., Insulet Corporation, Novo Nordisk, Sanofi, Vertex Pharmaceuticals Incorporated, Other Relationship; Abbott, Medtronic, Sanofi, Research Support; Novo Nordisk, Bank of Montreal (BMO). M.Wijkstrom: None. S.Paraskevas: None. B.Bruinsma: Employee; Vertex Pharmaceuticals Incorporated. G.Marigowda: Employee; Vertex Pharmaceuticals Incorporated.

53-OR: Efficacy and Safety of Coadministered s.c. Semaglutide and s.c. Cagrilintide in Type 2 Diabetes

Combining sema (semaglutide 2.4 mg) and amylin analog cagri (cagrilintide 2.4 mg) has weight loss benefits, but the impact on HbA1c is unknown. This study is the first to assess the efficacy and safety of CagriSema (co-administered) vs sema or cagri alone in participants (pts) with T2D. In this phase 2 (NCT04982575), multicenter, double-blind trial, adults with T2D (HbA1c 7.5-10.0%) and BMI ≥27 kg/m2 on metformin ± SGLT2i, were randomized to once-weekly s.c. CagriSema, sema, or cagri for 32 weeks (all escalated over 16 weeks to 2.4 mg). The primary endpoint was change from baseline in HbA1c; key secondary endpoints were body weight and safety. Of the 92 pts randomized (64% male; mean age 58 years and T2D duration 8.7 years), those receiving CagriSema had significantly greater reductions in HbA1c (vs cagri) and body weight (vs sema and cagri) at week 32 (Figure). The proportion of pts achieving HbA1c <7.0% and ≤6.5%, were 89% and 75% for CagriSema, 69% and 48% for sema, and 33% and 17% for cagri at week 32. GI AEs were most common (58% for CagriSema, 32% for sema, and 33% for cagri), were mainly mild/moderate, occurred during dose escalation, and lead to treatment discontinuation in 0%, 3%, and 0% of pts with CagriSema, sema, and cagri, respectively; no level 2 or 3 hypoglycemia was reported. CagriSema improved glycemic control and led to significant weight loss vs both sema or cagri, and was well tolerated with no new safety signals. Disclosure J.P.Frias: Advisory Panel; Becton, Dickinson and Company, Pfizer Inc., Sanofi, Consultant; Akero Therapeutics, Inc., 89bio, Inc., Aimmune, Boehringer Ingelheim Inc., Eli Lilly and Company, Carmot Therapeutics, Inc., Echosens, Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Employee; Ionis Pharmaceuticals, Research Support; Akero Therapeutics, Inc., 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Carmot Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Oramed Pharmaceuticals, Novartis, Pfizer Inc., Sanofi, Speaker's Bureau; Eli Lilly and Company, Sanofi. S.Deenadayalan: Employee; Novo Nordisk A/S. L.Erichsen: None. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. I.Lingvay: Advisory Panel; Novo Nordisk A/S, Lilly Diabetes, Boehringer-Ingelheim, Sanofi, Consultant; Carmot Therapeutics, Inc., Merck Sharp & Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc., Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer, Research Support; Novo Nordisk A/S, Boehringer-Ingelheim. S.Macura: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated. S.D.Pedersen: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim (Canada) Ltd., AstraZeneca, HLS Therapeutics Inc., Bayer Inc., Viatris Inc., Bausch + Lomb, Research Support; Eli Lilly and Company, Novo Nordisk, AstraZeneca, Applied Therapeutics Inc., Speaker's Bureau; Abbott Diabetes, Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim (Canada) Ltd., AstraZeneca, Medtronic, Pfizer Inc., HLS Therapeutics Inc., Bayer Inc., Bausch + Lomb. M.J.Davies: Advisory Panel; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Lexicon Pharmaceuticals, Inc., Pfizer Inc., Medtronic, ShouTi Pharma Inc., Consultant; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Research Support; AstraZeneca, Novo Nordisk, Sanofi-Aventis U.S., Boehringer-Ingelheim, Janssen Pharmaceuticals, Inc., Speaker's Bureau; Lilly, Boehringer-Ingelheim, Novo Nordisk, AstraZeneca, Napp Pharmaceuticals Limited, Novartis, Sanofi. Funding Novo Nordisk A/S

54-OR: Effect of Coadministered s.c. Semaglutide and s.c. Cagrilintide on Glycemic Levels Measured by CGM

