bluuebunny/crossref_metadata_2025_split huggingface dataset:
763-P: Dorzagliatin Add-On to Metformin Achieved Sustained Efficacy and Good Safety Profiles in T2D Patients in a 52-Week Phase 3 Trial (DAWN)
Authors: CHEN LI , ZHANG YI , YANG WENYING 
Published: June 2021

Metformin, as recommended in various guidelines, is the currently preferred first-line treatment for T2D and often used in combination with other antidiabetic agents. Despite advances in diabetes therapeutics, there was still a lack of improvement in reaching clinical targets. Previous results on dorzagliatin from a monotherapy trial (SEED) have shown sustained efficacy and safety profiles in drug-naive T2D patients over 52 weeks. In this randomized, double-blind, placebo-controlled trial, the efficacy and safety of dorzagliatin add-on to metformin in T2D patients were evaluated. Patients were treated with metformin at 1500 mg/day as basic therapy throughout the 52-week treatment period. A total of 767 eligible Chinese patients were randomized to 75 mg dorzagliatin or placebo (1:1) BID groups for 24 weeks, followed by another 28 weeks with dorzagliatin (75 mg BID) in both groups. The primary endpoint was the change of the HbA1c from baseline at week 24. The HbA1c from baseline was reduced by 1.02% at week 24 in the dorzagliatin group, superior to the placebo (P&lt;0.0001), with effects sustained till the end of the 52-week treatment. The target response rate (HbA1c &lt;7.0%) at week 24, was 44.4% in the dorzagliatin group compared to 10.7% in the placebo group (P&lt;0.0001). At week 24, the 2h-PPG was reduced from baseline by 5.45 mmol/L with dorzagliatin, significantly lower than placebo (P&lt;0.0001). Dorzagliatin significantly improved β-cell function at week 24, as measured by HOMA2-β and HOMA2-IR (P&lt;0.05). No drug-related serious adverse events, and severe hypoglycemia were reported. There was less than 1% hypoglycemia (blood glucose &lt;3.0 mmol/L) during the 52 weeks. With a novel mechanism of action, dorzagliatin add-on to metformin has shown sustained glycemic control and good safety profiles over 52 weeks, offering a new solution to T2D patients with insufficiently controlled blood glucose on metformin.

Disclosure
L. Chen: None. Y. Zhang: Employee; Self; Hua Medicine. W. Yang: None.
764-P: Preventive Effect of Cranberry Extract for SGLT2i-Associated Urinary Tract Infection: A Case Control Study
Authors: GAUTAM ASHISH , AGRAWAL PRABHAT K. , PURSNANI NIKHIL , MAHESHWARI PRADEEP K. , RANI RUCHI 
Published: June 2021

Introduction: Glycosuric effect of SGLT2i is often complicated by Genito-urinary tract infection (GUTI). Despite all measures (hydration, hygiene, and healthy toilet habits) the risk is still 4-9%. Withdrawing SGLT2i from treatment deprives patient of its multiple benefits. On the contrary, frequent antibiotics and antifungal use emerges risk of drug resistance. Cranberry contain fungistatic benzoic acid and proanthocyanidins which inhibit the adherence of p-fimbriae of E.Coli.
Aim and Objective: This study was designed to observe the preventive effect of cranberry extract for recurrent GUTI due to SGLT2i use in T2DM.
Methods: One hundred and three subjects having T2DM, using SGLT2i as OHA were selected as cases. Cases were prescribed cranberry extract 300mg BD for 6 months. Comparators were also 98, age and sex-matched subjects having T2DM and using SGLT2i. Comparators were not prescribed cranberry extract. Subjects with uncontrolled glycemic targets and other risk factors for recurrent GUTI were excluded. Both groups were followed for 6 months and periodically evaluated for symptomatic and/or pathologically proven UTI using standard definition.
Result: Nine out of 103 cases and, 6 out of 98 comparators were excluded from observation either due to loss to follow-up, poor compliance, or getting complicated UTI leading to permanent drug withdrawal. Average incidence of GUTI among 94 cases (M=1.9, SD=1.4) matched to 92 comparators (M=2.6, SD=1.8), demonstrated significantly lesser frequency, z=-2.21, u=3510.5 and p=.027. No demonstratable or significant side effect due to cranberry extract was reported during the observation period. Average HbA1c reduction after observation period among cases (M=-0.3) compared with comparators (M=0.2) didn’t demonstrated significant difference (z=-1.84, p=.06). Cranberry extract didn’t show any effect over glycemic values.
Conclusion: Cranberry extract when used as an add-on to SGLT2i demonstrated a significant reduction in the incidence of GUTI.

