bluuebunny/crossref_metadata_2025_split huggingface dataset:
38-OR: Differences in Diabetes Medication Use between Commercial and Medicare Advantage Beneficiaries, 2013-2018
Authors: MCCOY ROZALINA G. , HOUTEN HOLLY VAN , ROSS JOSEPH , KARACA-MANDIC PINAR , MONTORI VICTOR M. , SHAH NILAY 
Published: June 2020

DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors have low hypoglycemia risk, do not cause weight gain, and post-marketing outcomes trials found cardiovascular and renal benefits with GLP-1RA and SGLT2i use. Using 2013-2016 data, we previously found low and delayed early adoption of SGLT2i among Medicare Advantage (MA) beneficiaries compared to commercial beneficiaries, despite similar formulary coverage. With greater experience using these medications and emerging evidence supporting their preferred use by patients with comorbidities, prescribing patterns may have changed. Using OptumLabs Data Warehouse, a de-identified dataset of commercial and MA beneficiaries, we examined the proportions of pharmacologically-treated adults with type 2 diabetes with commercial vs. MA insurance who filled a DPP-4i, GLP-1RA, or SGLT2i each quarter between 2013-2018. We found significant differences across medications and health plans (Figure). Overall, after adjusting for age, gender, race/ethnicity, baseline medications, year, prescriber specialty, and comorbidities, the odds of DPP-4i, GLP-1RA, and SGLT2i use were significantly lower for MA vs. commercial beneficiaries: OR 0.61 (95% CI 0.60-0.63), 0.45 (95% CI 0.44-0.46), and 0.31 (95% CI 0.30-0.31), respectively. These findings call for better understanding of non-clinical factors contributing to treatment decisions.

Disclosure
R.G. McCoy: None. H. Van Houten: None. J. Ross: Research Support; Self; Centers for Medicare and Medicaid Services, Janssen Pharmaceuticals, Inc., U.S. Food and Drug Administration. P. Karaca-Mandic: None. V.M. Montori: None. N. Shah: None.

Funding
National Institutes of Health (K23DK114497); Agency for Healthcare Research and Quality (1U19HS024075, R01HS025164)
386-P: Acute Hypoglycemia Does Not Alter Serum Levels of Amyloid-Related Proteins Associated with Dementia
Authors: MOIN ABU , SATHYAPALAN THOZHUKAT , ATKIN STEPHEN , BUTLER ALEXANDRA E. 
Published: June 2020

Objective: Hypoglycemia is a common complication of tighter glucose control regimens in type 2 diabetes (T2D) and may increase the risk of dementia, Alzheimer’s disease being the most common form. We measured amyloid-related proteins during induced hypoglycemia in a cohort of subjects with and without T2D, hypothesizing that these protein levels would be further elevated during hypoglycemia in T2D subjects.
Methods: A prospective, parallel study was conducted in individuals with T2D (n=23) and controls (n=22). Hypoglycaemia (&lt;2.2mmol/l: &lt;40mg/dl) was achieved by intravenous infusion of soluble insulin. Blood samples were collected at baseline and at 0, 30, 60, 120, 240 minutes and 24 hours following hypoglycaemia and proteomic (Somalogic) analysis of four amyloid-related proteins (Amyloid P component [APCS], Amyloid precursor protein [APP], Pappalysin [PAPPA] and Serum amyloid A1 [SAA1]) at baseline, at hypoglycemia and at 24-hours post-clamp was undertaken.
Results: No changes from baseline in serum levels of the four amyloid-related proteins were seen in subjects with or without T2D, either at the time of hypoglycemia or at 24-hours post-clamp.
Conclusions: Induced hypoglycemia is not associated with a significant increase in serum levels of amyloid-related proteins. Thus, no clear mechanistic link based on serum proteins between T2D-related hypoglycemic episodes and Alzheimer’s disease emerged from this study, although it is important to consider that protein levels in the cerebrospinal fluid may differ.

