bluuebunny/crossref_metadata_2025 huggingface dataset:
734-P: Use of GLP-1 Agonists and Perioperative Complications in Patients Undergoing Elective Surgery
Authors: MENDEZ CARLOS E. , THORGERSON ABIGAIL , DAWSON APRILL Z. , NELSON VICTORIA , BEHRENS ALLISON , PFEIFER KURT
Published: June 2024

A preoperative diabetes optimization program (PreDOP) is available at our institution for elective surgical patients with A1c> 8%. We previously reported on the positive impact of PreDOP on participants on whom medications, including GLP-1 agonists, were used to optimize glycemic control preoperatively. However, in June 2023 the American Society of Anesthesiologists recommended avoidance of GLP-1 agonists preoperatively due to concerns of possible complications related to delayed gastric emptying. Based on this, we extracted EPIC medical record data for adult surgical patients who participated in PreDOP between January 2016 and June 2023 (n=161), and identified those with an active prescription of a GLP-1 agonist at the time of surgery. Before June 2023, patients managed with GLP-1 agonists were not instructed to hold therapy before surgery. Table 1 shows sample characteristics of the study cohort by use of GLP-1 agonists (yes/no). Patients who received GLP-1 agonists were significantly more obese and had a higher BMI compared to those who did not. However, there were no significant differences in level of glycemic control before and at the time of surgery. Moreover, rates of perioperative complications, including any type of pneumonia within 30 days of surgery were not significantly different. In this review, use of GLP-1 agonists was not associated with increased risk of perioperative complications.

Disclosure

C.E. Mendez: Consultant; Siemens Healthcare Diagnostics. A. Thorgerson: None. A.Z. Dawson: None. V. Nelson: None. A. Behrens: None. K. Pfeifer: None.
736-P: Comparison of Semaglutide vs. Tirzepatide Therapy in Adults with Type 1 Diabetes (T1D)
Authors: GEBRE HENON , SNELL-BERGEON JANET K. , SHAH VIRAL N.
Published: June 2024

Introduction & Objective: Glucagon-like peptide receptor agonist (GLP-1R) semaglutide and a dual incretin agonist, tirzepatide are approved for the treatment of type 2 diabetes and obesity. However, little is known about the efficacy of GLP-1RA in T1D. This real-world study compared the efficacy of semaglutide and tirzepatide in adults with T1D.

Methods: Clinic patients with T1D who were treated with a GLP-1RA were identified from the electronic health record at the time of drug initiation and were followed up to 9 months. An age, sex, race and BMI-matched control group was selected from patients who were not treated with a GLP-1RA, matched to semaglutide users. Linear mixed models were used to compare anthropometric and glycemic outcomes over time by group.

Results: At baseline, HbA1c and total insulin dose were higher in controls than in both GLP-1RA groups, and BMI was higher in tirzepatide users (Table 1a). There was significantly more weight loss in the semaglutide and tirzepatide groups than the control group, with an average weight loss of more than 10% in tirzepatide users and more than 6% weight loss in semaglutide users by 9 months (Table 1b). Semaglutide users had an average 0.40% improvement in HbA1c, and tirzepatide users had an average 0.67% improvement in HbA1c (Table 1b).

Conclusion: Semaglutide and tirzepatide reduced weight and improved HbA1c in adults with T1D, with greater weight loss efficacy for tirzepatide.

Disclosure

H. Gebre: None. J.K. Snell-Bergeon: None. V.N. Shah: Consultant; Dexcom, Inc., Insulet Corporation. Research Support; Insulet Corporation. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Advisory Panel; Sanofi, Medscape. Consultant; embecta, Tandem Diabetes Care, Inc.
75-PUB: The Sartorius Fat Fraction Is Independently Associated with Myocardial Fibrosis in Chinese Patients with Obesity
Authors: WANG ZIXUAN , YUE JIANG , ZHAO HANG , JIANG MENG , BU JUN , MA JING
Published: June 2024

Objective: The study aimed to investigate the correlation between intramuscular adipose tissue (IMAT) accumulation in lower extremities and the myocardial tissue-level characteristics detected by MRI in Chinese individuals with obesity.

Methods: A cross-sectional analysis was performed in 51 Chinese adults with obesity (BMI ≥ 28 kg/m2), comprising 34 males and 17 females. All the patients underwent clinical assessment, anthropometric measurement, oral glucose tolerance test (OGTT) and laboratory assays. MRI was applied to access the IMAT content in lower extremities and cardiac magnetic resonance was utilized for all participants. Myocardial tissue-level characteristic, such as extra-cellular volume fraction (ECV), was measured as indicator of myocardial fibrosis. The relationship between the IMAT content of the lower extremities and myocardial dysfunction was further assessed.

Results: Fifty-one subjects were included in this study, with 27 individuals classified as having normal glucose tolerance (NGT) and 24 individuals with impaired glucose regulation (IGR). We found that the levels of aspartate aminotransferase (AST) and triglycerides (TG) were higher in IGR group compared to those in NGT group (both P <0.05). Additionally, higher fat accumulation was noted in vastus lateralis, vastus intermedius, biceps femoris, semitendinosus, adductor magnus, gracilis, and sartorius in patients with IGR as opposed to those with NGT (all P < 0.05). The ECV in IGR group was higher than that in NGT group. Multivariate regression analysis identified increased IMAT in sartorius may be an independent risk factor for myocardial fibrosis after adjustment for age, gender, BMI, NEFA (odds ratio: 1.22, 95% CI: 1.02-1.46, P = 0.028).

Conclusion: In Chinese subjects with obesity, an increase in adipose tissue accumulation of sartorius was associated with myocardial fibrosis. It may independently serve as one of possible risk factors for myocardial fibrosis in the obesity.

