bluuebunny/crossref_metadata_2025_split huggingface dataset:
827-P: Effects of Elexacaftor/Tezacaftor/Ivacaftor Triple Combination Therapy on Glycaemic Control and Body Composition in Patients with Cystic Fibrosis–Related Diabetes
Authors: GRANCINI VALERIA , GRAMEGNA ANDREA , ZAZZERON LAURA , ALICANDRO GIANFRANCO , PORCARO LAURA L. , PIEDEPALUMBO FEDERICA V. , LANFRANCHI CHIARA , DACCÒ VALERIA , ORSI EMANUELA 
Published: June 2023

Introduction: Cystic fibrosis related diabetes (CFRD) is the most common extra pulmonary complication of cystic fibrosis (CF). Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are a group of new drugs for the treatment of CF and elexacaftor+tezacaftor+ivacaftor (ETI) triple combination therapy has been approved as first choice therapy in the treatment of patients with at least 1 copy of F508del mutation. Data on the effects of CFTR modulators on glucose metabolism in patients with or without CFRD are limited to small studies with conflicting results.
Aim of the study: to evaluate the effectiveness of ETI on glucose metabolism, glucose variability and body composition in patients with CFRD.
Methods: We conducted a prospective observational study on 24 CF patients with CFRD requiring insulin therapy. We performed an evaluation of glycometabolic control, glucose variability (assessed with 14 days-flash glucose monitoring) and body composition (with bio-impedance analysis) before and six months after the beginning of ETI. Data are expressed as median and interquartile ranges.
Results: We demonstrated an improvement in both HbA1c [from 7.0% (6.5, 7.4) to 6.6 (6.0, 7.1), p&lt;0,05] and coefficient of variation [CV - from 35.0 (29.0, 44.5) to 28.2 (25.2, 33.1), p&lt; 0.01], despite unchanged insulin requirements. Over the treatment period, percent of fat mass (FM) significantly increased [from 12.1% (7.2, 16.2) to 15.4% (11.8, 18.6), p&lt;0.05].
Conclusions: ETI improves glycometabolic regulation in patients with CFRD on insulin therapy. A longer follow-up is needed to better characterize the body composition changes induced by ETI and their metabolic consequences.

Disclosure
V.Grancini: None. A.Gramegna: None. L.Zazzeron: None. G.Alicandro: None. L.L.Porcaro: None. F.V.Piedepalumbo: None. C.Lanfranchi: None. V.Daccò: None. E.Orsi: None.
832-P: Coadministration of Metformin with GLY-200, a Clinical-Stage Nonabsorbed Drug for the Treatment of Type 2 Diabetes (T2D), Has No Significant Impact on the Oral Absorption of Metformin in the Rat
Authors: FINEMAN MARK , BRYANT CHRISTINE , JOZEFIAK THOMAS H. , NIMGAONKAR ASHISH , CARLSON TAYLOR 
Published: June 2023

Background: GLY-200 is a non-absorbed polymer drug currently in Phase 2 clinical trials for the treatment of T2D. GLY-200 was designed to reversibly enhance the barrier properties of the intestinal mucus lining to non-invasively mimic gastric bypass and duodenal exclusion devices. In view of this mechanism of action, GLY-200 has the potential to interfere with the absorption of orally available drugs. As such, we investigated the effect of GLY-200 on the oral absorption of metformin, an antidiabetic agent commonly used in combination with other glucose-lowering medications.
Methods: Metformin (100 mpk) was administered by oral gavage in saline to male Sprague Dawley rats (6-8 weeks old). GLY-200 (400 mpk) was dosed either simultaneously in the same gavage solution, or prior (1- or 3-hours) to the metformin dose. Blood samples were drawn at 0, 0.25, 0.5, 1, 2, 4, 7, 10, and 24 hours following the metformin dose, and a pharmacokinetic (PK) analysis was performed using a noncompartmental model (Phoenix WinNonlin v. 8.3).
Results: GLY-200 altered the rate but did not meaningfully alter the extent of metformin absorption. The greatest effect was observed when the two drugs were dosed together (Cmax ↓34%; tmax ↑100%; AUC ↑11%). The observed changes may be a result of slowed GI transit with GLY-200 administration.
Conclusions: The oral absorption and PK profile of metformin was not significantly altered when the drug was coadministered with GLY-200 or given 1- or 3-hours after a GLY-200 dose. These results suggest that GLY-200 could be used in combination with metformin, whose pharmacologic action is not dependent on Cmax.

