bluuebunny/crossref_metadata_2025_split huggingface dataset:
41-OR: ADA President's Select Abstract: The Beneficial Effect of Fenofibrate on Diabetic Retinopathy Is Influenced by PPARA Genetic Variability and Is Mediated by an Increase in FGF21 Levels
Authors: MORIERI MARIO LUCA , SHAH HETAL , TANG YALING , MENDONCA CHRISTINE , JOBE JENNY MARIE , MYCHALECKYJ JOSYF , DORIA ALESSANDRO 
Published: May 2022

A PPARA genetic variant (rs6008845) influences the cardiovascular effectiveness of the PPAR-alpha agonist fenofibrate independent of changes in lipid profile. Here we investigated whether the same variant influences fenofibrate effectiveness on diabetic retinopathy (DR) . This was evaluated with regard to DR progression in 592 subjects with prior DR history from the ACCORD Eye Study, and with regard to other pre-specified diabetic eye outcomes in the ACCORD Lipid Study (n=3,650) . The effect of fenofibrate on 93 inflammatory biomarkers was studied in 320 rs6008845 T/T homozygotes from ACCORD Lipid and a large retina-eQTL dataset (GtExEye) was used to evaluate the association between rs6008845 and PPARA expression and derive a Genetic Score (eQtGS) of PPARA expression in the retina. rs6008845 modulated fenofibrate effectiveness on DR progression in a way similar to that previously reported for MACE, with the largest benefit being in rs6008845 T/T (OR 0.10, 95% C.I. 0.02-0.74) and the smallest (OR 0.54, 95% C.I. 0.21-1.42) in C/C homozygotes (p for interaction = 0.01) . The same synergism was found for severe vision loss (p=0.03) . The T allele was associated with higher PPARA retinal expression (P=4×10-38) in GtExEye, and ACCORD subjects with higher eQtGS for PPARA expression had better response to fenofibrate on DR progression (P=0.008) . Among T/T homozygotes, fenofibrate caused a marked increase in serum FGF21 (+0.87 S.D.; 95% C.I. 0.67-1.07, P=10×10-13) . Each S.D. increase in log2 FGF21 was associated with a 45% lower risk of severe vision loss (HR 0.55; 95%C.I. 0.34-0.91, p=0.01) , explaining 90% of fenofibrate benefit on this outcome in T/T subjects (p=0.03) .
In conclusion, fenofibrate effectiveness on DR depends on genetic variants affecting PPARA expression and is mediated by an increase in serum FGF21 - a metabolic and anti-inflammatory cytokine that may therefore be a therapeutic target to treat diabetic eye disease.

Disclosure
M.Morieri: Advisory Panel; Merck Sharp & Dohme Corp., Consultant; neopharmed gentili, SLAPharma, Other Relationship; Lilly, Novo Nordisk, Servier Laboratories. H.Shah: None. Y.Tang: None. C.Mendonca: None. J.Jobe: None. J.Mychaleckyj: None. A.Doria: Research Support; Novo Nordisk Foundation.

Funding
NHLBI HL110400 e HL153559-Italian Ministry of Health - Ricerca Finalizzata - GR-2019-12369702.
425-P: Lessons Learned from a Patient-Centered, Team-Based Intervention for Patients with Type 2 Diabetes at High Cardiovascular Risk: Year 1 Results from the CINEMA Program
Authors: NEELAND IAN , AL-KINDI SADEER G. , TASHTISH NOUR , EATON ELKE , RAHMANI SARA , BERG DIAMOND , RANA MARIAM N. , SULLIVAN CLAIRE , HATIPOGLU BETUL 
Published: May 2022