Disclosure

Z. Wang: None. J. Yue: None. H. Zhao: None. M. Jiang: None. J. Bu: None. J. Ma: None.
750-P: Association of Glucagon-Like Peptide 1 Receptor Agonists with Incident Parkinson’s Disease in U.S. Older Adults with Type 2 Diabetes
Authors: TANG HUILIN , LU YING , OKUN MICHAEL S. , DONAHOO WILLIAM T. , RAMIREZ-ZAMORA ADOLFO , HUANG YU , ARMSTRONG MELISSA J. , SVENSSON MIKAEL , VIRNIG BETH , BIAN JIANG , GUO JINGCHUAN
Published: June 2024

Background: Previous studies suggested the possibility of disease-modifying effects for glucagon-like peptide-1 receptor agonists (GLP-1RAs), but the evidence on the association between GLP-1RAs and risk of Parkinson’s disease(PD) remains to be clarified.

Methods: This population-based new-user cohort study included individuals with T2D who were newly prescribed a GLP-1RA or a dipeptidyl peptidase 4 inhibitor (DPP4i) using Medicare administrative data from Jan 2016 to Dec 2020. The primary endpoint was a new diagnosis of PD. A stabilized inverse probability of treatment weighting (sIPTW) - adjusted Cox proportional hazards regression was employed to estimate the hazard ratio (HR) of PD and 95% confidence intervals (CI) between GLP-1RA users and DPP4i users. Stratified analyses were performed, such as by age, sex, race/ethnicity, glucose-lowering drug (GLD) use at baseline, obesity at baseline, and molecule of GLP-1RA.

Results: A total of 89,074 Medicare beneficiaries who initiated either GLP-1RA inhibitor (n=30,091) or DPP4i (n=58,983) were included in the analysis. The crude incidence rate of PD was lower among GLP-1RA users (2.85 cases per 1000 person-years) when compared to DPP4i users (3.92 cases per 1000 person-years). An sIPTW-adjusted Cox model showed that GLP-1RA users were associated with a 23% lower risk of PD than DPP4i users (HR, 0.77; 95%CI, 0.63-0.95). Our findings were largely consistent across different subgroup analyses except for GLD use at baseline. A significantly lower risk of PD was observed among those using insulin at baseline and those with no GLD use at baseline, while no significant difference was detected among the groups using 1 GLD at baseline and ≥ 2 GLDs at baseline.

Conclusion: New use of GLP-1RAs was significantly associated with a lower risk of PD compared to new use of DPP4i in a large cohort of older adults with T2D.

Disclosure

H. Tang: None. Y. Lu: None. M.S. Okun: None. W.T. Donahoo: None. A. Ramirez-Zamora: None. Y. Huang: None. M.J. Armstrong: None. M. Svensson: None. B. Virnig: None. J. Bian: None. J. Guo: None.

Funding

American Foundation for Pharmaceutical Education Predoctoral Fellowship, PhRMA Foundation Predoctoral Fellowship, National Institutes of Health (NIH)/National Institute on Aging (NIA) (R01AG076234), and NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01DK133465).
752-P: Evaluating the Efficacy of Oral Semaglutide in Chinese Patients with Type 2 Diabetes by Baseline Characteristics—Post Hoc Analysis of PIONEER 11 and 12
Authors: JI LINONG , YUAN GUOYUE , LIU JUN , ZHANG BINGJIE , LIU WENYAN , SHEN ZEWEI
Published: June 2024

Introduction & Objectives: Oral semaglutide, the only oral glucagon-like peptide-1 receptor agonist (GLP‑1RA) available for the treatment of T2D, is efficacious and has a safety profile consistent with the GLP-1RA class. This post hoc analysis of Chinese patients with T2D included in the PIONEER 11 and 12 trials investigates the efficacy of oral semaglutide vs comparators by different baseline (BL) characteristics.

Methods: Chinese patients with T2D (HbA1c 7.0-10.0% in PIONEER 11; 7.0-10.5% in PIONEER 12), aged ≥18 years, were randomized to once-daily oral semaglutide 3, 7 or 14 mg or comparator (placebo [PIONEER 11] or sitagliptin 100 mg [PIONEER 12]). Estimated change from BL in HbA1c and body weight were analyzed at week 26 by subgroups of BL characteristics, including age, GI disease and HbA1c.

Results: In total, 390 (PIONEER 11) and 1,084 (PIONEER 12) Chinese patients were evaluated. At baseline, mean HbA1c and body weight values were similar across most BL subgroups (data not shown). Overall, greater reductions in HbA1c and body weight were seen with oral semaglutide vs placebo or sitagliptin across the BL subgroups (Table 1).

Conclusion: Significant reductions in HbA1c and body weight were observed with oral semaglutide across BL subgroups, including age, GI disease and HbA1c,vs comparator.

Disclosure

L. Ji: None. G. Yuan: None. J. Liu: None. B. Zhang: None. W. Liu: Employee; Novo Nordisk A/S. Z. Shen: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S.
757-P: Near-Normoglycemia and Insulin Regression Induced by Tirzepatide in Basal Insulin–Treated Type 2 Diabetes
Authors: ROSENSTOCK JULIO , TOFE SANTIAGO , WYSHAM CAROL H. , THIEU VIVIAN , KILJANSKI JACEK I. , LEE CLARE , WANG HUI , PATEL HIREN
Published: June 2024

Introduction & Objective: In the SURPASS-6 trial, addition of tirzepatide (TZP) to basal insulin glargine U100 in participants with inadequately controlled long-standing type 2 diabetes (T2D), substantially improved HbA1c and body weight. We evaluated degrees of insulin dose reductions and the efficacy and safety of TZP based on residual insulin use at Week 52.

Methods: “Insulin regressor” was defined as basal insulin discontinuation or <10 IU/day, and “insulin non-regressor” as ≥10 IU/day, at 52 weeks. Included only participants receiving TZP at Week 52 (≥75% compliance) without rescue medication. Efficacy analyses used a mixed model for repeated measures.

Results: Overall, 145 and 496 TZP-treated participants were included in the insulin regressor vs. insulin non-regressor groups, respectively. At baseline, mean age was 58.4 vs. 58.2 years, and median basal insulin dose was 40.0 vs. 48.0 IU/day. From baseline to Week 52 in the insulin regressor and insulin non-regressor groups, respectively, mean HbA1c of 8.5% and 8.9% was reduced to 5.9% and 6.7%, while weight was substantially reduced by 16 kg and 8 kg. Clinically significant hypoglycemia was also less frequent in the insulin regressor group (Table).