Continuous glucose monitoring (CGM) offers insight into glycemic levels beyond the conventional measurement of HbA1c. This phase 2, multicenter, 32-week, double-blind trial (NCT04982575) compared the effects of CagriSema (co-administered semaglutide [sema] 2.4 mg and cagrilintide [cagri] 2.4 mg) vs sema (2.4 mg) or cagri (2.4 mg) alone, all as once-weekly subcutaneous injection, on CGM parameters (secondary endpoints). In total, 92 adult participants with T2D (HbA1c 7.5-10.0%), on metformin ± SGLT2i, and BMI ≥27 kg/m2 were randomized. Time in range (70-180 mg/dL) increased in all groups, reaching 88.9% with CagriSema at week 32 (Figure). Time in tight range (70-140 mg/dL; post-hoc analysis) increased from 16.0%, 8.8%, and 26.2% at baseline to 66.4%, 50.0%, and 36.7% at week 32 for CagriSema, sema, and cagri, respectively, with 0.8% or less in time below range for all groups. Mean glucose (measured by CGM) decreased from baseline to week 32 (CagriSema, -63.9; sema, -43.6; cagri, -23.4 mg/dL; estimated treatment difference [95% CI]: CagriSema vs sema, -20.2 [-39.8, -0.7; p=0.04], and CagriSema vs cagri, -40.5 [-59.4, -21.6; p<0.0001] mg/dL). Time in range with CagriSema reached nearly 90% at week 32, with little time below range in the first trial of CagriSema in people with T2D. Furthermore, CagriSema led to a greater reduction in mean glucose vs both sema or cagri alone. Disclosure C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated. S.Deenadayalan: Employee; Novo Nordisk A/S. L.Erichsen: None. J.P.Frias: Advisory Panel; Becton, Dickinson and Company, Pfizer Inc., Sanofi, Consultant; Akero Therapeutics, Inc., 89bio, Inc., Aimmune, Boehringer Ingelheim Inc., Eli Lilly and Company, Carmot Therapeutics, Inc., Echosens, Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Employee; Ionis Pharmaceuticals, Research Support; Akero Therapeutics, Inc., 89bio, Inc., Altimmune, Axcella Health Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Carmot Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Metacrine, Inc., Novo Nordisk, Oramed Pharmaceuticals, Novartis, Pfizer Inc., Sanofi, Speaker's Bureau; Eli Lilly and Company, Sanofi. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. I.Lingvay: Advisory Panel; Novo Nordisk A/S, Lilly Diabetes, Boehringer-Ingelheim, Sanofi, Consultant; Carmot Therapeutics, Inc., Merck Sharp & Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc., Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer, Research Support; Novo Nordisk A/S, Boehringer-Ingelheim. E.W.Lehmann: Employee; Novo Nordisk A/S. S.D.Pedersen: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim (Canada) Ltd., AstraZeneca, HLS Therapeutics Inc., Bayer Inc., Viatris Inc., Bausch + Lomb, Research Support; Eli Lilly and Company, Novo Nordisk, AstraZeneca, Applied Therapeutics Inc., Speaker's Bureau; Abbott Diabetes, Eli Lilly and Company, Novo Nordisk, Boehringer Ingelheim (Canada) Ltd., AstraZeneca, Medtronic, Pfizer Inc., HLS Therapeutics Inc., Bayer Inc., Bausch + Lomb. M.J.Davies: Advisory Panel; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Lexicon Pharmaceuticals, Inc., Pfizer Inc., Medtronic, ShouTi Pharma Inc., Consultant; Lilly, Boehringer-Ingelheim, Novo Nordisk, Sanofi, Research Support; AstraZeneca, Novo Nordisk, Sanofi-Aventis U.S., Boehringer-Ingelheim, Janssen Pharmaceuticals, Inc., Speaker's Bureau; Lilly, Boehringer-Ingelheim, Novo Nordisk, AstraZeneca, Napp Pharmaceuticals Limited, Novartis, Sanofi. Funding Novo Nordisk A/S

396-P: The Humanistic Burden of Type 1 Diabetes in U.S. Adults With or Without Recurrent Severe Hypoglycemic Events—A Qualitative Interview Study

Introduction: Despite advances in technology, many people with type 1 diabetes (T1D) still experience severe hypoglycemic events (SHEs). This study explored the perceived humanistic burden of T1D in adults using continuous glucose monitor (CGM) in the US with or without recurrent SHEs. Methods: In 60-minute semi-structured interviews, adult CGM users with self-reported T1D diagnosis (≥5 yrs.) described the burden of TID on quality of life (QoL). Participants ranked the ‘top 3’ negative impacts of T1D on QoL. Subgroup analyses were conducted in participants with recurrent SHE (rSHE; ≥2 SHEs last yr.) and without recurrent SHE (nSHE; ≤1 SHEs last yr.). Results: Participants (N=31; 42% rSHEs, 58% nSHEs) were 74% female and 81% were married. Mean age of T1D diagnosis was 28 yrs. Median SHEs in the past year in the rSHE group were 3 and in the nSHE group were 0. Both groups had mean HbA1c of 7.1%. rSHE and nSHE participants used hybrid closed loop systems (hCLS) (53.8% vs. 44.4%), multiple daily injections (23.1% vs. 33.3%) and continuous subcutaneous insulin infusion pump without hCLS (23.1% vs. 22.2%), respectively. All participants reported negative impacts on physical health, mental health, sleep, relationships, leisure activities, work/studies, and sex life. The ‘top 3’ ranked impacts for the rSHE cohort were physical health and sleep (tied at first) followed by leisure activities. Impacts to physical health, mental health, and relationships were ‘top 3’ for the nSHE cohort. Conclusions: Recurrent severe hypoglycemia is observed to persist despite use of advanced diabetes technology. Negative impacts on physical health ranked as the primary concern in both rSHE and nSHE cohorts. However, moderate variability in ranked negative impact order was observed between the cohorts. Disclosure A.Boateng-kuffour: None. P.Callahan: Consultant; Rhythm Pharmaceuticals, Inc., Abbott Diabetes, HealthCore Inc., BMS, Employee; Vertex Pharmaceuticals Incorporated, Genesis Research. K.Chandarana: Employee; Vertex Pharmaceuticals Incorporated, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. J.L.Gaglia: Advisory Panel; Dompé, Consultant; Vertex Pharmaceuticals Incorporated, Abata Therapeutics, Avotres Inc., Current Health, Research Support; Avotres Inc., Dompé, Imcyse, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. M.Phinney: None. E.Guzman ortega: Research Support; Vertex Pharmaceuticals Incorporated. R.N.Krupnick: Consultant; Vertex Pharmaceuticals Incorporated. M.Reaney: None. W.H.Polonsky: Consultant; Abbott Diabetes, Boehringer Ingelheim and Eli Lilly Alliance, Eli Lilly and Company, Insulet Corporation, Intuity Medical, Inc., MannKind Corporation, Provention Bio, Inc., Sanofi-Aventis U.S., Vertex Pharmaceuticals Incorporated.

