bluuebunny/crossref_metadata_2025_split huggingface dataset:
73-OR: Multiancestry Genetic Clustering of Type 2 Diabetes Loci Highlights the Contribution of Non-European Variants to Disease Heterogeneity
Authors: SMITH KIRK , KIM HYUNKYUNG , WESTERMAN KENNETH E. , HSU SARAH , MANDLA RAVI , SCHROEDER PHILIP H. , MAJARIAN TIM , KAUR VARINDERPAL , FLOREZ JOSE C. , MANNING ALISA , MERCADER JOSEP M. , UDLER MIRIAM 
Published: June 2023

To identify potential subtypes of type 2 diabetes (T2D) anchored in genetics but informed by physiology, we previously used a soft clustering method to cluster T2D single nucleotide variants (SNVs) by their associated metabolic traits. The resulting European-based clusters represent likely disease mechanistic pathways. However, ancestry-specific SNVs, phenotype characteristics and prevalence rates suggest that a portion of the T2D’s heterogeneity is population-based, requiring expansion of this work to non-European populations.
We created a semi-automated Bayesian non-negative matrix factorization (bNMF) pipeline to generate new ancestry-specific clusters in European (EUR, 390 SNVs), East Asian (EAS, 326 SNVs) and African (AFR, 172 SNVs), as well as trans-ancestry (TA, 498 SNVs), using up to 89 T2D-related traits. We validated the clusters by replicating their trait associations in the Mass General Brigham Biobank cohort (MGBB, N=62,252).
The new ancestry-specific and TA clusters captured previously identified clusters, as well as novel clusters related to possible mechanisms of insulin resistance. In the 11 TA clusters, 127/498 SNVs were from non-EUR T2D studies, with 87 SNVs not represented in the EUR clusters. In the non-European subset of MGBB (N=8,990), 8 of 10 TA cluster pPS were more strongly associated with T2D compared to the corresponding EUR cluster pPS. We assessed in MGBB whether the proportion of cumulative genetic risk attributed to each cluster differed between sub populations. A significantly higher proportion was attributed to the Lipodystrophy cluster in EAS, to the Obesity cluster in EUR, and to the Liver/Lipid cluster in AFR (all t-test P&lt;10-15).
By expanding our previous clusters to include non-European SNVs, we were able to identify new genetic clusters and improve the predictive ability of cluster pPS. Our results suggest that polygenic processes contribute in different proportions across populations.

Disclosure
K.Smith: None. A.Manning: None. J.M.Mercader: None. M.Udler: None. H.Kim: None. K.E.Westerman: None. S.Hsu: None. R.Mandla: None. P.H.Schroeder: None. T.Majarian: Employee; Vertex Pharmaceuticals Incorporated. V.Kaur: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R03DK131249)
745-P: The Impact of COVID-19 and the Public Health Emergency on the Medicare Diabetes Prevention Program
Authors: JACOBS SARA , HOERGER THOMAS J. , ALLAIRE BENJAMIN T. , AMICO PETER , MARKOVICH PATRICIA , ROMAIRE MELISSA 
Published: June 2023