Disclosure
A. Moin: None. T. Sathyapalan: Research Support; Self; Amgen, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S. Other Relationship; Self; Ipsen Biopharmaceuticals. S. Atkin: None. A.E. Butler: None.
417-P: Impact of Preventative Therapies on the Extent of Coronary Artery Disease in People with and without Diabetes
Authors: KIBURG KATERINA V. , MACISAAC ANDREW I. , MCCLUSKEY GEORGIA E. , SUNDARARAJAN VIJAYA , MACISAAC RICHARD 
Published: June 2020

Objective: To assess the impact of preventative therapies on the extent of coronary artery disease (CAD) in people with and without diabetes in a real-world setting.
Research Design and Methods: Patient-level linked coronary angiography and hospital separation data at a large Australian tertiary referral hospital between 2013 and 2019 were obtained and a random sample of patient charts reviewed for medication use (renin-angiotensin system (RAS) inhibitors, statins and antiplatelets). Indication for angiography and extent of CAD were based on the original classification by treating cardiologists, classified as no disease, mild, moderate or severe. Propensity scores were estimated and used to weight in the ordinal logistic regression models. Models were fitted to assess trends in CAD severity in people with and without diabetes with adjusted odds ratios (adjOR) reported.
Results: For 805 people identified in the coronary angiography database with medication use information available, 386(48%) were diagnosed with diabetes. Angiographic evidence of CAD was found in 297(71%) and 301(78%) of people without and with diabetes, respectively. People with diabetes were at an increased risk of more extensive CAD disease compared to people without diabetes (adjOR: 1.37 95% C.I. 1.00, 1.88). However, when adjusted for the use of RAS inhibitors, statins and antiplatelets there was no difference in the extent of CAD between people with and without diabetes (adjOR: 1.22 95% C.I. 0.87, 1.69).
Conclusions: These findings highlight the increased risk that people with diabetes have for more extensive CAD than people without diabetes. Our results also suggest that with the aggressive and appropriate use of traditional cardiovascular disease preventative therapies it may be possible to significantly reduce the excess CAD burden observed in people with diabetes.

Disclosure
K.V. Kiburg: None. A.I. MacIsaac: None. G.E. McCluskey: None. V. Sundararajan: None. R. MacIsaac: None.
450-P: Development and Validation of a Predictive Major Adverse Cardiac Events (MACE) Risk Model for Diabetes Patients with Acute Coronary Syndrome (ACS)
Authors: HU PENGWEI , DI XIN , ZHANG YUAN , TANG ZEFANG , LI SHAOCHUN , MEI JING , MA CHANGSHENG 
Published: June 2020

Background: Studies have shown that acute coronary syndrome (ACS) has a higher incidence of MACE in diabetic patients than in nondiabetic patients by 39%. The complexity of the MACE limits clinical predictions, the success rate is shallow. Several existing MACE risk prediction models, including some developed specifically for ACS patients, also stuck with low accuracy and are not suitable for complications scenarios.
The objective of this study is to develop and validate a model based on EHR data to predict MACE risk in patients with type 2 diabetes mellitus (T2DM) complicated with ACS.
Methods: This study recruited 16,807 in-hospital T2DM patients with ACS from 38 urban and rural hospitals. Patients with 41 variables, including age, demographics, living habits, ACS type, and Killip class. The criteria for the diagnosis of MACE developed for this study consider cardiovascular death, myocardial infarction, or ischemic stroke. There are 711 MACE records diagnosed by doctors during patients’ hospitalization and recorded in medical records, only 4.2% of the total cohort. Very low morbidity inspires us to introduce a model called Support Vector Data Description (SVDD) to combat this uneven distribution of data. SVDD only maps the features of MACE patients to the high-dimensional space and constructs a minimum sphere to contain all the target data, taking the sphere as the boundary to classify the risk of newly admitted patients. Models were developed and validated on 80% and 20% of the sample, respectively. The model performance was assessed by C-statistics and the F1.
Results: The model performed with C-statistics of 0.873 and F1 of 0.833. We found 5 variables had a significant univariate association with MACE included Age, Heart rate, Killip class, white blood cell count and Creatinine at p&lt;10-4.
Conclusions: This novel study suggests that the well trained SVDD model would be possible to predict the harmful MACE among T2DM patients with ACS.

