bluuebunny/crossref_metadata_2025_split huggingface dataset:
834-P: Efficacy and Tolerability of Initial Triple Combination Therapy with Metformin, Dapagliflozin, and Saxagliptin Compared with Conventional Stepwise Add-on Therapy in Drug-Naïve Patients with Type 2 Diabetes—A Randomized, 104-Week, Open-Label, Active-Controlled Trial
Authors: HOON KIM NAM , YOON KIM JI , SUNG MOON JUN , LEE YONG-HO , HEON KWAK SOO , LIM SOO , KYONG MOON MIN , GON KIM SIN 
Published: June 2023

Background: Early combination therapy is recommended in type 2 diabetes (T2D) patients with inadequately controlled hyperglycemia to avoid treatment failure and clinical inertia. This study aimed to evaluate the efficacy and tolerability of an initial triple combination with metformin, dapagliflozin and saxagliptin compared with conventional stepwise add-on therapy in drug-naïve patients with T2D.
Methods: This multicenter, randomized, 104-week, open-label trial was conducted at 9 medical centers in South Korea. Eligible patients were aged ≥18 years, inadequately controlled (HbA1c ≥ 8.0% to &lt;11.0%), drug-naïve patients with recent-onset T2D. Eligible participants were randomly assigned (1:1) to triple combination therapy (TCT, 1000mg of metformin, 10mg of dapagliflozin and 5mg of saxagliptin once daily) or conventional stepwise therapy (CST) group. CST was started with metformin followed by glimepiride, and sitagliptin sequentially. The primary outcome was the proportion of patients who achieved HbA1c &lt;6.5% without hypoglycemia, weight gain ≥5% and discontinuation due to adverse events at week 104.
Results: A total of 105 eligible participants were randomly assigned to either TCT or CST groups. 89.6% of participants completed the study and treatment. The primary outcome was achieved in 42.5% of the TCT group and 17.5% of the CST group (p=0.015). The proportion of achieving HbA1c &lt;6.5% at week 104 was 50.0% of the TCT group and 45.0% of the CST group. Hypoglycemia, weight gain &gt;5%, or discontinuation due to adverse events occurred in 14.9% of the TCT group, and 59.2% of the CST group.
Conclusion: Initial combination therapy with metformin, dapagliflozin and saxagliptin effectively lowered HbA1c with higher tolerability compared with conventional stepwise treatment in recent-onset T2D.

Disclosure
N.Kim: None. J.Kim: None. J.Moon: None. Y.Lee: None. S.Kwak: None. S.Lim: None. M.Moon: None. S.Kim: None.

Funding
AstraZeneca Korea Ltd (ESR-15-11420)
839-P: Alpha-1 Antitrypsin Augmentation Therapy in Chronic Pancreatitis Patients Undergoing Total Pancreatectomy and Islet Autotransplantation
Authors: WANG HONGJUN , GOU WENYU , ADAMS DAVID , MORGAN KATHERINE , NIETERT PAUL J. , HIRSCH JASON , STRANGE CHARLIE 
Published: June 2023

Stress-induced islet graft loss reduces the efficacy of islet transplants. In this single-center, randomized, double-blind, and controlled clinical trial, we evaluated the safety and efficacy of human alpha-1 antitrypsin (AAT) infusion in chronic pancreatitis (CP) patients undergoing total pancreatectomy and islet autotransplantation (TP-IAT) at the Medical University of South Carolina. Among 48 qualified subjects randomized in a 1:2 (placebo vs AAT) ratio, 43 received TP-IAT. Subjects were given saline or AAT infusion at 60mg/kg weekly for 4 weeks and were followed for 12 months. The primary efficacy endpoint was the islet function measured by the C-peptide area under the curve during a mixed meal tolerance test (MMTT) at Month 12 (M12). Adverse events (AEs) were measured throughout the study. Safety, glycemic control, insulin use, and quality of life (QoL) were compared between groups. Safety evaluation showed no significant differences in the types and severity of participant AEs. The primary efficacy outcome was not significantly different between groups. Baseline characteristics including age, body weight, BMI, HbA1C, etc, were comparable in the randomized populations. The oxygen consumption rate before the transplant was higher in the AAT group. Serum C-peptide (an indicator of islet death) was lower in the AAT group, suggesting less islet injury. AAT subjects trended toward better SF-12 physical QoL and lower insulin use at both 75 and 365 days post-IAT. Despite intensive efforts to get participants to return for the Day 365 MMTT, only 10/14 (71%) in the placebo group and 18/29 (62%) in the AAT group returned for this test. Although we did not observe a statistical difference in islet function using AAT therapy, we gained a better understanding of this patient population. Minimizing numbers of follow-up visits, use of fewer doses of medication with higher doses, and providing travel are all important for future clinical trials in TP-IAT.