1086-P: Humanistic Burden of Type 1 Diabetes in U.S. Adults across Different Age Cohorts—A Qualitative Interview Study

Introduction: This study explores the perceived humanistic burden of type 1 diabetes (T1D) across different age cohorts of adults (18-35 yrs., 36-64 yrs., and 65+ yrs.) in the US who are using continuous glucose monitors (CGM). Methods: Adult CGM users (≥18 years of age) with self-reported T1D diagnosis (≥ 5 yrs.) were interviewed to evaluate the impact of T1D on quality of life (QoL). Participants ranked the ‘top 3’ negative impacts of T1D on QoL using a “Wheel of Life” visual framework, which helped participants identify and describe the multi-faceted impacts of T1D on QoL. Interview transcripts were thematically analyzed. Subgroup analyses were conducted by age cohort. Results: Overall, 31 participants (18-35 yrs., n=10; 36-64 yrs., n=12; 65+ yrs., n=9) took part in the study. Participants were mostly female (74%) and married (81%), with a mean age at diagnosis of 28 yrs. and a reported mean HbA1c level of 7.1% (range: 5.0% - 9.9%); 42% reported having ≥ 2 severe hypoglycemic events (SHEs) in the past year. Impacts on physical health, mental health, sleep, relationships, leisure activities, work/studies, and sex life were reported by participants as affecting their daily lives. Physical health impacts were most frequently ranked in “top 3” negative impacts across age cohorts. Negative impacts on physical health, mental health and sleep were ranked as “top 3” for both the 18-35 yrs. and the 36-64 yrs. age cohorts, while negative impacts on physical health, leisure activities, and relationships were top ranked by the 65+ yrs. cohort. Conclusions: Despite use of advanced diabetes technologies, the humanistic burden of T1D persists across adults of different age cohorts. Participants in all age cohorts reported physical health as the leading negative impact to QoL, while other perceived negative impacts varied in rank order across age cohorts. Disclosure P. Callahan: Employee; Vertex Pharmaceuticals Incorporated, Genesis Research. Consultant; Rhythm Pharmaceuticals, Inc., Abbott Diabetes, HealthCore Inc., BMS. A. Boateng-Kuffour: None. K. Chandarana: Employee; Vertex Pharmaceuticals Incorporated. Stock/Shareholder; Vertex Pharmaceuticals Incorporated. J.L. Gaglia: Consultant; Vertex Pharmaceuticals Incorporated. Stock/Shareholder; Vertex Pharmaceuticals Incorporated. Consultant; Abata Therapeutics, Avotres Inc. Research Support; Avotres Inc. Advisory Panel; Dompé. Research Support; Dompé, Imcyse. Consultant; Current Health. M. Phinney: None. E. Guzman Ortega: Research Support; Vertex Pharmaceuticals Incorporated. R.N. Krupnick: Consultant; Vertex Pharmaceuticals Incorporated. M. Reaney: None. W.H. Polonsky: Consultant; Abbott Diabetes, Boehringer Ingelheim and Eli Lilly Alliance, Eli Lilly and Company, Insulet Corporation, Intuity Medical, Inc., MannKind Corporation, Provention Bio, Inc., Sanofi-Aventis U.S., Vertex Pharmaceuticals Incorporated.

804-P: Similar Hypoglycemia Duration with Once-Weekly Icodec vs. Degludec or Glargine U100 in Insulin-Treated T2D—A Post Hoc CGM Analysis from ONWARDS 2 and 4

Once weekly (OW) icodec is a basal insulin in development. Hypoglycemia duration during the switch (weeks 0-4) and steady state (weeks 22-26) periods from two phase 3, randomized, treat-to-target trials in T2D was investigated, using double-blinded Dexcom G6 CGM. Insulin-treated individuals were randomized to OW icodec or once-daily (OD) degludec (ONWARDS 2), or OW icodec or OD glargine U100 with mealtime insulin aspart (ONWARDS 4). When switching, a one-time only additional 50% icodec dose was administered. Basal insulins were titrated weekly. Median hypoglycemia <70 mg/dL duration for episodes lasting ≥ 15 minutes and the proportion of such episodes spent <54 mg/dL were assessed. Median duration of hypoglycemia <70 mg/dL was similar between icodec and comparators during switch and at steady state (Figure), with no apparent clustering in either time-period. At steady state (icodec/degludec and icodec/glargine U100), of the episodes <70 mg/dL, 66.6/63.9% and 60.4/60.0% spent no time <54 mg/dL; 23.2/26.6% and 29.2/28.8% included episodes <54 mg/dL for ≥15 minutes; and 10.2/9.5% and 10.4/11.2% included episodes <54 mg/dL for <15 minutes, respectively. In insulin-treated T2D, the duration of hypoglycemic episodes <70 mg/dL was similar, with no apparent clustering, during switch and at steady state for OW icodec versus OD degludec or glargine U100. Disclosure H.S.Bajaj: Research Support; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Anji Pharmaceuticals, Eli Lilly and Company, Kowa Company, Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Tricida, Inc. B.Ásbjörnsdóttir: Employee; Novo Nordisk. L.Carstensen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. L.Lang lehrskov: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated. A.Philis-tsimikas: Advisory Panel; Dexcom, Inc., Novo Nordisk A/S, Sanofi, Other Relationship; Medtronic, Research Support; Novo Nordisk A/S, Lilly, Viking Therapeutics, NIH - National Institutes of Health. T.Battelino: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Sanofi, Medtronic, Abbott Diabetes, Consultant; Indigo Diabetes, Research Support; Novo Nordisk, Sanofi, Medtronic, Novartis, Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi, Medtronic, Abbott Diabetes, Dexcom, Inc. Funding Novo Nordisk A/S

661-P: Associations of Food Security Status with Diet Quality and Glycemic Control over Two Years in Adults with Type 2 Diabetes on Medicaid