Disclosure
M.Fineman: Employee; Glyscend Inc., Stock/Shareholder; Glyscend Inc. C.Bryant: Employee; Glyscend Inc. T.H.Jozefiak: Employee; Glyscend Inc., Stock/Shareholder; Glycologix, LLC. A.Nimgaonkar: Employee; Glyscend Inc. T.Carlson: Employee; Glyscend Inc.
833-P: Duodenal Targeting by Oral Pharmacologic Duodenal Exclusion Therapy for Treatment of Type 2 Diabetes (T2D)
Authors: NIMGAONKAR ASHISH , BRYANT CHRISTINE , CARLSON TAYLOR , GUERINA FLORENCE V. , COLBERT KEVIN , POLOMOSCANIK STEVEN , PETERSEN JOHN S. , JOZEFIAK THOMAS H. , FINEMAN MARK 
Published: June 2023

GLY-200 is an oral, non-absorbed polymeric drug designed to non-invasively and reversibly enhance the mucus lining of the proximal small intestine to mimic the effects of metabolic surgery and duodenal exclusion devices. In healthy volunteers and rat models of T2D (GK, ZDF, and DIO), GLY-200 produced reductions in postprandial glucose and bodyweight compared to control. This study aimed to visualize the retained duodenal barrier in rats using appropriate imaging modalities.
Methods: Imaging of GLY-200 after gavage administration to fasted Sprague-Dawley rats was performed using Computed Tomography (CT) and an In Vivo Imaging System (IVIS). For CT imaging, GLY-200 was covalently conjugated with diatrizoate; images were obtained after transient isoflurane administration 1, 2, and 4 hours after gavage. For IVIS imaging, GLY-200 was reacted with FITC to produce a fluorescein-GLY-200 conjugate. Rats were euthanized 0.5, 1, 2, 4, and 8 hours after dosing and the GI tracts were immediately removed for imaging.
Results: In CT imaging, GLY-200-diatrizoate was retained in the proximal small intestine 1 and 2 hours after administration, with an intense signal only in the duodenum. In comparison, a diatrizoate control was broadly distributed over the small intestine distal to the duodenum by 1 hour. In IVIS imaging, GLY-200-FITC showed intense fluorescence in the proximal small intestine that was predominantly associated with the gut wall and persisted for &gt;4 hours after administration. In comparison, a FITC-dextran70 control was distributed broadly throughout the distal intestine and cecum by 30 minutes with no retention in the duodenum.
Conclusion: Imaging studies confirm that GLY-200 conjugates are retained in the duodenum after oral administration. These data support the hypothesis that GLY-200 treatment results in a pharmacologic duodenal exclusion that could potentially recapitulate the glycemic and weight effects of metabolic surgery and duodenal exclusion devices.

Disclosure
A.Nimgaonkar: Employee; Glyscend Inc. C.Bryant: Employee; Glyscend Inc. T.Carlson: Employee; Glyscend Inc. F.V.Guerina: Employee; Glyscend Inc. K.Colbert: Consultant; LifeSprout, Employee; Glyscend Inc. S.Polomoscanik: None. J.S.Petersen: None. T.H.Jozefiak: Employee; Glyscend Inc., Stock/Shareholder; Glycologix, LLC. M.Fineman: Employee; Glyscend Inc., Stock/Shareholder; Glyscend Inc.
86-LB: Real-World Impact of Oral Semaglutide on Glycemic Control and Weight Outcomes in Type 2 Diabetes (RELATE–Oral Semaglutide)
Authors: AMAMOO JAMES , DOSHI RIDDHI P. , NOONE JOSHUA , TAN XI , XIE LIN , GAMBLE CORY L. , GUEVARRA MICO , CHEN JUSTIN , KING AARON A. 
Published: June 2023

