bluuebunny/crossref_metadata_2025_split huggingface dataset:
83-LB: Pharmacokinetic and Pharmacodynamic Studies of Supaglutide in Rats and Monkeys
Authors: LIAO YIJING , MA ANRAN , WANG ZHIHONG , ZHOU YUE , ZHANG LI , LIU LIN , ZHANG NA , PRUD’HOMME GERALD J. , WANG QINGHUA 
Published: May 2022

Supaglutide, a novel GLP-1-IgG Fc fusion protein, exerts hypoglycemic effects in type 2 diabetic db/db mice and spontaneous diabetic monkeys. In this study, we investigated the pharmacokinetics and pharmacodynamics of supaglutide by single or repeated subcutaneous and intravenous injection (s) in rats and rhesus monkeys. We found that the half-life of supaglutide at 0.1 mg/kg in rhesus monkeys was 39.7 hours and 35.8 hours upon subcutaneous or intravenous administration, respectively. The plasma supaglutide peaked at 8-10 hours, while the plasma drug exposure levels increased with the increase of dose, showing approximately a linear pharmacokinetic characteristic. The elimination kinetics was similar between subcutaneous (∼0.025 in rats and ∼0.018 in monkeys) and intravenous administration (0.021 in rats and 0.020 in monkeys) , whereas the bioavailability was found to be 31.1% in rats and 63.9% in monkeys. In monkeys, the marked glucose-lowering effect of a single dose injection of supaglutide peaked at 14-16 hours and lasted for 72 hours. 125I-supaglutide distributed mainly in the serum and organs rich in blood supply. Urine was found to be the primary excretion route of supaglutide, following by feces, but the least by bile. Our results demonstrate that supaglutide has an excellent pharmacokinetic profile with prolonged hypoglycemic effects and is a potential weekly dosing therapeutic agent for the treatment of type 2 diabetes.

Disclosure
Y. Liao: None. A. Ma: None. Z. Wang: None. Y. Zhou: None. L. Zhang: None. L. Liu: None. N. Zhang: None. G. J. Prud’homme: None. Q. Wang: None.
834-P: Two-Year Effects of Carbohydrate-Restricted Nutrition Therapy Delivered via Continuous Remote Care among Veterans with Type 2 Diabetes: A Nationwide, Real-World Study
Authors: MCKENZIE AMY L. , VANTIEGHEM MICHELLE , FELL BRANDON , RATNER ROBERT E. 
Published: May 2022

Type 2 diabetes (T2D) affects about one in four Veterans, a rate nearly three times the general population, and diabetes medications and supplies constitute about one quarter of these Veterans’ pharmacy spend. The Veterans Health Administration partnered with Virta Health to provide carbohydrate restricted nutrition therapy via a continuous remote care model to Veterans in a pilot program. Five-month outcomes demonstrated significant reductions in HbA1c, BMI, diabetes medications and cost, and outpatient visits, but long term sustainability in this population is unknown. This retrospective, real-world, longitudinal analysis assessed the 1- and 2-year effects of the treatment on glycemia, diabetes medications, and body weight using medical record data. Veterans retained at least two years at time of analysis were included (n=254, 58.5% of 434 eligible enrolled, 60±8 years, 12% female) . With initiation of nutritional intervention, glycemia fell necessitating medication titration and elimination to prevent hypoglycemia. The number of diabetes medications prescribed to each person significantly decreased from 2.4±0.9 to 1.3±0.9 and 1.6±0.8 at one and two years, respectively (ps&lt;0.0001) . Despite this significant reduction in pharmacologic therapy, HbA1c was significantly reduced at one year (-0.7±1.6%, p&lt;0.0001) and two years (-0.6±1.7%, p&lt;0.0001) compared to enrollment (8.1±1.5%) . Body weight also declined from 241.1±50.1 lb to 223.2±44.4 lb at one year and 222.1±46.8 lb at two years (ps&lt;0.0001) , reflecting 6.8±7.6% and 7.0±9.4% weight loss per person at one and two years, respectively. These findings demonstrate that sustained improvement in glycemia concurrent with medication deprescription and clinically significant weight loss are achievable in the real world among Veterans who choose this therapy.