Conclusion: In basal insulin-treated T2D, participants who regressed on insulin use also achieved near-normoglycemia and substantial weight loss.

Disclosure

J. Rosenstock: Research Support; Biomea Fusion, Inc. Other Relationship; Lilly Diabetes. Research Support; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Corcept Therapeutics. Other Relationship; Novo Nordisk. Research Support; Pfizer Inc. Other Relationship; Sanofi, Boehringer-Ingelheim. Research Support; Shionogi & Co., Ltd. Other Relationship; Structure Therapeutics, Inc. Advisory Panel; Terns Pharmaceuticals, Zealand Pharma A/S. Other Relationship; Applied Therapeutics, Hanmi Pharm. Co., Ltd., Oramed Pharmaceuticals. Advisory Panel; Scholar Rock. S. Tofe: None. C.H. Wysham: Research Support; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Research Support; Novo Nordisk. Consultant; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Advisory Panel; Abbott. Research Support; Bayer Inc. Advisory Panel; Biomea Fusion, Inc. Research Support; Corcept Therapeutics, AbbVie Inc. V. Thieu: Employee; Eli Lilly and Company. J.I. Kiljanski: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. C. Lee: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. H. Wang: None. H. Patel: None.
760-P: TERN-501 Enhances Weight Loss Efficacy of a GLP-1R Agonist in Obese Mice via Increased Fat Mass Loss without Additional Loss of Lean Mass
Authors: JONES CHRISTOPHER , OSBORN OLIVIA , QUINN KEVIN P. , FEIGH MICHAEL , NYGAARD MADSEN ANDREAS , JASPER JEFFREY R.
Published: June 2024

Introduction & Objective: GLP-1R agonists suppress food intake resulting in weight loss but efficacy is limited by metabolic adaptation, a compensatory process that lowers energy expenditure (EE). Thyroid hormone receptor beta (THRβ) regulates EE providing a potential mechanism to mitigate metabolic adaptation. TERN-501, a highly selective THRβ agonist, has shown excellent safety and significant liver fat reduction in a Ph2a study in patients with metabolic dysfunction-associated steatohepatitis. The combined effects of TERN-501 and GLP-1R agonism may offer benefits over either agent alone in reducing body weight.

Methods: Male C57BL/6JRj mice were fed high fat diet (60% HFD) for 24 weeks prior to study start. Mice (~55 g BW) were treated once daily with vehicle, TERN-501 (6 mg/kg PO), semaglutide (sema, 30 nmol/kg SQ), or 501+sema for up to 6-weeks at thermal neutrality. Body weight and food intake were measured daily. Body composition was assessed by EchoMRI and EE was measured in metabolic chambers.

Results: TERN-501 significantly enhanced the weight loss efficacy of sema (-26% vs -33%, p <0.05) with increased fat mass loss (-11.8 g vs -15.2 g, p <0.05) without additional loss of lean mass. In contrast, the effect of TERN-501 alone on body weight was similar to vehicle (-1.6% vs 1.5%, p >0.05). In mice with higher initial body weight, 501+sema resulted in an additional 17% body weight loss vs sema alone. In combination with sema, TERN-501 prevented lowering of EE typically induced by weight loss and was associated with increased levels of UCP-1 expression in subcutaneous adipose tissue.

Conclusion: In obese mice, TERN-501 significantly improved the efficacy of a GLP-1R agonist by normalizing EE, resulting in greater weight loss, increased fat mass loss, and relative preservation of lean mass. These results suggest that TERN-501, a potent and highly selective THRβ agonist, may be an ideal combination partner for GLP-1 therapies.

Disclosure

C. Jones: Employee; Terns Pharmaceuticals. O. Osborn: None. K.P. Quinn: None. M. Feigh: Employee; Gubra. A. Madsen: None. J.R. Jasper: Employee; Terns Pharmaceuticals. Advisory Panel; Rubedo Life Sciences.
764-P: Discovery of ASC30, a Highly Potent and Orally Available Novel Nonpetide GLP-1 Receptor Biased Agonist
Authors: JASON WU JINZI
Published: June 2024

Introduction & Objective: Injectable peptidic GLP-1 receptor (GLP-1R) agonists are established treatments for Type 2 Diabetes Mellitus (T2DM) and obesity. An nonpeptide oral GLP-1R agonist without injection and cold chain storage offers many benefits for patients. Here we report the discovery of ASC30, a highly potent and orally available novel nonpeptide GLP-1R biased agonist as a potential once-daily oral therapy.

Methods: ASC30 was tested for its activity against GLP-1 receptor by cAMP assay in Flp-In-293-GLP1R cells and for β-arrestin recruitment in cell-based assay. Further, ASC30 was tested in an intravenous glucose tolerance test (IVGTT) in nonhuman primates (NHPs). Orforglipron was used as a reference compound.

Results: ASC30 strongly activated GLP-1R Gαs cAMP pathway with a mean EC50 of 0.011 nM (n=8), compared to a mean EC50 of 0.024 nM (n=8) for orforglipron. Both ASC30 and orforglipron did not induce measurable β-arrestin recruitment signaling (EC50 > 30,000 nM), which indicated both were GLP-1R biased agonists. In IVGTT NHP model, efficacy of ASC30 on insulin secretion, C-peptide secretion and glucose control was compared to orforglipron. With a single i.v. bonus injection of 1.5 mg/kg ASC30 and 6 mg/kg orforglipron, ASC30 stimulated statistically and significantly more insulin secretion than vehicle control (p<0.01) and orforglipron (p<0.05). Further, ASC30 stimulated statistically and significantly more C-peptide secretion than vehicle control (p<0.001) and orforglipron (p<0.01). After a single oral dosing in rats, ASC30’s exposure over 48 hours (AUC0-48h) is 14-fold of that of orforglipron. Overall, ASC30 demonstrated more potent in vitro cAMP activation and more in vivo efficacy in stimulating insulin and C-peptide secretion than orforglipron.

Conclusion: ASC30 is a highly potent and orally available GLP-1R biased agonist. Human clinical trials are warranted to further evaluate ASC30 as a potential oral therapy for T2DM and obesity.

