ObjectiveThe present study was designed to determine the anti-inflammatory and antioxidant effects of dulaglutide (DUL) on doxorubicin (DOX) -induced acute kidney injury (AKI).MethodsTwenty-eight male rats were randomly allocated into four groups: the negative control group (received Distilled water), the positive control group (received Distilled water and a single dose of DOX), DUL 0.2 mg/kg group (received DUL 0.2 mg/kg twice weekly and single dose of DOX), and DUL 0.6 mg/kg group (received DUL 0.2 mg/kg twice weekly and single dose of DOX). All DOX doses (20 mg/kg) were given at day 13th of the study and all treatments were administered intraperitoneally for 14 days. On day fifteenth, the rats were sacrificed, and blood was collected to measure the complete blood count (CBC), Neutrophile/Lymphocyte Ratio (NLR), Monocyte/Lymphocyte Ratio (MLR), And Platelet/Lymphocyte Ratio (PLR), C-reactive protein (CRP), blood urea nitrogen (BUN), and serum creatinine (SCr). The right kidney was used for histopathological examination, while the left kidney was homogenized to assess the renal tissue levels of malondialdehyde (MDA), total antioxidant capacity (TAOC), interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL).ResultsDOX induces acute kidney injury was demonstrated by significant elevations in BUN, SCr, and CRP levels. DUL significantly lowered the levels of BUN, SCr, and CRP, and reduced the levels of blood inflammation markers, including NLR and MLR. Additionally, it resulted in a significant reduction in the renal tissue levels of MDA, IL-1β, and TNF-α, while the level of TAOC was significantly elevated. These findings were supported by histopathological assessments.ConclusionThe present study indicates that DUL mitigates doxorubicin-induced kidney damage by reducing oxidative stress and inflammation.

Introduction and Objective: Switching from dulaglutide (DU) 0.75 mg/1.5 mg to tirzepatide (TZP) has shown clinically meaningful improvements in HbA1c and body weight (BW) in adults with T2D in SURPASS-SWITCH. These benefits were further explored through patient-reported outcomes (PROs) measuring BW-related self-perception and health-related quality of life (HRQoL), ability to perform daily physical activities, and emotional impact of two treatments for T2D. Methods: Participants were randomized 1:1 to escalate to DU 4.5 mg or maximally tolerated dose (MTD), or switch to tirzepatide with escalation to 15 mg/MTD. PRO measures assessed at baseline and week 40 were IWQOL-Lite-CT, IW-SP, APPADL, and GIEH. Higher scores indicate better perceived outcomes. Results: After switching from DU 0.75 mg/1.5 mg to TZP 15 mg/MTD, a statistically significant improvement in IW-SP score vs. DU was observed. Although not statistically significant vs. DU, improvements in IWQOL-Lite-CT, APPADL, and GIEH were numerically larger in the TZP treatment group. Conclusion: In addition to improvements in key clinical markers, switching from DU 0.75 mg/1.5 mg to TZP 15 mg/MTD was associated with statistically significant improvement vs. DU in BW-related self-perception and non-statistically significant improvements vs. DU in BW-related HRQoL, ability to perform daily physical activities, and global impression of emotional health. Disclosure K. Boye: None. P. Sharma: None. K.K. Chivukula: Employee; Eli Lilly and Company. A. Kwan: Employee; Eli Lilly and Company.

Introduction and Objective: This work investigates the potential benefits of switching from weekly dulaglutide (DU) to weekly tirzepatide (TZP) in adults with T2D across baseline subgroups from SURPASS-SWITCH. Methods: SURPASS-SWITCH was a Phase 4 trial enrolling adults with T2D and inadequate glycemic control treated with weekly DU (0.75 mg/1.5 mg) for at least 6 months plus 0-3 oral antihyperglycemic medications (OAMs). Participants were assigned 1:1 to escalate to DU 4.5 mg/maximally tolerated dose (MTD), or switch with escalation to TZP 15 mg/MTD. Treatment effect on HbA1c and BW were analyzed by baseline subgroups of HbA1c (≤8.5%, >8.5%), duration of T2D (≤5 years, >5-≤10 years, >10 years), baseline DU dose (0.75 mg, 1.5 mg), and duration of DU dose (<1 year, ≥1 year). Results: Switching to TZP versus escalating DU was associated with statistically significant reductions from baseline to week 40 in HbA1c and BW across all baseline subgroups. Conclusion: In SURPASS-SWITCH, switching to TZP 15 mg/MTD from DU 0.75 mg /1.5 mg was associated with significant and consistent improvements in HbA1c and weight reductions versus DU across all baseline subgroups. For those not at treatment goals across a range of baseline characteristics, switching to TZP may be a clinical option when current treatment plans are not yielding desired clinical outcomes. Disclosure R. Violante: None. L. Rose: None. P. Sharma: None. K.K. Chivukula: Employee; Eli Lilly and Company. A. Kwan: Employee; Eli Lilly and Company.