Background: Little is known about the association of food insecurity (FI) with changes in diet quality and hemoglobin A1c (HbA1c) over time in people with type 2 diabetes (T2D). Methods: In an analysis of adults with Medicaid and T2D enrolled in a longitudinal cohort study in 2020, demographics, depression (Patient Health Questionnaire-8 [PHQ-8]), food security status (USDA Food Security Module), Healthy Eating Index-2015 (HEI-15) diet quality scores, and other social determinants of health were assessed with annual surveys. Primary outcomes were HEI-15 and HbA1c, obtained from electronic health records. Separate propensity-score adjusted linear mixed models with a random intercept were used to test associations of baseline FI with changes in HEI-15 and A1c over 2 years. Results: Of 846 participants, 133 (16%) had T2D at baseline; 79 (59.4%) of those with T2D had FI. Those with baseline FI vs. food security had higher PHQ-8 scores and prevalence of housing instability, financial stress, and cost-related barriers to care (p<0.05). Over 2 years, changes in HEI-15 (p=0.45) and HbA1c (p=0.86) did not differ by baseline food security status (Table 1). Conclusion: In adults with T2D on Medicaid, diet quality remained low and HbA1c high over 2 years regardless of food security status, highlighting the importance of addressing nutrition when managing T2D in Medicaid patients. Disclosure K.D.Gu: None. J.Cheng: None. S.H.Mcgovern: None. J.L.Mccurley: None. D.E.Levy: None. V.Fung: Other Relationship; Vertex Pharmaceuticals Incorporated, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. C.Clark: None. A.N.Thorndike: None. Funding National Institutes of Health (T32DK007028, 5T32HL098048, R01DK124145)

1162-P: Promoting Career Development of Physicians Engaged in Type 1 Diabetes (T1D) Research—The New DiabDocs Multicenter National K12 Program

Background: Given low rates of physicians entering diabetes research, NIH recently funded a multi-center National K12 “DiabDocs” Program to train and support physician-scientists for productive academic careers in T1D. Specific aims for the program include: 1) Expand the geographical access to diabetes K12 programs in the US, 2) Create a diverse nationwide cohort of promising physician-scientists through shared programmatic training experiences, 3) Develop a national mentor community, 4) Ensure consistency and effectiveness of mentoring, including focused attention on diversity, equity and inclusion. Methods: DiabDocs program administration is comprised of 2 Program Directors, an Executive Leadership Committee, a National Advisory Committee and Scientific Review Committee. Recruitment for the first cohort of program Scholars began in August 2022. Candidates self-nominated with a Letter of Intent (LOI). Eligible Scholars were then invited to submit a full application and attend a program retreat. Of the 12 LOIs received from 12 different institutions, 10 candidates were invited to submit a full application and attend the program retreat. At the retreat, 19 reviewers from 16 different institutions participated in diversity training, conducted interviews, and gathered as a study section to discuss applications. Results: Ultimately 4 scholars were selected: 2 with pediatric endocrinology and 2 with adult endocrinology backgrounds. Three scholars are women, and 1 scholar self-identifies as from a group underrepresented in medicine (25%). The next application cycle is planned for Jan-March 2023. Conclusions: The DiabDocs program will address the critical shortage of trained physician-scientists focused on T1D. We anticipate that the planned program training combined with existing research infrastructures will engage a talented and diverse pool of scholars and accelerate their career trajectories. Disclosure K.D.Dasani: None. L.Dimeglio: Advisory Panel; Merck & Co., Inc., Consultant; Abata Therapeutics, Vertex Pharmaceuticals Incorporated. F.K.Bishop: None. S.Golden: Advisory Panel; Abbott Diabetes, Medtronic. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. R.G.Mirmira: None. A.Steck: None. W.V.Tamborlane: None. S.M.Willi: Advisory Panel; Boehringer Ingelheim International GmbH, Medtronic. D.M.Maahs: Advisory Panel; Medtronic, LifeScan Diabetes Institute, MannKind Corporation, Consultant; Abbott, Research Support; Dexcom, Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases (K12DK133995)

810-P: Do People Living with T1D Use the Dosing Flexibility of Degludec and Does This Depend on Patient Characteristics?

Flexibility in insulin degludec injection timing of 8-40 hrs between doses allows people with diabetes to adapt their treatment around daily life. This real-world multinational study explored flexible dosing (≥6hr difference in time of day [clock-time] between consecutive doses) in terms of prevalence and associated characteristics in 1136 people with T1D (mean [SD] age 31.3 [17.7] years, 54% male, median observation period 124 days [IQR 41, 234]) who were administering insulin degludec with smart pens. Of these participants, 14.4% regularly flexed dosing time (≥1 time every month). The probability of having ≥1 flexible dose in a given 2-week period was shown by a generalized linear mixed model (log link) with participant ID as a random effect and individual characteristics as fixed effects. Estimated LS-mean probability of ≥1 flexible dose in a given 2-week period was 25.0% (95% CI: 21.5%, 28.9%), with higher probability for young adults (aged 18-25), those who usually inject 9am-6pm, and those with a higher (>30 U/day) basal dose (all p<0.01). Probability decreased with time from smart pen initiation (p<0.01). In the subgroup of 455 adults with CGM data, flexibility in dosing time did not affect glycemic control. Overall, a group of people with T1D used the degludec dosing flexibility; these were most often young adults aged 18-25, those injecting 9am-6pm, and those requiring higher degludec doses. Disclosure Y.Winhofer: Speaker's Bureau; Abbott Diabetes, Amgen Inc., Boehringer-Ingelheim, Eli Lilly and Company, Novartis, Novo Nordisk, Medtronic, Sanofi-Aventis Deutschland GmbH, Daiichi Sankyo. A.Kaas: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. N.N.Knudsen: Employee; Novo Nordisk. J.H.J.Martiny: Employee; Novo Nordisk. C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated. Funding Novo Nordisk A/S

783-P: Baseline HOMA2-B Can Predict Tirzepatide Efficacy—Post Hoc Analysis of the SURPASS-1 and SURPASS-2 Studies

