bluuebunny/crossref_metadata_2025_split huggingface dataset:
431-P: Diabetic Retinopathy and Risk of Lower-Extremity Artery Disease in Type 2 Diabetes
Authors: FOUSSARD NINON , SAULNIER PIERRE , BERTRAND CAPUCINE , GAND ELISE , RAGOT STEPHANIE , POTIER LOUIS , VELHO GILBERTO , MARRE MICHEL , ROUSSEL RONAN , RIGALLEAU VINCENT , MOHAMMEDI KAMEL , HADJADJ SAMY 
Published: June 2019

Diabetic retinopathy (DR) has been linked to lower-extremity artery disease (LEAD), but there remains some uncertainty as whether this association is mediated by other conditions. We assessed the association between DR and LEAD risk; and the influence of diabetes duration and control, systolic (SBP) or diastolic (DBP) blood pressure, smoking, diabetic kidney disease (DKD), or cardiovascular disease (CVD) in such association in the French prospective SURDIAGENE (SURVIe, DIAbete de type 2 et GENEtique) type 2 diabetes cohort. Baseline DR was staged as absent, non-proliferative, or proliferative. Major LEAD was defined as lower-limb amputation or peripheral revascularization requirement. Cox regression model was fitted to compute hazard ratio (HR) and 95% CI for major LEAD during follow-up by baseline DR stages. The prognostic value of DR in LEAD discrimination was tested using C-statistics. Among 1412 participants at baseline (men 58%, age 64.7±10.6 years, non-proliferative 37% and proliferative DR 7%), 112 (7.9%) developed a major LEAD during 6 years of follow-up. The incidence of LEAD increased with worsening DR: 4.1% (absent), 12.6% (non-proliferative), and 14.1% (proliferative)(p&lt;0.0001). This association remained significant after adjustment for confounding variables (non-proliferative versus absent DR 2.29 [1.44-3.63], p&lt;0.0001; proliferative versus absent DR 3.03 [1.54-5.96], p=0.001). No heterogeneity was observed across subgroups by diabetes duration, HbA1c, SBP, DBP, smoking, DKD, and CVD (all p-interaction&gt;0.05). In addition to usual risk factors, DR improved LEAD discrimination (C-statistics change +0.023 [0.004-0.038], p=0.01). LEAD risk increases proportionally with DR severity, independently of diabetic, blood pressure, renal or cardiovascular conditions. DR has a significant prognostic value in LEAD prediction in people with type 2 diabetes.

Disclosure
N. Foussard: None. P. Saulnier: None. C. Bertrand: None. E. Gand: None. S. Ragot: None. L. Potier: Advisory Panel; Self; Merck Sharp & Dohme Corp. Consultant; Self; Sanofi. G. Velho: None. M. Marre: Advisory Panel; Self; Servier. Board Member; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S. R. Roussel: Advisory Panel; Self; Merck Sharp & Dohme Corp., Sanofi. Consultant; Self; Abbott, AstraZeneca, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Physiogenex. Research Support; Self; Janssen Pharmaceuticals, Inc. V. Rigalleau: None. K. Mohammedi: None. S. Hadjadj: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Servier. Research Support; Self; Bayer AG, Janssen Research & Development. Speaker's Bureau; Self; Abbott, Valbiotis.
438-P: Comparative Cardiovascular Effectiveness of Glucagon-Like Peptide-1 Receptor Agonists vs. Other Glucose-Lowering Agents in Patients with Type 2 Diabetes—A Nationwide Cohort Study Using Prevalent New-User Design
Authors: YANG CHUN-TING , YANG CHENYI , KUO SHIHCHEN , OU HUANG-TZ 
Published: June 2019