Disclosure
A. Gautam: None. P. K. Agrawal: None. N. Pursnani: None. P. K. Maheshwari: None. R. Rani: None.
766-P: DA-1241, a Novel GPR119 Agonist: Data on Safety, Tolerability, and Pharmacokinetics (PK) from Part 1 of a Phase 1b Multiple Ascending Dose (MAD) Study in Healthy Volunteers (HV)
Authors: KIM MI-KYUNG , LEE DAE YOUNG , JEONG JIYOON , GRIMM MICHAEL , FRANEY BRIDGETTE B. , HOMPESCH MARCUS 
Published: June 2021

Background and Aim: DA-1241 is a novel small molecule selective GPR119 agonist. In preclinical studies DA-1241 enhanced insulin and GLP-1 secretion, reduced glucose excursions, lowered blood glucose and improved dyslipidaemia. The primary objective of Part 1 of this study was to assess the safety and tolerability of multiple once daily oral doses of DA-1241 compared to placebo in HV. Secondary objective was to estimate the plasma PK characteristics.
Methods: Part 1 was a double blind placebo-controlled, single-center study of DA-1241 in HV. Three sequential cohorts of HV (n=8/cohort) were blinded and randomized (3:1) to receive DA-1241: 50, 100 or 200 mg (n=6/cohort) or placebo (n=2/cohort), as single daily oral doses for 28 days. Safety data reviews and dose escalation decisions between cohorts took place after all subjects of an ongoing cohort had completed procedures through day 14.
Results: Overall 24 male subjects participated in Part 1 (Age 38.4 ± 10.7, BMI 26.0 ± 2.7). All doses tested were safe and well tolerated. There were no SAEs and no discontinuations due to AE. All TEAE’s were mild with no obvious dose relation and resolved spontaneously. The day 28 Cmax and AUC0-tau PK parameters showed dose proportional characteristics across the tested dose range, with Cmax (50mg: 464.9 ± 284.1; 100mg: 569.3 ± 173.2; 200mg: 1653.2 ± 615.4 ng/mL) and AUC0-tau (50mg: 5168.4 ± 1651.2; 100mg: 7620.0 ± 1837.7; 200mg: 19167 ± 9088.8 h*ng/mL). Tmax was reached at 2.9 ± 1.8; 2.3 ± 1.2 and 1.9 ± 0.6 hours respectively with a t1/2 of 590 ± 370; 368 ± 355 and 537 ± 395 hours, values for 50, 100, and 200 mg doses respectively.
Conclusion: Data from this phase 1b study in HV confirmed a favorable safety, tolerability and PK profile of DA-1241, and supported a progression of the clinical development program into patients.

Disclosure
M. Kim: Employee; Self; Dong-A ST Co. Ltd. D. Lee: Employee; Self; Dong-A ST Co. Ltd. J. Jeong: Employee; Self; Dong-A ST Co. Ltd. M. Grimm: None. B. B. Franey: None. M. Hompesch: Other Relationship; Self; Wiley, Stock/Shareholder; Self; ProSciento, Inc.
77-LB: A Retrospective Analysis of the Association between HbA1c and Continuous Glucose Monitor Use for U.S. Patients with Type 2 Diabetes
Authors: NORMAN GREGORY J. , PAUDEL MISTI L. , BANCROFT TIM , LYNCH PETER M. 
Published: June 2021