Type 2 diabetes (T2D) mellitus is increasing exponentially in India, with overweight/obesity being prime contributors. This study aimed at assessing the clinical impact of the combination therapy of a glucagon-like peptide-1 receptor agonist (GLP-1RA) injection (inj.) and a sodium-glucose cotransporter-2 inhibitor (SGLT-2i) in overweight/obese patients from the Indian subcontinent. In two real-world evidence (RWE) studies (RWE1 and 2), we retrospectively observed the effect of the combination therapy of a GLP-1RA, injection dulaglutide (DU) 1.5 mg/week, and an SGLT-2i, canagliflozin (CAN) 100 mg/day at weeks 16, 32, and 52 on HbA1c, body weight (weight), systolic blood pressure (SBP), lipids, change in doses of antidiabetic agents (ADA) and antihypertensive agents (AHA) in overweight/obese Asian Indian subjects with T2D, who had suboptimal glycemic control. A total of 95 T2D patients [51 males (M), 44 females (F)] completed the two RWE studies. In RWE 1, 40 patients (20 M/20 F), mean [standard deviation (SD)] age 49.4 (10.7) years (Y), weight 92.6 (6.6) kg, body mass index (BMI) 30.6 (2.3) kg/m2, duration of T2D 8.1 (3.2) Y, completed the study. At week 32, the mean (SD) reduction in A1c (%) was -1.3% [8.4 (0.7) to 7.1 (0.3); p < 0.01] and mean (SD) weight (kg) loss was -5.5 [92.6 (6.6) to 87.9 (7.02); p < 0.00001]. This group was then followed up until week 52. In RWE 2, 55 patients (31 M/24 F), age 51 (5.8) Y, weight 92.6 ± 3.4 kg, BMI 31.1 ± 2.1 kg/m2, SBP 142.4 ± 3.9 mm Hg, estimated glomerular filtration rate (eGFR) 62 ± 5 mL/minute/1.73 m2, with 8.4 ± 3.3 Y duration of diabetes met the inclusion criteria. In 71% of subjects, A1c decreased by -1.4% [8.5 ± 0.4 to 7.1 ± 0.2; p < 0.0001] at week 16 and was 6.8 ± 0.3 (p = 0.0002) in 18% at week 32. A statistically significant (SS) improvement in glycemic control, weight, and improvement in cardiovascular (CV) risk factors was observed with the GLP-1RA/SGLT-2i combination, which was well tolerated.

Orforglipron (OFG), an oral, non-peptide GLP-1 receptor agonist, demonstrated significantly greater glycemic control and weight loss at doses ≥12 mg vs placebo (PBO) or dulaglutide (DU) 1.5 mg in a 26-week phase 2 study of adults with type 2 diabetes (T2D) (Table). These exploratory analyses investigated mechanisms by which OFG improved glycemic control in T2D by analyzing exploratory biomarkers. Participants with T2D (mean age, 58.9 years; baseline HbA1c, 8.1%; weight, 100.3 kg) treated with diet and exercise, with/without metformin, were randomized to PBO, DU 1.5 mg, or once-daily OFG 3, 12, 24, 36, or 45 mg. Biomarkers of β-cell function and insulin sensitivity were analyzed by mixed model repeated measures, excluding data after study drug discontinuation or rescue drug initiation. Biomarkers of β-cell function were improved by OFG at 26 weeks from baseline (Table). HOMA-B significantly increased with OFG at doses ≥12 mg vs PBO or DU. HOMA-IR (computed with insulin) significantly decreased from baseline with OFG at doses ≥24 mg but was not significantly different vs PBO and DU. Fasting glucose-adjusted glucagon significantly decreased with OFG at doses ≥12 mg vs PBO and with OFG 12, 24, and 45 mg vs DU. These analyses suggest improved glycemic control with OFG vs DU may be partly explained by improved β-cell function and insulin sensitivity. Additional studies are ongoing to understand these mechanisms. Disclosure J. Rosenstock: Research Support; Biomea Fusion, Inc. Other Relationship; Lilly Diabetes. Research Support; Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Corcept Therapeutics. Other Relationship; Novo Nordisk. Research Support; Pfizer Inc. Other Relationship; Sanofi, Boehringer-Ingelheim. Research Support; Shionogi &amp; 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. D.A. Robins: None. K.L. Duffin: Employee; Eli Lilly and Company. J.M. Wilson: Employee; Eli Lilly and Company. K.J. Mather: Employee; Eli Lilly and Company. H. Banerjee: None. Y. Lin: Stock/Shareholder; Eli Lilly and Company, Pfizer Inc., AstraZeneca. S. Eyde: None. C.M. Kazda: Employee; Eli Lilly and Company. M. Konig: None. Funding Eli Lilly and Company