Introduction: Clinical trials have shown cardiovascular disease (CVD) benefits associated with glucagon-like peptide 1 receptor agonists (GLP-1ra) vs. placebo in patients with type 2 diabetes (T2DM). However, only few rigorous clinical trials and real-world studies exist for head-to-head comparison of GLP-1ra with other glucose-lowering agents (GLA). We aimed to investigate CV outcomes of GLP-1ra vs. dipeptidyl peptidase 4 inhibitors (DPP-4i), sulfonylureas (SU), and insulin.
Method: A nationwide cohort study was conducted using Taiwan’s National Health Insurance Research Database. Study cohort consisted of patients older than 18 years old and diagnosed with T2DM during 2004-2014, and followed until death or the end of 2015. Prevalent new-user design was adapted where all users who initiated GLP-1ra stably were retained for analyses and the comparability between GLP-1ra and other GLA users was matched by various confounders in patient characteristics. Study outcomes included composite CVD and 3-point major adverse CV event (MACE). Cox models were employed to assess the association between drug exposure and study outcomes.
Result: After 1:1 propensity score matching, 1,893, 1,573, and 1,367 GLP-1ra users were compared to DPP-4i, SU, and insulin users, respectively. Using GLP-1ra was associated with significantly lower risks of composite CVD (GLP-1ra vs. DPP-4i, SU, and insulin: hazard ratio, 0.73 [95% confidence interval, 0.57-0.96]; 0.71 [0.54-0.95]; 0.64 [0.49-0.83]) and 3-point MACE (GLP-1ra vs. DPP-4i, SU, and insulin: 0.55 [0.35-0.86]; 0.71 [0.44-1.15]; 0.46 [0.28-0.76]). In patients without CVD history, using GLP-1ra yielded a greater risk reduction in both CVD outcomes.
Conclusion: In real-world clinical practice, using GLP-1ra vs. other 3 major classes of GLA in Taiwanese T2DM patients showed CVD benefits, especially in those without CVD history.

Disclosure
C. Yang: None. C. Yang: None. S. Kuo: None. H. Ou: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK092926)
445-P: Modified LDL-Immune Complexes (IC) and the Risk of CVD in Type 1 Diabetes
Authors: LOPES-VIRELLA MARIA F. , BEBU IONUT , HUNT KELLY J. , VIRELLA GABRIEL , BAKER NATHANIEL L. , BRAFFETT BARBARA , LACHIN JOHN ,   DCCT/EDIC RESEARCH GROUP
Published: June 2019

We have previously shown that high levels of oxidized LDL and AGE-LDL in circulating IC are strong predictors of atherosclerosis progression in 518 subjects with type 1 diabetes from the DCCT/EDIC cohort. In this study we investigated whether oxLDL, MDA-LDL and AGE-LDL in circulating IC measured in the same subjects at DCCT baseline were associated with acute CVD events. Three overlapping CVD outcomes were considered: any CVD events, major adverse cardiac and cerebrovascular events (MACE) and myocardial infarction (MI). Cox proportional hazards models assessed the association between IC biomarker values and the subsequent risk of CVD, using inverse probability weighting to obtain results representative of the full DCCT/EDIC cohort.
Results: Levels of AGE-LDL, oxLDL and MDA-LDL in circulating IC, measured at baseline (Table) were significantly associated with the 3 CVD outcomes in unadjusted models and were minimally attenuated after adjustment for age and mean HbA1c. After adjustments for conventional CVD risk factors, including LDL-Chol, high levels of oxLDL-IC and MDA-LDL-IC remained independently associated with increased subsequent risk of any CVD, and higher oxLDL-IC with increased risk of MACE and MI events.
Conclusions: High levels of oxLDL-IC measured more than one decade prior to the occurrence of CVD events identified patients at high risk, even after adjustment by LDL-C and conventional CVD risk factors.

Disclosure
M.F. Lopes-Virella: None. I. Bebu: None. K.J. Hunt: None. G. Virella: None. N.L. Baker: None. B. Braffett: None. J. Lachin: Board Member; Self; Tolerion, Inc.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases
446-P: Associations of Blood Pressure (BP) with Incidence of Coronary Artery Disease (CAD)/Cerebrovascular Disease (CVD) According to Glucose Tolerance Status (GTS)
Authors: HARADA MAYUKO , FUJIHARA KAZUYA , YAMAMOTO MASAHIKO , KANEKO MASANORI , KITAZAWA MASARU , SUZUKI HIROSHI , MATSUBAYASHI YASUHIRO , YAMADA TAKAHO , YAMANAKA NAUTA , SEIDA HIROYASU , OGAWA WATARU , SONE HIROHITO 
Published: June 2019