Background: Use of real-time continuous glucose monitoring (rtCGM) reduces HbA1c in individuals with type 2 diabetes (T2D) treated with intensive insulin regimens in randomized clinical trials. However, the effects of CGM use on glycemia in T2D patients in real world settings, particularly those treated with less intensive therapies, has not been well studied.
Materials and Methods: This large retrospective, observational analysis utilized data from the Optum Research Database (ORD) to assess the glycemic effects of CGM use (any CGM or real-time CGM [rtCGM]) compared with self-monitoring of blood glucoses (SMBG) within a large T2D population treated with intensive insulin therapy (IIT) and non-intensive therapies (NIT), including basal insulin only, and non-insulin medications. Outcomes were changes from baseline in HbA1c up to 6 months post index date in all patients and by treatment regimen. The percentage of patients who achieved ≥1.0 HbA1c reductions was also assessed.
Results: Data from 82,983 eligible patients were assessed (Any CGM, n=1,406; rtCGM, n=148; SMBG, n=81,575). Significant HbA1c reductions were observed with Any CGM (-0.46) and rtCGM (-0.72) vs. SMBG (-0.09), ps &lt; 0.001. HbA1c reductions were significant in CGM vs. SMBG users in the ITT (Any CGM, -0.38%; rtCGM, -0.68%, ps&lt;0.001) and NIT groups (Any CGM, -0.67%, p&lt;0.001, and rtCGM, -0.87, p=0.008). Significantly higher percentages of Any CGM and rtCGM vs. SMBG users achieved ≥1.0 HbA1c reductions in the IIT and NIT groups. Effects of Any CGM and rtCGM were attenuated but remained statistically significant in multivariate adjusted models for the overall T2D cohort.
Conclusions: Use of CGM (Any CGM or rtCGM) confers notable benefits in improving glycemic control regardless of therapy regimen. These findings support expanding CGM access to the broader T2D population.

Disclosure
G. J. Norman: Employee; Self; Dexcom, Inc. M. L. Paudel: None. T. Bancroft: None. P. M. Lynch: Employee; Self; Dexcom, Inc.
770-P: The Glucose-Lowering Effect of the Bile Acid Sequestrant Sevelamer Is Not Mediated by Glucagon-Like Peptide-1
Authors: NERILD HENRIETTE H. , BRØNDEN ANDREAS , SONNE DAVID P. , HOLST JENS J. , VILSBØLL TINA , KNOP FILIP K. 
Published: June 2021

Bile acid sequestrants are cholesterol-lowering drugs, which also improve glycemic control in patients with type 2 diabetes (T2D). The mechanism behind the glucose-lowering effect of bile acid sequestrants is unknown but has been proposed to involve glucagon-like peptide 1 (GLP-1) secretion. Using the GLP-1 receptor antagonist exendin(9-39), we investigated the GLP-1-mediated contribution to the glucose-lowering effect of the bile acid sequestrant sevelamer in patients with T2D.
In a randomized, double-blind, placebo-controlled, crossover study, patients (9 men/6 women) with T2D (median [interquartile range] age 68 [63-71] years, BMI 30.1 [26.6-33.0] kg/m2, HbA1c 48 [45-61] mmol/mol (6.5 [6.3-7.7]%), on metformin mono-therapy) underwent two 14-day treatment periods with either sevelamer or placebo in a randomized order. After each treatment period, patients participated in two experimental days, each involving a four-hour liquid meal test with concomitant infusion of exendin(9-39) or saline.
Compared to placebo, sevelamer lowered both fasting plasma glucose concentrations ((mean ± SEM) 8.7 ± 0.3 vs. 10.2 ± 0.5 mmol/L, P &lt;0.001) and postprandial plasma glucose excursions (baseline-subtracted area under the curve (bsAUC): 456.5 ± 40.3 vs. 620 ± 63.6 mmol/L × min, P &lt;0.001). In both treatment periods, exendin(9-39) increased the glucose bsAUC compared to saline (P &lt;0.001) with no absolute or relative difference between the two treatment periods (∆bsAUC: 365 ± 34.4 mmol/L × min [170 ± 27.6%] (sevelamer) vs. 428 ± 58.2 mmol/L × min [165 ± 40.2%] (placebo treatment), P = 0.17).
In conclusion, using the GLP-1 receptor antagonist exendin(9-39), we were not able to detect a GLP-1-mediated glucose-lowering effect of sevelamer; leaving the mechanism behind the glucose-lowering effect of sevelamer unresolved.