Tirzepatide (TZP) is a once weekly GIP and GLP-1 receptor agonist approved for the treatment of type 2 diabetes (T2D). In the SURPASS-1 (S-1) (monotherapy) and SURPASS-2 (S-2) (on metformin) Phase 3 trials, TZP substantially reduced HbA1c and body weight (BW) in people with T2D. Exploratory post hoc analyses examined the predictive value of HOMA2-IR (insulin) and HOMA2-B (C-peptide) by quartiles low (lower beta-cell function or insulin resistance) [Q1] to high [Q4] for achieving HbA1c (<5.7%, ≤6.5%) and BW reduction (≥10%, ≥15%) targets for those adherent to TZP treatment at Week 40. Odds ratios (OR) were calculated from logistic regression models using the overall mean as the reference. The results showed that TZP was equally likely to achieve BW and HbA1c targets in S-1 and S-2 regardless of baseline HOMA2-B and -IR quartiles, with the exception of S-2 where subjects with Q1 HOMA2-B (lowest beta-cell function) were significantly less likely and those with Q4 HOMA2-B (highest beta-cell function) were significantly more likely to reach HbA1c ≤6.5% (Figure). We conclude that baseline HOMA2-B, but not HOMA2-IR, may predict the likelihood of subjects achieving the HbA1c target ≤6.5% for patients enrolled in S-2 not controlled with metformin alone. Disclosure S.H.Hsia: Research Support; Eli Lilly and Company. M.K.Thomas: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated. H.Wang: None. J.Peleshok: Employee; Eli Lilly and Company. Funding Eli Lilly and Company

1161-P: Patterns of Diabetes Distress (DD) and Glycemic Outcomes in Teens with Type 1 Diabetes (T1D)

Background: DD distracts from T1D self-management, contributing to suboptimal glycemia. Yet, DD can change day-to-day and over time. We compared A1c trends in teens with increasing vs. decreasing DD over time. Methods: At baseline, 6, 12, and 18 months, participants (N=301) ages 13-17 years completed the Problem Areas in Diabetes Survey—Pediatric scale; higher scores indicate more DD with ≥41 indicating elevated DD. We identified three trajectories: participants with low baseline DD, who then reported persistent high DD; participants with high baseline DD, who then had persistent low DD levels; all others. Mean A1c levels were compared at baseline and 18 months. Results: At baseline, participants (49% male, 78% white) were 15.0±1.3 years old with T1D duration 6.5±3.7 years; 59% used insulin pumps; 12% used CGM; A1c was 8.5±1.1%. Twenty-six participants (9%) had elevated DD at baseline and then low DD at subsequent time points; A1c did not change significantly from 0 to 18 months for these participants (p=.33). Thirty-five participants (12%) had low DD at baseline and then elevated DD at subsequent time points; A1c increased significantly from 0 to 18 months for these participants (p=.01). The remaining participants (n=240) had varying levels of DD with no significant change in A1C (p=.05). Conclusion: Adolescents who initially had low DD and reported increasing DD over time may be at risk for worsening glycemic outcomes. Disclosure K.Wentzell: None. L.J.Tinsley: None. L.K.Volkening: None. D.E.Mcgill: Employee; Vertex Pharmaceuticals Incorporated. B.J.Anderson-thomas: None. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. Funding National Institutes of Health (T32DK007260); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK095273); JDRF (2-SRA-2014-253-M-B)

1279-P: The INNODIA Natural History Study of Children, Adolescents, and Adults Newly Diagnosed with Type 1 Diabetes

Using the INNODIA consortium European infrastructure, we aimed to discover novel biomarkers of T1D progression. Here we report clinical and biochemical characteristics of people with new-onset T1D during the first year from diagnosis. Children and adults (age 1-45 yrs) were recruited within 6 weeks from T1D onset in 11 European countries. Baseline clinical characteristics, C-peptide (fasted and mixed meal tolerance test), HbA1c, autoantibodies, and their overtime changes were assessed across 3 age groups: <10, 10-17, ≥18yrs. The study population included 655 individuals (280: <10 yrs; 274: 10-17 yrs; 101: ≥18 yrs): 57% male; age: 12.1±8.4 yrs; 96% were positive for ≥1 autoantibodies. Autoantibody frequency was IAA 77%, GAD 73%, IA-2A 69%, ZnT8A 66%. Diabetic ketoacidosis prevalence was 35%, with the highest rate in the 10-17 yrs group (44%). At baseline, median [IQR] fasting and area-under-the curve (AUC) C-peptide were 242[140-384] and 753[469-1109]pmol/L, with levels increasing with age (p<0.001; Fig). Over time C-peptide remained lower in participants <10yrs but rates of decline were similar between age groups. HbA1c significantly decreased during the first 3 months (p<0.001). In this large cohort with new-onset T1D, we identified age-related differences in clinical and biochemical parameters. Of note, C-peptide was lower in younger children but there was no age effect on its rate of decline. Disclosure M.Marcovecchio: None. C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated. Innodia consortium: n/a. C.Delfin: Employee; Novo Nordisk A/S. M.Hulsmans: None. L.Overbergh: None. S.S.Pazmino: None. D.E.Picton: None. N.Steenackers: None. B.Van der schueren: None. A.E.J.Hendriks: Advisory Panel; Alira Health. Funding Innovative Medicines Initiative 2 Joint Undertaking (115797, 945268)