Background: Persons with type 2 diabetes mellitus (T2DM) often experience fragmented and complex care and across multiple specialties. We implemented a patient-centered, multidisciplinary team-based intervention called CINEMA to improve care delivery and outcomes.
Methods: Patients with T2DM at high-risk for cardiovascular disease events, including those with established atherosclerotic cardiovascular disease, elevated coronary artery calcium score &gt;100, chronic heart failure with reduced ejection fraction, and/or chronic kidney disease stages 2-4 were included in the program in Cleveland, OH. The program included 5 cardiologists with a special focus on T2DM, a pharmacist, a certified diabetes care and education specialist/dietician, a nurse navigator, and collaboration with endocrinologists and nephrologists. Data was collected from baseline within 3 months prior to patients’ first visit to up to 1 month after the follow-up visit. From May 2020 through May 2021, there were 316 referrals to the program. Of those referred, 47% met inclusion criteria. Among eligible patients, 96 (64%) completed a baseline and follow-up visit, with mean (std dev) follow-up time of 1 (34) days. Among patients completing the initial 3-month visit, 50% were ≥age 60 years with 48% female and 34% Black patients. Patients had significant reductions from baseline in Hb A1c (-8.7%) , total (-10.4%) , LDL (-15.7%) , and non-HDL (-14.9%) cholesterol, body weight (-3.7%) , and body mass index (-3.8%) (p&lt;0.0for all) . In addition, among eligible patients, 87.5% were started on evidenced-based therapy with SGLT2i (n=24) , GLP-1 RA (n=40) , or both (n=20) to reduce the risk of CVD.
Conclusions: A team-based, patient-centered approach to high-risk disease management appears to be a promising paradigm for care delivery associated with greater use of evidence-based therapies and improved control of multiple CV risk factors.

Disclosure
I. Neeland: Advisory Panel; Boehringer Ingelheim International GmbH, Merck & Co., Inc. Consultant; Nestlé Health Science. S.G. Al-Kindi: None. N. Tashtish: None. S. Rahmani: None. D. Berg: None. M.N. Rana: None. C. Sullivan: None. B. Hatipoglu: None.
429-P: Pro-B-Type Natriuretic Peptide Strongly Predicts Major Cardiovascular Events and Mortality in Cardiovascular Disease Patients with Type 2 Diabetes as Well as in Those without Diabetes
Authors: MAECHLER MAXIMILIAN , SPRENGER LUKAS , MADER ARTHUR , LARCHER BARBARA , VONBANK ALEXANDER , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H. 
Published: May 2022

Elevated pro-B type natriuretic peptide (pro-BNP) has been found to be a strong marker of cardiovascular risk in several high-risk populations. However, the power of pro-B type natriuretic peptide (pro-BNP) to predict major cardiovascular events (MACE) and mortality in patients with the combination of established cardiovascular disease and type 2 diabetes (T2DM) is unclear and is addressed in the present study. We enrolled 873 patients with established cardiovascular disease, 579 with angiographically proven stable CAD and 294 with sonographically proven peripheral artery disease. Prospectively, cardiovascular events were recorded over a mean follow-up period of 7.9±3.6 years. At baseline, pro-BNP was significantly higher in patients with T2DM (n=285) than in those who did not have diabetes (1010±26vs. 727±2327 mg/dl; p=0.003) . During follow-up, 257 patients suffered MACE; the event rate was significantly higher in patients with T2DM than in subjects without T2DM (37.8 vs. 26.0%; p&lt;0.001) . pro-BNP predicted both MACE and mortality in the total study population, with standardized adjusted hazard ratios (HR) of 1.37 [1.26-1.48]; p&lt;0.0 and 1.30 [1.21-1.40]; p&lt;0.001, respectively. Further, pro-BNP predicted MACE and mortality in patients with T2DM (HRs 1.37 [1.21-1.55]; p&lt;0.0 and 1.24 [1.10-1.40]; p&lt;0.001, respectively) as well as in those who did not have diabetes (HRs 1.45 [1.26-1.67]; p&lt;0.0 and 1.41 [1.25-1.60]; p&lt;0.001, respectively) . Interaction terms pro-BNP x T2DM were non-significant for both MACE and mortality (p=0.590 and 0.3respectively) , indicating that the power of pro-BNP to predict MACE and mortality did not differ significantly between cardiovascular disease patients with T2DM and those who did not have diabetes. We conclude that pro-BNP strongly predicts MACE and mortality in cardiovascular disease patients with T2DM as well as in those without diabetes.