Disclosure
H. H. Nerild: Employee; Spouse/Partner; Novo Nordisk. A. Brønden: None. D. P. Sonne: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S.
779-P: Prescribing of SGLT2 Inhibitors in Primary Care: A Qualitative Study of Primary Care Physicians and Endocrinologists
Authors: MILDER TAMARA , STOCKER SOPHIE , BAYSARI MELISSA , DAY RICHARD O. , GREENFIELD JERRY 
Published: June 2021

Aims: To explore: 1) Primary Care Physicians’ (PCPs) perspectives regarding initiating SGLT2 inhibitors (SGLT2i) in patients with type 2 diabetes and their current and preferred sources of education about SGLT2i and type 2 diabetes pharmacotherapy more generally; and 2) The support provided to PCPs by Endocrinologists in relation to prescription of type 2 diabetes medications.
Methods: Semi-structured interviews were conducted with 15 PCPs and 12 Endocrinologists working in diverse demographic areas in New South Wales, Australia. A purposive approach was used to recruit PCPs and Endocrinologists. Emergent themes were identified from the transcripts. Interviews were conducted until thematic saturation was reached.
Results: We identified factors contributing to some PCPs’ hesitancy to prescribe SGLT2i. These included an under-appreciation of the cardiovascular and renal benefits of SGLT2i, uncertainty about the role of comparatively new drug classes including SGLT2i, a preference for an Endocrinologist to decide on therapy and patients’ experiences with adverse effects. PCPs expressed a preference to receive education about this topic from Endocrinologists, ideally via case-based discussions. Challenges faced by Endocrinologists in providing education to PCPs included potential constraints on talk content imposed by a pharmaceutical company if speaking at a company-sponsored event (focus being on an individual agent), prioritising time for PCP education, and the need to provide support about other endocrine conditions in addition to diabetes. Several Endocrinologists believed that interactive sessions with PCPs were most useful to PCPs, which could occur virtually.
Conclusion: Despite the evidence for the cardio-renal benefits of SGLT2i, there are barriers to PCPs prescribing these agents. Case-based discussions between PCPs and Endocrinologists about type 2 diabetes treatment including the role of SGLT2i are of great value to PCPs.

Disclosure
T. Milder: None. S. Stocker: Consultant; Self; Nutromics. M. Baysari: None. R. O. Day: None. J. Greenfield: None.

Funding
The Heart Foundation (102279)
782-P: Machine Learning to Identify Diabetes Patients Initiating SGLT2i at High-Risk of Acute Kidney Injury
Authors: YANG LANTING , GABRIEL NICO , HERNANDEZ INMACULADA , WINTERSTEIN ALMUT G. , KIMMEL STEPHEN , GUO JINGCHUAN 
Published: June 2021

One of the main safety concerns associated with SGLT2 inhibitors (SGLT2i) is the increased risk of acute kidney injury (AKI), likely attributed to their diuretic effect and the induced hypovolemia. Yet, little is known about what patients are at highest risk of developing AKI when using SGLT2is. We applied machine learning techniques to predict AKI in type 2 diabetes (T2D) patients treated with SGLT2i and identify risk factors associated with AKI. Using a 5% random sample of Medicare claim data, we identified 17,694 T2D patients who filled ≥1 prescription for canagliflozin, dapagliflozin or empagliflozin prescriptions between 04/01/2013 and 12/31/2016. The cohort was split randomly and equally into training and testing sets. We measured 65 predictor candidates using claims data from the year prior to SGLT2i initiation and applied 3 machine learning models, i.e., random forests (RF), elastic net, least absolute shrinkage and selection operator (LASSO). The incidence rate of AKI was 1.1 % over a median 1.5-year follow up. Among 3 machine learning methods applied, RF produced the best prediction (C- statistic =0.72 ,95% CI 0.68, 0.76), followed by LASSO (C-statistic=0.69 95% CI 0.65,0.73). Among individuals classified in the top 10% of the RF risk score (i.e., high risk group), the actual incidence rate of AKI was as high as 3.7%. RF and LASSO selected similarly sets of important predictors, such as age, Medicaid eligibility, and loop diuretics use. In the logistic regression including 14 predictors selected by LASSO, use of loop diuretics [adjusted OR: 3.72 (2.44, 5.76)] and history of AKI [adjusted OR: 2.78 (1.06,7.3)] had the strongest associations with incidence of AKI. Our machine learning model efficiently identified patients who are at high risk of AKI after SGLT2i initiation. Strikingly, we identified an almost four-fold increased risk of AKI associated with background loop diuretic use among SGLT2i users.