Disclosure
P. Hu: None. X. Di: None. Y. Zhang: None. Z. Tang: None. S. Li: None. J. Mei: None. C. Ma: None.
482-P: The GLP-1 Receptor Agonist Liraglutide Improves Glomerular Filtration Rate, Renal Inflammation, and Fibrosis in the Type 2 Diabetic SDT Fatty Rat
Authors: BRIAND FRANCOIS , SHINOHARA MASAMI , BROUSSEAU EMMANUEL , KAGEYAMA YASUSHI , SULPICE THIERRY 
Published: June 2020

The Glucagon-Like Peptide 1 (GLP-1) receptor agonist liraglutide (LIRA) may reduce the rate of development and progression of diabetic kidney disease in type 2 diabetic patients. To evaluate its impact on kidney function, we evaluated the effects of LIRA on glomerular filtration rate (GFR), in both the hyperfiltration and GFR decline phases in the Spontaneously Diabetic Torii (SDT) fatty rat, a preclinical model of type 2 diabetes. SDT fatty male rats were treated subcutaneously, once daily with vehicle or LIRA 0.4mg/kg for 10 weeks. To measure the effects of LIRA on glomerular hyperfiltration, rats were injected with FITC-sinistrin at 4 weeks of treatment to measure GFR. After 5 weeks of treatment, rats underwent unilateral nephrectomy and were put on a 0.3% salt diet to induce a GFR decline for the last weeks of treatment, then GFR was measured at 10 weeks of treatment. Urine biochemistry and kidney histology analysis were also performed. Compared with vehicle, LIRA resulted in significant body weight loss and lower body weight. LIRA also reduced blood glucose levels significantly by up to ∼20%, as expected. During the hyperfiltration phase, LIRA attenuated hyperfiltration, with a 19% lower GFR vs. vehicle (vehicle: 21 ± 1.1 mL/min/kg; LIRA: 17.1 ± 1.0 mL/min/kg, p&lt;0.05 vs. vehicle). In vehicle treated animals, unilateral nephrectomy and 0.3% salt diet induced a major reduction (-56%) in GFR, as expected. After 10 weeks of treatment, LIRA markedly attenuated this GFR decline (vehicle: 9.3 ± 0.5 mL/min/kg; LIRA: 13.3 ± 0.9 mL/min/kg, p&lt;0.001 vs. vehicle). In line with the benefits observed on GFR, LIRA lowered urine albumin to creatinine ratio both in the hyperfiltration and GFR decline phases. Moreover, histology analysis showed that LIRA significantly reduced kidney inflammation and fibrosis scores, as compared with vehicle.
In conclusion, LIRA shows significant benefits on GFR, renal inflammation and fibrosis in the SDT fatty rat model.

Disclosure
F. Briand: Employee; Self; Physiogenex. Stock/Shareholder; Self; Physiogenex. M. Shinohara: None. E. Brousseau: Employee; Self; Physiogenex. Y. Kageyama: None. T. Sulpice: Employee; Self; Physiogenex. Stock/Shareholder; Self; Physiogenex.
499-P: Clinical Validation of an AI-Enabled Prognostic Test (KidneyintelX) to Accurately Predict Rapid Kidney Function Decline in Patients with Type 2 Diabetic Kidney Disease
Authors: CHAN LILI , NADKARNI GIRISH N. , FLEMING FERGUS , SALEM FADI E. , MURPHY BARBARA , DONOVAN MICHAEL J. , COCA STEVEN , DAMRAUER SCOTT M. 
Published: June 2020