Disclosure

J. Wu: None.
772-P: GLP1RA Use and Risk of Pancreatitis and Biliary Disease in Adults with Type 2 Diabetes and Low to Moderate CV Risk
Authors: PAIK JULIE M. , TESFAYE HELEN , JANE CROMER SARA , DICESARE ELYSE O. , ALIX CAROLINE , WEXLER DEBORAH J. , PATORNO ELISABETTA
Published: June 2024

Introduction & Objective: Glucagon-like peptide-1 receptor agonists (GLP1RA) may increase pancreatitis and biliary disease risk. We investigated the association between GLP1RA initiation and the risk of pancreatitis or biliary disease among patients with type 2 diabetes (T2D) at low-to-moderate cardiovascular (CV) risk, a population that remains largely unexplored in clinical trials.

Methods: We estimated hazard ratios (HRs), rate differences (RD) and 95% confidence intervals (CI) of acute pancreatitis or biliary disease among 1:1 propensity score-matched adults initiating GLP1RA vs. dipeptidyl peptidase-4 inhibitor (DPP4i) or sodium glucose cotransporter 2 inhibitor (SGLT2i) in Medicare and 2 private health plans (2013-2023).

Results: Over a mean follow-up of ~11 months, the HR for pancreatitis in the GLP1RA group was 1.19 (95%CI 1.00-1.42; RD 0.20 per 1,000 person-years (PY) [0.01-0.39]) compared with the DPP4i group and 0.99 (0.82-1.20; RD -0.01 per 1,000 PY [-0.17-0.16]) compared with the SGLT2i group (Table). The HR for biliary disease in the GLP1RA group was 1.10 (0.96-1.26; RD 0.13 per 1,000 PY [-0.10-0.37]) compared with the DPP4i group and 1.12 (0.97-1.30; RD 0.22 per 1,000 PY [0.01-0.43]) in the SGLT2i group.

Conclusion: GLP1RA initiation was not associated with meaningful differences in the risk of acute pancreatitis or biliary disease in patients with T2D and low-to-moderate CV risk.

Disclosure

J.M. Paik: None. H. Tesfaye: None. S. Cromer: Other Relationship; Johnson & Johnson Medical Devices Companies. Advisory Panel; Alexion Pharmaceuticals, Inc. Other Relationship; Wolters Kluwer Health. E.O. DiCesare: None. C. Alix: None. D.J. Wexler: Other Relationship; Novo Nordisk. E. Patorno: Research Support; Boehringer-Ingelheim, Food and Drug Administration (FDA), National Institutes of Health, Patient-Centered Outcomes Research Institute.

Funding

Patient Centered Outcomes Research Institute (DB-2020C2-20326)
773-P: Trends in Obesity Drug Initiation after the Approval of Tirzepatide in Adults without Type 2 Diabetes
Authors: PAIK JULIE M. , ORTEGA-MONTIEL JANINNE , TESFAYE HELEN , ALIX CAROLINE , DICESARE ELYSE O. , JANE CROMER SARA , WEXLER DEBORAH J. , PATORNO ELISABETTA
Published: June 2024

Introduction & Objective: Tirzepatide was approved for the treatment of type 2 diabetes (T2D) (May 2022) and more recently for obesity (November 2023). However, tirzepatide has been used off-label for the treatment of obesity in adults without T2D prior to November 2023. The utilization trends and uptake among adults without T2D is unknown.

Methods: Using a US commercial claims database, we identified adults without T2D who initiated anti-obesity drugs between 1/2021 and 6/2023 and 1) plotted monthly drug initiation trends before and after tirzepatide approval for T2D (May 2022), and 2) compared the uptake of tirzepatide to the historical uptake of other GLP-1RA during their first 13 months after FDA approval.

Results: From 1/2021 to 6/2023, semaglutide initiation decreased (from 26.9% to 23.5%), whereas tirzepatide use increased dramatically (from 0.3% to 45.4%) (Figure A). Compared with the uptake of other GLP-1RA drugs among patients without T2D during their first 13 months after FDA approval, the uptake of tirzepatide was steep and sustained (Figure B). All other medications were initiated less frequently, with liraglutide and phentermine experiencing notable declines after the approval of tirzepatide.

Conclusion: Off-label use of tirzepatide increased sharply among adults without T2D during its first 13 months on the market, even though it was not approved for the treatment of obesity until November 2023.

Disclosure

J.M. Paik: None. J. Ortega-Montiel: None. H. Tesfaye: None. C. Alix: None. E.O. DiCesare: None. S. Cromer: Other Relationship; Johnson & Johnson Medical Devices Companies. Advisory Panel; Alexion Pharmaceuticals, Inc. Other Relationship; Wolters Kluwer Health. D.J. Wexler: Other Relationship; Novo Nordisk. E. Patorno: Research Support; Boehringer-Ingelheim, Food and Drug Administration (FDA), National Institutes of Health, Patient-Centered Outcomes Research Institute.
774-P: Impact of Newer GLP-1 RAs on HbA1c in U.S. Adults with Type 2 Diabetes—A Population-Level Time-Series Analysis
Authors: LV LEI , WANG YAN , XIE LIN , NOONE JOSHUA , ALVAREZ SARA B. , ZHANG YUEHAN , SONG YAN , ROTROFF DANIEL M.
Published: June 2024

Introduction & Objective: It is unclear whether glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatments improve population-level diabetes-related outcomes. This study examined the impact of GLP-1 RA uptake on population-level HbA1c in US adults with type 2 diabetes.

Methods: This retrospective study used data from the Optum Clinformatics® Data Mart (01/2004-12/2022). Time series regressions were used to examine associations between HbA1c-related outcomes and the proportion of patients on newer GLP-1 RAs of interest (dulaglutide, once-weekly or oral semaglutide, and tirzepatide). Interrupted time series analyses were used to assess temporal trends in population-level HbA1c outcomes. Both analyses were adjusted for potential confounders.