Disclosure
L. Yang: None. N. Gabriel: None. I. Hernandez: Consultant; Self; Bristol-Myers Squibb Company, Pfizer Inc. A. G. Winterstein: Research Support; Self; Merck Sharp & Dohme Corp. S. Kimmel: Consultant; Self; GE Healthcare, GlaxoSmithKline plc. J. Guo: None.
811-P: Durable Insulin Pumps vs. Multiple Daily Injections for Type 1 Diabetes: Health Care Utilization and A1C
Authors: SHAH MONA , ZHU CYRUS , WHERRY KAEL 
Published: June 2021

Objectives: The healthcare utilization benefits associated with insulin pump therapy compared to multiple daily injections (MDI) therapy are not well known. This study sought to compare the impact of using a durable insulin pump versus MDI therapy on healthcare utilization and A1C among individuals with type 1 diabetes (T1D).
Methods: This population-based, longitudinal analysis used a large repository of healthcare claims data to compare diabetes-related and all-cause inpatient admissions (IP) and emergency room (ER) visits in individuals with T1D using durable pumps (N=1,286) versus MDI (N=3,854). The study period was June 1, 2017 to July 31, 2019. The study index date was assigned to the first date of pump use in the pump cohort and a random index date was assigned to the MDI cohort. Continuous insurance enrollment 1-year before and 1-year after adoption/index date was required. Generalized linear model regression was used to test the difference-in-difference effect of therapy type on rates of utilization and A1C. The U.S. Agency for Healthcare Research and Quality (AHRQ) Prevention Quality Indicator (PQI) algorithm was used to define diabetes-related utilization.
Results: Individuals on insulin pump therapy had a significant decrease in IP utilization compared to little change among individuals using MDI therapy (-41% vs. +3%, p=0.01), and similar decreases in ER utilization (-27% vs. -16%, p=0.64). Combining diabetes-related IP and ER utilization, individuals on insulin pump therapy experienced a decrease of 34% compared to decrease of 8% among those using MDI therapy (p= 0.02). Individuals on insulin pump therapy also experienced a larger decrease in A1C (-7% vs. -1%, p=&lt;0.0001).
Conclusions: Compared to MDI therapy, use of a durable insulin pump associated with a significantly smaller increase in diabetes-related healthcare utilization and A1C over time.

Disclosure
M. Shah: Employee; Self; Medtronic. C. Zhu: Employee; Self; Medtronic. K. Wherry: Employee; Self; Medtronic.
825-P: Glycemic Control in Hospitalized Patients Receiving Enteral Nutrition
Authors: HAWKINS R. MATTHEW , SEGGELKE STACEY A. , GIBBS JOANNA , LINDSAY MARK C. , LOW WANG CECILIA C. 
Published: June 2021