Disclosure
H. Wang: None. W. Gou: None. D. Adams: None. K. Morgan: Speaker's Bureau; Johnson & Johnson Medical Devices Companies. P.J. Nietert: None. J. Hirsch: None. C. Strange: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK105183, DK120394, DK118529); U.S. Department of Veterans Affairs (I01BX004536 to H.W.)
841-P: Phenomapping-Derived Tool to Personalize Chiglitazar Treatment in Type 2 Diabetes—A Post Hoc Analysis of Randomised Clinical Trials
Authors: HUANG QI , ZOU XIANTONG , JIA WEIPING , JI LINONG 
Published: June 2023

﻿Chiglitazar is a peroxisome proliferator-activated receptor (PPAR) pan-agonist showing comparable glucose-lowering efficacy with ﻿sitagliptin ﻿in patients with type 2 diabetes. To identify the subgroup with higher benefits with chiglitazar thus personalizes drug therapy, ﻿a post-hoc analysis using a machine learning algorithm was applied in ChiglitAzar Monotherapy with Placebo (CAMP) and ﻿ChiglitAzar Monotherapy with Sitagliptin (CAMS) study. We constructed a phenomap based on 13 baseline variables from 1069 patients with diabetes assigned to chiglitazar (32mg or 48mg, n=822) and sitagliptin (n=247). Personalized HbA1c decline at week 24 was estimated using least squares regression weighted for phenotypic distances between each participant. High-benefit group (HBG) was defined as patients with estimated HbA1c decline higher in chiglitazar ﻿than sitagliptin, and low-benefit group (LBG) was defined as the opposite.677 (63.3%) patients were allocated to the HBG and 392 (36.7%) were allocated to the LBG.﻿ Chiglitazar showed higher HbA1c decline than sitagliptin In the HBG and lower HbA1c decline in the LBG (relative decline 0.67%, 95%CI [0.50, 0.83] in HBG and -0.93% [-1.18, -0.68] in LBG, p for interaction&lt;0.001). There was no significant inter-group heterogeneity in changes in HOMA-IR, HDL, ﻿triglyceride and body weight. Dosage analysis suggested the majority (n=635, 77.3%) would gain more glucose-lowering benefits from chiglitazar 48mg than 32mg. To facilitate efficient identification of HBG in the clinic, we developed ML-PANPPAR, a machine learning model based on extreme gradient boosting algorithm (XGBoost). The model showed robust performance (AUC=0.933 in the internal testing subset) to recognise HBG with five simple variables including sex, BMI, HbA1c, HDL and fasting insulin.﻿Our phenomapping-derived tool provides support to ﻿select specific patients to receive chiglitazar for better glucose-lowering efficacy.

Disclosure
Q.Huang: None. X.Zou: None. W.Jia: None. L.Ji: Other Relationship; Eli Lilly and Company, Novo Nordisk, Merck & Co., Inc., Bayer Inc., Sanofi-Aventis U.S., Roche Pharmaceuticals, MSD Life Science Foundation, AstraZeneca, Boehringer Ingelheim Inc., Abbott, Metronics.

Funding
Beijing Nova Cross Program (Z211100002121169); Beijing Nova Program of Science and Technology (Z191100001119026 to X.Z.)
843-P: Effects of Pemafibrate on Glucose Metabolism in Adults with Type 2 Diabetes and Hypertriglyceridemia—Subanalysis of the PARM-T2D Study
Authors: NOMOTO HIROSHI , KITO KENICHI , NAKAMURA AKINOBU , KAMEDA HIRAKU , OMORI KAZUNO , YANAGIYA SHINGO , IESAKA HIROSHI , OE YUKI , KAWATA SHINICHIRO , ATSUMI TATSUYA , MIYOSHI HIDEAKI 
Published: June 2023