Results: With more patients taking newer GLP-1 RAs, average population-level HbA1c decreased significantly (at 7-9 months of lag), and the proportion of patients with HbA1c <7% increased significantly (at 5-9 months of lag; Fig 1A). Interrupted time series analyses (Fig 1B-C) showed that average HbA1c decreased and the proportion of patients with HbA1c <7% increased after the introduction of newer GLP-1 RAs in 2014.

Conclusion: Increased adoption of newer GLP-1 RAs is associated with lower average HbA1c and higher proportion of HbA1c <7% at the population level. Population-level HbA1c control was improved after the first newer GLP-1 RA approval.

Disclosure

L. Lv: Employee; Novo Nordisk. Y. Wang: Other Relationship; Novo Nordisk. L. Xie: None. J. Noone: Employee; Novo Nordisk. S.B. Alvarez: Employee; Novo Nordisk. Y. Zhang: Other Relationship; Novo Nordisk. Y. Song: Other Relationship; Novo Nordisk. D.M. Rotroff: Consultant; Novo Nordisk. Research Support; Bayer Inc.
779-P: Clinical Characteristics and Treatment Patterns among Glucagon-Like Peptide Receptor Agonist (GLP-1RA) Users in a U.S. EHR and Claims Linked Database
Authors: GIRGUIS MARIAM S. , LILLIE MARK , BODNER ERIC , KASRAI CORDIE K. , SPENCER JESSICA R. , PAULA CANCINO NUNEZ ANA , O'KELLY JAMES
Published: June 2024

Introduction & Objective: Certain glucagon-like peptide receptor agonists (GLP-1RA) are indicated in different formulations for the treatment of obesity and diabetes. The study objective was to describe real-world demographics, clinical characteristics, and treatment patterns among GLP-1RA users by indication (type 2 diabetes mellitus [T2DM] and chronic weight management [CWM]).

Methods: This was a descriptive retrospective cohort study using Optum’s Market Clarity database, which has linked EHR and claims data. Patients with ≥1 prescription for GLP-1RAs of interest (semaglutide and liraglutide) between 2010 and 2020 were included in the cohort if they had at least 90 days of enrollment/clinical activity prior to index and 365 days of follow-up. Analyses were stratified by GLP-1RA indication.

Results: There were 517,876 GLP-1RA users identified, 473,355 for T2DM and 44,521 for CWM. BMI was similar, while CWM patients were younger, more likely to be female, and have lower prevalence of certain comorbidities compared to T2DM patients (Table). GLP-1RA duration differed by indication for use ≥6 months (T2DM: 46%, CWM: 28%) and > one year (T2DM: 29%, CWM: 13%).

Conclusion: Real-world patients using GLP-1RAs for T2DM and CWM have comparable BMI despite differences in age, sex, and clinical characteristics. Duration of GLP-1RA use is short in clinical practice.

Disclosure

M.S. Girguis: Employee; Amgen Inc. M. Lillie: Employee; Amgen Inc. E. Bodner: None. C.K. Kasrai: None. J.R. Spencer: None. A. Cancino Nunez: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. Employee; Amgen Inc. Stock/Shareholder; Amgen Inc. J. O'Kelly: Employee; Amgen Inc. Stock/Shareholder; Amgen Inc.
790-P: The Effect of Tirzepatide vs. Placebo on Changes and Shifts in BMI Category in Adults with Type 2 Diabetes—A Post Hoc Analysis of the SURMOUNT-2 Study
Authors: GALINDO RODOLFO J. , LAZARUS ETHAN , WANG HUI , GARCIA-PEREZ LUIS-EMILIO , ZHANG MICHELLE X. , GRANT GARY , MALIK RALEIGH
Published: June 2024

Tirzepatide (TZP) is a GIP and GLP-1 receptor agonist indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults. The SURMOUNT-2 (SM-2) trial demonstrated significant reductions in body weight in participants treated with TZP with a BMI ≥27 kg/m2 and T2D. This subgroup analysis explored changes in BMI during the SM-2 trial. Prespecified subgroup analyses were conducted on the mITT population in the SM-2 trial to assess the effects of weekly treatment (TZP 10 or 15 mg vs placebo (PBO)) on change from baseline in BMI category at week 72. Table shows shifts in BMI category from baseline to week 72. At Week 72, TZP 10 and 15 mg each resulted in statistically significant reductions in BMI from baseline versus PBO (-4.87 and -5.66 versus -1.18 kg/m2 respectively, p<0.001). For TZP 10 mg and 15 mg arms, 64.7% and 69.5% of participants shift down at least one BMI category, versus 20.9% for PBO. A normal BMI (<25kg/m2) at endpoint was achieved by 18.0% of participants in the 15 mg, and 12.2% in the 10 mg TZP arm compared with 1.9% for PBO. The most common adverse reactions were GI across subgroups, consistent with the results of SM-2.

In conclusion, participants on TZP had significant mean reductions in BMI from baseline and a greater proportion of participants treated with TZP shifted to a lower BMI category compared with PBO.

Disclosure

R.J. Galindo: Consultant; Abbott. Other Relationship; Dexcom, Inc. Consultant; Bayer Inc. Other Relationship; Novo Nordisk, Eli Lilly and Company. Consultant; Boehringer-Ingelheim, AstraZeneca. E. Lazarus: Speaker's Bureau; Novo Nordisk, Eli Lilly and Company. H. Wang: None. L. Garcia-Perez: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. M.X. Zhang: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. G. Grant: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. R. Malik: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.

Funding

Eli Lilly and Company
792-P: A Novel Gene Therapy Platform Using GLP1 and EX4 Attenuates Hyperglycemia in a Preclinical Model of Type 2 Diabetes
Authors: LOURIE JARED , GORALTCHOUK ALEX , FUJISHIRO ATSUTARO , BERGER NICOLAS , ROSEN HANNAH G. , HOLLANDER JUDITH , LUPPINO FRANCESCO , SEREGIN ALEXEY , ZOU KAI
Published: June 2024

Introduction and Objective: We recently reported the development of the first dose adjustable lipid nanoparticle (LNP) gene delivery platform with high durability and functional up/down-titration. Incretin therapies are effective in treating type 2 diabetes (T2D) but require frequent dosing and are plagued by high discontinuation rates. To overcome these challenges, we aimed to develop an adjustable-dose incretin gene therapy using LNP and evaluate its efficacy in a mouse model of T2D.