Background: The MDPP has been significantly affected by the COVID-19 public health emergency (PHE). Prior to the PHE, the MDPP was designed as an in-person program delivered to participants in community settings. The Centers for Medicare & Medicaid Services (CMS) moved quickly in March 2020 to waive the in-person requirement for MDPP sessions and allow classes to continue on a virtual basis. CMS also permitted beneficiaries to temporarily pause participation.
Purpose: To examine the impact of the COVID-19 PHE on MDPP suppliers and on beneficiary participation, attendance, and weight loss.
Methods: We analyzed data collected as part of the MDPP evaluation and Medicare claims from April 2018 to December 2021. Results: In the 6 months following the start of the PHE, new enrollment fell to 11 beneficiaries per month, a decrease of 236% from the same period in 2019. In addition, 32% of suppliers had more than half of the MDPP beneficiaries drop out, and 22% of suppliers had more than half of their MDPP beneficiaries pause for at least 30 days. In comparison, in 2019, only 2% of suppliers had more than half of their MDPP beneficiaries drop out, and 8% of suppliers had more than half of their beneficiaries pause. For participants who continued or returned after a pause, the share of virtual sessions increased from &lt;1% prior to March 2020 to 92% in April 2020. Thereafter, the percentage of virtual sessions declined, but the overall percentage still exceeded 50% through December 2021. Among beneficiaries who started in January or February and continued in the program without dropping out or pausing, weight loss is very similar between those that participated in 2019 (6.4%; n=245) compared to those in 2020 (6.5%; n=188). Conclusions: Although the PHE altered the way MDPP sessions were delivered and substantially reduced new enrollment in the program, changes in session delivery mode (e.g., in-person to virtual) did not appear to impact overall weight loss among continuing beneficiaries.

Disclosure
S.Jacobs: None. T.J.Hoerger: Research Support; Gilead Sciences, Inc. B.T.Allaire: None. P.Amico: None. P.Markovich: None. M.Romaire: None.

Funding
Centers for Medicare & Medicaid Services (HHSM-500-2014-0037I/75FCMC18F0003)
756-P: A Phase 1c Evaluation of a Novel GLP-1 Analog Ecnoglutide (XW003) for Weight Loss in Adults with Overweight and Obesity
Authors: WANG GUANG , HU WEI , QIN HONG H. , ZHENG QING , NING JING , MENGYING GUO , BU YUE , JONES CATHERINE , FENAUX MARTIJN , XU SUSAN , JUNAIDI MOHAMMED K. 
Published: June 2023

Ecnoglutide (XW003) is a novel, long-acting GLP-1 analog being developed for the treatment of type 2 diabetes and obesity.
We conducted a Phase 1c randomized, double-blind, placebo-controlled study of ecnoglutide, which enrolled 60 nondiabetic adults with BMI 24-35 kg/m2. The study was conducted in China. PK, change in mean body weight and BMI, safety, and tolerability were evaluated. Participants received 1.8 or 2.4 mg ecnoglutide or placebo as once weekly injections for 14 weeks, including dose escalation. This core treatment was followed by an open-label extension of the ecnoglutide groups, for a total duration of 26 weeks.
At baseline, participants had a mean body weight of 84.61 ± 10.44 kg and BMI of 29.53 ± 1.73 kg/m2. After 14 weeks of core treatment, mean weight reduction from baseline was -8.29 ± 0.52 kg in the 1.8 mg ecnoglutide group and -7.24 ± 0.56 kg in the 2.4 mg group, compared to -0.61 ± 0.82 kg for placebo (P&lt;0.0001 vs placebo for both doses). At Week 14, the proportion of participants achieving ≥5% weight loss from baseline was 87.5% (95% CI, 67.6 to 97.3) and 70.0% (95% CI, 45.7 to 88.1) for 1.8 and 2.4 mg ecnoglutide, respectively, and 22.2% (95% CI, 2.8 to 60.0) for placebo. Continued weight reduction was observed until the end of study at Week 26, with a mean percent change from baseline of -15.0% (95%CI, -16.8 to -13.2) and -13.2% (95% CI, -15.3 to -11.1) for 1.8 and 2.4 mg ecnoglutide, respectively. At Week 26, ≥5% weight loss was observed for 94.7% (95% CI, 74.0 to 99.9) of participants in the 1.8 mg group and 100.0% (95% CI, 75.3 to 100.0) in the 2.4 mg group.
At steady state, ecnoglutide showed a mean Cmax of 310 - 468 ng/mL, Tmax of 26 - 29 h, and half-life of 139 - 162 h.
Overall, ecnoglutide was safe and well tolerated. The proportion of participants reporting any AE was similar between cohorts (95.2 to 100% for ecnoglutide vs 90% for placebo). The most frequent AEs were gastrointestinal, including diarrhea and vomiting. No drug-related SAE or drug-related AEs ≥Grade 3 were reported.

