bluuebunny/crossref_metadata_2025 huggingface dataset:
737-P: Targeted Maximum Likelihood Estimation (TMLE) to Estimate the Effect of Liraglutide on Cardiovascular (CV) Outcomes in Race/Ethnicity Subgroups: Post Hoc Analysis of LEADER
Authors: CHEN DAVID , ABRAHAMSEN TRINE J. , DANG LAUREN E.E. , LAWSON JACK , PRATLEY RICHARD E.
Published: May 2022

Important race/ethnicity subgroups at high risk of CV disease are underrepresented in type 2 diabetes CV outcomes trials, limiting the strength of conclusions drawn. Until data are available, TMLE may be more efficient than conventional analysis, giving a better estimation of treatment effects to support clinical decision-making. TMLE makes minimal assumptions on data distribution and prioritizes fitting the most salient parts of the data to the statistical estimand, thus producing more precise and less biased estimates. Relative cumulative risk (RR) of major adverse CV events at 4 years with liraglutide vs. placebo for race/ethnicity subgroups in LEADER was estimated by TMLE + super learner. Comparison to the original Cox regression hazard ratio (HR) and unadjusted Kaplan-Meier RR is shown. Although RR and HR are different estimands, for rare events and proportional hazards they can be numerically close. While the original HR was not significant in any race/ethnicity subgroups, TMLE led to statistically significant treatment effects in all but the ‘Black’ subgroup (Figure) . Statistical power to detect the full population RR in the ‘Black’ subgroup was 0.13 (vs. 0.70 in the ‘White’ subgroup) . These data provide reassurance on the beneficial effects of liraglutide vs. placebo on CV outcomes in underpowered race/ethnicity subgroups.

Disclosure

D.Chen: None. T.J.Abrahamsen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. L.E.E.Dang: Research Support; Novo Nordisk. J.Lawson: Employee; Novo Nordisk A/S. 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.

Funding

Novo Nordisk A/S
745-P: Short-Acting Exenatide Added Three Times Daily to Insulin Therapy Improves Insulin Sensitivity in Type 1 Diabetes
Authors: JOHANSEN NICKLAS , DEJGAARD THOMAS F. , LUND ASGER , VILSBØLL TINA , ANDERSEN HENRIK U. , KNOP FILIP K.
Published: May 2022

Average life expectancy in type 1 diabetes is reduced by more than a decade due to cardiovascular (CV) disease. Reduced insulin sensitivity as assessed by low values of estimated glucose disposal rate (eGDR) has been observed to correlate with increased risk of CV events. How short-acting glucagon-like peptide 1 receptor agonists (GLP-1RA) influence eGDR in type 1 diabetes remains unknown. We analyzed eGDR post-hoc in a phase 2, double-blind, randomized (1:1) , clinical trial (NCT03017352) that evaluated the short-acting GLP-1RA exenatide μg added three times daily to insulin therapy as compared with placebo over 26 weeks of treatment in 1individuals with type 1 diabetes (76/32 men/women, age 50 (14) years (mean (standard deviation)) , diabetes duration 21 (12) years, BMI 28 (4) kg/m2, glycated hemoglobin A1c 8.2 (0.7) % / 66 (7) mmol/mol) . Exenatide significantly increased eGDR by 0.36 mg/kg/min (95 % confidence interval 0.03; 0.69, P = 0.032) (Table 1) as compared with placebo after 26 weeks’ treatment. Short-acting exenatide apparently improved insulin sensitivity in patients with long-standing type 1 diabetes and inadequate glycemic control, alluding to potential CV benefits of this GLP-1RA in type 1 diabetes.

Disclosure

N.Johansen: Employee; Novo Nordisk A/S. T.F.Dejgaard: Advisory Panel; Novo Nordisk, Research Support; Novo Nordisk, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. A.Lund: Speaker's Bureau; Novo Nordisk A/S. T.Vilsbøll: Consultant; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk, Sun Pharmaceutical Industries Ltd. H.U.Andersen: Advisory Panel; Abbott Diabetes, Stock/Shareholder; Novo Nordisk A/S. F.K.Knop: Advisory Panel; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, ShouTi, Zucara Therapeutics, Consultant; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pharmacosmos A/S, Sanofi, ShouTi, Zealand Pharma A/S, Zucara Therapeutics, Research Support; AstraZeneca, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Stock/Shareholder; Antag Therapeutics.

Funding

Partly funded by AstraZeneca
749-P: Clinically Relevant Predictors of Cardiovascular Events: Exploratory Analysis from the VERIFY Study of Initial Treatment of Type 2 Diabetes Mellitus
Authors: MATTHEWS DAVID R. , DEL PRATO STEFANO , PALDANIUS PAIVI M. , BADER GIOVANNI
Published: May 2022

The VERIFY study of primary treatment in type 2 diabetes mellitus (T2DM) , showed delayed glycemic failure (HbA1c ≥7.0% at two consecutive scheduled visits post randomization) with early combination of vildagliptin and metformin (EC) versus initial metformin monotherapy in patients with newly diagnosed T2DM (HbA1c 6.5%-7.5%) . Throughout the 5-year study, 57 adjudicated cardiovascular (CV) events were collected but the study was not powered to test the hypothesis that EC was also able to decrease CV events. Here we explore whether simple clinical data at T2DM onset (Framingham risk equation, CV disease history [CVD-Hx]) could identify patients at risk of subsequent CV events. At baseline, Framingham risk score (FRS) was 14.9±9.2% and 220 (12.3%) patients had CVD-Hx. A significant higher risk in patients with CVD-Hx and FRS ≥20% was visually apparent on KM curves and log rank-test (p=0.001; Figure) . Baseline HbA1c, age and gender were not significantly associated with the CV outcome, whereas treatment failure within the first 3 years was significantly associated with a higher risk of CV events (HR [95% CI]: 3.1 [1.7, 5.6]; p=0.0001) . These analyses suggests that both CV risk stratification at onset of T2DM and early loss of glycemic control may identify patients at higher risk of subsequent CV events.