Methods: C57BL6 mice were fed either low-fat or high-fat diet, followed by low-dose streptozotocin (40mg/kg BW) to induce T2D. T2D mice were treated subcutaneously with LNP-GLP1, LNP-EX4 or vehicle. Animals were followed for 14 weeks. Body weight, GTT and ITT tests were measured.

Results: LNP-GLP1 and EX4 treatment produced 20% and 14% weight loss at 4 weeks relative to vehicle, 37% and 38% reduction in fasting glucose, 29% and 26% reduction in area under the curve of GTT, and 25% and 22% reduction in ITT, respectively (p≤0.05). The transgene was localized to the injection site with no detection in the liver, heart, spleen, or kidney. There were no significant changes in systemic markers of inflammation (IL6 and TNFα) or liver damage (ALP).

Conclusion: Our study demonstrates the ability of a novel incretin gene therapy delivered by LNP to induce weight loss, improve insulin resistance, and glycemic control in T2D.

Disclosure

J. Lourie: None. A. Goraltchouk: Board Member; Remedium Bio, Inc. Employee; Remedium Bio, Inc. A. Fujishiro: None. N. Berger: None. H.G. Rosen: None. J. Hollander: Employee; Remedium Bio, Inc. Stock/Shareholder; Remedium Bio, Inc. F. Luppino: None. A. Seregin: Employee; Remedium Bio. K. Zou: Research Support; Remedium Bio.

Funding

National Science Foundation (#2240683)
795-P: Balancing the Scales—The Effect of Tirzepatide on Lean Body Mass and Fat Mass
Authors: BODENSTAB MONICA , ISKANDER MINA , MINTZ JOEL , LIEBERMAN-ULM MONICA P. , SOLIMAN DIANA , GALINDO RODOLFO J.
Published: June 2024

Introduction & Objective: Tirzepatide is a novel GIP/GLP-1 receptor agonist recently approved for diabetes and chronic weight management. Its effects on bodyweight loss are well-established. However, its effect on lean body mass (LBM) and fat mass (FM) loss is less established. This review aims to assess the effects on LBM and FM in patients treated with tirzepatide, with or without type 2 diabetes (T2DM). Methods Following PRISMA guidelines, this systematic review included data from randomized controlled and observational studies evaluating tirzepatide’s effect on body composition. The ratio of FM/LBM loss was then assessed.

Results: Of 5847 prospective abstracts, three studies were included in the final analysis (Table 1). The FM/LBM loss ratio in patients with T2DM treated with tirzepatide doses of 5-15 mg ranged from 2.9-6.1 across two studies. Ratios could not be calculated from the SURMOUNT-1 trial but a change from baseline of -33.9% in FM and -10.9% in LBM in patients without diabetes was reported. Significant heterogeneity existed among the included studies due to varying therapy duration, dosing schedules, inclusion criteria, and body composition assessment modalities.

Conclusion: Data is limited on tirzepatide’s effect on LBM loss, but our study suggests a decrease in LBM with its use. Further research should address LBM loss with these therapies. Clinicians should counsel patients on methods to preserve LBM.

Disclosure

M. Bodenstab: None. M. Iskander: None. J. Mintz: None. M.P. Lieberman-Ulm: None. D. Soliman: None. R.J. Galindo: Consultant; Abbott. Other Relationship; Dexcom, Inc. Consultant; Bayer Inc. Other Relationship; Novo Nordisk, Eli Lilly and Company. Consultant; Boehringer-Ingelheim, AstraZeneca.
798-P: Potential Cardioprotective Effects of HM15275, a Novel, Long-Acting GLP-1/GIP/GCG Triple Agonist, in Animal Models of Hypertension
Authors: MYEONG LEE SEON , KUK KIM JUNG , PARK EUNJIN , REYEON KANG HYE , KIM JEONG A. , KIM YOHAN , HONG SUNGHEE , BAE SUNGMIN , HYUN LEE SANG , YOUNG CHOI IN
Published: June 2024

Introduction & Objective: Obesity is a major risk for development of cardiovascular disease (CVD). Both cardiac output and total blood volume are elevated in obesity, which eventually leads to cardiac hypertrophy and fibrosis. To date, therapeutic benefits of several incretin drugs were observed in cardiovascular outcomes trials. Based on these findings, the present study evaluates the cardioprotective effects of HM15275, a novel long-acting GLP-1/GIP/GCG triple agonist, in animal models of hypertension.

Methods: Spontaneously hypertensive rat (SHR) was administered with HM15275 for 16 weeks. In angiotensin II (Ang II)-infused mice and AMLN mice, HM15275 was administered for 2 ~ 6 weeks, followed by the determination of cardiomyocytes size, and cardiac fibrosis (MT staining, collagen levels). To highlight CV benefits of HM15275, tirzepatide (TZP) was included as comparative control.

Results: In SHR, cardiomyocytes cell size determined by WGA staining was significantly reduced by HM15275 treatment compared to TZP (-52.3% vs. TZP; p<0.001). In line with these results, both interstitial and perivascular fibrosis (% of extracellular collagen area using MT staining) were significantly improved by HM15275 treatment (-52.8% vs. TZP; p<0.001). In Ang II mice, the levels of pro-collagen-1α1 were significantly decreased by HM15275 in the heart (-40.5% vs. TZP; p<0.001). Moreover, cardiomyocyte enlargement caused by Ang II was significantly reduced by HM15275 treatment for 2 weeks. Similar benefits were also confirmed in AMLN mice.

Conclusion: Collectively, the results showed that HM15275 could have more potent cardioprotective effects than TZP in hypertension mediated cardiac damage. Further mechanistic studies are needed to elucidate the MoA for the beneficial effects of HM15275.