Disclosure
M.Maechler: None. L.Sprenger: None. A.Mader: None. B.Larcher: None. A.Vonbank: None. A.Leiherer: None. A.Muendlein: None. H.Drexel: None. C.H.Saely: None.
431-P: Waist-to-Body-Mass-Index Ratio and Type 2 Diabetes Mellitus Are Mutually Independent Predictors of Cardiovascular Events in Patients with Coronary Artery Disease
Authors: MADER ARTHUR , SPRENGER LUKAS , VONBANK ALEXANDER , LARCHER BARBARA , MAECHLER MAXIMILIAN , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H. 
Published: May 2022

The waist circumference-to-body-mass-ratio (W/BMI-Ratio) has attracted interest as a predictor of cardiovascular risk. Its power to predict cardiovascular events in patients with established coronary artery disease (CAD) is not known and is addressed in the present study. We prospectively recorded cardiovascular events in 1472 patients with angiographically verified coronary artery disease. The mean follow-up time was 6.3±3.2 years. At baseline, there the W/BMI-Ratio did not differ significantly between patients with T2DM and nondiabetic patients (3.5±0.4 vs. 3.6±0.3; p=0.234) . Prospectively, the W/BMI-Ratio significantly predicted the incidence of cardiovascular events (n=439) both univariately (standardized HR 1.36 [1.20-1.52]; p&lt;0.001) and after adjustment for age, gender, smoking, LDL cholesterol, HDL cholesterol, hypertension and T2DM (standardized adjusted HR=1.12 [1.03-1.21], p=0.006) , whereas T2DM predicted cardiovascular events indepently from the W/BMI-Ratio (HR=1.34 [1.09-1.64], p=0.006) . We conclude that the W/BMI-Ratio and T2DM are mutually independent predictors of cardiovascular events in patients with established CAD.

Disclosure
A.Mader: None. L.Sprenger: None. A.Vonbank: None. B.Larcher: None. M.Maechler: None. A.Leiherer: None. A.Muendlein: None. H.Drexel: None. C.H.Saely: None.
433-P: The A Body Shape Index and Type 2 Diabetes Are Mutually Independent Predictors of Major Cardiovascular Events in Patients with Established Cardiovascular Disease
Authors: SPRENGER LUKAS , MAECHLER MAXIMILIAN , VONBANK ALEXANDER , LARCHER BARBARA , MADER ARTHUR , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H. 
Published: May 2022

The A Body Shape index (ABSI) is a validated measure of visceral adiposity that is calculated based on waist circumference, height and BMI. Its power to predict major cardiovascular events in patients with established cardiovascular disease (CVD) is unclear and is addressed in the present study.
We prospectively recorded cardiovascular events in a large cohort of 1544 patients with established CVD (1297 patients with angiographically proven stable coronary artery disease and 247 patients with sonographically verified PAD) over a mean follow-up time of 10.0±4.6 years.
At baseline, the ABSI was higher in patients with type 2 diabetes (T2DM; n=502) than in those who did not have diabetes (8.4±0.6 vs. 8.3±0.6; p&lt;0.001) . Prospectively, the ABSI significantly predicted the incidence of MACE (n=507) after adjustment for age, gender, smoking, hypertension, LDL cholesterol, HDL cholesterol, and T2DM (standardized adjusted HRs 1.14 [1.04-1.24]; p=0.004, respectively) . T2DM in turn in this model also significantly predicted MACE with a HR of 1.61 [1.33-1.94]; p&lt;0.0after adjustment for ABSI.
We conclude that ABSI and T2DM are mutually independent risk factors for MACE in patients with established cardiovascular disease.