Disclosure

D.R.Matthews: Advisory Panel; Novo Nordisk A/S, Other Relationship; Novartis AG, Speaker's Bureau; Servier Laboratories. S.Del prato: Advisory Panel; Applied Therapeutics, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Consultant; Menarini Group, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Sanofi, Stock/Shareholder; Novo Nordisk A/S. P.M.Paldanius: Consultant; Glyconics Ltd, UPM Biomedicals, Speaker's Bureau; Novartis AG, UPM Biomedicals. G.Bader: Employee; Novartis AG.

Funding

Novartis
764-P: A Random-Order, Double-Blinded, Placebo-Controlled Study of the Bionic Pancreas in the Bihormonal vs. the Insulin-Only Configuration Using Two Different Glucose Targets in Adults with Type 1 Diabetes in a Standardized Exercise Setting
Authors: CASTELLANOS LUZ E. , BALLIRO COURTNEY A. , SHERWOOD JORDAN , HILLARD MALLORY , SELAGAMSETTY RAJENDRANATH , ZHENG HUI , EL-KHATIB FIRAS , DAMIANO EDWARD , RUSSELL STEVEN J.
Published: May 2022

Objective: We evaluated glycemic outcomes at two glucose targets with each of two configurations (bihormonal and insulin-only) of the bionic pancreas (BP) in the setting of standardized exercise in adults with type 1 diabetes.

Methods: 20 participants completed a double-blinded, placebo-controlled (glucagon vs. placebo) , random-order, cross-over trial comparing the bihormonal (BH) and insulin-only (IO) configurations of the BP, each using two glucose targets (1 and 130 mg/dl) ; each arm lasted three days. On the last morning of each arm, fasted subjects exercised on a stationary bike with a heart rate of 120-140 bpm for ∼30 minutes. The primary outcome was number of subjects discordant between the BH and IO arms using the same glucose target for events with plasma glucose (PG) <60 mg/dl for more than minutes (McNemar's Test) . Secondary endpoints included the area over the glucose curve and <60 mg/dl and grams of carbohydrates given for hypoglycemic events (Wilcoxon Signed Rank Test) .

Results: When using the 130 mg/dl glucose target, there were no events with PG<60 mg/dl in either the BH or IO configurations; AOC <60 mg/dl was 0 min*mg/dl for both configurations and no carbohydrates were given. When using the 1mg/dl glucose target, three subjects in the IO arm had an event with a PG <60 mg/dl for more than minutes; no subjects had an event using the BH configuration (p=0.25) . Median AOC <60 mg/dl was 0 [0-0] min*mg/dl for both configurations (p=0.18) , and the median amount of carbohydrates required to recover from hypoglycemic events was 0 [0-0] grams for both configurations (p=0.56) .

Conclusions: Both configurations of the BP provided safe glycemic regulation using both glucose targets during exercise use. Larger studies will be needed to quantify differences in exercise outcomes between the IO and BH configurations of the BP.

Disclosure

L.E.Castellanos: None. C.A.Balliro: Consultant; Beta Bionics, Inc., Zealand Pharma A/S. J.Sherwood: None. M.Hillard: None. R.Selagamsetty: Employee; Beta Bionics, Inc. H.Zheng: None. F.El-khatib: Employee; Beta Bionics, Inc., Stock/Shareholder; Beta Bionics, Inc. E.Damiano: Other Relationship; Beta Bionics, Inc. S.J.Russell: Advisory Panel; ConvaTec Inc., Eli Lilly and Company, Consultant; Beta Bionics, Inc., Other Relationship; Beta Bionics, Inc., Research Support; Beta Bionics, Inc., Dexcom, Inc., Novo Nordisk, Zealand Pharma A/S, Stock/Shareholder; Companion Medical.

Funding

NIDDK (T32DK007028)
781-P: Progressive Acceleration of Insulin Exposure over Seven Days of Infusion Set Wear
Authors: BAILEY TIMOTHY S. , KASTNER JASMIN R. , STRANGE POUL , SHI LEI , OBERG KEITH A. , JOSEPH JEFFREY I. , STRASMA PAUL J. , MUCHMORE DOUGLAS B.
Published: May 2022

Insulin exposure and action are known to differ on each of 3 days of infusion set wear during CSII. We extend these observations to 1 week in a pilot phase study comparing conventional Teflon angled infusion sets to a prototype extended wear set using Capillary Biomedical SteadiFlow™ technology. Participants with T1DM for >12 months, A1C <8.5%, c-peptide <0.6 nmol/L, and ≥6 months use of Medtronic model 530G or higher were enrolled in a 2-period crossover euglycemic clamp study; clamps were performed after fasting overnight stabilization with IV insulin. Five men and 2 women, mean duration of diabetes 22.5 (16.6 SD) years and mean BMI 27.6 (3.8 SD) kg/m2 were enrolled; 4 completed all 8 clamps, 2 completed 7 clamps and 1 completed 1 clamp. We present the pharmacokinetic profiles of insulin lispro, 0.15 U/kg delivered by bolus infusion on Days 0, 3, 5 and 7 of infusion set wear. The Figure shows aggregate results from Control and Investigational infusion sets for insulin concentration (mean±SEM) vs. time by day of set wear. Statistically significant decreases from Day 0 to Day 7 were seen for tmax (p≤0.001) , t50% (early) (p<0.002) , t50% (late) (p<0.001) , and Mean Residence Time (p<0.001) . AUC0-300 declined by approximately 20% from Day 0 to Day 7 (p<0.11) . These results confirm and extend previous observations showing significant progressive acceleration of insulin exposure as a function of duration of infusion set wear time.