Disclosure
G. Wang: None. W. Hu: None. H.H. Qin: Employee; Sciwind Biosciences, Sichuan Anerobic Biotech. Q. Zheng: Employee; Sciwind Biosciences. J. Ning: None. G. Mengying: None. Y. Bu: Employee; Sciwind Biosciences. C. Jones: Employee; Sciwind Biosciences. M. Fenaux: Employee; Sciwind Biosciences. Stock/Shareholder; Terns Pharmaceuticals. S. Xu: Employee; Sciwind. M.K. Junaidi: None.

Funding
Sciwind Biosciences
778-P: Efficacy and Safety of Supaglutide as Add-on to Metformin in Patients with Type 2 Diabetes
Authors: ANWAR DILBAR , BAO YUQIAN , ZHOU YUE , CHEN SI , ZHOU JIAN , LI LIANG , CHENG ZHIFENG , DONG XIAOLIN , SHI XIAOXIA , SU XIUHAI , LI LIPING , WANG HAIFANG , WANG YIHUA , LI SHU , LI QINGJU , LI XING , LIU MING , SUN JIAO , ZHAO NAIQING , YANG YEHONG , MA JIANHUA , LI YIMING , WANG QINGHUA , JIA WEIPING 
Published: June 2023

GLP-1 is an incretin hormone with broad pharmacological potential. GLP-1 receptor agonists (GLP-1RA) are successfully in clinical use for T2D and obesity. Several GLP-1-based therapies are in clinical evaluation for treating metabolic diseases. Supaglutide (supa), a novel GLP-1RA, is in late-stage clinical investigation for T2D. The efficacy and safety are being investigated in 340 patients with T2D inadequately controlled on metformin in this randomized, double-blind, placebo-controlled phase 3 clinical trial (NCT04998032). Supa 3 mg QW treatment resulted in a statistically significant reduction in HbA1c of -1.81% from baseline at week 24 (p&lt;0.001). Body weight was decreased by 3.80% from baseline in supa 3 mg group, with a significant difference versus placebo group (p&lt;0.001). Supa also significantly improved glucose excursion, and increased meal-stimulated insulin and C-peptide secretion as determined by MMTT, suggesting improved glucose tolerance and enhanced β-cell function. Overall TEAEs occurred in 66.7% and 73.4% with placebo and supa 3 mg, respectively. The most common TEAEs with supa were GI symptoms, such as nausea, vomiting, diarrhea and decreased appetite mostly in mild or moderate severity. Supa 3 mg improved glycemic and metabolic control and was well tolerated in T2D inadequately controlled on metformin, suggesting supa as a novel alternative therapy for T2D and metabolic disorders.

Disclosure
D.Anwar: None. X.Su: None. L.Li: None. H.Wang: None. Y.Wang: None. S.Li: None. Q.Li: None. X.Li: None. M.Liu: None. J.Sun: None. N.Zhao: None. Y.Bao: None. Y.Yang: None. J.Ma: None. Y.Li: None. Q.Wang: None. W.Jia: None. Y.Zhou: None. S.Chen: None. J.Zhou: None. L.Li: None. Z.Cheng: None. X.Dong: None. X.Shi: None.
784-P: Characteristics of People with Young-Onset T2D in the SURPASS Program
Authors: GALINDO RODOLFO J. , ZEITLER PHILIP , DAVIES MELANIE J. , LEE CLARE , THIEU VIVIAN , NICOLAY CLAUDIA , ALLEN SHERYL , BERGMAN BRANDON 
Published: June 2023