Background: The study objective was to evaluate the impact of oral semaglutide type 2 diabetes (oral sema T2D) on changes in HbA1c and weight outcomes in adults with T2D.
Methods: This retrospective cohort study from October 2019 to September 2021 analyzed a linked US database from IQVIA’s Longitudinal Prescription Claims, Professional Fee Claims, and Ambulatory Electronic Medical Records. Adults with T2D with HbA1c ≥7% were included. Analyses were conducted to compare pre- and post-index (12 months) HbA1c and weight-related outcomes.
Results: The final sample included 398 patients. Over 12 months post-index, mean HbA1c decreased significantly from 8.8% to 7.8% (p&lt;0.001), with 32.4% of patients achieving HbA1c &lt;7.0%. Mean BMI decreased significantly from 35.2 to 34.1 kg/m2 (p&lt;0.001), with the proportion of patients with BMI ≥40.0 kg/m2 decreasing from 25.6% to 20.1%, and the proportion of those with BMI ≥30.0 kg/m2 decreasing from 75.6% to 70.4%. Mean weight decreased significantly from 102.4 to 98.9 kg (p&lt;0.001), with 33.4% and 11.1% of patients experiencing a ≥5% and ≥10% decrease in weight, respectively.
Conclusion: At 12-month follow-up, adults initiating oral sema T2D had statistically significant decreases in HbA1c, weight, and BMI from baseline. Further regression analyses will be conducted to control for covariates.

Disclosure
J. Amamoo: None. R. P. Doshi: Employee; IQVIA Inc. J. Noone: Employee; Novo Nordisk. X. Tan: Employee; Merck & Co., Inc., Novo Nordisk, Stock/Shareholder; Merck & Co., Inc., Novo Nordisk. L. Xie: Employee; Pfizer Inc., Novo Nordisk A/S. C. L. Gamble: Employee; Novo Nordisk. M. Guevarra: Employee; Novo Nordisk. J. Chen: Employee; IQVIA Inc. A. A. King: Advisory Panel; Novo Nordisk, Board Member; JDRF, Speaker's Bureau; Sanofi, Abbott, Dexcom, Inc., Lilly Diabetes.
862-P: Reduced Metformin Clearance Is Associated with Increased Metformin-Related Side Effects in Older Adults with Type 2 Diabetes (T2D)
Authors: YEN KEVIN , SRINIVASAN SHYLAJA , DAPKUS LAURA A. , TAMRAZ BANI , MASHARANI UMESH , MCCABE SHANNON E. , KROON LISA 
Published: June 2023

The safe use of metformin in the elderly population and in patients with impaired renal function has not been clearly defined. Metformin has side effects that limit use particularly in vulnerable populations. In this pilot study, we aimed to investigate the interplay between metformin pharmacokinetics, pharmacogenetics of metformin transporters and metformin-related side effects. Participants were recruited based on age ≥ 65 years or eGFR=30-59 mL/min. Two sample PK sampling was performed; lactic acid, vitamin B12 and creatinine levels were measured. Participants completed a survey on GI side effects. Metformin clearance (Cl) and area under the curve (AUC) were calculated using previously described limited sampling strategy by Chen et al. Participants were genotyped for variants in the following transporters affecting metformin clearance: OCT1, OCT2, OCT3, OCTN1, MATE1, MATE2-K and PMAT. Nineteen participants with T2D and mean age 72y (range: 56-86y) completed the study. Mean eGFR was 79±27mL/min and median morning dose of metformin was 1000mg (range: 500-1500mg). Mean metformin Cl was 302 ±227ml/min, consistent with previous reports based on age and renal function. Those with GI side effects had lower Cl (389ml/min vs 191ml/min, P = 0.03). There was a positive correlation between metformin AUC and baseline lactic acid levels (R2 = 0.46, P &lt;0.01). There was no relationship between metformin Cl or AUC and vitamin B12 levels. Individuals homozygous for rs272893 in OCTN1 had lower metformin Cl based on a univariate generalized linear model (β: -181 per allele, SE=62, P = 0.003) We confirm that metformin Cl is lower in older adults with T2D and show that lower Cl is associated with increased GI side effects. Genetic variation in metformin transporter OCTN1 was associated with reduced Cl. Larger studies are needed to examine the impact of metformin dose modification in patients with reduced clearance based on pharmacogenetics to minimize side effects.