Disclosure

T.S.Bailey: Advisory Panel; Abbott Diabetes, CeQur SA, MannKind Corporation, Medtronic, Novo Nordisk, Consultant; LifeScan, Sanofi, Research Support; Abbott Diabetes, Abbott Diagnostics, Biolinq, Capillary Biomedical, Inc., Dexcom, Inc., Eli Lilly and Company, Kowa Research Institute, Inc., Livongo, MannKind Corporation, Medtronic, Novo Nordisk, REMD Biotherapeutics, Sanofi, Sanvita Medical, Senseonics, ViaCyte, Inc., vTv Therapeutics, Zealand Pharma A/S, Speaker's Bureau; Becton, Dickinson and Company, Medtronic, Sanofi. J.R.Kastner: Consultant; Capillary Biomedical, Inc. P.Strange: Other Relationship; Capillary Biomedical, Inc., Stock/Shareholder; Capillary Biomedical, Inc. L.Shi: None. K.A.Oberg: Consultant; Beta Bionics, Inc., Companion Medical, Tandem Diabetes Care, Inc. J.I.Joseph: Advisory Panel; Capillary Biomedical, Inc., Stock/Shareholder; Capillary Biomedical, Inc. P.J.Strasma: Board Member; Capillary Biomedical, Inc., Employee; Capillary Biomedical, Inc., Stock/Shareholder; Capillary Biomedical, Inc. D.B.Muchmore: Consultant; Capillary Biomedical, Inc., Diasome, Zucara Therapeutics, Stock/Shareholder; Capillary Biomedical, Inc., Diasome.

Funding

National Institutes of Health (2R44DK110969-02)
79-LB: The Effects of Glucose Reporting Tools on Therapeutic Decision Making—A Comparative Reading Study with Primary Care Providers
Authors: NOVAK MATTHEW T. , HAYTER GARY , WRIGHT EUGENE , MIDYETT KURT , WOLPERT HOWARD , VIRDI NAUNIHAL
Published: May 2022

The discordance between the amount of new therapies for Type 2 diabetes (T2D) and improved outcomes highlights an unmet need for tools to help primary care providers (PCPs) make appropriate therapy adjustments. Here we present a novel CGM-based Glucose Pattern Insights Report (GPIR) that identifies patterns of suboptimal glycemic control, highlights the clinically most important pattern (MIP) , and offers therapy recommendations to address the MIP. To assess utility of the GPIR in clinical decision making, a reading study was conducted comparing it against a current standardized glucose report (SGR) . Clinical data from ten T2D subjects were used to generate complementary GPIRs and SGRs. Non-specialist PCPs (n=35) evaluated each case in each report design alongside A1c and medication regimen to make a therapy change recommendation. The study was structured as a two-round, full crossover session. Each round contained all ten cases for a given report design. PCPs were randomized to determine the initial report design presented. Therapy change recommendations were categorized by whether they addressed the MIP present, with a priority on treating hypoglycemia if it occurs coincident with other patterns within a given case. PCPs addressed the MIP equally well with each report in cases presenting patterns other than hypoglycemia. Across all cases and all subjects, therapy change categorizations were different in 79 instances with sixty-seven of these instances presenting hypoglycemia (ie: a PCP recommendation using one report addressed hypoglycemia, while that using the other report did not) . Within this subset, in all but one instance (66 of 67; 99%) PCPs correctly addressed low glucose with the GPIR when they did not for the same case using the SGR. These findings indicate the GPIR aides in identification and treatment of hypoglycemia that would otherwise be missed using current standardized reports.

Disclosure

M. T. Novak: Employee; Abbott Diabetes. G. Hayter: n/a. E. Wright: Advisory Panel; Abbott Diabetes, Bayer AG, Boehringer Ingelheim International GmbH, Gelesis, GlaxoSmithKline plc., Lilly Diabetes, MannKind Corporation, Medtronic, Sanofi-Aventis U. S., Consultant; Abbott Diabetes, Bayer AG, Bigfoot Biomedical, Inc., Boehringer Ingelheim International GmbH, Lilly Diabetes, Stability Health, Other Relationship; UpToDate, Speaker’s Bureau; Abbott Diabetes, American Diabetes Association, Bayer AG, Boehringer Ingelheim International GmbH, Sanofi-Aventis U. S. K. Midyett: Consultant; Abbott Diabetes. H. Wolpert: Employee; Lilly Diabetes. N. Virdi: Employee; Abbott Diabetes.
806-P: Correlation of Derived Time in Range (dTIR) and Time in Range (TIR) in People with Type 2 Diabetes (T2D) Treated with IDegLira (IDL) , Degludec, or Liraglutide: A Post Hoc Analysis of the DUAL I Trial
Authors: PHILIS-TSIMIKAS ATHENA , DCRUZ JOHN M. , SIVARATHINASAMI RAMSATHISH , DE BLOCK CHRISTOPHE
Published: May 2022

Background and Aims: TIR (blood glucose 70-180 mg/dL) , measured by continuous glucose monitoring (CGM) , provides a more comprehensive picture of glycemic control than A1c alone. Derived TIR (dTIR) , a calculated estimate of TIR, is useful when CGM data are unavailable. This post hoc analysis of DUAL I investigated the correlation between dTIR and TIR in patients with CGM data.

Materials and Methods: In DUAL I, people with T2D uncontrolled on oral antidiabetic drugs (n=1663) were randomized 2:1:1 to IDL, degludec or liraglutide, for up to 52 weeks. CGM data were collected using IPro1 and IPro2 (Medtronic) . dTIR was calculated from 9-point self-measured blood glucose (SMBG) profiles (minimum 6 points) . The Pearson correlation coefficient was used to assess correlation between dTIR and TIR at baseline, and at weeks 26 and 52. Also assessed were the correlation between change in dTIR and change in TIR, from baseline to end of trial (EOT) , and the proportion of patients achieving a ≥5% increase in TIR or dTIR at weeks 26 and 52.