Background and Aims: Pemafibrate, a novel selective peroxisome proliferator-activated receptor modulator, has been demonstrated to have potent effects on abnormalities of lipid metabolism in adults with type 2 diabetes (T2DM) and hypertriglyceridemia in real-world clinical practice (PARM-T2D study). However, the effects of pemafibrate on glucose metabolism have not been fully clarified.
Materials and Methods: In this multicenter, open-labeled, prospective, observational study, adults with T2DM were treated with pemafibrate (PEMA group) or continued on their current therapy (CTRL group) for dyslipidemia for 52 weeks. This subanalysis consisted of participants who did not change their treatment for diabetes and who did not receive insulin or insulin secretagogues during the study period. Glycemic control, insulin secretion, and insulin resistance were assessed by HbA1c levels, HOMA2-β, and HOMA2-R, respectively. The changes of these parameters between baseline and the end of the study were compared between the groups.
Results: In total, 279 of 650 participants met the criteria for this analysis. There were no statistical differences in baseline characteristics between PEMA (n = 141) and CTRL groups (n = 138). There were no significant changes in HbA1c levels and beta-cell function over 52 weeks between the groups, whereas pemafibrate significantly improved insulin resistance assessed by HOMA2-R versus the CTRL group (−0.20 vs. 0.01; estimated treatment difference, −0.23% [95% confidence interval = −0.44, −0.02]; p&lt;0.05). Pemafibrate also ameliorated lipid profiles and liver dysfunction. Changes in serum triglyceride, HDL-cholesterol, γ-GTP, and ALP levels were significantly correlated with those in HOMA2-R (p = 0.024, p = 0.002, p &lt; 0.001, and p = 0.032, respectively).
Conclusions: Pemafibrate reduced insulin resistance and improved lipid profiles and liver dysfunction in individuals with T2DM and hypertriglyceridemia.

Disclosure
H.Nomoto: Speaker's Bureau; Novo Nordisk, Sumitomo Pharma, Co., Ltd. T.Atsumi: Speaker's Bureau; Eli Lilly Japan K.K., Kowa Company, Ltd. H.Miyoshi: Research Support; Abbott, LifeScan Diabetes Institute, Taisho Pharmaceutical Holdings Co., Ltd., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Kowa Company, Ltd., MSD Life Science Foundation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation. K.Kito: None. A.Nakamura: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim Japan, Inc., Daiichi Sankyo, Taisho Pharmaceutical Holdings Co., Ltd., Teijin Pharma Limited, Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation. H.Kameda: None. K.Omori: None. S.Yanagiya: None. H.Iesaka: None. Y.Oe: None. S.Kawata: None.
847-P: SGLT2 Inhibitors and GLP-1s Are Falling Short of Expectations among Patients with Type 2 Diabetes Newly Initiating Therapy
Authors: HOLLEMAN CLAIRE , XU EMILY , COX EVELYN , BRISTOW TRACY L. 
Published: June 2023

SGLT-2s and GLP-1s have demonstrated significant glucose lowering, cardiorenal, and weight loss benefits. However, the exisiting research on patients’ perception of these benefits is limited. Thus, the present study aims to identify and compare new users' expectations of SGLT-2s and GLP-1s and the degree to which their expectations have been met.
In September 2022, 3,785 adults living with T2D took an online survey in which they indicated their SGLT-2 and GLP-1 usage and start date. Those who initiated SGLT-2 (n=108) or GLP-1 (n=128) use in the past year reported their expected changes upon starting the therapy. Participants were then asked the degree to which their expectations were met for each expectation held. Met expectations were calculated based on the percent of people selecting a 9 or 10 on a 10-point Likert scale.
New SGLT-2 users expected lower A1c, increased protection against kidney disease, and weight loss (76%, 43%, and 40%, respectively), although less than a third of SGLT-2 new users expecting a lower A1c and weight loss felt that their expectations were met (29% and 28%, respectively). GLP-1 new users expected lower A1c, weight loss, and fewer instances of hyperglycemia (80%, 74%, and 48%, respectively). Only a third of new users felt their expectations of lower A1c and weight loss were met (34% and 33%, respectively). Expectations of A1c lowering were similar between GLP-1s and SGLT-2s (80% vs. 76%); however, weight loss expectations were significantly higher among GLP-1 users compared to those on SGLT-2s (74% vs. 43%, p&lt;.01).
Among patients initiating SGLT-2 or GLP-1 therapy, A1c lowering and weight loss expectations were not met for the majority of participants. These findings emphasize the need for improved expectation management and realistic goal setting. Future research is needed to understand how failed expectations translate into clinical outcomes and medication adherence, and to identify steps to better align patient expectations and outcomes.