Disclosure
A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. M.Vantieghem: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. B.Fell: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.E.Ratner: Employee; Virta Health Corp.
839-P: Pharmacological Inhibition of Mammalian INDY Ameliorates Western Diet–Induced NASH in Mice: Possible Implication of Fgf21-AMPK Signaling
Authors: EL-AGROUDY NERMEEN , ZAHN GRIT , HERRMANN CHRISTINE , MINGRONE GELTRUDE , ALVES TIAGO C. , BIRKENFELD ANDREAS L. 
Published: May 2022

Background: Recent data proposed a role of the citrate transporter INDY (I’m Not Dead Yet) in the development of obesity, insulin resistance and NAFLD suggesting its potential as a therapeutic target for metabolic-related disorders. The aim of our study is to determine if mammalian INDY (mINDY) inhibitors can be introduced as a new therapeutic option for NAFLD/NASH.
Methods: Six-week-old C57Bl/6N mice were fed a western diet (WD) for 18 weeks to induce NASH. After 12 weeks of feeding, mice received mINDY inhibitor (PF-06649298, mINDYi; 100 mg/kg) or vehicle bid until end of week 18. During the treatment period, body weight and composition were monitored. ipGTT and FACS analysis of liver inflammatory cells were performed.
Results: mINDYi-treated mice exhibited lower body weight, fat mass and higher lean mass compared to vehicle-treated mice. Results from ipGTT revealed improved glucose tolerance and insulin sensitivity. The latter was further confirmed through increased insulin-stimulated Akt phosphorylation in liver, gonadal WAT and BAT. Treatment with mINDYi attenuated WD-induced hepatic injury, steatosis and inflammation as shown histologically and biochemically by reduction in plasma ALT and AST, decrease in hepatic triglyceride accumulation and reduced hepatic lymphoid and myeloid immune cell populations. Interestingly, these effects were associated with a significant rise in plasma and hepatic Fgf21 together with increased hepatic phosphorylation of LKB1 and AMPK and decreased mTOR. Results from primary mouse hepatocytes revealed that mINDYi-induction of Fgf21 is partially dependent on AMPK activation.
Conclusion: Our study shows for the first time that mINDYi attenuates diet-induced steatohepatitis; offering a promising novel treatment strategy for NAFLD. Further investigations are currently ongoing to elucidate the molecular mechanisms underlying mINDY inhibition and whether it is dependent on Fgf21-AMPK signaling.

Disclosure
N.El-agroudy: None. G.Zahn: Employee; Eternygen GmbH. C.Herrmann: None. G.Mingrone: Advisory Panel; Fractyl Health, Inc., Novo Nordisk, Consultant; ReCor Medical, Inc. T.C.Alves: None. A.L.Birkenfeld: None.
854-P: Statin Use and New-Onset Diabetes in People with Prediabetes
Authors: PARK JEAN Y. , GHAZI ADLINE , PITTAS ANASTASSIOS G. , VICKERY ELLEN , NELSON JASON P. , ARODA VANITA R. ,   D2D RESEARCH GROUP
Published: May 2022