Disclosure
L.Sprenger: None. M.Maechler: None. A.Vonbank: None. B.Larcher: None. A.Mader: None. A.Leiherer: None. A.Muendlein: None. H.Drexel: None. C.H.Saely: None.
435-P: Sex Differences in Diabetic Cardiovascular Outcomes amongst Patients Admitted for Pneumonia: A Study from the National Inpatient Sample (NIS)
Authors: LEVENTHAL SARAH , RUBINFELD GREGORY , BERGER JEFFREY S. , NEWMAN JONATHAN D. , SMILOWITZ NATHANIEL R. 
Published: May 2022

Background: While women have lower risks of cardiovascular disease (CVD) than men, type 2 diabetes mellitus (T2D) seems to be a stronger risk factor for major adverse cardiac events (MACE) for women. No study has evaluated sex differences in MACE for patients with T2D admitted for non-CVD diagnoses in the NIS. Pneumonia is one of the most common primary diagnoses in the inpatient setting.
Methods: Patients hospitalized in 2013 for a primary diagnosis of pneumonia were identified from the NIS. MACE was defined as acute myocardial infarction (AMI) , ischemic stroke, cardiac arrest, or cardiogenic shock, and was compared by sex in patients with T2D. Multivariable logistic regression models were used to estimate odds of in-hospital MACE adjusted for demographics, cardiovascular risk factors, comorbidities, and pneumonia severity.
Results: In 2013, 192,100 patients were admitted for a primary diagnosis of pneumonia, and 50,776 of these patients had T2D. Of the patients with T2D, 50.9% were female. Female patients with T2D were less likely to smoke and had fewer comorbidities than male patients with T2D (all P&lt;0.001) . After adjustment, T2D was associated with increased risk of AMI for women (aOR 1.2; 95% CI 1.1-1.4, P=0.006) but not for men (aOR 1.1; 95% CI 1.0-1.2, P=0.2) . Amongst patients with T2D, there was a similar risk of MACE for women compared to men (aOR 0.9; 95% CI 0.8-1.1, P=0.257) .
Conclusion: While T2D seems to be a stronger risk factor for AMI in female patients, male and female patients with T2D have an overall similar risk of in-hospital MACE when admitted for pneumonia.

Disclosure
S.Leventhal: None. G.Rubinfeld: None. J.S.Berger: Advisory Panel; Amgen Inc., Janssen Scientific Affairs, LLC. J.D.Newman: None. N.R.Smilowitz: Advisory Panel; Abbott.
437-P: NOX5 in Human Peripheral Blood Mononuclear Cells Is a Potential Biomarker for Unstable Diabetic Vascular Disease
Authors: BLOCK TOMASZ J. , SOURRIS KARLY , KHAN WAHEED , KANTHARIDIS PHILLIP , JHA JAY C. , COOPER MARK E. , SHAW JAMES , JANDELEIT-DAHM KARIN 
Published: May 2022

Background: Human NADPH oxidase 5 (NOX5) is expressed and functionally active in peripheral blood mononuclear cells (PBMCs) . In those with diabetes, there is increased NOX5 expression in atherosclerotic plaques with associated coronary artery disease (CAD) and within the glomeruli in kidney biopsies. We hypothesise that NOX5 expression in circulating PBMCs is increased in patients with diabetes, particularly in those with comorbid unstable CAD and chronic kidney disease (CKD) .
Methods: 55 males aged 33-83 years underwent elective or emergency coronary angiography/angioplasty at the Alfred Hospital Catheter Laboratory. PBMCs from whole blood were processed for flow-cytometry to measure NOX5 protein. In parallel, NOX5 expression was measured in PBMCs by qPCR. In vitro, human macrophages (THP-1) were incubated in normal (5 mM) and high glucose (25 mM) . NOX5 expression and inflammatory markers were measured by qPCR.
Results: NOX5 protein expression in PBMCs was primarily driven by expression in monocytes (CD 45+/CD14+ cells) and was increased in diabetic and non-diabetic patients with CKD (28.7±4.2 vs. 17.3±1.7 AU; p=0.0038) and in diabetic patients with CKD versus without CKD (27.5±4.1 vs. 14.6±2.3 AU; p=0.012) . CAD with acute presentation was associated with increased NOX5 expression versus elective presentation (25.9±2.9 vs. 16.8±1.9 AU; p=0.0085) , particularly in diabetic patients presenting acutely versus electively (29.1±4.2 vs. 13.9±2.4 AU; p=0.0025) . A 4-fold upregulation of NOX5 gene was observed in patients with CKD versus without CKD irrespective of diabetes or CAD (p=0.018) . In vitro, there was a 2-fold increase in NOX5, TNF-α and IL-6 expression in THP-1 cells exposed to high glucose.
Conclusion: CKD and unstable CAD appear to be key factors for increased NOX5 expression in circulating PBMCs. Measurement of NOX5 in PBMCs may serve as a valuable prognostic biomarker and attractive therapeutic target in patients with clustering diabetic complications.