Young-onset T2D, defined as diagnosed before age 40, is increasing around the world. Recent data suggest a faster deterioration in beta-cell function and earlier development of complications in this population, compared to later-onset T2D. This post-hoc analysis evaluated the baseline characteristics of people with young-onset vs later-onset T2D in the SURPASS clinical trial program. Baseline demographics and clinical characteristics were compared in participants with young-onset vs later-onset T2D from the SURPASS-1, -2, -3, and -5 clinical trials (N=4267). Analyses were performed by study. Across the SURPASS program, which included participants at various stages of T2D management, participants with young-onset T2D were younger, had longer duration of diabetes, worse glycemic control, higher mean body weight and BMI, and a worse lipid profile at baseline vs patients with later-onset T2D. Data from SURPASS-1 and SURPASS-2 also showed participants with young-onset T2D had greater insulin resistance (HOMA2-IR) at baseline. Despite their younger age at baseline, participants with young-onset T2D in the SURPASS program had an overall worse health status as compared to patients with later-onset T2D. Early intervention in young-onset T2D may be important to optimize long-term outcomes.

Disclosure
R.J.Galindo: Consultant; Novo Nordisk, Eli Lilly and Company, Sanofi, Pfizer Inc., Bayer Inc., WW (Weight Watchers), Research Support; Novo Nordisk, Eli Lilly and Company, Dexcom, Inc. P.Zeitler: Consultant; Eli Lilly and Company, Boehringer Ingelheim Inc., Johnson & Johnson. 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. C.Lee: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. V.Thieu: None. C.Nicolay: Employee; Eli Lilly and Company. S.Allen: None. B.Bergman: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.

Funding
Eli Lilly and Company
785-P: Comparative Effectiveness of Second-Line Glucose-Lowering Medications—Emulation of a Target Trial Using Real-World Data
Authors: DENG YIHONG , POLLEY ERIC , WALLACH JOSHUA D. , HERRIN JEPH , ROSS JOSEPH , MCCOY ROZALINA G. 
Published: June 2023

The comparative effectiveness of commonly used 2nd-line type 2 diabetes medications with respect to lowering hemoglobin A1c (HbA1c) is unknown, as the GRADE trial did not include a SGLT2 inhibitor arm and was limited to patients with moderately uncontrolled HbA1c. We used claims and laboratory data OptumLabs® Data Warehouse (a de-identified dataset of enrollees in private and Medicare Advantage health plans across the U.S.) between 3/29/13 and 6/30/21 to compare the effectiveness of initiating glimepiride, sitagliptin, liraglutide, canagliflozin, and insulin glargine by adults with type 2 diabetes, treatment-naïve or on metformin monotherapy, with respect to time to HbA1c ≥7.0%. Propensity scores were estimated using the gradient boosting method and inverse propensity score weighting was used to emulate randomization to the treatment groups, which were then compared using Cox proportional hazards regression. Liraglutide initiators had the lowest 1-year cumulative incidence rate of achieving HbA1c ≥7.0% (0.31 [95% CI, 0.27-0.35]) followed by sitagliptin (0.42 [95% CI, 0.40-0.43]), canagliflozin (0.43 [95% CI, 0.40-0.46]), and glimepiride (0.43 [95% CI, 0.42-0.44]); Figure. The glargine arm was excluded due to insufficient control of confounding, reflecting limitations of emulating trials using real-world data if study conditions are not represented in practice.

Disclosure
Y.Deng: None. E.Polley: None. J.D.Wallach: Consultant; Hagens Berman Sobol Shapiro LLP and Dugan Law Firm APLC, Other Relationship; Johnson & Johnson, Research Support; NIH - National Institutes of Health, Arnold Ventures. J.Herrin: Consultant; Johnson & Johnson Medical Devices Companies. J.Ross: Research Support; Johnson & Johnson. R.G.Mccoy: Consultant; Emmi.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (K23DK114497)
791-P: Comparing the Real-World Effects of Once-Weekly GLP-1 RAs and DPP-4 Inhibitors on Ischemic Stroke and Myocardial Infarction in Individuals with T2D and ASCVD
Authors: TAN XI , LIANG YUANJIE , RAJPURA JIGAR R. , YEDIGAROVA LARISA , NOONE JOSHUA , XIE LIN , DE HAVENON ADAM 
Published: June 2023