Results: 260 patients had CGM data. Using dTIR calculated from patients with ≥6-point SMBG profiles, a strong correlation was seen between dTIR and TIR at baseline (n=2observations; correlation 0.8838) , with a moderate correlation also seen at week 26 (n=165; correlation 0.5512) and week 52 (n=152; correlation 0.5184) . Change in dTIR and change in TIR, from baseline to EOT, were also correlated (n=137; correlation 0.7686) . Similar results were seen using dTIR calculated using ≥7- or ≥8-point SMBG profiles. A numerically greater proportion of patients achieved a ≥5% increase in dTIR vs. TIR at weeks 26 and 52 (78% vs. 54% and 62% vs. 50%, respectively) , perhaps due to missed nocturnal hypoglycemia, and limited data points, measured by SMBG.

Conclusion: These data support the use of dTIR as a surrogate endpoint when CGM data are unavailable, to provide additional information on glycemic control.

Disclosure

A.Philis-tsimikas: Advisory Panel; Bayer AG, Novo Nordisk, Research Support; Lilly Diabetes, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk, Viking Therapeutics. J.M.Dcruz: Employee; Novo Nordisk Global Business Services. R.Sivarathinasami: None. 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.

Funding

Novo Nordisk A/S
823-P: The Long-Acting Dual Amylin and Calcitonin Receptor Agonist KBP Has Increased Efficacy on Weight Loss and Glucose Control Compared with Cagrilintide in Obese and Diabetic Rats
Authors: LARSEN ANNA T. , SONNE NINA , MOHAMED KHALED ELHADY , BREDTOFT EMMA-MARIE , ANDERSEN FREDERIK , KARSDAL MORTEN A. , HENRIKSEN KIM
Published: May 2022

Long-acting dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for treatment of type 2 diabetes (T2D) and obesity due to their beneficial effects on both body weight, glucose control and insulin action. Cagrilintide, which is currently in clinical trials, has shown promising effects on weight loss. In this study we compared a new long-acting DACRA (KBP) to cagrilintide in pre-clinical models of obesity and T2D. In vitro potencies were assessed using receptor assays. In vivo efficacies were investigated head-to-head in high fat diet (HFD) fed obese and T2D (ZDF) rat models. In vitro data showed that both peptides active both the amylin and the calcitonin receptor, with KBP being more potent on both receptors. This was further confirmed in vivo by assessment of acute effects on food intake and CTX suppression. KBP (1.5, 4.5 and 13.5 nmol/kg) and cagrilintide (10, 30 and 100 nmol/kg) induced a potent and dose-dependent weight loss in HFD rats, with the highest dose of KBP being superior to cagrilintide. In diabetic ZDF rats, DACRA treatment improved glucose control and preserved plasma insulin compared to vehicle. Interestingly, despite similar levels of plasma insulin, KBP treatment was superior to cagrilintide in improving glucose control. This was further reflected in the HbA1c levels at study end, where KBP treatment resulted in significantly lower levels compared to cagrilintide.

In summary, both DACRAs induced weight loss and improved glucose tolerance, insulin action as well as glucose control. However, KBP treatment results in superior efficacy on both weight loss and glucose control. These findings highlight KBP as a promising once-weekly agent for treatment of obesity and T2D.

Disclosure

A.T.Larsen: Employee; Nordic Bioscience. N.Sonne: None. K.Mohamed: None. E.Bredtoft: None. F.Andersen: None. M.A.Karsdal: Employee; Nordic Bioscience A/S, Nordic Bioscience A/S, Nordic Bioscience A/S. K.Henriksen: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S.
845-P: Advancing Therapy in Basal Insulin–Treated Type 2 Diabetes: Exploratory Analysis of the SoliMix Trial by Baseline HbA1c, Insulin Dose, and BMI
Authors: HOME PHILIP , MCCRIMMON RORY J. , ROSENSTOCK JULIO , BLÜHER MATTHIAS , PEGELOW KATRIN , MELAS-MELT LYDIE , DJABALLAH KHIER , GIORGINO FRANCESCO
Published: May 2022

Introduction: SoliMix (EudraCT: 2017-003370-13) found better HbA1c, weight benefit, and lower hypoglycemia risk requiring less insulin with once-daily iGlarLixi vs. twice-daily premix BIAsp 30 in people with type 2 diabetes (T2D) advancing from basal insulin (BI) and oral antihyperglycemic drugs (OADs) .

Methods: Adults with T2D and HbA1c 7.5-% on BI + 1-2 OADs were randomized to iGlarLixi or BIAsp 30 for 26 weeks. Primary outcomes were non-inferiority in HbA1c change or superiority in body weight change with iGlarLixi vs. BIAsp 30. This post hoc analysis assessed SoliMix endpoints by baseline HbA1c (7.5-8, >8-9, >9-%) , insulin dose (<30, ≥30 U/day) , and BMI (<25, ≥25-<30, ≥30-<35, ≥35 kg/m2) .

Results: No differences in treatment effect were seen across subgroups for change in HbA1c or BMI (heterogeneity p>0.10; Table) ; both primary objectives were met in the HbA1c >8-≤9 %, BMI ≥25-<30 kg/m2, and insulin dose subgroups. No differences in treatment effect were seen across subgroups for the lesser insulin dose increments with iGlarLixi vs. BIAsp 30 (p>0.10) . Level 2 hypoglycemia incidence and rates were unaffected by baseline HbA1c and BMI (p>0.10) , but p<0.for events by insulin dose.

Conclusions: Primary SoliMix findings for iGlarLixi vs. BIAsp 30 were consistent across baseline HbA1c and BMI subgroups but inconsistent for baseline insulin dose.

Disclosure

P.Home: Advisory Panel; Kriya Therapeutics, Consultant; Mundipharma, Sanofi, Other Relationship; AstraZeneca, Sanofi, Research Support; Gan & Lee Pharmaceuticals, Sanofi, Speaker's Bureau; Gan & Lee Pharmaceuticals, Medscape. R.J.Mccrimmon: Advisory Panel; Novo Nordisk, Sanofi, Research Support; Diabetes UK, European Union, MedImmune. 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. M.Blüher: Consultant; AstraZeneca, Lilly, Novo Nordisk A/S, Pfizer Inc., Sanofi, Speaker's Bureau; Bayer AG, Boehringer Ingelheim International GmbH, Novartis AG. K.Pegelow: Employee; Sanofi-Aventis Deutschland GmbH. L.Melas-melt: None. K.Djaballah: Employee; Sanofi. 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.