Disclosure
K.Yen: None. S.Srinivasan: None. L.A.Dapkus: None. B.Tamraz: Advisory Panel; Codex Genetics. U.Masharani: Research Support; Clementia Pharmaceuticals. S.E.Mccabe: None. L.Kroon: None.
865-P: Hypoglycemia Risk Is Similar with Dipeptidyl Peptidase-4 Inhibitors (DPP-4i) Monotherapy vs. Metformin Monotherapy
Authors: PERIYANAYAGAM USHA , WEI YUQIN 
Published: June 2023

Introduction: Prescribing DPP-4i medications versus metformin as a first-line treatment is common, although large-scale safety evidence favoring DPP-4is monotherapy is scarce. The goal of this study is to compare the incidence of hypoglycemia in patients with a DPP-4i monotherapy versus metformin monotherapy
Methods: US patients in Komodo's Healthcare Map with diabetes were studied. 2,016,156 patients (59.3% female) on a single-gradient metformin monotherapy and 45,826 patients (52.6% female) on a DPP-4i monotherapy were found from 2016 - 2020. No antidiabetic treatment was prescribed in the previous year and patients were continuously enrolled 1 year before/6 months after their first medication prescription. Propensity score matching (PSM) was performed using age, gender, US regions, chronic kidney disease (CKD), obesity, emergency room visits, Charlson Comorbidity Index (CCI), and proportion of Days Covered (PDC). The PSM sample comprised 45,400 1:1 matched users of each group. The incidence rate of hypoglycemia was calculated using Poisson regression.
Results: Patients in the DPP-4i group were older, 64.3 (SD14.0) versus 50.5 (15.8) years in the metformin group. CKD was recorded in 28.1% of the DPP-4i users and 4.3% of metformin users. A CCI score ≥5 was seen in 53.7% of DPP-4i users and 15.9% of Metformin users. PDC was ≥ 80% in 37.0% and 42.7% of DPP-4I and metformin users. The estimated pre-matched incidence of hypoglycemia was 19.04 and 16.88 per 1000 person-years in DPP-4i and metformin users. The post-matching incidence rates were 19.17 for DPP-4i and 16.82 for metformin users. The DPP-4i to metformin incidence rate ratio was 1.14 (95% CI 0.99 - 1.31, p = 0.062).
Conclusion: The incidence rate of hypoglycemia in a large cohort of patients treated with DPP-4i was comparable to those treated with metformin. The sizable risk of hypoglycemia after DPP-4is should be considered in prescription decision-making.

Disclosure
U. Periyanayagam: None. Y. Wei: None.
869-P: Effect of Dapagliflozin on Renal Oxygen Delivery and Consumption in T2DM and NGT Subjects
Authors: TRIPATHY DEVJIT , CHEN XI , CHILTON ROBERT , HANSIS-DIARTE ANDREA A. , SALEHI MARZIEH , SOLIS-HERRERA CAROLINA , CERSOSIMO EUGENIO , DEFRONZO RALPH A. 
Published: June 2023

Improved renal oxygenation is proposed as a potential reno-protective mechanism of SGLT2 inhibitors in T2DM. Bold-MRI studies in nondiabetic subjects showed no effect with dapagliflozin and improved renal cortical oxygenation with empagliflozin in T1DM. No studies have examined renal oxygenation in T2DM. We examined the effect of dapagliflozin (10 mg) on renal oxygen delivery and oxygen consumption in 7 T2DM (age=58±3 yrs, BMI = 30±1.8 kg/m2) and 7 NGT (age = 47±3.4 yrs, BMI = 28.6±1.6kg/m2) subjects who received a single dose of dapagliflozin or placebo. Renal vein (SvO2) and radial artery (SaO2) hemoglobin saturation were measured with i-STAT point of care analyzer and renal blood flow with PAH infusion before and 4 hours after dapagliflozin/placebo.
At baseline arterial (CaO2, 19 ± 0.8 vs 19 ± 0.7 ml/dl, p=NS) and renal venous (CvO2, 16 ± 0.9 vs 18 ± 0.7 ml/dl, p=NS) oxygen Content were similar in DAPA and PLAC. Thus, there was no difference in renal oxygen delivery (478 ± 29 vs 533 ±27 ml/min/m2) between DAPA and PLAC groups. Following DAPA/PLAC renal plasma flow did not change, and there was no change in arterial (CaO2) (19 ± 0.8 vs 18.2 ± 0.7 ml/dl, p=NS) or renal venous (CvO2) (16 ± 0.9 vs 15.5 ± 0.9 ml/dl) oxygen content in DAPA or PLAC groups. Renal oxygen consumption following DAPA (67 ± 10 vs 78 ±13 ml/min/m2, p=NS) and PLAC (42 ± 8 vs 50 ± 6 ml/min/m2, p=NS) groups were not different versus baseline.
Conclusion: A single acute dose of dapagliflozin does not alter renal oxygen delivery or consumption in T2DM or NGT subjects.