Although the 2017 ACC/AHA guidelines indicated a generalized BP goal of less than 130/80 mm Hg, the impact of BP separately on CAD or CVD in people with different GTSs has yet to be clarified. To clarify this, data from a nationwide claims database involving 293,396 participants without prior CAD or CVD during 2008-16 were analyzed. Multivariate Cox regression model was used to identify risks of a CAD and/or CVD event. Hazard ratios (HRs) were compared among 4 groups of participants divided according to stratified levels of BP [i.e., &lt;130/90 mmHg, systolic BP (SBP) =130-139 and/or diastolic BP (DBP) =80-89 mmHg, SBP≥140 or DBP&gt;90 mmHg, ≥140/90 mmHg] according to GTS [i.e., normal glucose tolerance (NGT), prediabetes (pre-DM), diabetes mellitus (DM)]. During the study period, 1099 CAD and 1990 CVD events occurred. Despite that a significant trend between BP and incident CAD was observed regardless of GTS, risk for CVD was dependent on BP only in the NGT and pre-DM groups. Moreover, there were no significant differences in CVD risks between categories of BP&lt;130/90 mmHg and SBP=130-139 and/or DBP=80-89 mmHg among patients with DM. These results implied the necessity of setting specific BP goals according to GTS for prevention of CAD/CVD.

Disclosure
M. Harada: None. K. Fujihara: None. M. Yamamoto: None. M. Kaneko: None. M. Kitazawa: None. H. Suzuki: None. Y. Matsubayashi: None. T. Yamada: None. N. Yamanaka: None. H. Seida: None. W. Ogawa: Consultant; Self; Abbott. Research Support; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Daiichi Sankyo Company, Limited, Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Lilly Diabetes, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd. H. Sone: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited.
449-P: Pulsed Electromagnetic Field Attenuates Cardiomyocyte Damages Induced by Ischemia in Hyperglycemic H9c2 Cells
Authors: TERRUZZI ILEANA , SENESI PAMELA , VACANTE FERNANDA , LUZI LIVIO 
Published: June 2019

Cardiovascular complications are known as the main cause of mortality in subjects with diabetes mellitus (DM). In particular, ischemic heart disease is more common in patients with DM than in nondiabetics and promising therapeutically strategies to repair heart damages, including progenitor cell therapy or reprogramming non-cardiac cells, are inadequate in patients with DM. Emerging evidence indicates that hyperglycemia and oxidative stress are the primary causes of cardiac regenerative therapies’ failure in DM. Thus, it is essential to develop new therapeutic approaches aimed at contrasting the cardiac hyperglycemic microenvironment. Several researchers have proposed pulsed electromagnetic field (PEMF), an innovative medical device, to regenerate bone tissue, but very few works have studied PEMF possible use in other pathological condition and, in particularly, in cardiac damages. For the first time, we investigated the effects of PEMF preconditioning treatment on ischemic damages in H9c2 rat cardiomyocytes grown in hyperglycemic condition (25 mmol/L glucose). H9c2 cardiomyocytes were directly exposed to PEMF for 30 minutes (PEMF were generated by a commercially device having these features: 1,33 ms pulses at 75 Hz-1,5 mT) before ischemic injury. Ischemia was simulated by treating H9c2 cells with 5μM rotenone for 3 hours. Control cells were not pretreated with PEMF. Protein kinase B (Akt) and extracellular signal-regulated kinases (ERKs) activation were increased by PEMF stimuli: these kinases are closely related to attenuated cell apoptosis and oxidative stress. Indeed, our results indicated that PEMF treatment could significantly reduce reactive oxygen species (ROS) levels in hyperglycemic H9c2. Taken together, our preliminary study indicated that PEMF could be a potential strategy to improve the efficacy of cardiac regenerative therapies in diabetic patients.

Disclosure
I. Terruzzi: None. P. Senesi: None. F. Vacante: None. L. Luzi: Consultant; Self; McKinsey & Company. Research Support; Self; Allergan, Gelesis, SunStar Inc. Speaker's Bureau; Self; A. Menarini Diagnostics, AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Menarini Group, Novartis AG, Novo Nordisk Inc., Sunstar Foundation.
45-LB: Results of a Pilot Evaluation of a Novel Autologous Homologous Skin Construct Treatment of Diabetic Foot Wounds Refractory to Conventional Treatments
Authors: ZELEN CHARLES , ARMSTRONG DAVID G. 
Published: June 2019