Statins lower the risk of cardiovascular disease, yet may adversely affect glucose metabolism. In the D2d study, which evaluated the effect of vitamin D versus placebo in a contemporary cohort of people with high-risk prediabetes (n=2,423) , we evaluated the association between statin use at baseline and progression to diabetes.
In the D2d study, 1396 participants (58%) were on statin at baseline. Kaplan Meier curves of incident diabetes over 2.5 years by baseline status of statin use and adjusted hazard ratio (95%CI) of the difference in incident diabetes between statin and no statin use were estimated. We tested for a statin use * D2d assignment (vitamin D or placebo) interaction on incident diabetes.
Mean age (SD) was 57±years and 64±8 for those not on vs. on statin; baseline HbA1c was 5.9 ± 0.2% in both groups. 27% of statin users developed diabetes vs. 24% of non-statin users (adjusted HR [95%CI] 1.23 [1.04-1.46]) (Figure) . There was no significant interaction (p=0.67) with vitamin D treatment assignment; therefore, subgroup analyses by D2d treatment assignment are not presented.
Conclusions: In this observational analysis among people at high risk for diabetes, baseline statin use was associated with a 23% higher risk of progression to diabetes after 2.5 years compared to no use. Increased risk of diabetes progression should be considered along with the cardiovascular benefits of statin therapy and diabetes prevention measures re-enforced.

Disclosure
J.Y.Park: None. A.Ghazi: None. A.G.Pittas: None. E.Vickery: None. J.P.Nelson: None. V.R.Aroda: Consultant; Applied Therapeutics, Fractyl Health, Inc., Novo Nordisk, Pfizer Inc., Sanofi, Other Relationship; Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Research Support; Applied Therapeutics, Fractyl Health, Inc., Novo Nordisk, Sanofi. D2d research group: n/a.

Funding
American Diabetes Association (1-14-D2d-01) ; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases and Office of Dietary Supplements (U01DK098245)
856-P: Cardiovascular (CV) and Kidney Outcomes with Canagliflozin (CANA) According to Type 2 Diabetes (T2D) Treatment Targets at Baseline (BL) : Data from the CANVAS Program and CREDENCE
Authors: WOO VINCENT C. , TSOUKAS MICHAEL , TOBE SHELDON , SLEE APRIL , RAPATTONI WALLY , ANG FERNANDO , SEUFERT JOCHEN , WHEELER DAVID C. 
Published: May 2022

In T2D, treatment targets include maintaining HbA1c ≤7.0%, LDL-C &lt;2 mmol/L (&lt;77 mg/dL) , and BP &lt;130/80 mmHg. It is also recommended to improve urinary albumin:creatinine ratio (UACR) , a marker of renal damage and CV risk. We examined effects of CANA vs. placebo on CV and kidney outcomes in patients with T2D and high CV risk and/or chronic kidney disease according to BL treatment targets and risk factors. Pooled data from the CANVAS Program (N=10,142) and the CREDENCE trial (N=4401) were analyzed according to treatment target achievement and by number of targets achieved at BL. Hazard ratios and 95% CIs were estimated using Cox regression models. Of 14,432 participants at BL, 3683 (26%) had achieved 0, 5851 (41%) had achieved 1, 3680 (25%) had achieved 2, and 1218 (8%) had achieved either 3 or 4 targets. At BL, 8415 (58%) participants had UACR &gt;2 mg/mmol. CANA consistently reduced risk of MACE, HHF/CV death, and ESKD or doubling of serum creatinine vs. placebo, regardless of whether BL targets were met or if UACR was elevated (Figure) . The number of uncontrolled targets at BL did not impact the beneficial effect of CANA on CV and kidney outcomes (all P interaction &gt;0.17) .
In conclusion, CANA demonstrated consistent CV and renal benefits in patients with T2D, regardless of risk factor control.

Disclosure
V.C.Woo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk, Speaker's Bureau; Janssen Pharmaceuticals, Inc. M.Tsoukas: Speaker's Bureau; AstraZeneca, Bausch Health, Canada, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Johnson & Johnson, Novo Nordisk Canada Inc. S.Tobe: Other Relationship; Bayer AG, Speaker's Bureau; AstraZeneca, Otsuka Pharmaceutical Co., Ltd. A.Slee: Consultant; Alydia Health, Elixir Medical , IHP Therapeutics , iLumen Scientific, Intuitive Surgical, Janssen Global Services, LLC, Laborie, Providence Medical, Pulse Biosciences, SonoMotion. W.Rapattoni: Employee; Janssen Pharmaceuticals, Inc. F.Ang: Employee; Bristol-Myers Squibb Company, Janssen Pharmaceuticals, Inc. J.Seufert: Advisory Panel; Abbott, Sanofi-Aventis Deutschland GmbH, Research Support; Boehringer Ingelheim International GmbH, Speaker's Bureau; Abbott Diabetes, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. D.C.Wheeler: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., GlaxoSmithKline plc., Janssen Global Services, LLC, Merck Sharp & Dohme Corp., Mundipharma, Tricida, Inc., Vifor Pharma Management Ltd., Consultant; AstraZeneca, Speaker's Bureau; Amgen Inc., Astellas Pharma Inc.