825-P: Novel Autologous Dendritic Cell Therapy AVT001 for Type 1 Diabetes

Studies in several animal models and of humans with type 1 diabetes (T1D) have suggested that Qa-1/HLA-E restricted CD8+ T regulatory cells (Tregs) are important in maintaining self-tolerance and a defect thereof playing a key role in T1D pathogenesis. To evaluate the safety and efficacy of targeting this pathway in T1D we undertook a first in human, phase 1/2 study of AVT001, an investigational autologous dendritic cell-based vaccine designed to address this immunologic mechanism. This double-blind, randomized (2:1 treated vs placebo) trial enrolled individuals (n=25) who were 16 years and older, within 1 year of clinical diagnosis of T1D, and with an ex-vivo correctable defect in the function of HLA-E-restricted CD8+ Tregs. All participants underwent leukapheresis, the first step in the generation of AVT001. AVT001 treatment (n=16) or placebo (n=9) was delivered as a series of three-monthly intravenous infusions. The primary endpoint of the study was safety/tolerability at day 150. AVT001 was safe and well tolerated with all participants completing treatment, no peri-infusion reactions noted, and adverse events reported as being mild or moderate in the AVT001 treated group, with rates similar to placebo. A pre-specified efficacy endpoint was change from baseline in C-peptide area under the curve (AUC) during a 4-hour mixed meal tolerance test utilizing a mixed-effect model for repeated measurements (MMRM). The baseline mean (SD) AUCs were treated 0.531 (0.363) and placebo 0.611 (0.178) nmol/L. At day 150, the C-peptide AUCs were significantly different between groups, namely 0.518 (0.430) and 0.472 (0.134) respectively. Per MMRM, the least square mean difference between AVT001 and placebo at day 150, is estimated to be 0.172 (p=<.0001). There was an increase in AUC or no change for 6 (37.5%) in the AVT001 treated group and 1 (11.1%) in the placebo group. These results indicate that AVT001 treatment was safe and well tolerated with evidence of significant preservation of endogenous insulin secretion. Disclosure J.L.Gaglia: Advisory Panel; Dompé, Consultant; Vertex Pharmaceuticals Incorporated, Abata Therapeutics, Avotres Inc., Current Health, Research Support; Avotres Inc., Dompé, Imcyse, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. J.Ritz: Advisory Panel; Novartis, Taleris, AvroBio, Clade Therapeutics, LifeVault Bio, Smart Immune, Garuda, Tscan, Research Support; Gilead Sciences, Inc., Novartis. H.Jiang: Employee; Avotres Inc. M.Mackey: None. H.L.Daley: None. N.Bryant: None. D.Y.Kim: None. T.Dong: Employee; Avotres Inc., Novartis. E.E.Fan: None. J.Vora: Other Relationship; Avotres Inc., Glyscend Inc. J.S.Skyler: Advisory Panel; Adocia, Altheia Sciences, Arecor, Avotres Inc., Bayer Inc., COUR Pharmaceuticals, Dance Biopharm/Aerami, Diasome, Enthera, Immnomolecular Therapeutics, Kriya Therapeutics, Oramed Pharmaceuticals, Orgenesis Inc., Precigen, Inc., ViaCyte, Inc., Board Member; Applied Therapeutics Inc., Dexcom, Inc., Consultant; Novo Nordisk, Sanofi, Signos, 4Immune, Other Relationship; Imcyse, Provention Bio, Inc. Funding Avotres Inc.

549-P: Assessing Feasibility of a Diabetes Mellitus Program Using Behavioral Economics to Optimize Outreach and Self-Management Support with Technology—The DM-BOOST Project

Introduction: The DM-BOOST intervention was developed to enhance engagement with diabetes self-management training (DSMT). Participants received peer-written text message tips with nudges to reply with personal preferences. They then completed a video call with the DM-BOOST team to confirm patient portal access, review key functions, and set a diabetes behavior goal. This was later followed by receipt of a patient portal message with their goal, which they commit to sending to the DSMT provider they are scheduled to meet with. Methods: Adults with poorly controlled type 2 diabetes (HbA1c ≥ 8) received mailed invitations and a recruitment phone call. Participants (n=60) were randomized (1:1) to usual care or DM-BOOST. All participants received assistance obtaining a DSMT referral and scheduling a DSMT appointment. The primary outcome of interest was the DSMT appointment no-show/cancellation rate. Results: Enrolled participants (n=60) were 60.0% female with a mean age of 45.5 years (SD = 8.3). The average HbA1c at enrollment was 10.1% (SD = 1.8). All intervention participants (30/30) had a DSMT appointment scheduled compared to 86.7% of comparison participants (26/30). Intervention group participants had fewer DSMT no-shows/cancellations (3/30, 10%) compared to comparison group participants (10/26, 35%) (p = 0.01). Conclusions/Discussion: Technology-based interventions guided by behavioral economics can increase initial engagement with DSMT. Several system-level barriers, including challenges in obtaining referrals and scheduling appointments, were identified. Secondary outcomes, including patient-reported changes in diabetes self-efficacy, self-management skills, and treatment satisfaction are being evaluated. Future research efforts include cultural adaption of DM-BOOST for Spanish-speaking patients and rigorous implementation evaluation. Disclosure D.J.Amante: None. L.L.Shenette: None. G.Puerto: None. S.Lemon: None. D.M.Harlan: Advisory Panel; Novartis, Vertex Pharmaceuticals Incorporated, Diabeloop SA, Other Relationship; Stability Health, Wolters Kluwer Health. B.S.Gerber: Other Relationship; Abbott. Funding National Center for Advancing Translational Sciences (KL2TR001455); National Institute for Diabetes and Digestive and Kidney Diseases (1K01DK131318)

789-P: Real-Life Effectiveness of iGlarLixi (Insulin Glargine 100 U/ml and Lixisenatide) in People with Type 2 Diabetes (T2D) according to Prior Insulin Use