Retatrutide (RETA), a triple-hormone receptor agonist of GIP, GLP-1, and glucagon receptors, showed clinically meaningful improvements in HbA1c and robust body weight reductions in adults with T2D in a Phase 2 study. We compared eating behavior during treatment with RETA vs. placebo or dulaglutide (DU) in this study. Adults with T2D were randomized to subcutaneous placebo QW, DU 1.5 mg QW, or RETA 0.5, 4, 8, or 12 mg QW for 36 weeks in this double-blind, double-dummy Phase 2 study. Eating behavior was assessed at baseline and Week 36 using the 51-item Eating Inventory comprised of three domains: Cognitive Restraint of Eating, Disinhibition, and Perceived Hunger. Overall, 281 adults with mean baseline age 56 y, T2D duration 8.1 y, HbA1c 8.3%, and BMI 35.0 kg/m2 were randomized. At Week 36, adults treated with RETA 8 mg and 12 mg had significantly reduced Eating Inventory Disinhibition and Perceived Hunger scores vs. placebo. Adults treated with RETA 12 mg also had significantly reduced Disinhibition and Perceived Hunger scores vs. DU and a significantly reduced Cognitive Restraint of Eating score vs. placebo at Week 36. RETA treatment significantly improved some eating behaviors such as overeating and hunger management more than placebo or DU in a dose-dependent manner, and improved other eating behaviors such as portion control and avoiding high calorie foods more than placebo in adults with T2D. Disclosure C. Kanu: None. K. Boye: Employee; Eli Lilly and Company. J. Poon: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. I.A. Goetz: Employee; Eli Lilly and Company. S.E. Williamson: Consultant; Eli Lilly and Company, Takeda Pharmaceutical Company Limited, GlaxoSmithKline plc, Novo Nordisk, Lundbeck. J. Lou: None. T. Coskun: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company

Abstract Disclosure: M. Hoog: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. J. Maldonado: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. R. Wangia-Dixon: Employee; Self; Optum Inc. Other; Self; Eli Lilly &amp; Company. R. Halpern: Employee; Self; Optum Inc. Other; Self; Eli Lilly &amp; Company. E. Buysman: Employee; Self; Optum Inc. Other; Self; Eli Lilly &amp; Company. G. Gremel: Employee; Self; Optum Inc. Other; Self; Eli Lilly &amp; Company. A. Huang: Employee; Self; Tigermed. Other; Self; Eli Lilly &amp; Company. M. Konig: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. Hispanic/Latino (H/L) adults in the US have a greater prevalence of type 2 diabetes (T2D) and diabetes-related complications compared to non-H/L adults. Optimal glycemic control remains a challenge in H/L adults with T2D, resulting in poor health outcomes and a substantial comorbidity burden. This study compared glycemic and cost outcomes among H/L adults with T2D who initiated treatment with dulaglutide (DU) or basal insulin (BI). This retrospective cohort study used claims data from the Optum Research Database from July 2014 - March 2022 (commercial and Medicare Advantage). H/L patients with ≥1 pharmacy claim for DU or BI during the identification period (IDP), January 01, 2015 - March 31, 2021, were included. Index date was the date of first claim for DU or BI during the IDP and cohorts were assigned based on index date medication. Patients were required to have continuous enrollment during the 6-month baseline and 12-month follow-up periods; ≥1 claim with baseline T2D diagnosis; ≥1 glycated hemoglobin (HbA1c) test result each in the baseline period and 4-12 months after index date; and no injectable T2D medications at baseline. Cohorts were propensity-score matched on demographic and baseline clinical characteristics. Measures of glycemic control included change in HbA1c from baseline to 12-month follow-up, which was modelled using ordinary least squares regression (OLS) on the matched cohorts, and proportion of patients achieving the HbA1c target of &amp;lt;7.0%. Bootstrap sampling with 5,000 samples was used to compare total costs per 1% change in HbA1c between cohorts. The propensity-score matched cohorts comprised of 2,872 patients with 1,436 patients in each cohort (DU and BI). Most demographic and baseline characteristics were balanced between the cohorts except for age, income, office visit counts, and medical costs. Mean [standard deviation (SD)] age in the DU and BI cohorts was 59.8 [12.8] and 61.4 [12.9] years, respectively. About half of the matched population was male (DU: 54.3%; BI: 51.4%). At 12 months, the mean change from baseline in HbA1c was significantly greater in the DU cohort than BI (DU: -1.4% [1.9]; BI: -0.9% [2.1]; p&amp;lt;0.001) and the total cost per 1% change in HbA1c was significantly lower in the DU cohort than BI (DU: $13,768; BI: $19,128; p&amp;lt;0.001). The proportion of patients achieving HbA1c &amp;lt;7.0% at 12 months was significantly higher among patients initiating DU than BI (DU: 37.9%; BI: 22.1%; p&amp;lt;0. 001). Results from OLS showed that the DU cohort had a larger decrease in HbA1c compared to BI (estimate: -0.57; p&amp;lt;0.001). Patients initiating DU had twice the odds of achieving HbA1c &amp;lt;7.0% compared to BI (odds ratio: 2.19; p&amp;lt;0.001). DU demonstrated better glycemic outcomes and lower costs per 1% HbA1c reduction among H/L adults with T2D compared with those initiating BI. DU may be an effective therapeutic option for this vulnerable population and may help with achieving improved T2D outcomes. Presentation: Friday, June 16, 2023