Disclosure
T.J.Block: None. K.Sourris: None. W.Khan: None. P.Kantharidis: None. J.C.Jha: None. M.E.Cooper: Advisory Panel; Bayer AG, Merck Sharp & Dohme Corp., Consultant; Boehringer Ingelheim International GmbH, Research Support; Novo Nordisk, Speaker's Bureau; AstraZeneca, Servier Laboratories. J.Shaw: None. K.Jandeleit-dahm: None.
438-P: Cardiorenal Benefits of Newer Glucose-Lowering Drugs by Hispanic Ethnicity: A Meta-analysis of Results from Randomized Outcome Trials in Type 2 Diabetes
Authors: TANG HUILIN , CHEN WEI-HAN , BIAN JIANG , O'NEAL LATOYA J. , LACKLAND DANIEL T. , SCHATZ DESMOND , GUO JINGCHUAN 
Published: May 2022

Background: Hispanic individuals are at increased risk of diabetes and related complications compared to non-Hispanic White individuals. Thus, we aimed to compare cardiorenal outcomes of newer glucose-lowering drugs between Hispanic and non-Hispanic populations via a meta-analysis of randomized outcome trials.
Methods: We included randomized placebo-controlled cardiovascular (CV) and renal outcome trials of SGLT2 inhibitors, GLP-1RAs, and DPP-4 inhibitors that reported major adverse cardiovascular events (MACE) , CV death/heart failure hospitalization (HHF) , or composite renal outcome, stratified by the Hispanic ethnicity (Hispanic vs. non-Hispanic) . We calculated pooled hazard ratios (HR) with 95% CI using fixed-effects models and tested the differences between the two groups (Pinteraction ) .
Results: We included outcome trials reporting outcomes by Hispanic ethnicity in 89,393 patients with type 2 diabetes. In three SGLT2 inhibitor trials, the risk of MACE varied by ethnicity (HR = 0.70 [0.54-0.91] in Hispanic population and HR = 0.96 [0.86-1.07] in non-Hispanic population) with a Pinteraction = 0.03, while the risks of CV death/HHF (Pinteraction = 0.46) and composite renal outcome (Pinteraction = 0.31) were similar across ethnicity. In five GLP-1RA trials, we observed a similar MACE risk between Hispanic (HR = 0.82 [0.70-0.96]) and non-Hispanic (HR = 0.92 [0.84-1.00]) populations (Pinteraction = 0.22) . In three DPP-4 inhibitor trials, the risk of MACE was greater in Hispanic (HR=1.15 [0.98-1.35]) than non-Hispanic (HR= 0.96 [0.88-1.04]) populations (Pinteraction = 0.045) , while the risk of composite renal outcome was similar between the two groups (Pinteraction = 0.51) .
Conclusion: Compared with non-Hispanic individuals, Hispanics with type 2 diabetes obtain a greater benefit on lowering MACE risk with the use of SGLT2 inhibitors, while a lower benefit with DPP-4 inhibitors.

Disclosure
H.Tang: None. W.Chen: None. J.Bian: None. L.J.O'neal: None. D.T.Lackland: None. D.Schatz: Advisory Panel; Abbott Diabetes, Medtronic. J.Guo: None.
44-OR: NFAT Inhibition Reduces Retinal Vascular Leakage and Inflammation in Diabetic Retinopathy
Authors: DE LA HUERTA IRINA , NUNEZ JORGE L. , POLOWAY JACOB M. , REDDY VARUN , PENN JOHN 
Published: May 2022