Little is known in real life clinical practice about the effectiveness and safety of iGlarLixi in insulin naïve compared to insulin treated people with T2D. In the European REALI pooled database, we analyzed patient-level data of 1317 people with T2D initiating a 24-week iGlarLixi treatment: 718 were insulin naïve (55%) and 598 insulin treated (45%), with a median treatment duration of 2.5 years. Demographics were similar among groups with an overall mean±SD age of 61±9 years and BMI 32.2±5.5 kg/m². Median T2D duration was 8 years in the naïve group and 10 years in the treated group. At Baseline, mean HbA1c was 9.39% in the naïve and 8.76% in the treated (p<0.001). The least square (LS) mean HbA1c change from Baseline to Week 24 (using MMRM) was -1.57% in the naïve and -1.29% in the treated (Fig 1); the LS mean [95% CI] fasting plasma glucose change was -52.5 [-54.9; -50.1] and -50.4 [-53.4; -47.5] mg/dL, respectively. Mean±SD body weight decreased by 1.8±4.6 kg at Week 24, with no difference between groups. Mean iGlarLixi daily dose at Baseline was 14.3U in the naïve and 24.4U in the treated, and reached 30.7U and 36.4U, respectively, at Week 24. Symptomatic hypoglycemia reports and gastrointestinal side effects were low in both groups. This analysis demonstrated effectiveness and safety of iGlarLixi in both insulin naïve and insulin treated people with T2D in clinical practice. Disclosure J.Seufert: Advisory Panel; Abbott Diabetes, Boehringer Ingelheim Pharma GmbH&Co.KG, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Abbott Diabetes, Bayer Inc., Boehringer Ingelheim Pharma GmbH&Co.KG, Merck Sharp & Dohme Corp., Sanofi-Aventis Deutschland GmbH, Novartis, Novo Nordisk. N.Freemantle: Advisory Panel; AstraZeneca, Research Support; Galderma, ALK-Abelló A/S, Ipsen Biopharmaceuticals, Inc., Vertex Pharmaceuticals Incorporated, Thea, Speaker's Bureau; Abbott Singapore, ALK Shanghai. C.Guja: Advisory Panel; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Speaker's Bureau; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Servier Laboratories, Viatris Inc. M.Haluzik: Advisory Panel; Novo Nordisk, Lilly Diabetes, Boehringer-Ingelheim, Research Support; Sanofi, Speaker's Bureau; Abbott, AstraZeneca. G.Bigot: None. M.Tournay: None. M.Bonnemaire: Employee; Sanofi, Stock/Shareholder; Sanofi. J.T.Kis: None. Funding Sanofi

681-P: Insulin Pump Use in Teens with Executive Function (EF) Problems and Type 1 Diabetes Is Associated with Lower A1C

Aim: Providers may avoid offering pump therapy to teens with EF challenges (planning, organization). We assessed whether the association of pump use and A1c is modified by EF status, adjusting for relevant factors. Methods: EF was assessed by parent proxy-report using Behavior Rating Inventory of Executive Function (BRIEF). T-score ≥60 defined risk of EF problems for Global Executive Composite (GEC), Behavioral Regulation Index (BRI), and Metacognition Index (MI). Parents also completed the Diabetes Family Conflict Scale (DFCS). T-tests stratified by EF status compared A1c by pump use and non-use. Generalized linear models were adjusted (Tukey) for variables with p<.1 in univariate analysis. Results: Teens (N=169, 54% male) had mean age 14.9±1.3 yrs, diagnosis age 7.5±3.6 yrs, A1c 8.5±1%, 69% pump use, 9% CGM use, and 31% with GEC ≥60. With GEC <60, A1c was similar in pump users and non-users (8.3 vs 8.6%, p=.25); with GEC ≥60, A1c was lower in pump users vs non-users (8.5 vs 9.2%, p=.009). Similar A1c patterns were seen when stratified by EF problems in BRI or MI. In multivariate analysis, with GEC <60, A1c did not differ in pump users vs non-users (8.4 vs 8.6%, p=.36), adjusting for DFCS; a similar pattern was seen with BRI <60 (p=.26) and MI <60 (p=.25). With GEC ≥60, there was a trend towards lower A1c in pump users vs non-users (8.1% vs 8.7%, p=.07), adjusting for income and CGM use. With BRI ≥60, A1c was lower in pump users vs non-users (7.8 vs 8.4%, p=.03), adjusting for CGM use and DFCS score. With MI ≥60, A1c was not significantly different in pump users vs non-users (8.0% vs 8.4%, p=.25), adjusting for income, CGM use, and DFCS score. With elevated GEC, BRI, or MI scores in above multivariate analyses, A1c was lower in CGM users vs non-users (all p<.05). Conclusion: The association of diabetes technology use with lower A1c in those with elevated BRIEF scores suggests a need to re-evaluate provider reluctance to recommend use of diabetes technologies in teens presenting with potential EF problems. Disclosure R.J.Vitale: None. L.K.Volkening: None. L.J.Tinsley: None. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. Funding National Institutes of Health (P30DK036836, R01DK095273); JDRF (2-SRA-2014-253-M-B); Iacocca Family Foundation

1091-P: Genetic Ancestry Influences Metformin Treatment Response in Youth with Type 2 Diabetes

In youth with type 2 diabetes (T2D), glycemic response to metformin varies by racial and ethnic group. In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study metformin failure rates were lower in non-Hispanic White (NHW) youth by self-report compared with non-Hispanic Black (NHB) and Hispanic youth. Understanding and addressing the mechanisms for differences in response are critical to reducing health disparities. We aimed to examine the association between genetic ancestry and risk for metformin treatment failure and evaluate whether individual global ancestry proportions predict metformin response in TODAY participants. Global ancestry proportions were estimated using FastStructure. Cox-proportional hazards analysis with genetic ancestry as a covariate was performed with the primary outcome the need for insulin or A1C ≥ 8%. Age, sex, BMI Z score, baseline A1C, and treatment arms were the other covariates. After quality control, 506 participants of mean age 14±2 y, 65% female, mean BMI Z score 2.2±0.5 kg/m2 and mean baseline A1C 6.0±0.7% were analyzed. Similar to by self-report, when stratified by genetic ancestry NHB youth had significantly higher treatment failure rates compared with other groups (P=0.02). The proportion of European ancestry in self-reported ethnic strata of admixed participants was associated with improved metformin response in the NHB (n=185) and Hispanic (n=208) groups (HR 0.4, 95% CI 0.16-0.98, P=0.04). Proportion of Native American ancestry was associated with worse response (HR 1.5, 95% CI 1.02-2.2, P=0.04) across all participants and associations with proportion African ancestry were not significant. In sum, genetic ancestry influences metformin response with greater proportion of European and Native American ancestry associated with improved and worse glycemic response respectively in TODAY. These differences could be related to biological, social or cultural factors and should be examined to reduce health disparities in T2D. Disclosure S.Srinivasan: None. T.I.Pollin: None. A.Manning: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc. L.Chen: None. M.M.Kelsey: Other Relationship; Boehringer Ingelheim Inc., Janssen Pharmaceuticals, Inc., Rhythm Pharmaceuticals, Inc., Lilly. J.Todd: None. S.A.Arslanian: Advisory Panel; Novo Nordisk, Eli Lilly and Company, Consultant; Société des Produits Nestlé SA,, Other Relationship; Eli Lilly and Company, AstraZeneca, Research Support; Novo Nordisk, Eli Lilly and Company. N.T.Chang: None. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. L.L.Levitsky: None. J.E.Sprague: Research Support; Eli Lilly and Company, Rhythm Pharmaceuticals, Inc. Funding National Institutes of Health (K23DK120932)