Dulaglutide (DU) 1.5 mg was associated with improved composite renal outcomes that included new-onset macroalbuminuria in people with type 2 diabetes with previous cardiovascular disease or cardiovascular risk factors in the REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes) trial. This exploratory post hoc analysis evaluated kidney function-related outcomes, excluding the new-onset macroalbuminuria component, among the REWIND participants. Intent-to-treat analyses were performed on REWIND participants (n = 4,949 DU, n = 4,952 placebo). Time to occurrence of a composite kidney function-related outcome (≥40% sustained decline in estimated glomerular filtration rate [eGFR], per the Chronic Kidney Disease Epidemiology Collaboration 2009 equation, end-stage renal disease, or renal-related death), and mean annual eGFR slope were examined. Analyses were conducted overall and within subgroups defined by baseline urinary albumin-to-creatinine ratio (UACR <30 or ≥30 mg/g) and baseline eGFR (<60 or ≥60 mL/min/1.73 m2). The post hoc composite kidney function-related outcome occurred less frequently among participants assigned to DU than placebo (hazard ratio [HR] 0.75, 95% CI 0.62-0.92, P = 0.004), with no evidence of a differential DU treatment effect by UACR or eGFR subgroup. A ≥40% sustained eGFR decline occurred less frequently among participants assigned to DU than placebo (HR 0.72, 95% CI 0.58-0.88, P = 0.002). The mean annual decline in eGFR slope was significantly smaller for participants assigned to DU than placebo (-1.37 vs. -1.56 mL/min/1.73 m2/year, P < 0.001); results were similar for all subgroups. The estimated 25% reduced hazard of a kidney function-related outcome among participants assigned to DU highlights its potential for delaying or slowing the development of diabetic kidney disease in people with type 2 diabetes.

Currently, the most frequently prescribed once weekly glucagon-like peptide-1 receptor agonists (GLP-1RA) in Japan are dulaglutide (DG) and semaglutide (SG). However, little is known about the differences between these two compounds in clinical practice in Japan. This study compared the efficacy and safety of DG and SG using professional CGM in 12 patients attending our outpatient with poorly controlled type 2 diabetes mellitus (T2DM) while using GLP-1RA. The study subjects were 12 T2DM patients with HbA1c ≥ 7.0% on treatment with 0.75mg/week DG for at least 24weeks. All patients wore the professional CGM twice, once while receiving DG and once when the SG dose was increased to 0.5mg/week. Time inrange was significantly better with SG than with DG, which was the main outcome measure. Regarding the secondary outcome measures, standard deviation of glucose, average sensor glucose, time above range, maximum sensor glucose, interquartile range, SD of glucose during the nocturnal period (0000-0559), and average nocturnal sensor glucose (0000-0559) were significantly better with SG than DG. In contrast, SG had no effect on the time below range and minimum sensor glucose compared to DG. Switching from 0.75mg DG to 0.5mg SG in patients with T2DM improved glycemic variability, mean glycemic index, and daily variability without increasing the hypoglycemic index. The results suggest that switching to SG may be a useful option in patients experiencing inadequate glycemic control with DG. The online version contains supplementary material available at 10.1007/s13340-023-00640-2.

A novel protective modality against rotenone-induced Parkinson's disease: A pre-clinical study with dulaglutide.

Prevalence of type 2 diabetes represent an epidemic problem especially for aging of population. Median age of people affected is rising and Internation Diabetes federation suggest that 1 patients of 5 has more than 65 years. Same situation affected also Italy where in 2020 about 20% of T2D patients were older than 70 years old. This class of patients present often-severe comorbidity as cardiovascular and kidney impairment and are undergoing complex therapies with multiple daily therapy intakes and difficulties in adherence to prescribed therapy. New developed drug, as GLP1-receptor agonist, like Dulaglutide (DU), may be useful in elderly for drug’s ancillary effects and for demonstrated safety on hypoglycemic events. Nevertheless, majority of knowledge, derived from RCT-study, enrolled patients aged 20-65 years and data in elderly patients are limited. Data from real world experience could be useful to understand safety and efficacy of this drug. We retrospectively analyzed data from 751 T2D patients to evaluate DU after 6, 12 and 18 months, comparing people older and younger than 70 years. The introduction of DU, with a relevant number of insulin and sulphanilureas suspensions, statistically reduced HbA1C and body weight after 6 months while glomerular filtration rate (GFR) remained stable and these results lasted over time. About 23% patients dropped-out (8% for gastrointestinal disturbances). No significative differences in tolerability and efficacy, between the two groups were found. DU is a safe, efficacious and easy to use option even for elderly T2D patients