Funding

Sanofi
848-P: Efficacy and Safety of GlucoLo Plus in Type 2 Diabetes Management
Authors: ZARRUK ALEXANDRO R.
Published: May 2022

Background and Aims: Diabetes is globally increasing in prevalence and patients are constantly on the lookout for Complementary and Alternative Medicines (CAM) that are safe and efficacious including biologically-based practices such as vitamins and dietary supplements.

Methods: This double-blind randomised placebo-controlled trial evaluated the effects of daily GlucoLo Plus, a newly formulated biologically-based CAM for diabetes type 2 management. The primary outcome was to evaluate the effect of GlucoLo Plus on HbA1c and the secondary outcomes were to assess its effect on fasting glycemia, lipid profile, weight and assess its safety profile.

Results: Of 64 individuals assessed for eligibility, 60 (mean HbA1c 6.98% [52.8 mmol/mol], mean age 67.3 years [SD 9.5], 26 [43%] women, mean diabetes duration 3.2 years, and mean body mass index 27.9 kg/m2) were randomly assigned to GlucoLo Plus (n=32 [53%]) , or placebo (n=28 [47%]) . At 12 weeks, GlucoLo Plus decreased HBA1c by 0.843% (P=0.0121) while placebo reduced it by 0.132% (p = 0.5951) . GlucoLo Plus was also associated with non-significant reduction in fasting glycemia, total cholesterol, triglyceride, and LDL-cholesterol. GlucoLo Plus arm had a mean 1.84 lbs weight loss while the placebo arm had a 0.21 lbs weight gain. The most frequent adverse events with GlucoLo Plus were mild and transient gastrointestinal events including nausea (9.3% vs. 3.5%) and dyspepsia (15.6% vs. 10.7%) .

Conclusion: GlucoLo Plus significantly lowered HbA1c and had positive effect on bodyweight, fasting glycemia, LDL-cholesterol and had a minimal side effect profile. These results suggest that GlucoLo Plus could be an alternative and adjunct to type 2 diabetes management in people who are reluctant to initiate or add new antidiabetic agents.

Disclosure

A.R.Zarruk: Advisory Panel; Amgen Canada, AstraZeneca, Bausch Health, Canada, Boehringer Ingelheim International GmbH, Eisai Inc., Eli Lilly and Company, HLS Therapeutics Inc., Novo Nordisk Canada Inc., Sanofi, Takeda Canada, Valeant Pharmaceuticals, Other Relationship; Groupe Nature Pharma, Research Support; Abbott Diabetes, Novo Nordisk Canada Inc., Orimed Pharma, Speaker's Bureau; Abbott, Abbott Diabetes, Amgen Canada, AstraZeneca, Bausch Health, Canada, Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics Inc., Janssen Pharmaceuticals, Inc., Mylan N.V., Novo Nordisk Canada Inc., Orimex Pharma, Sanofi, Takeda Canada, Valeant Pharmaceuticals, Viatris Inc.

Funding

Groupe Nature Pharma
85-OR: Thalamic H1-MRS Metabolite Parameters Are Related to Mood Disorders in Type 1 Diabetes
Authors: GREIG MARNI , SLOAN GORDON P. , SHILLO PALLAI RAPPAI , SELVARAJAH DINESH , WILKINSON IAIN D. , TESFAYE SOLOMON
Published: May 2022

Objective: We have previously demonstrated increased thalamic blood volume and preserved HMRS neuronal metabolite ratios in painful diabetic peripheral neuropathy (P-DPN) . We hypothesised that perfusion measures and neuronal function measured by metabolite ratios may be related. However, as brain metabolite ratios may also be affected by mood disorders, common in P-DPN, this may be a significant confounding factor.

Methods: 52 type 1 diabetes (T1D) subjects (18 P-DPN, 23 DPN, 13 without neuropathy-DM-NN) and 18 healthy volunteers (HV) were recruited. 1HMRS was performed at 3T (Philips, Netherlands) . Single voxel spectra were obtained from a 2.25cm3 (15x10x15mm) volume of interest within the thalamus, TE=135ms, TR=1600ms, NSA=256 using point resolved (PRESS) technique. Metabolite ratios were calculated for choline, Creatine, and N-Acetyl Aspartate (NAA) . MR-DSC images were obtained at 3T using a T2*-weighted technique (TR/TE=1250/35ms; 72 dynamics) to assess the passage of bolus intravenous gadolinium-chelate through the thalamus.

Results: There was significant negative correlation between NAA/Cr (measure of neuronal function) and measures of depression: Hospital Anxiety and Depression Scale R= -0.33 (p=0.01) , Becks Depression Inventory R= -0.25 (p=.048) ; and anxiety: State-Trait Anxiety inventory- State (STAI-S) R= -.37 (p=.002) , STAI- Trait (T) R= -.32 (p=0.01) and Behavioural Inhibition R= -0.25 (p=0.04) . There were no differences in metabolite ratios between groups; and no significant correlations between perfusion measures and metabolite ratios.

Conclusion: This is the first study to show thalamic 1HMRS metabolite ratios are correlated with measures of mood disorders in T1D. The high prevalence of mood disorders in P-DPN and DPN have confounded previous 1HMRS studies and may explain conflicting reports in the literature. The link between neuropathy and mood disorders needs further exploration to understand whether both may arise from a common neurobiological pathway.

Disclosure

M.Greig: None. G.P.Sloan: None. P.Shillo: None. D.Selvarajah: None. I.D.Wilkinson: None. S.Tesfaye: Advisory Panel; Astellas Pharma Inc., Bayer AG, Grünenthal Group, Nevro Corp., Wörwag Pharma GmbH & Co. KG, Speaker's Bureau; Eva Pharma, Pfizer Inc., Viatris Inc.