Disclosure

S. Lee: None. J. Kim: None. E. Park: None. H. Kang: None. J.A. Kim: None. Y. Kim: None. S. Hong: None. S. Bae: None. S. Lee: None. I. Choi: None.
815-P: Performance of Previously Identified Predictors of >=15% Body Weight Reduction with Tirzepatide in Participants with Type 2 Diabetes in SURMOUNT-2
Authors: LINGVAY ILDIKO , MALECKI MACIEJ , BENABBAD IMANE , FALCON BEVERLY , LEE CLARE , WANG HUI , DUNN JULIA P.
Published: June 2024

Introduction and Objective: In SURPASS-1-4 (SP), baseline factors associated with higher likelihood of achieving body weight (BW) reduction ≥15% at WK 40/42 with tirzepatide (TZP) in participants with T2D were: higher TZP dose, female sex, White or Asian race, metformin use, better glycemic status and lower non-HDL-C. We assessed performance of these predictors in BW reduction ≥15% at WK 48 in SURMOUNT-2 (SM-2), a study of TZP in chronic weight management in adults with T2D with obesity or overweight.

Methods: The multivariate model from SP was run in SM-2 participants who were on TZP at WK 48, ≥75% compliance and no rescue medication during the study treatment period. The AUC (area under curve) of the SM-2 model was calculated to determine its accuracy.

Results: BW reduction ≥15% was achieved in 41.8% (n = 230) participants on TZP at WK 48 and 91.3% (n = 210) sustained BW reduction ≥15% at WK 72. Factors identified in SP that were replicated with respect to the estimated effect size in SM-2: higher TZP dose, female, and lower HbA1c, FSG and non-HDL-C (Table 1). In SM-2, unlike in SP, Asian race and metformin use were not positively associated with BW reduction ≥15%. The AUC was 65.6%.

Conclusion: In the current study there are some consistencies in SM- 2 when applying the SP model. However, the overall performance of the predictors of the model demonstrates a need for refinement.

Disclosure

I. Lingvay: Consultant; Altimmune, Astra Zeneca, Bayer, Biomea, Boehringer-Ingelheim, Carmot, Cytoki Pharma, Eli Lilly, Intercept, Janssen/J&J, Mannkind, Mediflix, Merck, Metsera, Novo Nordisk, Pharmaventures, Pfizer, Sanofi. Research Support; NovoNordisk, Sanofi, Mylan, Boehringer-Ingelheim. Consultant; TERNS Pharma, The Comm Group, Valeritas, WebMD, and Zealand Pharma. M. Malecki: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Sanofi, Abbott, Dexcom, Inc., Boehringer-Ingelheim. Speaker's Bureau; AstraZeneca, Merck & Co., Inc. Advisory Panel; Krka. Speaker's Bureau; Servier Laboratories. I. Benabbad: Employee; Eli Lilly and Company. B. Falcon: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company, Sangamo Therapeutics. C. Lee: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. H. Wang: None. J.P. Dunn: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.

Funding

Eli Lilly and Company
821-P: Comparison of In-Hospital Glucose Management of People with Type 2 Diabetes Made by Artificial Intelligence Chatbot vs. Physicians—A Cross-Sectional Study
Authors: ROJAS-LÓPEZ TATIANA , ALVAREZ-MARTIN DANIEL , PUJOL-DECASTRO ANTONIO , MORENO-DOMINGUEZ OSCAR , BARQUIEL BEATRIZ , GARCIA-PEREZ-DE-SEVILLA ELENA , PARRA-RAMÍREZ PAOLA , GONZALEZ-PEREZ-DE-VILLAR NOEMI
Published: June 2024

Introduction and Objective: in-hospital glucose management of people living with type 2 diabetes (PLWT2D) has a direct impact on morbidity and mortality. Artificial intelligence (AI) tools could improve patient care. This study aimed to assess the correlation between in-patient glucose management suggested by an AI chatbot and hospital protocols and compare it with real life medical management.

Methods: we conducted a cross-sectional study of PLWT2D hospitalized in a tertiary care center in 2023 who required an Endocrinology consultation during their hospital stay. We excluded patients with corticosteroid treatment or need for intravenous insulin.  We provided Chat-GPT4 with the protocol for T2D management used in the hospital and asked for a suggested prescription based on individual de-identified variables. We assessed the accuracy of the output using Spearman (r) and interclass correlation (ICC) coefficients. We then analyzed the correlation between the treatment prescribed by physicians on the first day of hospital stay and the protocol.

Results: 85 patients met the inclusion criteria. There was a strong correlation between the dose of basal insulin suggested by Chat-GPT and the protocol (r=0.995), CCI=0.996 [IC 95% 0.994;0.998] as opposed to a weak correlation between the basal insulin dose prescribed by physicians and the protocol (r=0.223), ICC=0.134 [IC95% -0.072;0.331]. The same strong correlation was found between the dose of prandial insulin suggested by Chat-GPT and the protocol (r=0.978), CCI=0.984 [IC 95% 0.975;0.990], and a moderate correlation between physicians and the protocol (r=0.399), CCI=0.466 [IC95% 0.283;0.616]. The chatbot suggested the discontinuation of non-insulin therapies in all patients, as stipulated in the protocol.

Conclusions: the use of an AI chatbot resulted in a higher correlation with established protocols compared with medical prescription.

Disclosure

T. Rojas-López: None. D. Alvarez-Martin: None. A. Pujol-deCastro: None. O. Moreno-Dominguez: Speaker's Bureau; Novo Nordisk, Lilly Diabetes. Research Support; Sanofi. B. Barquiel: None. E. Garcia-Perez-de-Sevilla: None. P. Parra-Ramírez: None. N. Gonzalez-Perez-de-Villar: Speaker's Bureau; Abbott Diagnostics. Advisory Panel; Medtronic. Speaker's Bureau; Air Liquide.
836-P: Adherence to App-Based Dose Guidance for Once-Weekly Insulin Icodec in Insulin-Naive Type 2 Diabetes—Post Hoc Analysis of ONWARDS 5
Authors: BAJAJ HARPREET S. , DONATSKY ANDERS M. , ENGBERG SUSANNE , MARTINY JOHANNES H.J. , VIANNA ANDRE G. , LINGVAY ILDIKO
Published: June 2024

Introduction & Objective: In ONWARDS 5, a 52-week, phase 3a trial, participants in the insulin icodec (icodec) group used a dosing guide app to assist titration. This post hoc analysis assessed adherence to app-based dose guidance and its association with prebreakfast self-measured blood glucose (SMBG).