1096-P: Plasma Metabolites Predict Loss of Glycemic Control in Youth with Type 2 Diabetes (T2D)

We aimed to identify metabolites that predict the loss of glycemic control in youth-onset T2D (Y-T2D), a disease characterized by more rapid decline in β-cell function than adults-onset T2D. The increasing incidence of Y-T2D highlights the need to understand its pathophysiology and develop appropriate interventions. We measured 40 plasma metabolites in 374 baseline and 10-year follow-up samples from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study, using mass spectrometry with a targeted ZipChip based assay. Loss of glycemic control was defined as HbA1c ≥8% for 6 months or inability to wean from temporary insulin after acute metabolic decompensation. We evaluated associations with time to loss of glycemic control in Cox proportional hazards models adjusted for HbA1c, triglycerides, systolic blood pressure, and estimated insulin sensitivity. Participants were 14±2 years of age, 63% female; 72% experienced loss of glycemic control. Five baseline plasma metabolites (threonine, asparagine, glycine, glutamine, L-alpha-aminobutyrate) associated with lower risk of loss of glycemic control, and one baseline plasma metabolite (citrate) associated with higher risk of loss of glycemic control. After multivariable adjustments, only plasma citrate remained statistically significant (HR: 1.16 per 1 SD [95% CI 1.04, 1.30]). At 10-year follow-up, of these plasma metabolites only threonine (logFC: -0.28, p=3.8×10-11) and glycine (logFC: -0.17, p=5.7×10-5) were significantly lower. Plasma metabolites, such as citrate that might originate from an excess of fatty acids, predicted loss of glycemic control in youth with T2D. Future work should validate these findings and investigate their response to promising therapies. Disclosure P.Bjornstad: Advisory Panel; AstraZeneca, Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem, Consultant; Bayer Inc., Bristol-Myers Squibb Company. R.Gubitosi-klug: None. K.Drews: None. K.L.Tommerdahl: None. J.B.Tryggestad: None. E.M.Isganaitis: None. F.Bacha: Other Relationship; Takeda Pharmaceutical Co., Ltd., AstraZeneca. L.Pyle: None. K.Sharma: Advisory Panel; Reata Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc. T.B.Vigers: None. I.De boer: Advisory Panel; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Boehringer Ingelheim International GmbH, Otsuka America Pharmaceutical, Inc., Bayer Inc., Consultant; George Clinical, Gilead Sciences, Inc., Medscape, Research Support; Dexcom, Inc. L.El ghormli: None. H.L.Heerspink: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Bayer Inc., Eli Lilly and Company, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., George Clinical, Merck & Co., Inc., Janssen Research & Development, LLC, Traveere Pharmaceuticals, Novo Nordisk. L.M.Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. J.R.Ryder: None. A.S.Shah: None. J.L.Lynch: Research Support; Novo Nordisk. Funding National Institute of Diabetes and Digestive and Kidney Diseases

161-OR: Validation of the Short Type 1 Diabetes Stigma Assessment Scale (DSAS-1) and Its Association with Affective States, Diabetes Distress, Diabetes Self-Management, and Glycemic Control

Introduction: We validated an 8-item version of the DSAS-1 and examined its relationship with momentary ratings of affective states, diabetes distress, diabetes self-care, and glycemic control over time. Methods: We recruited 184 adults with T1D from Los Angeles, California, and the Bronx, New York. Participants completed a short version of the DSAS-1, other validated questionnaires, and 10-14 days of intensive longitudinal data collection using blinded continuous glucose monitoring and Ecological Momentary Assessment (EMA) via smartphone. Psychometric validation included exploratory factor analysis (EFA), confirmatory factor analysis (CFA), and internal consistency reliability assessment. We used Spearman's rho correlations to explore the convergent validity using EMA data. Results: EFA indicated an acceptable fit of a 3-factor model (Bartlett's = 0.000; KMO = 0.774). This was corroborated with CFA, which demonstrated a reasonable three-factor fit (chi-squared = 36.44; RMSEA = 0.079; SRMR = 0.036; TLI = 0.985; CFI = 0.991); less so for a single-factor model. Satisfactory convergent and discriminant validity was demonstrated. The DSAS-1 was significantly correlated with momentary ratings of negative emotions (0.30, p = <0.001), diabetes distress (0.32, p = <0.001), insulin regimen adherence (-0.20, p = 0.007), diabetes self-care (-0.24, p = 0.002), mean blood glucose (0.20, p = 0.008) and time in range (-0.21, p = 0.006), but was not significantly associated with positive emotions. Conclusions: The 8-item DSAS-1 is a valid and reliable measure of T1D stigma. Convergent validity confirms the importance of diabetes-related stigma in relation to psychosocial and blood glucose outcomes, and underscores the need for further examination of stigma in diabetes, which may be facilitated by this shorter scale. Disclosure G.Crespo-ramos: None. H.Jin: None. E.Pyatak: Research Support; Abbott Diabetes. D.Spruijt-metz: None. J.S.Gonzalez: Consultant; Virta Health Corp. C.J.Hoogendoorn: None. S.Schneider: None. R.Hernandez: None. L.T.Pham: None. A.L.Peters: Advisory Panel; Abbott Diabetes, Medscape, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Research Support; Abbott Diabetes, Dexcom, Inc., Insulet Corporation, Stock/Shareholder; Omada Health, Inc., Livongo. V.F.Ruelas: None. J.P.Crandall: Research Support; Abbott. P.Lee: None. Funding National Institutes of Health (R01DK121298)