Funding

European Foundation for the Study of Diabetes (EFSD)
86-OR: Erectile Dysfunction in Men with Prediabetes and Type 2 Diabetes: The Diabetes Prevention Program Outcomes Study (DPPOS)
Authors: BLAIR YOONI , DOHERTY LINDSAY , TEMPROSA MARINELLA , WESSELLS HUNTER , POP-BUSUI RODICA , GADDE KISHORE M. , SINGH PRACHI , SARMA ARUNA V. ,   DPP RESEARCH GROUP
Published: May 2022

Introduction: Erectile dysfunction (ED) is more common and less responsive to pharmacotherapy in men with T2D. Data in men with prediabetes (PreD) and risk profiles in those with T2D, are lacking. We determined the burden and risk factors for ED in men with PreD and with T2D enrolled in the DPPOS.

Methods: Between 1996-1999, 3,234 adults with PreD were randomized to intensive lifestyle intervention, metformin, or placebo in the DPP. In 2001, metformin was continued for those originally randomized with modified lifestyle intervention offered to all. In 2016-2017, 568 (88%) of 648 male participants completed the International Index of Erectile Function (IIEF) . ED was defined as having low or very low confidence getting and keeping an erection and/or ED medication use. Backwards selection multivariable logistic regression models including DPP treatment estimated odds of ED for covariates significant in bivariate analysis in men with persistent PreD and T2D.

Results: Overall, 218 (38%) men met ED criteria. Prevalence of ED was similar in men with PreD (41%) and T2D (37%) (p=0.4) . In all men, older age (p<0.001) , non-white race (p<0.001) and depression (defined by Beck Depression Inventory or antidepressant use) (p<0.01) were associated with ED. Among men with PreD, those assigned to intensive lifestyle intervention, but not metformin, had decreased odds of ED compared with the placebo group (OR=0.26, 95%CI=0.09, 0.77) . Among men with T2D, metabolic syndrome (MetS) , defined by NCEP ATP III criteria, was associated with increased odds of ED (OR=1.72, 95%CI=1.05, 2.83) .

Conclusions: ED is highly prevalent in men with PreD and with T2D. In addition to demonstrated factors typically observed in the general population such as younger age and absence of depression, intensive lifestyle intervention was protective in men at increased risk for T2D. In men with T2D, ED was associated with MetS. Our findings suggest metabolic mechanisms contribute to the pathogenesis of ED in T2D.

Disclosure

Y.Blair: None. L.Doherty: None. M.Temprosa: None. H.Wessells: None. R.Pop-busui: Advisory Panel; Averitas Pharma, Inc., Boehringer Ingelheim International GmbH, Nevro Corp., Novo Nordisk, Reata Pharmaceuticals, Inc., Regenacy Pharmaceuticals, Inc. K.M.Gadde: Research Support; AstraZeneca, BioKier, Inc. P.Singh: None. A.V.Sarma: None. D.Research group: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (UDK048489, UDK048339, UDK048377, UDK048349, UDK048381, UDK048468, UDK048434, UDK048485, UDK048375, UDK048514, UDK048437, UDK048413, UDK048411, UDK048406, UDK048380, UDK048397, UDK048412, UDK048404, UDK048387, UDK048407, UDK048443, and UDK048400)
863-P: SGLT2i Use and the Risk of Nephrolithiasis in Patients with T2D
Authors: PAIK JULIE M. , TESFAYE HELEN , CURHAN GARY , MASTRORILLI JULIANNA M. , WEXLER DEBORAH J. , KIM SEOYOUNG C. , PATORNO ELISABETTA
Published: May 2022

Diabetes is associated with an increased risk of kidney stones. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) might lower the risk of nephrolithiasis, as they increase urinary flow. However, a prior meta-analysis was inconclusive, and only one Danish study reported a lower risk of kidney stones. We investigated the association between SGLT2i use and the risk of nephrolithiasis in routine practice. Using claims data from 2 private health plans and Medicare (2013-2020) , we identified 331,028 pairs of 1:1 propensity score-matched adults with type 2 diabetes (T2D) initiating an SGLT2i or a DPP4 inhibitor (DPP4i) , and 358,203 pairs initiating an SGLT2i or a GLP1 receptor agonist (GLP1RA) . Our primary outcome was nephrolithiasis diagnosed by ICD codes in the inpatient or outpatient setting. We estimated hazard ratios (HRs) , rate differences (RD) and 95% confidence intervals (CI) , adjusting for 57 baseline covariates in the PS model. Over a mean follow-up of ∼months on treatment, the risk of nephrolithiasis was lower in the SGLT2i group compared with the DPP4i group (HR 0.74 [95%CI 0.71-0.77]; RD 4.0 [95%CI, -4.6, -3.4]) or the GLP1RA group (HR 0.69 [95%CI 0.67-0.72]; RD -4.1 [95%CI, -4.7, -3.5]) (Table) . Secondary definitions of the outcome based on a hospital discharge diagnosis produced consistent results. In routine care, SGLT2i use was associated with a reduced risk of nephrolithiasis, compared to DPP4i or GLP1RA use in patients with T2D.

Disclosure

J.M.Paik: None. H.Tesfaye: None. G.Curhan: Employee; OM1, Inc, Other Relationship; UpToDate. J.M.Mastrorilli: None. D.J.Wexler: Other Relationship; Elsevier, Novo Nordisk, UpToDate. S.C.Kim: Research Support; AbbVie Inc., Bristol-Myers Squibb Company, Pfizer Inc., Roche Pharmaceuticals. E.Patorno: Research Support; Boehringer Ingelheim International GmbH, National Institutes of Health, Patient-Centered Outcomes Research Institute.
873-P: Machine-Learning Models to Predict CKD and HF in Type 2 Diabetes Patients
Authors: TSUBOTA HIROO , SUZUKI ATSUSHI , MAKINO MASAKI , KANDA EIICHIRO , YAJIMA TOSHITAKA , KIDANI YOKO , MORITA NARU , KANEMATA SATOMI
Published: May 2022