The ability to predict rapid kidney function decline (RKFD) in patients with early stages of type 2 diabetic kidney disease (T2DKD) can improve long-term health outcomes through earlier intervention. Our objective was to develop a robust risk score for patients with early stages of T2DKD. We obtained EHR and plasma from patients with T2DKD (Kidney Disease Improving Global Outcomes [KDIGO] G1-G2, A2-A3 or G3a-G3b, A1-A3) from the Mount Sinai BioMe Biobank and the Penn Medicine Biobank and measured soluble tumor necrosis factor receptor (sTNFR1, sTNFR2) and kidney injury molecule-1 (KIM-1) via a validated quantitative electrochemiluminescent assay. A machine learning model was trained using the EHR/biomarker data to predict RKFD, defined as eGFR decline of ≥5 ml/min/year or ≥40% sustained decline in eGFR or kidney failure within 5 years, and performance was compared to a clinical model and KDIGO risk-matrix. A total of 1146 subjects with a mean age of 63, baseline eGFR 54 ml/min, and median UACR 61 mg/g were randomly divided into 60% training (n=686) and 40% validation (n=460) sets. The median follow-up was 4.3 years and 241 (21%) experienced RKFD. The AUC of KidneyIntelX for RFKD was 0.85 (95% CI 0.84-0.86) in training and 0.77 (95% CI 0.76-0.79) in the validation set vs. AUC of 0.67 (95% CI 0.64-0.70) for a clinical model. Using pre-specified cutoffs from the training set, KidneyIntelX stratified 47%, 37% and 16% of the validation set into low-, intermediate- and high-risk strata, with a PPV of 62% (vs. 41% for KDIGO) in the high-risk group (p &lt;0.001), a net reclassification improvement for events of 41% (p &lt;0.05), and a NPV of 91% in the low-risk group (vs. 85% for KDIGO). KidneyIntelX, a machine learning model combining biomarkers and EHR data, improved prediction of RKFD over standard clinical metrics in patients with T2DKD. Future studies will prospectively evaluate KidneyIntelX in clinical decision-making and impact.

Disclosure
L. Chan: None. G.N. Nadkarni: Advisory Panel; Self; Renalytix AI. Consultant; Self; AstraZeneca, Reata, Renalytix AI. Stock/Shareholder; Self; Renalytix AI. Other Relationship; Self; Renalytix AI. F. Fleming: Board Member; Self; Renalytix AI plc. F.E. Salem: None. B. Murphy: Board Member; Self; RenalytixAI. M.J. Donovan: Consultant; Self; Renalytix AI plc. S. Coca: Advisory Panel; Self; Renalytix AI plc. Consultant; Self; Bayer Healthcare Pharmaceuticals Inc., CHF Solutions, Relypsa, Inc., Takeda Pharmaceutical Company Limited. Stock/Shareholder; Self; Renalytix AI plc. S.M. Damrauer: Consultant; Spouse/Partner; Rhythm Pharmaceuticals. Research Support; Self; CytoVas LLC, Renalytix AI plc.

Funding
Renalytix AI plc
517-P: Serum Galectin-3 and the Risk of Rapid Renal Function Decline in Type 2 Diabetes
Authors: TAN KATHRYN C.B. , ALAN LEE CHUN HONG , WONG YING , SHIU SAMMY 
Published: June 2020

Background and Aims: Galectin-3 is a broad-spectrum biological response modifier and belongs to the multifunctional galectin family. It is involved in tissue fibrosis, immunity, and inflammatory response and recent evidence suggests that galectin-3 is associated with chronic kidney disease (CKD) in both diabetic and nondiabetic populations. We therefore aim to determine whether serum galectin-3 level is associated with rapid kidney function decline in type 2 diabetic individuals without overt nephropathy.
Methods: Galectin-3 was measured in the baseline samples by ELISA in 998 type 2 diabetic patients with estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73m2 and no macroalbuminuria. Rapid renal progression during follow up was defined as a rate of eGFR decline &gt;5 ml/min/year according to Kidney Disease Improving Global Outcomes (KDIGO) Guideline.
Results: Over a median follow up of 12 years, 91 subjects had eGFR decline &gt;5 ml/min/year and they had significantly higher serum galectin-3 level than those with more stable renal function (8.52 ± 2.20 ng/ml vs. 7.58 ± 2.38 respectively, p&lt;0.01). In an unadjusted model, serum galectin-3 was associated with rapid decline in kidney function [hazard ratio (HR) 1.16, 95% CI 1.07-1.26, p&lt;0.001]. Serum galectin-3 remained a significant independent predictor even after adjustment for age, gender, body mass index, smoking, baseline eGFR, systolic blood pressure, HbA1c and duration of diabetes, the presence of microalbuminuria and renin-angiotensin system blockers therapy (p=0.004).
Conclusion: In type 2 diabetic subjects without overt nephropathy, serum galectin-3 was a significant independent risk factor for rapid decline in kidney function.