Despite guidelines advocating for their use, there is limited real-world evidence comparing the effects of once-weekly (OW) glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 inhibitors (DPP-4is) on the risk of cardiovascular events in individuals with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD). This retrospective cohort study compared the time to incidence of ischemic stroke, myocardial infarction (MI), and 2-point major adverse cardiovascular events (MACE; ischemic stroke or MI) while on treatment in new adult users of OW GLP-1 RAs and DPP-4is who had T2D and ASCVD using data from the Optum Clinformatics® Data Mart (2017-2021). Patients were followed until drug discontinuation, enrollment end, or an event. Inverse probability of treatment weighting was used to balance baseline characteristics, and survival analyses were conducted to compare risks during exposure, defined as continuous use of either drug. We found that users of OW GLP-1 RAs (weighted N=25,287) had significantly lower risks of ischemic stroke (HR=0.74 [95% CI, 0.63, 0.87]), MI (0.78 [0.67, 0.92]), and 2-point MACE (0.76 [0.68, 0.86]) compared with users of DPP-4is (weighted N=39,684; all P&lt;0.01). This study suggests that OW GLP-1 RAs reduce the risk of MI and stroke relative to DPP-4is in individuals with T2D and ASCVD.

Disclosure
X. Tan: Employee; Merck & Co., Inc. Stock/Shareholder; Merck & Co., Inc. Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. Y. Liang: Employee; Novo Nordisk. J.R. Rajpura: Employee; Novo Nordisk. L. Yedigarova: Employee; Novo Nordisk. Stock/Shareholder; AbbVie Inc. J. Noone: Employee; Novo Nordisk. L. Xie: Employee; Pfizer Inc., Novo Nordisk A/S. A. de Havenon: Consultant; Novo Nordisk, Integra Lifesciences Holdings Corp. Other Relationship; UpToDate. Stock/Shareholder; TitinKM, Certus.
824-P: Glycemic Improvement, Insulin Reductions, and Improved Body Weight 48 Weeks after Revita Duodenal Mucosal Resurfacing in T2D patients with Previously Inadequately Controlled Glucose Despite Multiple Glucose-Lowering Agents Including Insulin
Authors: FONSECA VIVIAN , BERGMAN JACQUES , SAEED ZEB I. , RAJAGOPALAN HARITH , SORONDO BARBARA , WHITE KELLY , ZHANG HUI , MINGRONE GELTRUDE 
Published: June 2023

Background: Due to the progressive nature of T2D, patients often escalate in disease severity, burden, and complexity. Revita® Duodenal Mucosal Resurfacing (DMR) is a non-pharmacologic, investigational, endoscopic treatment intended to restore normal physiology of the duodenum, a key regulator of metabolic homeostasis. Previous studies to date with &gt;300 patients have shown favorable safety and metabolic efficacy. Here we present initial data from open label phase of a pivotal study designed to improve glycemic control while reducing and/or eliminating insulin treatment burden.
Methods: Inclusion: 21-70yrs, BMI 24-40kg/m2, HbA1c 7.5-9.5%, FPG off insulin ≥180-&lt;270mg/dL, fasting C-peptide ≥0.6 ng/ml, insulin (20-60 U/day) with background glucose lowering agents (GLAs). Prior to procedure, GLAs other than metformin and basal insulin were washed out for ≥8wks followed by 4wk run in. Post DMR, insulin was reinstated if needed by a pre-specified treat-to-target design with preexisting metformin and de novo empagliflozin.
Results: N=9. Median (min, max) baseline characteristics: age 60 (45, 68) yrs, 66.7% male, HbA1c 8.5 (7.6, 9.1)%, C-peptide 1.7 (0.7, 3.2) ng/mL, weight 96 (85, 128) kg, diabetes duration 13 (7, 24) yrs; long-acting insulin dose 33 (20, 60) U/day. No device or procedure related SAEs. Unrelated to DMR procedure, two patients discontinued early. N=7: 48-week median change from baseline (min, max); HbA1c -1.5% (-1.8,-0.4), FPG -82 mg/dL (-104,-48), total body weight -9.3% (-16.8,-2.9). All (7/7) patients reduced insulin dose with 2 patients discontinuing insulin entirely.
Conclusion: Results from open label phase thus far show promising safety and efficacy of Revita DMR and suggest broad metabolic benefit while reducing treatment burden. Further results forthcoming from currently enrolling REVITALIZE-1 study.