The main research purpose is to compare the long-term cost-effectiveness of semaglutide (SEMA) with that of dulaglutide (DULA) for patients with inadequately controlled type 2 diabetes throughout their lifetime. If necessary, the second aim is to investigate a further price cut for SEMA to provide sound advice for government drug price adjustments. Cost-utility analysis was performed by the United Kingdom Prospective Diabetes Study Outcomes Model 2 (UKPDS OM2) from the perspective of health care providers in China. Baseline characteristics and clinical efficacy of SEMA and DULA were sourced from the high-dose comparison in the SUSTAIN-7 trial. A binary search was used to identify the scope for further reduction in the price of SEMA. The impact of individual parameters was assessed with sensitivity analyses. Main analysis (SEMA vs. DULA) revealed a mean difference in quality-adjusted life years (QALYs) of 0.04 QALYs and costs of $1132.29. The incremental cost-utility ratio was $26 957.44/QALY, showing that SEMA was a better option compared with DULA. In sensitivity analyses, the discount rate made the greatest contribution to the incremental cost-utility ratio. In the binary search, there was still scope to reduce the SEMA cost further by approximately 6.83% to be cost-effective, taking DULA as a reference. After its addition to the National Medical Insurance System in China, SEMA is expected to be a cost-effective choice compared with DULA for patients with type 2 diabetes with inadequately controlled from the cost-utility analysis. However, there is still scope to reduce the annual cost of SEMA further.

AWARD-PEDS was a Phase 3 trial to assess the efficacy and safety of dulaglutide (DU) , a once-weekly GLP-1 receptor agonist, in youth (10 to &amp;lt;18 years old) with T2D treated with lifestyle alone or on stable metformin with or without basal insulin. Participants (mean age, 14.5 yrs; mean BMI, 34.1 kg/m2) were randomized to placebo (N=51) , DU 0.75 mg (N=51) , or DU 1.5 mg (N=52) . The primary aim was to demonstrate superiority of DU (pooled doses) vs. placebo for change in HbA1c at 26 weeks. Analyses included all patients with ≥1 dose of study drug, excluding data after initiation of rescue therapy. DU was superior to placebo (figure) in improving glycemic control measured by change in HbA1c, percent of patients with HbA1c &amp;lt;7%, and change in fasting glucose at Week 26. No effect of DU was observed on BMI change (p=0.776) . Fewer patients assigned to DU compared to placebo required rescue therapy (2.9% vs. 17.6% respectively, p=0.003) . Incidence of common GI adverse events was higher in DU group vs. placebo [nausea (14.6% vs. 7.8%) , vomiting (15.5% vs. 3.9%) , diarrhea (18.4% vs. 13.7%) ] but comparable to that observed in adults. In conclusion, in youth with inadequately controlled T2D treated with or without metformin and/or basal insulin, once weekly DU 0.75 mg or 1.5 mg was superior to placebo in improving glycemic control without an effect on BMI through 26 weeks, with a safety profile consistent with that established in adults. Disclosure S. A. Arslanian: Advisory Panel; Eli Lilly and Company, Novo Nordisk. Research Support; Eli Lilly and Company, Novo Nordisk. Other Relationship; AstraZeneca. J. Cho: None. T. S. Hannon: Advisory Panel; Eli Lilly and Company. P. Zeitler: Consultant; Boehringer Ingelheim International GmbH, Daiichi Sankyo, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk, Takeda Pharmaceutical Company Limited. L. Chao: None. M. Barrientos: Research Support; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Research &amp; Development, LLC, Novo Nordisk. C. C. Boucher-Berry: None. E. Bismuth: None. S. A. Dib: None. D. Cox: Employee; Eli Lilly and Company. Funding Eli Lilly and Company