Funding
Janssen Inc., Toronto, ON, Canada
879-P: Effect of Combined SGLT2 Inhibitor and DPP-4 Inhibitor Therapy on the Production of Advanced Glycation End Products
Authors: KUSUNOKI MASATAKA , WAKAZONO NAOMI , HISANO FUMIYA , MIYATA TETSURO 
Published: May 2022

SGLT2 inhibitors (SGLT2is) prevent disease progression in diabetic patients with atherosclerotic disease. On the other hand, a similar beneficial effect on disease progression has not been reported for DPP-4 inhibitors (DPP-4is) , which are, however, widely used. To clarify the differences in effects between these two classes of drugs in diabetic patients, we focused on the production of advanced glycation end products (AGEs) and studied the effects of pretreatment with DPP-4i on the production of AGEs in patients who subsequently received SGLT2i. In the present study, Japanese patients with type 2 diabetes mellitus with unchanged glycemia control status for at least 6 months were administered SGLT2i (n = 11) for 3 months and then divided into a group that had already been receiving DPP-4i (n = 11) at the start of administration of the SGLT2i and the SGLT2i monotherapy group. We measured the blood levels of methylglyoxal-derived hydroimidazolone-1 (MG-H1) , which is an AGE, and also diabetes-related parameters before the start and after 3 months’ treatment with the SGLT2i. As a result, significant decreases of both HbA1c (from 8.6 ± 1.4 to 7.2 ± 1.4, P &lt; 0.01) and circulating MG-H1 levels (from 0.48 ± 0.to 0.44 ± 0.07, P &lt; 0.05) were observed in the SGLT2i monotherapy group. On the other hand, in the group that received SGLT2i in addition to a DPP-4i, the HbA1c value decreased significantly (from 7.2 ± 0.4 to 6.8 ± 0.5, P &lt; 0.01) , whereas no significant change of the MG-H1 level was observed after the SGLT2i therapy. In conclusion, SGLT2i monotherapy decreased both the HbA1c and blood MG-H1 levels. However, no significant effect on the blood level of MG-H1 was observed in the combined DPP4i plus subsequent SGLT2i therapy group, suggesting that DPP4i possibly suppress the effect of the SGLT2i in reducing the production of MG-H1.

Disclosure
M.Kusunoki: Other Relationship; Taisho Pharmaceutical Holdings Co., Ltd. N.Wakazono: None. F.Hisano: None. T.Miyata: None.
88-LB: Safety, PK, PD, and Efficacy of Weekly Dosing Supaglutide in Patients with T2D
Authors: ZHOU YUE , JIANG XIN , LOU YAN-RU , MA ANRAN , LI JIA , ZHAO YING , PRUD’HOMME GERALD J. , WANG QINGHUA 
Published: May 2022