Methods: The app provided weekly algorithm-driven icodec dose guidance based on prebreakfast SMBG. Regardless, investigators could suggest manual dose changes. Estimated mean prebreakfast SMBG over time was compared across app-based guidance adherence subgroups (Figure).

Results: On average 5.0% of administered icodec doses differed from app guidance (dose change by participant). Of 541 participants assessed, 56.7% had ≥1 manual dose change during the trial; most changes (82%) were increases to the dose recommended by the app. Estimated mean prebreakfast SMBG improved from baseline irrespective of adherence to app guidance. Medium/high adherence subgroups had statistically significantly lower mean prebreakfast SMBG (p<0.0001) with earlier achievement of target level (80-130 mg/dL) than the low adherence subgroup (Figure).

Conclusion: Most administered icodec doses were adherent with app guidance; medium/high vs low adherence to app guidance was associated with improved estimated SMBG. The findings support the use of dose guidance apps to assist real-world insulin titration.

Disclosure

H.S. Bajaj: Research Support; Abbott, Amgen Inc., Anji Pharmaceuticals, Boehringer-Ingelheim, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc. A.M. Donatsky: Employee; Novo Nordisk A/S. S. Engberg: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. J.H.J. Martiny: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. A.G. Vianna: Board Member; Abbott, Lilly Diabetes, Novo Nordisk, Medtronic. Speaker's Bureau; AstraZeneca, Novo Nordisk. Research Support; Novo Nordisk, Lilly Diabetes. Speaker's Bureau; Lilly Diabetes. Research Support; Servier Laboratories. I. Lingvay: Consultant; Altimmune, Astra Zeneca, Bayer, Biomea, Boehringer-Ingelheim, Carmot, Cytoki Pharma, Eli Lilly, Intercept, Janssen/J&J, Mannkind, Mediflix, Merck, Metsera, Novo Nordisk, Pharmaventures, Pfizer, Sanofi. Research Support; NovoNordisk, Sanofi, Mylan, Boehringer-Ingelheim. Consultant; TERNS Pharma, The Comm Group, Valeritas, WebMD, and Zealand Pharma.

Funding

Novo Nordisk A/S
844-P: Insulin-Like Growth Factor Binding Protein 3 Levels Modulate the Glucose-Lowering Effect of Intensive Lifestyle Intervention for Weight Loss in Type 2 Diabetes
Authors: MAURYA PRIYANSHI , YANG JUN , EVERETT ALLEN D. , BENNETT WENDY L. , VAIDYA DHANANJAY
Published: June 2024

Introduction: Insulin-like Growth Factor-1 (IGF1) and its primary binding protein IGFBP3 are markers of insulin resistance and may characterize an internal milieu affecting the course of diabetes. We examined if IGF1 and IGFBP3 levels modify the efficacy of intensive weight-reducing lifestyle intervention on glucose metabolism among people with overweight/obese and Type 2 Diabetes.

Methods: The Look AHEAD Study randomized persons aged 45-74 years with BMI ≥ 25 kg/m2 and verified Type 2 diabetes, to assigned to Intensive Lifestyle Intervention (ILI) versus Diabetes Support and Education (DSE). A random sample (n=80, male 50%, African Americans 16%) had measurement of IGF1 and IGFBP3 by ELISA at baseline. We examined changes in fasting glucose levels from baseline to 1 year by treatment assignment and biomarker levels.

Results: In the ILI group, lower baseline IGFBP3 levels predicted larger decreases in fasting glucose (p = 0.02), while there was no significant association in the DSE group (Figure, baseline IGFBP3 by treatment interaction, p = 0.055). There was no treatment by baseline level interaction for IGF1.

Conclusion: In overweight/obese Type 2 diabetes, the efficacy of ILI in reducing fasting glucose level is greater at lower IGFBP3 levels. Our findings, if confirmed, can guide personalization of intensive treatment of diabetes.

Disclosure

P. Maurya: None. J. Yang: None. A.D. Everett: Advisory Panel; Merck & Co., Inc. W.L. Bennett: None. D. Vaidya: None.

Funding

National Institutes of Health (DK127222)
874-P: Bromocriptine-QR Reduces Elevated Postprandial Cardiometabolic Risk Factors in Type 2 Diabetes Subjects
Authors: CHAMARTHI BINDU , EZROKHI MICHAEL , CINCOTTA ANTHONY H.
Published: June 2024

Bromocriptine-QR (BQR), a unique quick release formulation of micronized bromocriptine, is the only FDA-approved sympatholytic insulin sensitizer for T2D. Previously, circadian-timed (~0600-0800 hr) B-QR dosing reduced a prespecified cardiovascular disease (CVD) composite endpoint in the Cycloset Safety Trial by 40 - 50% within 1 year. Chronically elevated sympathetic tone is a driver of increased postprandial (PP) plasma glucose (G), triglyceride (TG) and free fatty acid (FFA) levels which composite is a major risk factor for CVD, especially in hypertensive (HT) T2D subjects. This study therefore explored the impact of 24 wks BQR therapy versus placebo on average daylong PP G, TG and FFA levels obtained at 1 and 2 hrs following standardized meals at breakfast, lunch, and dinner in normotensive T2D subjects with normal fasting plasma TG (FPTG) levels (< 150 mg/dl) or with FPTG levels ≥ 150, 200, or 300 mg/dl (hyperlipidemic [HL] groups) or in HL - HT T2D subjects. BQR therapy increasingly reduced PP plasma G, TG, and FFA levels (and HbA1c) in the HL groups versus placebo as FPTG level increased from ≥ 150 to ≥ 300 mg/dl, but not in normal lipidemic, normotensive subjects. Moreover, this BQR effect was accentuated in the HL - HT group (See Table). This BQR-induced reduction in all these CVD risk factors in HL and HL - HT T2D subjects may contribute to the therapy’s observed impact to reduce CVD outcomes in the T2D population.

Disclosure

B. Chamarthi: Employee; VeroScience LLC. M. Ezrokhi: Employee; VeroScience LLC. A.H. Cincotta: Employee; VeroScience LLC.