In the REWIND trial, dulaglutide (DU) reduced the risk of CV outcomes compared with placebo (PL) (Major Adverse Cardiovascular Event [MACE]-3 hazard ratio 0.88) . This post hoc analysis studied circulating protein biomarkers associated with CV events to better understand how DU reduces CV risk. Patients ≥50 years of age with T2D, A1C ≤9.5%, BMI ≥23 kg/m2, and CV risk were treated DU (1.5 mg weekly) or PL. This case/control study matched 9 cases with MACE with 9 non-MACE controls. A total of protein biomarkers were measured by immunoassay in plasma and serum. Biomarkers associated with DU were first identified by fitting the natural log (ln) of biomarker changes from baseline to 2 years of treatment to an ANCOVA model; the p value cutoff was 0.0026 after Bonferroni correction. Then, the identified biomarkers were fit to a logistic regression model for MACE case/control to test possible impact on CV outcome. Four biomarkers were associated with DU: C-reactive protein (hsCRP) , N-terminal prohormone of brain natriuretic peptide (NT-proBNP) , and Growth/Differentiation Factor-15 (GDF-15) had attenuated increases over 2 years for DU vs. PL, and C-peptide had a greater increase over 2 years for DU vs. PL. Logistic regression analyses showed that patients with smaller increases in hsCRP, NT-proBNP, and GDF-15 were less likely to have MACE. C-peptide levels did not significantly impact MACE occurrence. Disclosure J.M.Wilson: Employee; Eli Lilly and Company. K.L.Duffin: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company, Pfizer Inc. H.C.Gerstein: Advisory Panel; Abbott, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Viatris Inc., Consultant; Kowa Company, Ltd., Other Relationship; DKSH, Eli Lilly and Company, Sanofi, Zuellig Pharma Holdings Pte. Ltd., Research Support; AstraZeneca, Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk, Sanofi. G.Pare: Advisory Panel; Amgen Inc., Bayer AG, Sanofi, Research Support; Bayer AG. S.Lee: None. H.M.Colhoun: Advisory Panel; Bayer AG, Eli Lilly and Company, Novo Nordisk, Consultant; AstraZeneca, Research Support; AstraZeneca, Stock/Shareholder; Bayer AG, Roche Pharmaceuticals. H.Qian: Employee; Eli Lilly and Company, Stock/Shareholder; Apple, Eli Lilly and Company. V.Pirro: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Hoover: Employee; Eli Lilly and Company. M.Lakshmanan: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. G.Ruotolo: None. Funding Eli Lilly and Company

A retrospective, observational analysis of administrative claims data from the IBM MarketScan Databases assessed adherence and persistence among GLP-1 RA naive adult patients with T2D newly initiating dulaglutide (DU) or oral semaglutide (OS) between Sept 2019 and Nov 2020. Patients had continuous enrollment in the 6-mo pre-index period and 6-mo follow-up periods. The DU patients were propensity-score matched 1:1 to OS patients (6,166 pairs) . The median age was 54 years at index date, and 48% were female. At pre-index, mean aDCSI was 0.6 and 10% of patients had ASCVD. Most patients used oral anti-hyperglycemic medication (87%) ; a smaller proportion used insulin (15%) . The most common prescribing provider was primary care (62%) . More DU patients were adherent (proportion days covered [PDC] ≥80%) (65% vs. 50%, p&amp;lt;0.001) and had higher mean PDC vs. OS (0.78 vs. 0.68, p&amp;lt;0.001) . More DU patients were persistent on therapy compared to OS patients (72% vs. 57% p&amp;lt;0.001) and had longer mean duration of persistence (148 vs. 128, p&amp;lt;0.001) . Among patients with ≥2 fills of their index drug, 73% of DU and 62% of OS patients were adherent. During the 6-mo follow-up period, DU patients had significantly higher adherence and persistence compared to OS patients. Disclosure R. Paczkowski: Employee; Eli Lilly and Company. M. Hoog: Employee; Eli Lilly and Company, Stock/Shareholder; Abbott, Eli Lilly and Company. J. Peleshok: Employee; Eli Lilly and Company, Eli Lilly and Company. M. Yu: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A. Huang: None. B. Limone: None. J. Manjelievskaia: Employee; IBM Watson Health, Other Relationship; Eli Lilly and Company. Funding Eli Lilly and Company

Data on patient-reported outcome (PRO) measures in people living with T2D who initiate injectable glucagon-like peptide-1 receptor agonist (GLP-1 RA) medication in routine clinical practice are limited. Here we present final PRO data from the TROPHIES 24-month, prospective, non-comparative, observational study of adult patients with T2D in France, Germany and Italy who started their first injectable GLP-1 RA with either once-weekly dulaglutide (DU) or once-daily liraglutide (LIRA) . Patients’ scores on PRO questionnaires were assessed every 6 months. We present scores at 24 months compared with baseline values before starting DU or LIRA treatment. For each PRO measure, higher scores reflect better outcomes. Baseline characteristics (previously published) for patients prescribed DU (N=1,014) or LIRA (N=991) were similar between groups. Mean changes from baseline to 24 months in PRO scores indicate improvements in health outcomes in patients initiating DU or LIRA (Table) . In summary, among those patients still evaluable at 24 months we observed improvements in PRO scores from baseline in both groups, but with a more pronounced trend of improvement in the DU cohort for EQ-5D-5L VAS, IW-SP, DTSQs total, and DPM life and work productivity scores. Disclosure M.Fuechtenbusch: Advisory Panel; Berlin-Chemie AG, Consultant; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Speaker's Bureau; AstraZeneca, Novo Nordisk. K.Boye: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. B.Guerci: Advisory Panel; Amgen Inc., Medtronic, Board Member; Abbott Diagnostics, AstraZeneca, Bayer AG, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Consultant; Boehringer Ingelheim International GmbH, Intercept Pharmaceuticals, Inc., Novo Nordisk. 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. L.Garcia-perez: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. E.Heitmann: None. J.Lebrec: Consultant; Eli Lilly and Company. A.Barrett: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Dib: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. M.Orsini federici: Employee; Eli Lilly and Company.