Background: An autologous homologous skin construct (AHSC) has been developed to treat complex cutaneous wounds (burns, chronic defects, and acute trauma) and was evaluated for treating diabetic foot ulcers (DFUs).
Methods: AHSC was manufactured from 1.5cm2 healthy full-thickness skin harvest. All of the tissue is utilized and the endogenous regenerative populations are activated during processing. It is spread evenly across the wound bed and dressed similar to an autologous skin graft. Eleven Wagner 1 and Wagner 2 DFUs refractory to conventional therapies including advanced wound care products were treated with a single application of AHSC.
Results: All harvests and deployments were performed in the outpatient setting. Wounds were dressed with silicone, compression bolster, and off-loading for the first 3 weeks followed by standard of care until closure. All harvest sites were primarily closed with no complications. All 11 wounds demonstrated complete graft take with one application. One patient with prior lower extremity hardware developed an infection separate from the AHSC-treated wound requiring extensive debridement including the treated wound. The remaining 10/11 wounds were closed by 10 weeks with a median of 5.8 weeks. Wounds remained closed at 2-week post-closure follow-up. There were no adverse events related to the AHSC treatments.
Conclusions: AHSC was able to close DFUs refractory to standard of care with one treatment utilizing normal clinic work flow and requiring only one application. Further evaluation with randomized controlled trials are warranted.

Disclosure
C. Zelen: Research Support; Self; Musculoskelatal Transplant Foundation, Polarity TE. D.G. Armstrong: None.
454-P: Weight Loss and Type 2 Diabetes Are Mutually Independent Predictors of Mortality in Patients with Established Coronary Artery Disease
Authors: SAELY CHRISTOPH H. , VONBANK ALEXANDER , HEINZLE CHRISTINE , ZANOLIN-PURIN DANIELA , LARCHER BARBARA , MADER ARTHUR , SAID ABDURAHMAN , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ 
Published: June 2019

Obesity is a major risk factor for type 2 diabetes (T2DM), coronary artery disease (CAD) and premature mortality. This, however, does not necessarily imply that weight loss in patients who already have established CAD is associated with an improved outcome. In this study, we prospectively investigated the association of weight loss with mortality in a consecutive series of 483 patients with angiographically proven CAD. Weight was measured at baseline and after 4 years, and deaths were recorded over a mean follow-up period of 11.5±3.9 years. At baseline, weight was significantly higher in patients with T2DM (n=137) than in nondiabetic subjects (83±14 vs. 78±14 kg, p=0.003, amounting to BMI scores of 28.9±3.9 vs. 27.4±3.8 kg/m2; p&lt;0.001). Prospectively, 56 (42.4%) of the patients with T2DM and 104 (31.2%) of the nondiabetic patients died (p=0.022); weight loss occurred in 76.6% of the patients with T2DM and in 73.4% of the patients who did not have diabetes (p=0.464). The amount of weight loss significantly predicted cardiovascular mortality univariately (standardized HR 1.14 [1.03-1.27]; p=0.013), as well as after multivariate adjustment including T2DM status (standardized adjusted HR 1.18 [1.05-1.33]; p=0.005). Conversely, T2DM remained a significant predictor of mortality after multivariate adjustment including weight loss (HR 1.67 [1.19-2.33]; p=0.003). We conclude that weight loss and T2DM are mutually independent predictors of mortality in patients with established CAD.

Disclosure
C.H. Saely: None. A. Vonbank: None. C. Heinzle: None. D. Zanolin-Purin: None. B. Larcher: None. A. Mader: None. A. Said: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
457-P: One-Year Administration of Anti-PCSK9 Antibody Is Enough to Stabilize Vulnerable Coronary Plaques in Diabetic Patients, which Are Resistant to Intensive Statin Therapy
Authors: HIRAI AIZAN , FUJIMURA KOJI , HIRAI KEIJI , KONDO SEIYA , SHIRAKAMI ATSUSHI , SAKAI TAKENORI , MURATA KAZUYA , TANIAI HISANORI , OKUZAKI KAZUTOSHI , KAGEYAMA TAKAHIRO 
Published: June 2019

Purpose: Coronary plaque progression despite very low levels of LDL-C has been reported in the patients with coronary artery disease (CAD) who received intensive statin therapy (IST). Coronary CT Angiography (CCTA) has been applied to evaluate vulnerable coronary plaques having low attenuation of CT value. The major function of PCSK9 is the binding to hepatic LDL receptors, leading to their degradation. PCSK9 is produced also in vascular smooth muscle cells constituting the atherosclerotic lesion in addition to hepatocytes. PCSK9 promotes foam cell formation by suppressing the excretion of cholesterol from macrophages. Statin is demonstrated to promote PCSK9 production. PCSK9 has been proposed to play a crucial role in the pathogenesis of IST resistance. The present study was performed to establish a novel therapeutic approach to IST resistant vulnerable plaque of coronary artery in diabetic patients.
Methods: The present study included 142 T2DM patients with non-FHC asymptomatic CAD who developed vulnerable coronary plaques despite IST over 2 years. CCTA by use of 320-slice CT was applied to evaluate vulnerable coronary plaques. During the administration of anti-PCSK9 antibody, changes in serum lipids and CT value of vulnerable coronary plaques were determined.
Results: During 1 year administration of anti-PCSK9 antibody, 74% decrease in serum LDL-C was observed. Also, improvement of vulnerable coronary plaque, e.g., rise in the CT value of plaque (from 43.2 ±12.0 HU to 128.5 ± 52.3 HU, p&lt;0.0001) was observed. Of the 142 patients, 95 patients finished the administration of the drug.
Conclusion: One year administration of anti-PCSK9 antibody produced a significant stabilization of vulnerable coronary plaques in the patients with asymptomatic CAD who are resistant to IST. An analysis of the plaque quality by CCTA is useful method for the evaluation of the effect of the drug on vulnerable coronary plaques.