Supaglutide (Supa) is a weekly dosing GLP-1 analog. We conducted a randomized, double-blind, placebo-controlled, multiple dose-escalation study to investigate the safety, PK/PD and efficacy of Supa in patients with T2D. 40 subjects were randomized in a 4:1 ratio to receive Supa (sc., 1, 2, 3 and 4mg) or placebo. We performed intensive PK blood sampling for two weeks after the first dose, followed by weekly repeated dosing for 4 consecutive weeks. The 4mg group received an adaptive dose of 1mg to reduce gastrointestinal reactions. The PK results revealed that the T1/2 of Supa was ∼207 h with median Tmax of 60∼84 h. The PD results showed that after 7 weeks of therapy, Supa significantly reduced fasting blood glucose, and HbA1c decreased by 1.3%. Supa increased fasting insulin/C-peptide while decreasing body weight. OGTT results showed significantly reduced glucose excursion, and the glucose-stimulated insulin secretion assay demonstrated significantly increased insulin secretion, suggesting improved glucose tolerance and enhanced β-cell function. AEs identified during the study were mainly mild to moderate gastrointestinal symptoms. None of the subjects developed anti-drug antibodies. Safety assessments including AEs, vital signs, ECGs and laboratory parameters, revealed that Supa was safe and well-tolerated. These data suggest Supa is a novel alternative therapy for T2D and metabolic disorders.

Disclosure
Y. Zhou: None. X. Jiang: None. Y. Lou: None. A. Ma: None. J. Li: None. Y. Zhao: None. G. J. Prud'homme: None. Q. Wang: None.
883-P: Associations of State Earned Income Tax Credits with Self-Reported Health Status among U.S. Adults with Diabetes, 2000–2016
Authors: TANG SHICHAO , CHEN YU , ROLKA DEBORAH B. , IMPERATORE GIUSEPPINA , HOLLIDAY CHRISTOPHER S. , ZHANG PING 
Published: May 2022

Persons with low socioeconomic status are disproportionately affected by diabetes and among people with diabetes, those with lower incomes tend to have poorer health status than those with higher incomes. Few studies have examined whether policies to improve the financial status of low-income populations can improve health outcomes among people with diabetes. Using data on state earned income tax credit (EITC) policies from the National Bureau of Economic Research and self-reported health status from the 2000-2016 Behavioral Risk Factor Surveillance System (BRFSS) , we examined the association of state EITC with poor health status among United States (US) adults with self-reported diagnosed diabetes. Poor overall health was defined as self-reported general health status of “fair” or “poor” in BRFSS. Poor mental and physical health were defined as having at least 14 self-reported days in poor mental or poor physical health in the past 30 days, respectively. State EITC was defined as the state’s EITC amount as a percentage of the federal EITC. We used weighted logistic regression to model the effect of EITC variation across states and over years and calculated the marginal effects of state EITC on health status, controlling for poverty, race, education, unemployment, state gross domestic product (GDP) , state Medicaid expansion, and state minimum wage policy. Poisson regression models were conducted as a sensitivity analysis. A 10-percentage point increase in the state EITC was associated with a 3% lower rate of poor mental health status (-2,759 per 100,000, 95% CI = -5,494, -25) . The associations of the state EITC with physical health and overall health status were not statistically significant. The results were robust to choice of model based on the sensitivity analysis. Policies that increase income retained may help to improve self-reported mental health status of US adults with diabetes.

Disclosure
S.Tang: None. Y.Chen: None. D.B.Rolka: None. G.Imperatore: None. C.S.Holliday: None. P.Zhang: None.
886-P: Development and Validation of the Diabetes Outcome Model for the U.S. (DOMUS)
Authors: WINN AARON N. , HUANG ELBERT , CLARKE PHILIP , KARTER ANDREW J. , WAN WEN , MILLER DONALD R. , FRANCO MELISSA , DECKARD AMBER , LAITEERAPONG NEDA 
Published: May 2022