Disclosure
K.C.B. Tan: None. C. Lee: None. Y. Wong: None. S. Shiu: None.
542-P: Association of Cardiac Autonomic Dysfunction with Plasma Lipid Metabolites in Recent-Onset Type 2 Diabetes
Authors: BÖNHOF GIDON J. , STROM ALEXANDER , STRASSBURGER KLAUS , KNEBEL BIRGIT , KOTZKA JORG , AL-HASANI HADI , SZENDROEDI JULIA , ZAHARIA OANA P. , KARUSHEVA YANISLAVA , RODEN MICHAEL , ZIEGLER DAN 
Published: June 2020

Emerging evidence suggests that obesity and insulin resistance play a role in the development of diabetic cardiac autonomic neuropathy (CAN) characterized by reduced heart rate variability (HRV). In this context we assessed the relationship of 127 biomarkers of lipid metabolism (11 acylcarnitines, 39 free fatty acids, 12 sphingomyelins, 56 phosphatidylcholines, and 9 lysophosphatidylcholines) in plasma using mass spectrometry with HRV indices in individuals with recent-onset type 1 (T1D) or type 2 diabetes (T2D) from the baseline cohort (known diabetes duration (DD) ≤1 year) of the German Diabetes Study (T1D/T2D [mean±SD]: n=126/243; age: 34.5±12.9/53.4±11.0 years; BMI: 24.7±4.3/31.7±6.0 kg/m²; DD: 211±93/198±90 days; HbA1c: 6.8±1.4/6.5±0.9 %). Time domain and frequency domain HRV indices were derived from NN intervals recorded during a 3 h hyperinsulinemic-euglycemic clamp. After adjustment for age, sex, and BMI as well as Bonferroni correction including seven HRV parameters and the number of metabolites of the corresponding lipid class, higher levels of three free fatty acids (myristic acid: β=-0.14, p=0.049; palmitic acid: β=-0.19, p=0.007; palmitoleic acid: β=-0.15, p=0.048), eight phosphatidylcholines (e.g., phosphatidylcholine diacyl (PC aa) C32:0: β=-0.28, p&lt;0.001; phosphatidylcholine acyl-alkyl C34:3: β=-0.20, p&lt;0.004), and two sphingomyelins (sphingomyelin C16:0: β=-0.15, p=0.028; sphingomyelin C16:1: β=-0.18, p=0.020) were inversely associated with the standard deviation of NN intervals (SDNN) in recent-onset T2D but not T1D. PC aa C32:0 was inversely associated with both low (LF) and high frequency (HF) power spectrum in T2D (LF: β=-0.23, p=0.001; HF: β=-0.23, p=0.001).
In conclusion, the link between higher plasma levels of specific lipid metabolites and early cardiac autonomic dysfunction in recent-onset type 2 diabetes suggests that plasma lipid panels could be useful to improve the prediction of the development or progression of CAN.

Disclosure
G.J. Bönhof: None. A. Strom: None. K. Strassburger: None. B. Knebel: None. J. Kotzka: None. H. Al-Hasani: Consultant; Self; Bayer AG. J. Szendroedi: None. O.P. Zaharia: None. Y. Karusheva: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S. D. Ziegler: None.
560-P: The Liver Fibrosis Score Is Associated with Diabetic Peripheral Neuropathy in Type 2 Diabetes Mellitus
Authors: KIM KYUHO , OH TAE JUNG , SHIN YUJIN , CHOI SUNG HEE , JANG HAK CHUL 
Published: June 2020