Purpose: Macular edema resulting from retinal vascular leakage is the leading cause of vision loss in diabetic retinopathy (DR) . The nuclear factor of activated T-cells (NFAT) family of transcription factors is known to upregulate inflammatory cytokines in response to high glucose. This study explored the effect of NFAT inhibition on retinal vascular leakage and inflammation in DR in vivo and in vitro.
Methods: The streptozocin-induced (STZ) model was used as the mouse model of diabetic retinopathy. Hyperglycemia was induced at 4 weeks in C57BL/6J mice and confirmed when fasting plasma glucose became persistently elevated (&gt;300 mg/dL) . Experiments were performed at weeks of hyperglycemia. STZ mice were injected intravitreally with the NFAT signaling inhibitor INCA-6 (25 uM) or vehicle (0.1% DMSO in PBS) . Uninjected eyes of both STZ and control mice served as additional controls. Evans blue dye (EBD) was used to measure retinal vascular leakage. Primary mouse retinal microvascular endothelial cells (MRMECs) were used for in vitro experiments. MRMEC monolayers were treated with INCA-6 (2.5 uM) or with vehicle and cell permeability was induced with mouse VEGF165. The transendothelial electrical resistance (TEER) was measured with the electrical cell-substrate impedance sensing method. MRMEC IL-6 production was investigated by ELISA.
Results: In the STZ model of diabetic retinopathy, EBD vascular leakage was significantly reduced in INCA-6-treated eyes (INCA-6: 0.85 ± 0.57, n=5; vehicle: 1.78 ± 0.38, n= 7; P=0.007) , and in INCA-6 treated eyes compared to untreated eyes (untreated: 2.83 ± 1.63, n=4, P=0.04) . In the VEGF-induced MRMEC monolayer permeability model, INCA-6 significantly preserved TEER compared to vehicle (n=12, P&lt;0.05) and decreased the VEGF-induced production of IL-6 (n=5, P&lt;0.05) .
Conclusions: NFAT inhibition has therapeutic potential to prevent and treat retinal vascular leakage and inflammation in DR.

Disclosure
I.De la huerta: None. J.L.Nunez: None. J.M.Poloway: None. V.Reddy: None. J.Penn: None.

Funding
National Institutes of Health (EY032620) International Retinal Research Foundation Grant Knights Templar Foundation Career Starter Grant
449-P: Assessing Cardiovascular Risk in Prediabetes
Authors: ZIVKOVIC TEODORA BELJIC 
Published: May 2022

Prediabetes carries a risk of diabetes and cardiovascular disease (CVD) . Assessment of CVD risk in prediabetes is not as routine, as is assessment of diabetes risk. However, it is not less important. This can be done through conventional SCORE charts and through coronary artery calcium (CAC) score. CAC is examined through multislice CT. Calcifications indicate late-stage subclinical coronary atherosclerosis. The AIM of our study was to assess traditional CVD risk through score charts and CAC in subjects with prediabetes (preDM) and to evaluate whether any correlation exists between the two. After diagnosing preDM with an oral glucose tolerance test and HbA1c, ECG, lipids, body mass index and blood pressure measurements were performed. Subjects were evaluated for CVD risk through Score charts. Thereafter, all subjects were appointed for multi-slice CT to obtain the CAC. A writen consent was obtained from all subjects. Results: 80 subjects with preDM were screened for CVD. CAC score of 0 was present in 35 subjects. Minimal calcifications with a CAC score of 1-AU were present in subjects with preDM. Moderate calcification of 11-100 AU were present in 18 subjects. 12 subjects had significant calcifications with 101-400 AU. Five subjects had a CAC score &gt;400 AU. Evaluation of the Score charts reviled that Score risk below 2% was present in 20 subjects. Score risk of 3-4% was present in 10, 5-9% risk was present in 16 and a score risk of 10-14% was present in 8 subjects. Twenty six subjects with PreDM has a score risk of 15% and more. No significant correlation was found between Score charts and CAC. However, a trend of finding more calcifications in those with a 10% and above Score risk was noted. Conclusion: An approach to CVD risk assessment that combines the traditional Score charts with a more personalized atherosclerosis-imaging model may be appropriate for high risk subjects with pre diabetes.

Disclosure
T.Beljic zivkovic: None.