Disclosure
C.Holleman: Employee; Close Concerns, Other Relationship; Abbott Diabetes, Eli Lilly and Company, LifeScan Diabetes Institute, Tandem Diabetes Care, Inc., Medtronic, Ascensia Diabetes Care, MannKind Corporation, dQ&A. E.Xu: Employee; dQ&A. E.Cox: Employee; dQ&A. T.L.Bristow: Employee; dQ&A.
85-OR: Swi/Snf Controls Transcriptional Programs Required for ß-Cell Development and Postnatal Islet Function
Authors: DAVIDSON REBECCA K. , KANOJIA SUKRATI , OSMULSKI MEREDITH E. , SPAETH JASON 
Published: June 2023

A key feature of diabetes is insufficient functional β-cell mass. Strategies to augment functional β-cell mass include directed differentiation of stem cells towards a β-cell fate, which requires extensive knowledge of transcriptional programs governing differentiation in vivo. Pdx1, an essential transcription factor involved in β-cell differentiation, dynamically recruits coregulators to drive different gene expression programs. A recent study identified the ATP-dependent Swi/Snf chromatin remodeling complex as an important Pdx1-interacting partner. In the developing pancreas, conditional removal of the Brg Swi/Snf ATPase subunit compromised final pancreas mass, and loss of both ATPase subunits, Brg1 and Brm, led to glucose dyshomeostasis. While Swi/Snf is essential during early pancreas development and mature β-cell function, the role of Swi/Snf during endocrine cell development has yet to be explored. Here, we generated a conditional knockout of either Brg1 (Brg1ΔendoBrm+/-), Brm (Brg1Δendo/+Brm-/-), or both subunits (DKOΔendo) during endocrine development using Neurogenin 3 Cre. Four-week-old Brg1ΔendoBrm+/- mice are glucose intolerant, hyperglycemic, and hypoinsulinemic, with no phenotype observed in Brg1Δendo/+Brm-/-mice. Impaired glucose homeostasis of Brg1ΔendoBrm+/- mice was due in part to reduced islet number, impaired insulin secretion, and altered gene expression programs. DKOΔendo mice have not been found at weaning; however, postnatal day 6 DKOΔendo mice are severely hyperglycemic with reduced plasma insulin levels. Single-cell RNA-Seq of embryonic day 15.5 lineage-labeled cells revealed reduced insulin and glucagon transcript in the β-cell and α-cell clusters, respectively, in both Brg1ΔendoBrm+/- and DKOΔendo mice and reduced Neurogenin 3­ transcript in DKOΔendo endocrine progenitor clusters. These data suggest Swi/Snf plays a critical role in governing gene-expression programs essential for endocrine cell development.

Disclosure
R.K.Davidson: Employee; Eli Lilly and Company. S.Kanojia: None. M.E.Osmulski: None. J.Spaeth: None.

Funding
National Institutes of Health (R01DK129287, R03DK127129)
853-P: Effect of Ketogenic Diet with Weight Maintenance in Type 2 Diabetes (T2D)
Authors: MEROVCI AURORA , FINLEY BRITTANY , CHAVEZ ALBERTO , HANSIS-DIARTE ANDREA A. , NEPPALA SIVARAM , TRIPATHY DEVJIT , DEFRONZO RALPH A. 
Published: June 2023

Aim: To examine the effect of ketogenic diet in T2D patients on glucose tolerance, beta cell function, insulin sensitivity and body fat content.
Methods: 29 T2D subjects were randomized to receive for 10 days a weight maintaining diet containing: GROUP I - 30% protein, 50% CHO, 20% fat (n=8); GROUP II - isocaloric ketogenic diet with 15% protein, 5% CHO, 80% fat (n=10); GROUP III - isocaloric ketogenic diet plus ketone ester of β-OH-B, 8 grams every 8h (n=11). Subjects ate breakfast daily in the TDI Metabolic Kitchen and picked up food for lunch and dinner.
Results: After 10 days, body weight remained constant: Group I (89.0 vs 89.0 kg), II (93.0 vs 92.5) and III (96.0 vs 97.0), as did body fat content. HbA1c and fructosamine did not change in any of the 3 groups. During OGTT, FPG, 2-h PG, mean PG, fasting PI, mean PI, [Delta]I/[Delta]G, and Matsuda index of insulin sensitivity did not change in Groups I, II, III. Subjects received a 2-step euglycemic insulin clamp (20 and 60 mU/m2.min) with 3-3H-glucose and indirect calorimetry. Before and after 10 days basal HGP and suppression of HGP (step I) were similar in all 3 groups. Insulin-stimulated glucose disposal (step 2) did not change in group I (4.23 vs 4.38 mg/kg.min), II (3.62 vs 3.55), or III (3.26 vs 3.35). After 10 days, basal lipid oxidation increased, while CHO oxidation decreased (both P&lt;0.01) in groups II and III and was unchanged in group I.