Purpose: The purpose of this study is to develop a diabetes outcomes model for the US (DOMUS) using a multi-ethnic, real-world-data cohort of newly diagnosed Type II diabetics that can predict outcomes for a U.S. multi-ethnic type 2 diabetes population.
Methods: The Kaiser Permanente Northern California (KPNC) Diabetes Registry, which is a well-described epidemiologic cohort with up to 13 years of follow-up from EMR and claims, were used to identify over 150,000 newly diagnosed diabetes patients between 2005-2016 with up to 13-year follow-up. The DOMUS model integrates separate, but interdependent risk equations to predict events for each of the micro and macro-vascular events, hypoglycemia, dementia, depression, and death, and predictive models for eight biomarker levels. Model accounted for static demographic factors (e.g., race) , neighborhood deprivation, and dynamic factors, such as age, duration of diabetes, fifteen-possible glucose -lowering treatment combinations, biomarker levels, and history of diabetes-related events. Moreover, the models explicitly allow for a legacy effect (average A1c in the first year after diagnosis) for all outcomes.
Results: Data were randomly split into 75,000, 18,750, and 18,750 patients to perform estimation, out-of-sample calibration, and validation respectively. Model predictions in the validation sample closely aligned with the observed longitudinal trajectory of biomarkers and outcomes. Moreover, we examine the model performance within by age, race/ethnicity, and sex and found excellent predictive performance within subgroups.
Conclusion: The DOMUS Model is able to simulate event histories and biomarker trajectories that closely match observed outcomes in a real-world, multi-ethnic population of newly diagnosed diabetics. DOMUS has the potential to carry out many complex analyses that examine the effectiveness and cost-effectiveness of new medications, value of diabetes prevention, and serve as decision support tools in health care settings.

Disclosure
A.N.Winn: Consultant; Takeda Pharmaceutical Company Limited. E.Huang: Advisory Panel; Twin Health, Stock/Shareholder; AbbVie Inc. P.Clarke: None. A.J.Karter: Research Support; Dexcom, Inc. W.Wan: n/a. D.R.Miller: None. M.Franco: None. A.Deckard: None. N.Laiteerapong: None.
893-P: Incremental Health Care Utilizations and Medical Expenditures Associated with Cognitive Impairment among Older Adults with Diabetes
Authors: GUAN DAWEI , ZHANG PING , TANG SHICHAO , BROWN JOSHUA D. , FANG RUOGU R. , GUO JINGCHUAN , ZHANG YONGKANG , SHAO HUI 
Published: May 2022

Cognitive impairment (CI) poses a large economic burden on the US health care system, but little is known about how CI impacts health care (HC) utilization and medical expenditures among people with diabetes. Using data from the 2016-20Medical Expenditure Panel Survey, we quantified the incremental HC utilization and medical expenditures associated with CI among adults aged ≥ 60 years with diabetes. Diabetes status was based on self-report. Participants who reported having difficulty concentrating, remembering, or making decisions were defined as having CI. We used negative binomial regressions to model the number of ambulatory visits, prescriptions, and home health care days; logistic regressions to model the probabilities of ER visits and hospital admissions; and gamma regressions to model medical expenditures in total and by category. All models were adjusted for age, sex, race and ethnicity, income, education, and comorbidities. We included 6,714 adults ≥ 60 years with diabetes, of which 1,025 (15.27%) had CI. CI was associated with additional ambulatory visits (+4.7 [95% CI, 3.5-5.8]) , drug prescriptions (+10.6 [8.1-13.1]) , and home health care days (+32.6 [19.2-52.2]) ; and higher odds of ER visits (Odds Ratio (OR) : 1.55 [95% CI, 1.27-1.89]) and hospital admissions (OR: 1.27 [1.02-1.58]) . CI was also associated with additional expenditures for outpatient care (+$12[$731-$1720], or 28% higher than those without CI [17%-40%]) , prescription drugs (+$17[$1103-$2372], or 31% higher [20%-43%]) , and home health care (+$25[$445-$7060], or 197% higher [35%-555%]) . Overall, those with CI spent $70[$5168-$8835], or 42% [31%-53%] more than those without CI. All p &lt; 0.05. CI is associated with higher HC utilization and medical expenditures among older adults with diabetes. Early detection of CI and additional assistance to those with CI may lower CI-related HC utilization and expenditure in this population.

Disclosure
D.Guan: None. P.Zhang: None. S.Tang: None. J.D.Brown: None. R.R.Fang: None. J.Guo: None. Y.Zhang: None. H.Shao: Board Member; BRAVO4HEALTH, LLC.