Dulaglutide (DU) reduced the risk of CV outcomes compared with placebo (PL) in the REWIND trial (NCT01394952) , with a MACE-3 (major adverse CV events) hazard ratio of 0.88 over 5.4 years. Participants were ≥50 years of age with T2D, A1C ≤9.5%, BMI ≥23 kg/m2, and CV risk and received either DU (1.5 mg weekly) or PL. This post-hoc analysis explored the hypothesized relationship between metabolite biomarkers and MACE-3 in a nested case-control substudy comprising 600 MACE cases and 6non-MACE REWIND participants. A total of 135 plasma metabolites were measured by targeted metabolomics using mass spectrometry. Biomarkers significantly associated with DU were first identified in analyses that adjusted for 135 multiple comparisons (discovery approach) . Predefined clusters of the remainder based on non-REWIND data were then assessed using principal component analyses (hypothesis testing) . DU was associated with 2-year changes in 2-hydroxybutyric acid, threonine, acylcarnitines and homocitrulline; of these, only the acylcarnitines were linked with MACE (Table) . In the literature, higher levels of acylcarnitines are associated with CV events. These analyses suggest that DU-associated reductions in acylcarnitines are associated with its MACE benefit. Disclosure V.Pirro: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. H.C.Gerstein: Advisory Panel; Abbott, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Viatris Inc., Consultant; Kowa Company, Ltd., Other Relationship; DKSH, Eli Lilly and Company, Sanofi, Zuellig Pharma Holdings Pte. Ltd., Research Support; AstraZeneca, Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk, Sanofi. G.Pare: Advisory Panel; Amgen Inc., Bayer AG, Sanofi, Research Support; Bayer AG. S.Lee: None. H.M.Colhoun: Advisory Panel; Bayer AG, Eli Lilly and Company, Novo Nordisk, Consultant; AstraZeneca, Research Support; AstraZeneca, Stock/Shareholder; Bayer AG, Roche Pharmaceuticals. Y.Lin: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.M.Wilson: Employee; Eli Lilly and Company. H.Qian: Employee; Eli Lilly and Company, Stock/Shareholder; Apple, Eli Lilly and Company. A.Hoover: Employee; Eli Lilly and Company. K.L.Duffin: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company, Pfizer Inc. Funding Eli Lilly and Company

Introduction: The substantial financial burden associated with type 2 diabetes (T2D) over a lifetime cannot be neglected. Therefore, the objective of this study was to evaluate the pharmacoeconomic value of three once-weekly GLP-1 RAs, namely subcutaneous semaglutide (sc. SEMA), dulaglutide (DULA), and extended-release exenatide (e-r EXEN), in treating patients with T2D that cannot be controlled with metformin-based background therapy, and to find a suitable price reduction for non-cost-effective medications, to provide reasonable recommendations to the administration for adjusting drug prices.Methods: The baseline characteristics of the simulation patient cohort were sourced from a comprehensive meta-analysis synthesizing 453 trials evaluating 21 hypoglycemic agents from nine categories of drugs. The UKPDS OM2 was applied to project the long-term effectiveness and costs from a Chinese health care provider’s perspective. After cost-utility analysis, the reasonable price adjustment of non-cost-effective options was explored via binary search. Uncertainty was measured by means of sensitivity analysis.Results: After a 40-year simulation, the sc. SEMA, DULA, and e-r EXEN groups yielded 9.6315, 9.5968, and 9.5895 quality-adjusted life years (QALYs), respectively. In terms of expenditure, the total costs for the sc. SEMA, DULA, and e-r EXEN groups were $42012.47, $24931.27, and $40264.80, respectively. DULA was dominant over e-r EXEN due to the higher QALYs and lower total costs. The ICURs of sc. SEMA vs. DULA and sc. SEMA vs. e-r EXEN were $492994.72/QALY and $41622.69/QALY (ICUR > λ), respectively, indicating that sc. SEMA was not more cost-effective than DULA or e-r EXEN. The INMB and absolute NMB yielded the same conclusions which were robust to one-way, scenario, and probabilistic sensitivity analyses. After several assumptions in the binary search, sc. SEMA and e-r EXEN appear to become cost-effective when their annual costs are decreased by 57.67% and 70.34%, respectively, with DULA as a counterpart.Conclusion: From the cost-utility analysis, DULA appears to be the most cost-effective option among sc. SEMA, DULA, and e-r EXEN for the treatment of patients with T2D receiving metformin-based background therapy. With a 57.67% or 70.34% reduction in cost, sc. SEMA or e-r EXEN, respectively, would become as cost-effective as DULA in China.