Disclosure
A. Hirai: None. K. Fujimura: None. K. Hirai: None. S. Kondo: None. A. Shirakami: None. T. Sakai: None. K. Murata: None. H. Taniai: None. K. Okuzaki: None. T. Kageyama: None.
460-P: Treatment with Dipeptidyl Peptidase Inhibitors (DPP-4_Rx) Is Associated with Significant Reduction in Macrovascular Events Independent of Glucose Control
Authors: GARCIA-TOUZA MARIANA 
Published: June 2019

We have observed renal protective effects with DPP-4 inhibitor therapy in a prior study done at the VA. Effects of DPP-4_Rx on cardiovascular morbidity and macrovascular events are disputed. Data from a large cohort of veterans diagnosed with type 2 diabetes mellitus (T2DM) were used to identify patients on DPP-4_Rx and without (control). Groups were matched for age (years), sex, BMI, initial renal function, follow-up time (FU, minimum 365 days). Propensity score matching (PSM) was used to adjust groups with a best odds ratio about 1:1. Groups were compared to determine the effect of DPP-4_Rx on the emergence of new macrovascular events identified by ICD-9 and all-cause mortality. Data were extracted using the Veterans Administration Informatics and Computing Infrastructure (VINCI), and analyzed using SAS. Results were compared using t-tests, frequency tables, Kaplan Meier survival curves, hazard ratios (HR) and p values.
Results show that subject with DPP-4 (N=24,763) had baseline variables similar to control. DM control improved with DPP-4_Rx but remained worse than control. A significant reduction in new macrovascular events was seen in DPP-4 group (Table). Mortality from all causes was reduced by 78.1%, but time to death was not changed.
We conclude that DPP-4_Rx associates with a significant reduction in frequency of all-cause mortality and macrovascular events independent of glucose control. The reduction of macrovascular events explains in part the improved survival and improvements in renal outcomes we have seen before.

Disclosure
M. Garcia-Touza: None.
466-P: Effect of Metformin on Cardiovascular Function in Type 1 Diabetes
Authors: ABOLARIN JOSHUA , SCHAUER IRENE E. 
Published: June 2019

Cardiovascular (CV) disease remains the leading cause of mortality in type 1 diabetes (T1D) despite advances in glycemic control and to a greater extent than predicted by traditional CV risk factors. Metformin is generally thought to have vascular benefit in T2D and other insulin resistant states, though conclusive data for CV outcomes is lacking. In T1D metformin has been studied for glycemic control, but little attention has been paid to CV effects. We hypothesized that metformin would improve insulin sensitivity (IS), vascular function and compliance, and mitochondrial function in T1D. T1D participants (n=23) underwent a placebo-controlled, double-blind, random order, cross-over design intervention with 6 weeks of metformin vs. placebo. Glycemic control (CGM), cardiac function (echocardiography), vascular stiffness (Sphygmacor and Dynapulse), autonomic function, IS (hyperinsulinemic euglycemic clamp), and mitochondrial function in vivo (31P MRS) and ex vivo (muscle biopsy with high resolution respirometry) were measured after each phase. Glucose control and IS by clamp were not improved with metformin. Oxidative phosphorylation was increased in vivo, but ex vivo mitochondrial function was not improved. Cardiac contractility and output, arterial stiffness, systemic vascular resistance, and possibly autonomic function, were improved with metformin. These results suggest that metformin may provide CV benefit in T1D.

Disclosure
J. Abolarin: None. I.E. Schauer: Other Relationship; Spouse/Partner; Kestrel Labs.

Funding
National Institutes of Health