Disclosure
V.Fonseca: Consultant; Abbott, Corcept Therapeutics, Eli Lilly and Company, Other Relationship; BRAVO4HEALTH, LLC, Research Support; Fractyl Health, Inc., Stock/Shareholder; Amgen Inc. J.Bergman: Consultant; Endogenex, Fractyl Health, Inc., Digma Medical, Research Support; Endogenex, Fractyl Health, Inc., Digma Medical. Z.I.Saeed: None. H.Rajagopalan: Employee; Fractyl Health, Inc. B.Sorondo: Employee; Fractyl Health, Inc., LG Chem. K.White: Employee; Fractyl Health, Inc. H.Zhang: None. G.Mingrone: Advisory Panel; Fractyl Health, Inc., Board Member; Novo Nordisk, Consultant; Novo Nordisk, Fractyl Health, Inc., ReCor Medical, Inc.

Funding
Fractyl Health, Inc.
831-P: Allogeneic Neo-Islets (NIs), an Immune-Privileged Cellular Therapy for T1DM, Is Safe and Effective in Spontaneously Diabetic Pet Dogs, Reducing Insulin Need by up to 50% over Three Years
Authors: GOOCH ANNA , WESTENFELDER CHRISTOF 
Published: June 2023

The purpose of this INAD pilot study was to assess the safety, feasibility and efficacy of NIs in significantly reducing or eliminating a T1DM dog's need for insulin and/or preventing, halting or reversing DM-related damage to a dog's other organs. NIs (3-D organoids made of Mesenchymal Stromal Cells (MSCs) and cultured, partially dedifferentiated islet cells) have been shown preclinically (NOD mouse model) to eliminate the need for exogenous insulin when introduced i.p. Their MSC component provides immune isolation, allowing their allogeneic use without antirejection agents.
Hypothesis: Allogeneically administered NIs would safely, durably, and significantly reduce or eliminate the need for exogenous insulin in spontaneously T1DM dogs, as was found in experimental mice. 6 (4 M, 2 F) spontaneously DM, pet dogs; age 1-12 years were treated under INAD 012-776 and followed 3 years. 2×10e5 NIs/kg bw were introduced under ultrasound guidance to metabolically controlled (blood glucose, triglycerides, thyroid, adrenal functions), sedated animals. Dogs were maintained on insulin as needed, and were followed clinically (CBCs, Chemistry panels, Urinalyses, physical examination, imaging, endocrine function) by the PIs and the dogs’ regular veterinarians.
Results: Over 3 years, daily insulin needs, blood and urine glucose and fructosamine fell significantly in 5 of 6 dogs; renal function, body weights, CBCs, chemistries were unchanged. Urinary protein decreased; no hypoglycemic events, and immune response to NIs were observed; no AEs or SAEs were attributed to NIs. Redosing and dosing strategies are being tested to try to eliminate exogenous insulin need. Allogeneic NIs are safe and durably effective, and has significant translational relevance. Even partial effectiveness protects from end-organ damage and preserves renal function. A successful Pre-IND meeting for NI use in humans has been held.

Disclosure
A.Gooch: Board Member; SymbioCellTech, LLC, Employee; SymbioCellTech, LLC, Stock/Shareholder; SymbioCellTech, LLC. C.Westenfelder: Board Member; SymbioCellTech, LLC., Employee; SymbioCellTech, LLC., Research Support; SymbioCellTech, LLC., Stock/Shareholder; SymbioCellTech, LLC.