Background: Type 2 diabetes mellitus (T2DM) is interrelated with nonalcoholic fatty liver disease (NAFLD) and liver fibrosis. However, the association between NAFLD and diabetic peripheral neuropathy (DPN) has not been well studied.
Methods: We prospectively enrolled subjects with T2DM to evaluate risk factors of DPN and to develop a screening tool of DPN. In this study, we analyzed the data of 127 subjects in whom we could calculate NAFLD and liver fibrosis scores. DPN was diagnosed using the Michigan Neuropathy Screening Instrument. Non-invasive markers of NAFLD (hepatic steatosis index, and NAFLD liver fat score) and liver fibrosis (NAFLD fibrosis score, and fibrosis-4 score) were calculated using equations containing several combinations of age, the presence of obesity or metabolic syndrome, liver function test, fasting insulin level, and platelet count. Body composition was measured by bio-impedance analysis. Clinical parameters and various markers were compared according to the presence of DPN.
Results: The prevalence of DPN in our study was 39.3%. There was no significant difference in body mass index, diabetes duration, and liver function test between subjects with DPN and those without DPN. Subjects with DPN showed older age, and higher fasting blood glucose level. Hepatic steatosis index and NAFLD liver fat score were comparable between subjects with or without DPN. In contrast, subjects with DPN showed significantly higher NAFLD fibrosis score (-0.7 vs. -1.3, P = 0.004) and fibrosis-4 score (1.6 vs. 1.2, P = 0.014) compared to those without DPN. These two scores were negatively associated with lean body mass. After adjusting lean body mass, the association between liver fibrosis scores and DPN was still significant.
Conclusion: The liver fibrosis scores but not NAFLD scores were higher in subjects with DPN compared to those without DPN. Liver fibrosis and DPN might share common pathophysiology.

Disclosure
K. Kim: None. T. Oh: None. Y. Shin: None. S. Choi: None. H. Jang: Speaker’s Bureau; Self; Daiichi Sankyo, Handok, Pfizer Inc., Takeda Pharmaceutical Company Limited.
561-P: Activated Xanthine Oxidase in Serum Is a Potent Therapeutic Target for Experimental Diabetic Polyneuropathy
Authors: ICHINOHE HIROSHI , MIZUKAMI HIROKI , OSONOI SHO , KUDO KAZUHIRO , YAGIHASHI SOROKU 
Published: June 2020

Xanthine oxidase (XO), a potent inducer of reactive oxygen species, catalyzes purine metabolism. XO is expected to be implication of the macrophage activation. XO is also expressed in the peripheral nerve system, while its role in diabetic polyneuropathy (DPN) has not been clarified. We explored the implication of XO in DPN of db/db mice (db/db) treating with XO-inhibitor, topiloxostat (To). C57BL6 mice (C57) and db/db (5 wks of age) were daily treated with 1mg/kg (dbT1) and 2mg/kg (dbT2) To (per os) for 8 wks. During experimental period, peripheral nerve function was monitored. At end, serum and dissected sciatic nerves and dorsal root ganglia (DRG) served for evaluation of uric acid metabolism. Primary culture of DRG neuron was performed to evaluate the effects of To on neurite outgrowth in vitro. To improved significant delay of nerve conduction velocities and elevation of threshold for tail flick test in db/db in a dose dependent manner (p&lt;0.05 dbT2 vs. C57 for NCVs, p&lt;0.05 db/db vs. dbT1, p&lt;0.01 db/db vs. dbT2 for tail flick). XO activity was significantly up-regulated in DRG (p&lt;0.01) and serum of db/db compared to those of W (p&lt;0.05). To successfully suppressed the elevated XO activity in a dose dependent manner (p&lt;0.05, W vs. T1, p&lt;0.01, T1 vs. T2). Uric acid was significantly accumulated in serum and DRG of db/db compared to those of C57 (p&lt;0.05). To could significantly reduce the accumulation (p&lt;0.01). In primary culture of DRG neuron, extrinsic 100 μM XO depleted the neurite outgrowth more than 50 % than that of non-stimulated neurons (p&lt;0.01). 4.3ng/ml To could significantly restored the reduction of neurite outgrowth compared to that of non-treated neurons (p&lt;0.05).
As a conclusion, increase in XO activity in serum and DRG may be implicated in the pathophysiology of DPN in db/db. Activation of XO in serum may directly exacerbate neuronal injury for DRG in DPN. To has a beneficial effect on DPN through its specific property to suppress serum XO activity.

Disclosure
H. Ichinohe: None. H. Mizukami: None. S. Osonoi: None. K. Kudo: None. S. Yagihashi: None.