Chronic kidney disease (CKD) and heart failure (HF) are the first and most frequent, and life-threatening comorbidities in type 2 diabetes (T2D) patients. Early intervention is important to prevent CKD and HF onset and to improve prognosis of these patients; however, the risk assessment of CKD and HF remains to be established. We aimed to build a machine learning model to predict the risk of CKD or HF onset in the early-stage T2D patients without a history of CKD or cardiovascular diseases (CVD) . We developed prediction models using light gradient boosting machine (LightGBM) , neural network, logistic regression, and Cox proportional hazards model. The model was derived and validated in a sample of 217,054 T2D patients aged ≥18 years without a history of CKD or CVD extracted from a Japanese hospital-based administrative claims data. The outcomes used for the prediction model were diagnosis of incident CKD or HF and hospitalization for CKD or HF in 1, 2, 3, and 5 years. Based on the importance, 60 characteristics and laboratory data were selected and used for models. LightGBM outperformed other models in all outcomes, with AUROCs 0.777 for diagnosis of incident CKD or HF, and 0.785 for hospitalization for CKD or HF in 5years. (Figure) The present study demonstrated successful development of prediction algorithms to support identifying T2D patients with high-risk of CKD or HF onset, which will contribute to improvement of patient prognosis.

Disclosure

H. Tsubota: Employee; AstraZeneca. A. Suzuki: Research Support; Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Amgen K.K., Eli Lilly and Company, Novo Nordisk A/S. M. Makino: None. E. Kanda: None. T. Yajima: Employee; AstraZeneca. Y. Kidani: Employee; AstraZeneca. N. Morita: Employee; AstraZeneca.
884-P: Associations between Health Care Access/Utilization and Racial/Ethnic Disparities in Diabetes ABC Measures among U.S. Adults
Authors: TANG SHICHAO , ZHANG PING
Published: May 2022

Racial/ethnic disparities exist for both poor ABC measures (A1C > 9%, blood pressure (BP) >= 160/100 mmHg, and non-HDL cholesterol >= 160 mg/dL) and access to care or utilization measures (health insurance coverage, having >= 4 doctor visits in past year, and having a routine place of health care) among U.S. adults with diabetes. Using 2011-2018 National Health and Nutrition Examination Survey, we examined the associations between health care access/utilization and racial/ethnic disparities in poor ABC measures. We estimated the marginal effect of race/ethnicity on each ABC measure by each access-to-care/utilization measure, respectively, using weighted multivariate logistic regressions. Poor ABC measures were more prevalent in non-Hispanic Black (NHB) (A1C: 19%, BP:13%, non-HDL cholesterol: 22%) and Hispanic (25%, 9%, 34%) than non-Hispanic White (NHW) (11%, 7%, 21%) people. Similar disparities were observed for poor access to care/utilization: NHB (uninsured:11%, <4 visits:38%, no routine place for care:4%) , Hispanic (23%, 44%, 11%) , NHW (6%, 34%, 4%) . Effects of access to care/utilization on poor ABC measures varied by measures of both access-to-care/utilization and ABC control. Compared with NHW, having no insurance vs. having insurance was much more likely to be associated with poor A1C level in NHB (16% vs. 5%, p < 0.05) and Hispanic populations (26% vs. 7%, p < 0.01) . However, insurance status was not associated with racial/ethnic disparities on poor BP and cholesterol measures. Having >= 4 doctor visits in the past year and a routine place for care were not associated with racial/ethnic disparities of any poor ABC measures. Closing the insurance coverage gap by increasing insured rate among racial/ethnic minorities could help reduce the racial/ethnic disparity in A1C level. Future studies to explore reasons why other access-to-care/utilization measures were not associated with racial/ethnic disparities in poor ABC measures may be beneficial.

Disclosure

S.Tang: None. P.Zhang: None.
888-P: A Model to Assess the Financial Feasibility of Telemedicine-Based Pediatric T1D Care in Value-Based Care and Fee-for-Service Settings
Authors: PEI RYAN LEONARD , DUPENLOUP PAUL , PRAHALAD PRIYA , JOHARI RAMESH , ADDALA ANANTA , ZAHARIEVA DESSI P. , MAAHS DAVID M. , SCHEINKER DAVID
Published: May 2022

We previously examined a type 1 diabetes care model based on the use of a remote patient monitoring (RPM) tool that analyzes CGM data. The care model was associated with improved glucose management and reduced provider effort. We compare the financial feasibility of this care model in value-based care (VBC) and fee-for-service (FFS) settings.

We set parameters based on the current deployment of the care model. In the FFS setting, we estimated Medicare reimbursement rates and labor costs for in-person diabetes education. We compared these to costs in a VBC setting where providers make prospective payments for RPM services. We evaluated the financial impact of the care model across a variety of parameters (Fig) .

In a FFS setting, we estimated that in-person care incurs net costs of $1per patient. Under a VBC contract, we estimated that prospective payments are offset by reduced labor costs, incurring net costs of $65 per patient (i.e., 49% savings) . These results are sensitive to input parameters (Fig) .

We identified financially viable payment models for an algorithm-enabled telemedicine-based care model associated with improved T1D glucose management. The analysis may inform operational planning at the clinic level as well as reimbursement policy design.

Disclosure

R.Leonard pei: None. P.Dupenloup: None. P.Prahalad: None. R.Johari: None. A.Addala: None. D.P.Zaharieva: Research Support; Insulet Corporation, International Society for Pediatric and Adolescent Diabetes, Leona M. and Harry B. Helmsley Charitable Trust. D.M.Maahs: Advisory Panel; Abbott Diabetes, Eli Lilly and Company, Medtronic, Novo Nordisk, Sanofi, Consultant; Aditx Therapeutics, Inc., Biospex. D.Scheinker: None.