Disclosure
D. Tripathy: None. X. Chen: None. R. Chilton: None. A.A. Hansis-Diarte: None. M. Salehi: None. C. Solis-Herrera: None. E. Cersosimo: None. R.A. DeFronzo: Speaker's Bureau; AstraZeneca. Advisory Panel; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Novo Nordisk. Research Support; AstraZeneca, Boehringer-Ingelheim, Merck & Co., Inc.

Funding
AstraZeneca
87-LB: Real-World Impact of Once-Weekly Injectable Semaglutide on Glycemic Control and Weight Outcomes in Type 2 Diabetes (RELATE-OW Injectable Semaglutide)
Authors: AMAMOO JAMES , DOSHI RIDDHI P. , NOONE JOSHUA , TAN XI , XIE LIN , GAMBLE CORY L. , GUEVARRA MICO , CHEN JUSTIN , KING AARON A. 
Published: June 2023

Background: Given the scarcity of real-world evidence on long-term effectiveness, this study assessed the effect of a once-weekly injectable formulation of semaglutide type 2 diabetes (sema OW T2D) on HbA1c and weight outcomes in individuals with T2D.
Methods: This retrospective database study included adults with T2D and HbA1c ≥7%, initiating sema OW T2D from January 2018 to September 2021, using linked data from IQVIA’s Longitudinal Prescription Claims, Professional Fee Claims, and Ambulatory Electronic Medical Records in the US. Descriptive and bivariate analyses were conducted to evaluate pre- and post-index (12 months) changes in HbA1c and weight-related outcomes.
Results: Among the final sample of 1,926 patients, mean HbA1c decreased significantly from 8.9% to 7.6% (p&lt;0.001), with 40.2% of patients achieving HbA1c &lt;7.0% over 12 months post-index. Mean weight decreased from 106.3 to 102.2 kg (p&lt;0.001), with 37.9% and 13.3% of patients experiencing a ≥5% and ≥10% decrease in weight, respectively. Mean BMI decreased from 36.5 to 35.0 kg/m2 (p&lt;0.001), with the proportion of patients with BMI ≥40.0 kg/m2 and BMI ≥30.0 kg/m2 decreasing from 29.2% to 24.4% and 81.1% to 73.6%, respectively.
Conclusion: At 12-month follow-up, adults with T2D initiating sema OW T2D had statistically significant decreases in HbA1c, weight, and BMI.

Disclosure
J. Amamoo: None. R. P. Doshi: Employee; IQVIA Inc. J. Noone: Employee; Novo Nordisk. X. Tan: Employee; Merck & Co., Inc., Novo Nordisk, Stock/Shareholder; Merck & Co., Inc., Novo Nordisk. L. Xie: Employee; Pfizer Inc., Novo Nordisk A/S. C. L. Gamble: Employee; Novo Nordisk. M. Guevarra: Employee; Novo Nordisk. J. Chen: Employee; IQVIA Inc. A. A. King: Advisory Panel; Novo Nordisk, Board Member; JDRF, Speaker's Bureau; Sanofi, Abbott, Dexcom, Inc., Lilly Diabetes.
871-P: Study of Glucagon Response and Its Association with Glycemic Control and Ketogenesis after Administration of Ipragliflozin as an Adjunctive Treatment in Patients with Type 1 Diabetes (Suglat-AID)—A Multicenter, Open-Label, Prospective Exploratory Trial
Authors: NAKAMURA YUTA , HORIE ICHIRO , ABIRU NORIO , KITAMURA TADAHIRO , KUSUNOKI YOSHIKI , NISHIDA KENRO , YAMAMOTO AKANE , HIROTA YUSHI , FUKUI TOMOYASU , MAEDA YASUTAKA , MINAMI MASAE , MATSUI TAKANORI , KAWAKAMI ATSUSHI 
Published: June 2023