Objective: The incidence of hyperglycemia in patients receiving enteral nutrition ranges from 34.5-50% and is associated with increased morbidity and mortality. This study examined glycemic control in hospitalized patients receiving enteral nutrition on insulin therapy.
Methods: Admission level data for all adults (18 years or older) admitted to UC Health Central from Jan 1-Dec 31, 2019 treated with insulin while receiving continuous enteral nutrition were included. Patients were stratified by any pre-existing diagnosis of diabetes mellitus (DM) determined from diagnosis codes prior to the admission date. Blood glucose values from point of care testing performed up to 10 days while receiving enteral nutrition and insulin were included.
Results: A total of 662 patients accounted for 789 admissions in 2019 during which enteral nutrition and insulin were received. For each admission, the longest period of continuous tube feeding up to 10 days was selected, for a total of 5443 days for which data are available. Of the 662 patients, 348 (52.5%) had pre-existing DM (mean±SD 61.5±13.1 years) and 314 (47.4%) did not (mean±SD age 58.2 ±15.2 years); 260 (39.3%) were female and 402 (60.7%) were male. The glucose on days 2, 6, and 10 of enteral nutrition and insulin were 168.3±51.9, 160.1±41.1, and 153.4±38.6 mg/dL, respectively (n=621, 426, and 284 for respective days).. The percentage of inpatient days with a blood glucose value &lt; 70 mg/dL in patients without DM was 2.8% vs. 5.3% in patients with DM (p&lt;0.0001).
Conclusion: Mean glucose improved and variability decreased over time in hospitalized patients with or without diabetes on enteral nutrition and insulin therapy, but the mean glucose was within the goal range of 140-180 mg/dL. Patients without a prior diagnosis of diabetes had a lower percentage of inpatient days with a BG &lt; 70 mg/dL. Further analysis is needed to determine optimal insulin dosing strategies and to improve glycemic control in this population.

Disclosure
R. Hawkins: None. S. A. Seggelke: None. J. Gibbs: None. M. C. Lindsay: None. C. C. Low wang: None.
839-P: Impact of Culturally Specific Care Teams on Mitigation of Racial Disparities in Diabetes Care: A Five-Year EHR-Based Study
Authors: ADAM ATIF , LAU KA HEI KAREN , SHAH HETAL , YU MARC GREGORY , KING GEORGE L. 
Published: June 2021

Cultural and language barriers are known to reduce the likelihood of Asian-American patients (AA) with diabetes achieving recommended goals for HbA1c, blood pressure, and LDL, known as ‘ABCs of DM.’ Our previous study of an integrated Asian clinic for AA (AAC) at Joslin Diabetes Center, showed more AA patients achieving ABC goals 1-year after their initial visit, than whites in the Adult Diabetes clinic (WDC). AAC staff, including MDs, dietitians, educators, and patient coordinators, are all multi-lingual AAs who offer culturally-tailored management approaches. In a 5-year follow-up study between 2014 to 2019, we examined the clinical performance of new patients with T2D, comparing the following groups: AAC (n=166), AA in Adult Diabetes Clinic (ADC) (n=186), and WDC (n=2993). Compared to WDC and ADC, AAC patients were older (P=0.06), had lower BMI (P&lt;0.001), lower education levels (P&lt;0.001), more likely to be on Medicare (P&lt;0.001), more likely to be non-native English speakers, and had significantly more educator sessions (P&lt;0.001). At the initial visit, AAC patients had similar metabolic profiles as ADC and WDC (P=0.50). At the end of 5 years, 32.0% of AAC patients achieved the ABC goals, compared to 23.7% in WDC and 34.6% in ADC. Across all patients, the odds of meeting ABC goals are significantly higher (P&lt;0.01) by having English as a primary language (OR:1.51; 95% CI: 1.19 - 1.26) and not being on Medicare (OR:1.24; 95% CI: 1.09 - 1.41). After adjusting for these factors, over 5-years of follow-up, the odds of AAC patients meeting ABC goals are similar to WDC patients (OR:0.58; 95% CI:0.25- 2.31, P=0.11) and better than ADC patients (OR:1.30, 95% CI:0.98- 3.22; P=0.06). Despite the financial, language, and educational disadvantages, AAC patients have achieved similar ABC targets as WDC and ADC patients. These findings suggest that culturally-specific care for AA can mitigate healthcare disparity in T2D management and can be maintained over prolonged periods of time.

Disclosure
A. Adam: None. K. Lau: None. H. Shah: None. M. Yu: None. G. L. King: Consultant; Self; Agios, Inc., Medtronic, Other Relationship; Self; Janssen Pharmaceuticals, Inc.