Aims: The effect of β-cell function on glycemic response to dulaglutide (DU) is not fully understood in clinical settings. We explored a suitable clinical marker of β-cell function to predict glycemic response to DU in patients with type 2 diabetes (T2D). Methods: We retrospectively analyzed 141 patients who commenced once-weekly DU 0.75 mg after undergoing a meal tolerance test (MTT) with a standardized meal from September 2015 to December 2019 at our hospital. β-cell function was assessed by fasting and 2h postprandial serum C-peptide immunoreactivity (CPR) as well as increment of CPR (dCPR) in the MTT. We analyzed the suitability of each measurement as a marker for β-cell function and its association with glycemic response to DU using linear and logistic regression with adjustment for baseline HbA1c. Results: In 141 patients, 2h postprandial CPR (PCPR) and dCPR showed significant inverse correlation with baseline HbA1c (r = -0.25 and -0.33, respectively; P &amp;lt; 0.01 for both), while fasting CPR (FCPR) did not (r = 0.02; P = 0.853). Given the association of high baseline HbA1c and impairment of meal-stimulated insulin secretion measured with PCPR and dCPR, we adopted FCPR as a marker for β-cell function with less influence from baseline HbA1c in the following analysis. Of the 141 patients, 59 patients continued DU without initiating any additional glucose-lowering agents for more than 6 months. The baseline mean ± SD HbA1c, fasting plasma glucose, and FCPR of the 59 patients were 8.9 ± 1.2%, 9.2 ± 2.3 mmol/L, 0.50 ± 0.29 nmol/L, respectively. The mean ± SE change in HbA1c 0-6 months was -1.2 ± 0.2%. FCPR was significantly associated with a reduction in HbA1c (P = 0.031). Furthermore, FCPR was a significant predictor for achieving a reduction in HbA1c ≥ 1% over 6 months (OR, 1.40; 95% CI, 1.14-1.71; P = 0.039) with the area under the receiver operating characteristics curve of 0.83. Conclusions: FCPR is less affected by baseline HbA1c than PCPR and dCPR, and can be a useful marker for predicting glycemic response to DU. Disclosure M. Hasebe: None. S. Honjo: None. J. Fujikawa: None. A. Hamasaki: None. S. Yoshiji: None. Y. Iwasaki: None. S. Kimura: None. Y. Seno: None. Y. Keidai: None. T. Haraguchi: None. K. Iwasaki: None. Y. Wada: None.

The objective of this retrospective, observational study was to compare 6- and 12-month (mo) adherence and persistence among dulaglutide (DU) vs. matched semaglutide (SEMA) initiators using real-world administrative claims data from the IBM MarketScan Databases. Adult patients (pts) with T2D newly initiating DU or SEMA between January 2018-January 2020 (index date=earliest fill date), without evidence of GLP-1 RA use, pregnancy, gestational diabetes, or bariatric surgery in the 6-mo baseline period, and with continuous enrollment in the 6-mo baseline and 6- or 12-mo follow-up periods were included. DU initiators were propensity-score matched 1:1 to SEMA initiators for each 6- and 12-mo follow-up (26,284 and 13,837 pairs, respectively). Baseline characteristics were balanced with mean age 53 years and 50% females. More DU pts were adherent than SEMA pts (6mo:63% vs. 48%, 12mo: 54% vs. 43%, p values<0.001). More DU pts were persistent on therapy compared to SEMA pts (6mo: 72% vs. 62%, 12mo: 56% vs. 45%, p values<0.001) and had more mean persistent days (6mo: 145 vs. 132, 12mo: 254 vs. 221, p values<0.001). Among pts who escalated and remained on a higher dose of index drug, most were adherent at 6 mos (DU 83% vs. SEMA 75%) and 12 mos (DU 76% vs. SEMA 72%). At both 6 and 12 mos, DU initiators had significantly higher adherence and greater persistence on their therapy than SEMA initiators.View largeDownload slideView largeDownload slide DisclosureR. Mody: Employee; Self; Eli Lilly and Company. J. Manjelievskaia: Employee; Self; IBM Watson Health, Research Support; Self; Eli Lilly and Company. M. Yu: Employee; Self; Lilly Diabetes, Employee; Spouse/Partner; LifeLabs, Stock/Shareholder; Self; Lilly Diabetes, Stock/Shareholder; Spouse/Partner; Lilly Diabetes. E. H. Marchlewicz: Research Support; Self; Eli Lilly and Company. R. Malik: Employee; Self; Eli Lilly and Company. N. Zimmerman: Consultant; Self; Eli Lilly and Company, Employee; Self; IBM Watson Health. D. E. Irwin: Employee; Self; IBM Watson Health.