Objective: SGLT2 inhibitors including ipragliflozin have been used as adjunctive to insulin therapy for the treatment of type 1 diabetes (T1D) in Japan. Previous studies showed glucagon levels increased after initiating SGLT2 inhibitors, however, the effects of increased glucagon on glycemic control and ketogenesis in T1D remains unclear.
Methods: Twenty-five patients with T1D with HbA1c &gt;7.5% were administered ipragliflozin 50 mg as an add-on to insulin therapy. The patients underwent a mixed-meal tolerance test (MMTT) twice before (1st-MMTT) and 12 weeks after administration of ipragliflozin (2nd-MMTT) to evaluate glucagon responses and its associations with glycemic parameters including CGM data.
Results: The values of area under the curve from fasting to 120 min (AUC0-120min, pg/mL) of plasma glucagon in 2nd-MMTT were significantly increased than 1st-MMTT (75±37 vs. 66±37, p=0.044), but fasting glucagon levels were not changed. The levels of fasting β-OHBA and AUC0-120min of β-OHBA were significantly elevated in 2nd-MMTT compared to 1st-MMTT, but there were no correlations between glucagon and β-OHBA levels. In CGM analyses, the values of glycemic variability (SD, CV% and MAGE) significantly ameliorated and the percentage of time in range (70-180 mg/dL) significantly increased from baseline to 12 weeks (46±14% vs. 54±20%, p=0.005) without an increase of the time below range (TBR, &lt;70 mg/dL). A negative correlation between TBR% and fasting glucagon levels (r=-0.45, p=0.048) was found at 12 weeks but not at baseline. No severe adverse events including ketoacidosis developed in the participants during the study.
Conclusion: Adjunctive treatment of ipragliflozin was found to increase postprandial glucagon secretion and might contribute to prevention of hypoglycemia via mitigating glycemic variability in T1D.

Disclosure
Y.Nakamura: Research Support; Astellas Pharma Inc. Y.Maeda: None. M.Minami: None. T.Matsui: None. A.Kawakami: Research Support; Astellas Pharma Inc. I.Horie: Research Support; Astellas Pharma Inc. N.Abiru: None. T.Kitamura: None. Y.Kusunoki: None. K.Nishida: None. A.Yamamoto: None. Y.Hirota: Other Relationship; Lilly, Sanofi K.K., Terumo Corporation, Sumitomo Dainippon Pharma Co., Ltd., Research Support; Sumitomo Dainippon Pharma Co., Ltd. T.Fukui: None.

Funding
Astellas Pharma Inc.
873-P: Empagliflozin Compliance and Influencing Factors in Patients with Heart Failure and Diabetes
Authors: ALVAREZ CARLOS A. , PERKINS AARON , SIGLER MEREDITH A. , YANG HUI , CABERWAL HARJEET , EBRAHIMI RAMIN 
Published: June 2023

Treatment paradigms for patients with type 2 diabetes mellitus (DM) and heart failure (HF) has changed. Sodium glucose cotransporter 2 inhibitors, such as empagliflozin, are now considered potential first line therapies. Compliance to empagliflozin and the factors that may influence compliance are unknown. Methods: We assessed compliance and associated factors in patients with DM and HF from Veterans Affairs national data from 2015-22. Compliance was calculated using proportion of days covered (PDC). Compliance to empagliflozin was defined as PDC &gt; 80%. Patients who compliance could not be calculated were excluded. Generalized linear models were constructed to evaluate 1) demographic, 2) patient level, and 3) system level data.
Results: Total 28,581 patients exposed to empagliflozin were included. Proportion of empagliflozin compliance was 66.2%. Table 1 displays the significant demographic, patient, and system level factors associated with poor empagliflozin compliance.
Conclusions: There were demographic, patient, and system level factors that were associated with poor empagliflozin 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