Disclosure
A.Merovci: None. B.Finley: None. A.Chavez: None. A.A.Hansis-diarte: None. S.Neppala: None. D.Tripathy: None. R.A.Defronzo: Advisory Panel; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Novo Nordisk, Research Support; AstraZeneca, Boehringer-Ingelheim, Merck & Co., Inc., Speaker's Bureau; AstraZeneca.
872-P: Utilization of Empagliflozin in Patients with Type 2 Diabetes Mellitus and Congestive Heart Failure
Authors: ALVAREZ CARLOS A. , PERKINS AARON , SIGLER MEREDITH A. , YANG HUI , CABERWAL HARJEET , EBRAHIMI RAMIN 
Published: June 2023

Intro: Diabetes (DM) and heart failure (HF) are an epidemic. Randomized controlled trials demonstrated sodium glucose cotransporter 2 inhibitors (SGLT2i) are beneficial in these patients. Guidelines suggest SGLT2i, such as empagliflozin, as potential first line therapy. We sought to determine utilization patterns and compliance to empagliflozin.
Methods: We assessed utilization and compliance in patients with DM and HF from the Veterans Affairs national database from 2015-2022. Initiation was calculated as the number of new empagliflozin prescriptions per 1,000 eligible patients. Compliance was calculated using the proportion of days covered (PDC). Compliance to empagliflozin was defined as PDC &gt; 80%.
Results: A total of 44,608 patients exposed to empagliflozin were included. The majority of patients are white (n=33,663; 75.5%) male (n=43,335; 97.1%). A total of 6.6% were Hispanic or Latino (n=2,955). Table 1 shows incident empagliflozin prescription by year. The average proportion of days covered (PDC) was 0.83 (SD 0.21). The proportion of empagliflozin compliant patients was 66.2%.
Conclusions: Empagliflozin prescriptions have increased exponentially since 2015. Compliance to empagliflozin was moderate necessitating a potential intervention to increase compliance.

Disclosure
C.A.Alvarez: Research Support; Boehringer Ingelheim Inc. A.Perkins: None. M.A.Sigler: None. H.Yang: None. H.Caberwal: Employee; Boehringer Ingelheim Inc. R.Ebrahimi: Consultant; Pfizer Inc., Speaker's Bureau; Novo Nordisk.

Funding
Boehringer Ingelheim
884-P: Decentralized N=1 Study—A Feasible Approach to Evaluate Individual Therapy Response to Dapagliflozin
Authors: BEERNINK JELLE , LAVERMAN GOZEWIJN D. , HEERSPINK HIDDO L. , JONGS NIELS 
Published: June 2023

Background: The SGLT2 inhibitor dapagliflozin reduces kidney function decline and urine albumin:creatinine ratio (UACR) on a population level. However, there is marked heterogeneity in the efficacy among individual patients. We conducted a decentralized (i.e. at home) N=1 trial to assess the effect of dapagliflozin in individual patients and the feasibility of remote data collection.
Methods: Twenty patients with type 2 diabetes, UACR &gt;20 mg/g and eGFR &gt;30 mL/min/1.73m2 entered the randomized placebo-controlled double-blind N=1 trial. Patients were randomly assigned to two periods of 1-week treatment with dapagliflozin 10 mg/day and two periods of 1-week treatment with placebo in random order with 1-week wash-out periods in between. Patients collected and sent their own data with automatic uploading to an online platform and sent early morning urines 5 times/week to the laboratory for albumin and creatinine assessment. Primary outcome was UACR change from baseline (mixed effects model). The study had 80% power to detect a correlation in UACR change between first and second dapagliflozin period of 0.6.
Results: Patients had a mean eGFR of 70.2 mL/min/1.73m2 and median UACR of 94.7 mg/g. During the study, dapagliflozin compared to placebo reduced albuminuria by 15.1% (95%CI 3.3 - 28.2; p=0.013). There was a marked variation in the change from baseline in UACR during dapagliflozin treatment periods (range first and second exposure -26.9 to -4.7% and -30.5 to -5.8%, respectively). The individual change in UACR during the first and second exposure correlated in the dapagliflozin periods (r=0.50; p=0.026) but not in the placebo periods (r=0.09; p=0.69). Of all scheduled urine collections (N=816), only 5 collections (0.61%) were not delivered in the laboratory.
Conclusion: The individual UACR response to dapagliflozin varies among individual patients and is consistent upon re-exposure. Remote data collection was very reliable with nearly any missed urine collection.

Disclosure
J.Beernink: None. G.D.Laverman: Advisory Panel; AstraZeneca, Vifor Pharma Management Ltd., Boehringer Ingelheim Inc., Astellas Pharma Inc., Lilly, Other Relationship; Sanofi, AstraZeneca. H.L.Heerspink: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Bayer Inc., Eli Lilly and Company, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., George Clinical, Merck & Co., Inc., Janssen Research & Development, LLC, Traveere Pharmaceuticals, Novo Nordisk. N.Jongs: Speaker's Bureau; AstraZeneca.