Funding

Helmsley Charitable Trust.ISPAD-JDRF Fellowship.R18DK122422.SDRC.LPCH Auxiliaries.The Stanford REDCap platform (http://redcap.stanford.edu) is developed and operated by Stanford Medicine Research IT team. The REDCap platform services at Stanford are subsidized by a) Stanford School of Medicine Research Office, and b) the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through grant UL1 TR001085.Stanford Maternal and Child Health Research Institute.
892-P: Generating Intercorrelated Data for Simulation Samples in Diabetes Microsimulation Experiment
Authors: GUAN DAWEI , LEE JI-HYUN , LOU XIANGYANG , BIAN JIANG , GUO YI , GUO JINGCHUAN , SHAO HUI
Published: May 2022

Traditional data generating processes (DGP) in simulation treat input variables as independently distributed. Ignoring the intercorrelation between variables would reduce the accuracy of the simulation. A common solution is to use the correlation coefficient between variables to correct the DGP. However, challenges exist when the correlated variables are from different distribution types. Existing solutions restrict the correlation coefficients to cope with these challenges, limiting their practicality. This study aimed to validate a novel algorithm to relax the above restrictions. We have identified 426 individuals with self-reported diabetes from the National Health and Nutrition Examination Survey (2013-2018) . We extracted the distribution parameters (mean and SD) and the correlation coefficient matrix of 18 variables often used to characterize diabetes population, including demographics, biomarkers, and disease histories. Our algorithm involves two steps: all parameters were first simulated as correlated numeric variables with normal distribution, and then converted into values that follow their corresponding distributions (e.g., Bernoulli) . Simulation precision was evaluated by comparing observed and simulated data. There were no significant differences in any variables between the observed and the simulated data (all p> 0.05) . The mean (SE) absolute difference between observed and simulated correlation coefficients was 0.032 (0.002) . Among the 153 correlation coefficients, the differences between observed and simulated were less than 0.in 1 (77.8%) coefficients, between 0.and 0.1 in 30 (19.6%) coefficients, and higher than 0.1 in 4 (2.6%) coefficients. The precision levels were consistent across subgroups stratified by age or cardiovascular disease. Our algorithm, with relaxed restriction on intercorrelation, can accurately generate data close to the observed data based on distribution parameters and correlation coefficient matrix.

Disclosure

D.Guan: None. J.Lee: None. X.Lou: None. J.Bian: None. Y.Guo: None. J.Guo: None. H.Shao: Board Member; BRAVO4HEALTH, LLC.
91-LB: Glycemic and Metabolic Effects of Long-Acting GLP-1 in T1D
Authors: MOHANDAS DEENE , GAO CATHERINE , CALMA JAMIE , BASINA MARINA
Published: May 2022

GLP-1 receptor agonists were studied as adjunct therapies in T1D. While short-acting GLP-1 agents are not approved for T1D due to concern of increased DKA risk, long-acting GLP-1 medications are commonly prescribed for T1D. Our study aims to evaluate glycemic and metabolic benefits of long-acting GLP-1 therapy in T1D and assess safety concerns.

We conducted a retrospective chart review of T1D patients on a long-acting GLP-1 for at least six months. Parameters collected were A1c, 14-day CGM data at each visit, and metabolic data. Data from two years prior to starting GLP-1, and six or more months after starting GLP-1 were included.

We identified 54 participants with T1D on a long-acting GLP-1 (Semaglutide, Dulaglutide, long acting Exenatide, Albiglutide) . Mean GLP-1 duration was 23.85 mo ± 15.46. We found a significant increase in time in range, and significant reductions in A1c, time in hyperglycemia, 14-day Blood Glucose SD, DKA hospitalization, and weight after starting a long-acting GLP-1. Time in hypoglycemia decreased non-significantly. Full data can be found in Table 1.As more data emerges on cardiovascular and renal benefits of long acting GLP-1 in type 2 Diabetes, there have been no reported outcomes in T1D. Our study is the first and the only one that demonstrates glycemic and metabolic benefits of this class in T1D, and safety of its use over 1.5-2 years. It represents real life experience. This data needs to be confirmed by prospective studies.

Disclosure

D. Mohandas: None. C. Gao: None. J. Calma: None. M. Basina: None.
911-P: Longitudinal Trends in CGM and Pump Use: Real-World Data from the T1D Exchange QI Collaborative
Authors: EBEKOZIEN OSAGIE , MUNGMODE ANN , MIYAZAKI BRIAN , ROMPICHERLA SAKETH , LYONS SARAH , ALWAZEER MOUHAMMAD , SARHIS JENNIFER , MEKHOUBAD ALLISON B. , DESIMONE MARISA , AKTURK HALIS K.
Published: May 2022

Background: The T1D Exchange Quality Improvement Collaborative (T1DX-QI) is a learning network of over forty US type 1 diabetes clinics. Participating clinics share data for benchmarking, population health trends and monitoring quality improvement activities.

Method: T1DX-QI clinics complete an extensive data-mapping process to submit reports from clinic electronic medical records (EMR) system. The T1DX EMR database contains information for over 55,000 US patients and allows for robust population health analysis including percentage of patients using a continuous glucose monitor (CGM) or insulin pump. The percentage of patients using either device was calculated from 2016-2021.

Results: From 2016 to 2021, the percentage of patients using CGM increased from 59% to 72%. Over the same time period, the percentage of patients using pumps remained stable (median 54%) . For both devices, racial disparity persisted: there was a 27% and 31% difference in percentage of non-Hispanic White (NHW) and non-Hispanic Black (NHB) patients using CGM in 2016 (N = 17431) and 2021 (N = 20908) , respectively; in the same years, there was a 36% and 37% difference in percentage of NHW and NHB patients using a pump.

Conclusion: While there is robust increase in diabetes device uptake, inequities persist in access to these technologies.

Disclosure

O.Ebekozien: None. H.K.Akturk: Research Support; Dexcom, Inc., Eli Lilly and Company, REMD Biotherapeutics. A.Mungmode: None. B.Miyazaki: None. S.Rompicherla: None. S.Lyons: None. M.Alwazeer: None. J.Sarhis: None. A.B.Mekhoubad: None. M.Desimone: None.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust