Established CVD Research Articles

Second-year results from CINEMA: A novel, patient-centered, team-based intervention for patients with Type 2 diabetes or prediabetes at high cardiovascular risk

BackgroundThe care for patients with type 2 diabetes mellitus (T2DM) necessitates a multidisciplinary team approach to reduce cardiovascular (CV) risk but implementation of effective integrated strategies has been limited. Methods and ResultsWe report 2-year results from a patient-centered, team-based intervention called CINEMA at University Hospitals Cleveland Medical Center. Patients with T2DM or prediabetes at high-risk for CV events, including those with established atherosclerotic CVD, elevated coronary artery calcium score ≥100, chronic heart failure with reduced ejection fraction, chronic kidney disease (CKD) stages 2–4, and/or prevalent metabolic syndrome were included. From May 2020 through September 2022, 426 patients were enrolled in the CINEMA program. A total of 227 (54%) completed ≥1 follow-up visit after an initial baseline visit with median (IQR) follow-up time 4 [3–7] months with maximum follow-up time 19 months. Mean age was 60 years, 47 % were women, and 37 % were Black and 85% had prevalent T2DM, 48 % had established ASCVD, 29% had chronic HF, 27% had CKD and mean baseline 10-year ASCVD risk estimate was 25.1 %; baseline use of a SGLT2i or GLP-1RA was 21 % and 18 %, respectively. Patients had significant reductions from baseline in body weight (-5.5 lbs), body mass index (-0.9 kg/m2), systolic (-3.6 mmHg) and diastolic (-1.2 mmHg) blood pressure, Hb A1c (-0.5 %), total (-10.7 mg/dL) and low-density lipoprotein (-9.0 mg/dL) cholesterol, and triglycerides (-13.5 mg/dL) (p<0.05 for all). Absolute 10-year predicted ASCVD risk decreased by ∼2.4 % (p<0.001) with the intervention. In addition, rates of guideline-directed cardiometabolic medication prescriptions significantly increased during follow-up with the most substantive changes seen in rates of SGLT2i and GLP-1RA use which approximately tripled from baseline (21 % to 57 % for SGLT2i and 18 % to 65 % for GLP-1RA, p<0.001 for both). ConclusionsThe CINEMA program, an integrated, patient-centered, team-based intervention for patients with T2DM or prediabetes at high risk for cardiovascular disease has continued to demonstrate effectiveness with significant improvements in ASCVD risk factors and improved use of evidence-based therapies. Successful implementation and dissemination of this care delivery paradigm remains a key priority.

Abstract 15562: Coronary Artery Calcium Score for Allocating Emerging Obesity Therapies: Implications for the Ongoing SURMOUNT-MMO Outcome Trial

Background: Tirzepatide demonstrated substantial weight loss in patients with obesity yet without diabetes and the clinical trial (SURMOUNT-MMO) evaluating its CVD benefits is ongoing. We tested whether the CAC score provides substantial risk predictive value in this setting. Methods: Participants (N=16,163; mean age 53.0 ± 9.7 years; 72.5% men) with BMI≥ 27 kg/m 2 but without diabetes from the CAC Consortium were categorized based on the inclusion criteria of SURMMOUNT-MMO trial pertaining to individuals without an established CVD. The predictive value of CAC was evaluated for all-cause and cause-specific mortality after mean follow-up of 10.6 ± 2.9 years using multivariable-adjusted Cox proportional hazard and competing risks regression, respectively. Results: Of the 16,163 participants, 14,004 (86.6%) would not qualify for the SURMMOUNT-MMO trial. Of those, those with CAC ≥ 300 had a higher rate (per 1,000 person-years) of all-cause (7.10 vs. 1.43), CVD (2.62 vs. 1.0), and CHD (1.61 vs. 0.75) mortality compared to ones with CAC=0. After adjusting for age, sex, and race, individuals who would not qualify and with CAC≥ 300, had significantly higher risk of all-cause, CVD, and CHD mortality (all P-values &lt;0.001), compared to those who do not qualify and without CAC. Of note, individuals who would qualify but with CAC &lt;100 did not have increased all-cause, and cause-specific mortality compared to individual who would not qualify and without CAC (Table). Conclusions: CAC strongly predicts all-cause, CVD, and CHD mortality among individuals with obesity but without diabetes, and may better risk stratify than SURMOUNT-MMO inclusion criteria. CAC may serve as an effective risk stratification tool to prioritize the allocation of therapies for weight management.

THU283 Oral Semaglutide, Effectiveness, Safety And Tolerability In Real Life: A Short-term Retrospective Observational Study

Abstract Disclosure: O. Moreno-Perez: None. C. Guillen-Morote: None. T. Argüello: None. C. Soriano: None. E. SantaCruz: None. P. Lopez-Mondejar: None. C. Navarro-Hoyas: None. R. Sanchez-Ortiga: None. M. Sanchez-Pacheco: None. I. Modrego-Pardo: None. A.M. Pico: None. Introduction: Oral semaglutide (oSEMA) is the first and only oral aRGLP1 currently available on the market. Given its recent commercialization, there is little real-life evidence on its effectiveness, safety, and tolerability. Primary objective: to evaluate the effectiveness (HbA1c, Weight, Blood Pressure, Albumin Creatinine Ratio (ACR)) safety and tolerability of oSEMA 3-6 months after the start of treatment in the real world clinical practice. Secondary objective: to describe the main indications of oSEMA in real life. Material and methods: short-term retrospective observational study of all patients with oSEMA prescription in two health departments between November 2021 and November 2022. Statistical approach: descriptive analysis (median [IQR]); Wilcoxon test - paired data for evaluate changes in main outcomes and logistic regression to determine associations between provider speciality and short-term non-adherence. Ethics committee approval Ref.: 2022-0386. Results: 170 patients were included in these preliminary data. The median age was 63 [55.0 -70.0] years, with male predominance (60.5%), initial weight of 95 [83-112]kg and BMI 36.03 [31.04-39.34] Kg/m2. Median T2D evolution was 8 [2.0-12.0] years, 27.3% have an established CVD and 14% DKD. Prior therapy for T2D: 11% GLP1 receptor agonists (RA), 25.6% DPP4 inhibitors, 47.1% SGLT-2 inhibitors and 22.7% under insulin therapy. The oSEMA provider specialties were mainly: endocrinology (ENDO) 39.2%, primary physician (PCare) 35.7% and cardiology (CAR) 20.9%. At the time of this analysis, the maintenance dose was 7 mg in 98.4% of patients. The changes in the main clinical outcomes at 3-6 months of follow-up were: HbA1c 7.8 [6.9-8.6]% vs 6.9 [6.2-7.7]%, p= 0.0001; weight 95.5 [81-112] Kg vs 90 [74.5-105.2]Kg, p= 0.0001; ACR (baseline ACR subpopulation &amp;gt; 30) 57 [39. 5- 110.9] mg/g vs. CAC 37.0 [14.5-58.0], p=0.005; SBP 135 [125-150] mmHg vs. SBP 121.5 [109.50-31.00], p= 0.028. Treatment was discontinued in 23.8% of cases (ENDO 14%, PCare 26, CAR 30%). Having the index prescription ordered by ENDO were associated with lower odds of non-adherence (OR 0.48[0.22-1.05], p = 0.06). The most frequent causes of oSEMA discontinuation were the lack of continuity of care after hospitalization (renewal / titration) (10.5%) and digestive intolerance (8.7%). Conclusions: Oral SEMA at medium doses is effective in the short term with 1% reductions in HbA1c, 5% weight loss and a significant reduction in microalbuminuria. Oral SEMA is usually started in obese PLWT2D naïve to aRGLP1, with inadequate metabolic control and without CV disease. No serious adverse events have been recorded. Mistakes in the transition from hospital discharge to primary care were the cause of almost 50% of short-term non-adherence. Presentation: Thursday, June 15, 2023

Solar Cell Application of 1D Heterostructure Based on Single-Walled CNT

The experimental synthesis of one-dimensional (1D) van der Waals heterostructures, first introduced in 2020 [1], has attracted much research attention. Discussions upon this coaxial stack of different atomic layers are not only limited to synthesis and characteristics, but also extended to applications. Many unique properties of the 1D van der Waals heterostructures, such as the adjustable band gap, strong quenching of photoluminescence of MoS2 by inner single-walled CNT, enable this structure to be a potential active layer material for solar cells [2].For the synthesis of 1D van der Waals heterostructures, we first use dispersed high-purity semiconducting single-walled carbon nanotubes (s-SWCNT) solution obtained from Kataura group [3] as inner tube material. With an anodic aluminum oxide (AAO) membrane filter and HCl, we managed to fabricate a free-standing s-SWCNT film [4]. Then following our established CVD process [5], we are wrapping this inner s-SWCNT tube with an insulating boron nitride layer, and a semiconducting MoS2 layer. After that, the as-prepared 1D van der Waals heterostructures film will be utilized for solar cell fabrication.The solar cell is adopting an n-i-p structure, in the order of glass-ITO-SnO2-Active layer-Spiro-Au. After spin-coating and annealing SnO2 (electron transporting layer) onto ITO-patterned glass, the 1D van der Waals heterostructure film is laminated on the SnO2 layer. Spiro (hole transporting layer) will be then spin-coated onto the film. Finally, gold is vapor-deposited onto the device in a vacuum chamber, as the top electrode [6].Through photocurrent measurement of 1D van der Waals structure film using Esko film, a mixture of metallic-SWCNT and s-SWCNT, we found it is photosensitive with exposure to light and laser. The 1D van der Waals structure film using high-purity s-SWCNT is then expected to generate higher photocurrent, the experimental result will be updated in the future. By the IV measurement of the solar cell, we observed the photovoltaic effect of the device. Moreover, this new conceptual solar cell is believed to possess many advantages at the same time, such as flexibility, durability, non-toxicity, and sustainability [2]. However, further research on the choices of materials and optimizations of device parameters is still required in order to reach sufficient power conversion efficiency as a photovoltaic device.[1] R. Xiang et al., Science 367, 537–542 (2020)[2] R. Xiang et al., Natl Sci Open 1, 3 (2022)[3] J. Cui et al., ACS Appl. Nano Mater 2, 1, 343–350 (2019)[4] C. Zhang et al., ACS Nano 16, 11, 18630–18636 (2022)[5] M. Liu et al., ACS Nano 15, 5, 8418–8426 (2021)[6] J.-M. Choi et al, Adv. Funct. Mater. 32, 2204594 (2022)

Liver Stiffness Is Associated with the Burden of Carotid and Systemic Atherosclerosis in an Unorganized Cohort of Patients 40-64 Years Old.

Background: The aim of the study is to research the relationship between the severity of liver fibrosis and the burden of carotid and systemic atherosclerosis. Methods: The study includes 163 patients 40 to 64 years of age without atherosclerotic CVD or liver disease. All patients underwent duplex scanning of the carotid and lower limb arteries. All patients underwent transient liver elastometry using the FibroScan (Echosens, France). Results: Carotid plaque was detected in 110 (67.5%) patients. Based on the results of linear regression analysis, relationships between liver stiffness and carotid total plaque area (r = 0.21; p = 0.025) were found. Significant relationships were established between liver stiffness and atherosclerosis burden score based on the results of linear regression (r = 0.17; p = 0.029). Liver stiffness showed moderate diagnostic performance (AUC 0.666; p = 0.01) with regard to generalized atherosclerosis. An increase in liver stiffness >4.5 kPa was associated with an odds ratio of generalized atherosclerosis of 3.48 (95% CI 1.07–11.3; p = 0.038) after adjusting confounding factors. Conclusion: Among patients 40–64 years of age without established atherosclerotic CVD and liver disease, liver stiffness directly correlates with the burden of carotid and systemic atherosclerosis. Liver stiffness showed moderate diagnostic performance (AUC 0.666; p = 0.01) with regard to generalized atherosclerosis.

130-OR: The Association between High Out-of-Pocket Costs and Incidence of Treatment Intensification with an SGLT2 Inhibitor (SGLT2i) or GLP-1 Agonist (GLP-1a) in Patients with Type 2 Diabetes and Established Cardiovascular Disease: A Retrospective Cohort Study

The use of SGLT2i and GLP-1RA in patients with T2D remains low despite their known CV benefits. This may be due in part to high drug costs. We sought to assess the association between out-of-pocket (OOP) costs and the likelihood of initiating these two classes in patients with T2D and established CVD. We conducted a cohort study using claims data (Optum) , which included commercial and Medicare Advantage beneficiaries. Adults with T2D on metformin monotherapy between 12/5/17 and 12/31/were eligible. We excluded those:1) not continuously enrolled for ≥1 yr prior to their first metformin dispensing,2) with no evidence of established CVD, or3) whose OOP costs (defined as the sum of copays and deductibles for a 30-day supply) for SGLT2i or GLP-1RA could not be determined. We used Cox proportional hazards models adjusting for demographics, clinical characteristics, insurance plan, provider and laboratory characteristics to estimate hazard ratios (HR) of initiation across quartiles (Q) of OOP costs, with Q1 representing the lowest and Q4 the highest OOP costs. The cohort included 72,743 patients (mean[SD] age 72[9.4], 56% male) followed for a median of 914 days. Most (88%) were covered by a Medicare Advantage plan. The unadjusted incidence of initiating a SGLT2i (or GLP-1RA) was 2.8% (2.1%) in Q4 vs. 3.8% (2.8%) in Q1 of OOP costs. The median time to initiation of a SGLT2i/GLP-1RA was longer in Q4 (418/325 days) vs. Q1 (395/3 days) of OOP costs. In fully adjusted models, the HR for Q4 vs. Q1 of OOP costs was 0.79 (95%CI 0.70 to 0.90) for initiating a SGLT2i and 0.88 (95%CI: 0.77 to 1.01) for a GLP-1RA. In this national cohort of patients w/ T2D and established CVD, beneficiaries enrolled in plans in the highest quartile of OOP costs were significantly less likely to initiate a SGLT2i or GLP-1RA compared to those enrolled in plans in the lower quartile. Disclosure J.Luo: None. R.Feldman: None. S.D.Rothenberger: None. I.Hernandez: Consultant; Bristol-Myers Squibb Company, Pfizer Inc. M.T.Korytkowski: None. W.F.Gellad: None. Funding NIDDK (K23DK120956) NCATS (KL2TR001856)

Uric acid as a predictor of weight gain and cardiometabolic health in the Study of Novel Approaches to Weight Gain Prevention (SNAP) study

Young adulthood is often a period of substantial weight gain increasing risk for obesity and cardiometabolic disease. Uric acid (UA), a clinical marker of oxidative stress, is associated with cardiometabolic dysfunction in established CVD, type 2 diabetes, and CKD. Yet, few trials have examined UA as a predictor of cardiometabolic risk in young, healthy populations, particularly in the context of weight gain prevention intervention. The purpose of this ancillary study was to examine UA in the Study of Novel Approaches to Weight Gain Prevention (SNAP), a randomized, controlled trial of weight gain prevention strategies in young healthy adults. UA was examined as a predictor of weight and cardiometabolic outcomes over 6 years; the impact of weight gain prevention interventions on UA was also examined. We found that higher baseline UA was a significant predictor of less favorable BMI, triglycerides, HDL, glucose, insulin, and HOMA, independent of age, sex, baseline weight, baseline level of the outcome variable, and weight gain prevention intervention. Additionally, ≥1% weight loss was associated with lower UA. UA is a promising biomarker for future weight gain and cardiometabolic risk in young adults that may respond to weight gain prevention.Clinical trial registration: clinicaltrials.gov identifier NCT01183689.

Cardiovascular Risk Factors Mediate the Long-Term Maternal Risk Associated With Hypertensive Disorders of Pregnancy

BackgroundHypertensive disorders of pregnancy (HDP), including gestational hypertension and preeclampsia, are associated with an increased risk of CVD. ObjectivesThe purpose of this study was to evaluate associations between HDP and long-term CVD and identify the proportion of the association mediated by established CVD risk factors. MethodsParous participants without CVD in the Nurses’ Health Study II (n = 60,379) were followed for incident CVD from first birth through 2017. Cox proportional hazards models estimated HRs and 95% CIs for the relationship between HDP and CVD, adjusting for potential confounders, including prepregnancy body mass index, smoking, and parental history of CVD. To evaluate the proportion of the association jointly accounted for by chronic hypertension, hypercholesterolemia, type 2 diabetes, and changes in body mass index, we used the difference method. ResultsWomen with HDP in first pregnancy had a 63% higher rate of CVD (95% CI: 1.37-1.94) compared with women with normotensive pregnancies. This association was mediated by established CVD risk factors (proportion mediated = 64%). The increased rate of CVD was higher for preeclampsia (HR: 1.72; 95% CI: 1.42-2.10) than gestational hypertension (HR: 1.41; 95% CI: 1.03-1.93). Established CVD risk factors accounted for 57% of the increased rate of CVD for preeclampsia but 84% for gestational hypertension (both P < 0.0001). ConclusionsEstablished CVD risk factors arising after pregnancy explained most (84%) of the increased risk of CVD conferred by gestational hypertension and 57% of the risk among women with preeclampsia. Screening for chronic hypertension, hypercholesterolemia, type 2 diabetes, and overweight/obesity after pregnancy may be especially helpful in CVD prevention among women with a history of HDP.

Abstract 4: Derived time-in-range is associated with major adverse cardiovascular event in T2D: Data from the DEVOTE trial

Background: There is a need to validate time-in-range (TIR; percentage of time with plasma glucose between 70 and 180 mg/dL (3.9-10.0 mmol/L) as a surrogate endpoint for long-term clinical outcomes.Methods: We used data from patients with 8-point glucose profiles (8pp) from the double-blind cardiovascular outcomes trial, DEVOTE (NCT01959529). In total, 7637 patients with T2D and either established CVD or at high risk for CVD were included in the trial. The primary endpoint in DEVOTE was time to first MACE. The 8pp were collected at 1 year, 2 years and end-of-trial. Median length of follow-up was 2 years. For 5644 patients, 8pps with at least 7 points existed. Among the 681 major adverse cardiovascular events (MACEs) in DEVOTE, 360 were among patients with 8pps. Individual TIR was derived as the proportion of the 8pp within range. A Cox model was used to estimate the association between derived TIR and time to first MACE. Hazard ratios (HR) were estimated for patients with TIR>70% vs. TIR≤70%, and for TIR>70% and TIR 50 −70% vs. TIR≤50%.Results: Derived TIR was >70% for 65% of the patients. Estimated rate of first MACE was lower for TIR >70% and TIR 50-70% vs. TIR≤50% [Figure 1] and for TIR>70% vs. TIR≤70% (HR: 0.74 [0.60;0.91]95% CI; p<0.01). The associations were maintained when analyses were adjusted for baseline characteristics. Figure 1Association between derived time-in-range and major adverse cardiovascular event Conclusions: Derived TIR was associated with rate of first MACE for T2D patients in DEVOTE.

Abstract 12542: Prevalence and Characterization of Occult Coronary Atherosclerotic Disease Among Middle Aged Individuals Free of Clinical Cardiovascular Disease - Results From Miami Heart Study (MiHeart) at Baptist Health South Florida

Introduction: While prior population-based cohorts have extensively described burden of coronary artery calcification (CAC) among asymptomatic individuals, there is paucity of occult coronary atherosclerotic disease (CAD) assessment with coronary computed tomography angiography (CCTA) in the general population. The aims were to determine prevalence, burden and coronary plaque characteristics in the ongoing prospective Miami Heart Study (MiHeart) using both CAC and CCTA. Methods: MiHeart enrolled 2,549 middle-aged 40-65 years free of clinical cardiovascular disease participants (49% females, mean age 53, 47% Hispanic/Latino) from general population of Greater Miami Area (Florida, USA). Final study consisted of 2491 (98%) among whom non- cardiac-gated CT for CAC testing and contrast-enhanced CCTA cardiac-gated were performed. Results: In this study 58% had CAC=0, 13% had CAC≥100, and 45% had detectable plaque on CCTA. 143 (6%) participants had significant (≥50%) stenosis and 44 (2%) had severe (≥70%) stenosis. Overall, 26% participants had exclusive non-calcified plaque whereas 7% demonstrated high-risk plaque features (HRP) with positive remodeling being most frequently observed (5%). Among participants with CAC=0, 15% had any plaque on CCTA (62% in 1 segment); 1% had obstructive CAD and 2% any HRP, respectively. Burden of CAD (plaque segmental score, subtype, stenosis) as well as HRP on CCTA was strongly associated with increasing CAC scores (table). Overall, 31% and 20% with CAC≥100 had significant stenosis and HRP, respectively. Conclusions: In the first US general population based CCTA study, we demonstrate high burden of diverse coronary atherosclerotic plaque features in a middle-aged general population free of established CVD. Future studies in MiHeart will focus on biological associations and clinical implications of of coronary atherosclerotic disease severity and features on CCTA among asymptomatic individuals.

Applying REWIND cardiovascular disease criteria to SUSTAIN 6 and PIONEER 6: An exploratory analysis of cardiovascular outcomes with semaglutide.

In the REWIND trial, dulaglutide reduced cardiovascular (CV) risk versus placebo in patients with type 2 diabetes in both the “established CV disease” (CVD) and “CV risk factor” subgroups. The SUSTAIN 6 and PIONEER 6 trials of semaglutide used different criteria for established CVD from those used in REWIND. The present post hoc analysis assessed the effect of semaglutide on major adverse CV events (MACE) in a pooled population of SUSTAIN 6 and PIONEER 6 patients, re‐categorized into CV risk subgroups using the REWIND CVD criteria. In the pooled analysis (n = 6480), a lower percentage of patients were in the established CVD subgroup, when using the REWIND CVD criteria, compared with the original trial CVD criteria (66.5% vs. 83.8%, respectively). After re‐categorization, the risk of MACE was significantly lower with semaglutide versus placebo in the established CVD subgroup (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.59, 0.92) and nonsignificantly lower in the CV risk factor subgroup (HR 0.84, 95% CI 0.55, 1.28) (P‐interaction = 0.60). These results suggest that the CV effects of semaglutide may extend to patients with type 2 diabetes across the CV risk continuum.

89976 ASSESSING PROTEIN BIOMARKERS ROLE IN CVD RISK PREDICTION IN PERSONS LIVING WITH HIV (PWH)

ABSTRACT IMPACT: Our findings could potentially identify CVD at-risk persons living with HIV who might benefit from aggressive risk-reduction. OBJECTIVES/GOALS: PWH have higher rates of CVD than the general population yet CVD risk prediction models rely on traditional risk factors and fail to capture the heterogeneity of CVD risk in PWH. Here we identify protein biomarkers that are able to discriminate between CVD cases and controls in PWH, and we assess their added benefit beyond traditional risk factors. METHODS/STUDY POPULATION: We analyzed 459 baseline protein expression levels from five OLINK panels in a matched CVD (MI, coronary revascularization, stroke, CVD death) case-control study with 390 PWH from INSIGHT trials (131 cases, 259 controls). We formed 200 datasets via bootstrap. For each bootstrap set, a two-component partial least squares discriminant model (PLSDA) was fit. The importance of each variable in the discrimination of cases and controls in the PLSDA projection was assessed by the variable importance in projection (VIP) score. Proteins with average VIP scores &gt; 1 were used in penalized logistic regression models with elastic net penalty, and proteins were ranked based on the number of times the protein had a nonzero coefficient. Proteins in the top 25th percentile were considered to have high discrimination. RESULTS/ANTICIPATED RESULTS: Participants had mean age 47 years, 13% were females, 4.9% had CVD at baseline and 69% were on ART at baseline. Eight proteins including the hepatocyte growth factor and interleukin-6 were identified as able to distinguish between CVD cases and controls within PWH. A protein score (PS) of the top-ranked proteins was developed using the bootstrap (for weights) and the entire data. The PS was found to be predictive of CVD independent of established CVD and HIV factors (Odds ratio: 2.17 CI: 1.58-2.99). A model with the PS and traditional risk factors had a 5.9% improvement in AUC over the baseline model (AUC=0.731 vs 0.69), which is an increase in model predictive power of 18%. Individuals with a PS above the median score were 3.1 (CI: 1.83- 5.41) times more likely to develop CVD than those with a protein score below the median score. DISCUSSION/SIGNIFICANCE OF FINDINGS: A protein score developed improved discrimination of PWH with CVD and those without, and helped identify PWH with high risk for developing CVD. If validated, this score and/or the individual proteins could be used in addition with established factors to identify CVD at-risk individuals who might benefit from aggressive risk-reduction.

Imipridone enhances vascular relaxation via FOXO1 pathway.

Cardiovascular complications are a side effect of cancer therapy, potentially through reduced blood vessel function. ONC201 (TIC10) is currently used in phase 2 clinical trials to treat high-grade gliomas. TIC10 is a phosphatidylinositol 3-kinase (PI3K)/AKT/extracellular signal-regulated kinase (ERK) inhibitor that induces apoptosis via upregulation of TNF-related apoptosis-inducing ligand, which via stimulation of FOXO and death receptor could increase eNOS upregulation. This has the potential to improve vascular function through increased NO bioavailability. Our aim was to investigate the role of TIC10 on vascular function to determine if it would affect the risk of CVD. Excised abdominal aorta from White New Zealand male rabbits were cut into rings. Vessels were incubated with TIC10 and AS1842856 (FOXO1 inhibitor) followed by cumulative doses of acetylcholine (Ach) to assess vessel function. Vessels were then processed for immunohistochemistry. Incubation of blood vessels with TIC10 resulted in enhanced vasodilatory capacity. Combination treatment with the FOXO1 inhibitor and TIC10 resulted in reduced vascular function compared to control. Immunohistochemical analysis indicated a 3-fold increase in death receptor 5 (DR5) expression in the TIC10-treated blood vessels but the addition of the FOXO1 inhibitor downregulated DR5 expression. The expression of DR4 receptor was not significantly increased in the presence of TIC10; however, addition of the FOXO1 inhibitor downregulated expression. TIC10 has the capacity to improve the function of healthy vessels when stimulated with the vasodilator Ach. This highlights its therapeutic potential not only in cancer treatment without cardiovascular side effects, but also as a possible drug to treat established CVD.

1426-P: Utilization of Glucose-Lowering Drugs in Patients with T2DM and Established CVD in the U.S.

Background: People with T2DM have increased risks of CV morbidity and mortality. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to reduce risks of CV events, but the degree to which they are used in clinical practice remains unknown. Our objectives were to describe glucose-lowering drug utilization in U.S. patients with T2DM and established CVD (eCVD) in 2014-18. Methods: Annual drug use by adults (≥ 18 years) with T2DM and eCVD (during the same 12-months) was determined from the MarketScan claims database. Results: We identified 345,340 (2014) to 227,418 (half year 2018) patients with T2DM and eCVD; hypertension and ischemic heart disease were the most prevalent eCVDs. About 55-60% of patients used any type of glucose lowering drug. Although the use of GLP-1 RA and SGLT2i increased 6.2 and 9.5 percentage points respectively across 2014-18, the use of dipeptidyl peptidase-4 inhibitors (DPP-4i) decreased by 3.7 points and use of other glucose lowering drugs decreased by 10.8 points. Patients who used GLP-1 RA and SGLT2i were 8 years younger than users of DPP-4i or other glucose lowering drugs. SGLT2i users had the lowest prevalence of chronic heart failure and chronic kidney disease. Conclusion: Despite recent increases, GLP 1-RA and SGLT2i are significantly underused among patients with T2DM and eCVD in the MarketScan claims database. Disclosure M.L. Ganz: None. A.V. Ustyugova: Employee; Self; Boehringer Ingelheim International GmbH. N. Sawalhi-Leckenby: None. S. de Souza: None. R. Gao: None. D. Homsy: None. E. Gunnarsson: None. L. Zhang: None. N. Desai: None.

21-LB: Derived Time-in-Range Is Associated with MACE in T2D: Data from the DEVOTE Trial

Background: There is a need to validate time-in-range (TIR; percentage of time with plasma glucose between 70 and 180 mg/dL (3.9-10.0 mmol/L) as a surrogate endpoint for long-term clinical outcomes. Methods: We used data from patients with 8-point glucose profiles (8pp) from the double-blind cardiovascular outcomes trial, DEVOTE (NCT01959529). In total, 7637 patients with T2D and either established CVD or at high risk for CVD were included in the trial. The primary endpoint in DEVOTE was time to first MACE. The 8pp were collected at 1 year, 2 years and end-of-trial. Median length of follow-up was 2 years. For 5644 patients, 8pps with at least 7 points existed. Among the 681 major adverse cardiovascular events (MACEs) in DEVOTE, 360 were among patients with 8pps. Individual TIR was derived as the proportion of the 8pp within range. A Cox model was used to estimate the association between derived TIR and time to first MACE. Hazard ratios (HR) were estimated for patients with TIR&amp;gt;70% vs. TIR≤70%, and for TIR&amp;gt;70% and TIR 50 −70% vs. TIR≤50%. Results: Derived TIR was &amp;gt;70% for 65% of the patients. Estimated rate of first MACE was lower for TIR &amp;gt;70% and TIR 50-70% vs. TIR≤50% (Figure) and for TIR&amp;gt;70% vs. TIR≤70% (HR: 0.74 [0.60;0.91]95% CI; p&amp;lt;0.01). The associations were maintained when analyses were adjusted for baseline characteristics. Conclusions: Derived TIR was associated with rate of first MACE for T2D patients in DEVOTE. Disclosure R.M. Bergenstal: Consultant; Self; Ascensia Diabetes Care, Johnson &amp; Johnson. Other Relationship; Self; Abbott, Dexcom, Inc., Hygieia, Lilly Diabetes, Medtronic, Novo Nordisk A/S, Onduo, Roche Diabetes Care, Sanofi, UnitedHealth Group. E. Hachmann-Nielsen: Employee; Self; Novo Nordisk A/S. K. Kvist: Employee; Self; Novo Nordisk A/S. J.B. Buse: Consultant; Self; Cirius Therapeutics, CSL Behring, Neurimmune. Research Support; Self; American Diabetes Association, National Institutes of Health, Novo Nordisk A/S, Patient-Centered Outcomes Research Institute, Sanofi, Tolerion, Inc., vTv Therapeutics. Stock/Shareholder; Self; Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Stability Health. Other Relationship; Self; ADOCIA, AstraZeneca, Dance Biopharm Holdings, Inc., Eli Lilly and Company, MannKind Corporation, NovaTarg Therapeutics, Novo Nordisk A/S, Senseonics, Inc, vTv Therapeutics, Zafgen, Inc. Funding Novo Nordisk A/S

32-OR: The Bexagliflozin Efficacy and Safety Trial (BEST): A Randomized, Double-Blind, Placebo-Controlled, Phase IIII, Clinical Trial

Bexagliflozin (bexa) is a potent and selective inhibitor of SGLT2. To demonstrate its effects in patients (pts) at increased risk of cardiovascular (CV) events, pts with type 2 diabetes (T2D) ≥40 years old with HbA1c 7.5-11 % and eGFR ≥45 were enrolled in 1 of 3 groups: 1) established atherosclerotic CVD 2) heart failure (HF) or 3) ≥55 years with ≥2 CV risk factors. The primary endpoint was change in HbA1c at wk 24. Secondary endpoints included change in SBP at 24 wks in pts with SBP ≥140 mmHg, weight loss at 48 wks in pts with BMI ≥25 kg/m2, and time to hospitalization for HF or CV death. MACE+ (CV death, myocardial infarction, stroke, or unstable angina) was tested in a non-inferiority analysis to demonstrate upper 95% CI &amp;lt;1.8. Pts were randomized 2:1 to bexa 20 mg or placebo qd. Follow-up continued until all pts completed ≥52 wks and when ≥134 subjects had a MACE+ event. CV endpoints and deaths were adjudicated and analyzed using Cox proportional hazards regression. Placebo-corrected changes from baseline in HbA1c, weight and SBP were analyzed using a mixed model repeated measures approach to account for missing data. 1700 pts were enrolled (62.6% Group1, 14.5% Group 2, 22.9% in Group 3) and followed for a median of 30 months. At baseline mean (SD) HbA1c was 8.32 (0.91)%; BMI 32.6 (6.0) kg/m2 (92%≥25); SBP 134 (16) mmHg (39% ≥140); eGFR 77.9 (19.5) (19% &amp;lt;60). The primary endpoint showed a placebo-corrected reduction in HbA1c of 0.48% (95% CI -0.56, -0.39), p&amp;lt;0.0001; SBP fell 3.0 mmHg (- 5.5, -0.4), p=0.02; and weight declined 2.7kg (-3.1, -2.2), p&amp;lt;0.0001. CV death or HF hosp. occurred in 48 (4.2%) pts on bexa and 31 (5.5%) on placebo: HR 0.74 (0.47, 1.17). MACE+ occurred in 90/1133 (7.9%) pts on bexa and 57/567 (10.1%) on placebo: HR 0.79 (95%CI 0.56, 1.09). In high-risk T2D pts, bexagliflozin was well tolerated and improved HbA1c, SBP, and weight. Non-inferiority was demonstrated for MACE+, with point-estimates for MACE+ and CV death or HF hosp similar to other SGLT2 inhibitors. Disclosure J.J.V. McMurray: Other Relationship; Self; AbbVie Inc., Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Bristol-Myers Squibb, Cardurion, GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, Theracos, Inc. M.W. Freeman: Research Support; Self; Theracos, Inc. J. Massaro: Consultant; Self; Theracos, Inc. S. Solomon: Consultant; Self; AstraZeneca, Theracos, Inc. Research Support; Self; AstraZeneca, Theracos, Inc. P. Lock: None. M.C. Riddle: Consultant; Self; ADOCIA, Dance Biopharm Holdings, Inc., GlaxoSmithKline plc., Sanofi US, Theracos, Inc. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. E. Lewis: Consultant; Self; Novartis Pharmaceuticals Corporation. Research Support; Self; Amgen, Novartis Pharmaceuticals Corporation, Theracos, Inc. Y.C. Halvorsen: Research Support; Self; Theracos, Inc.

Abstract MP63: Established Cardiovascular Disease Risk Factors Mediate The Relationship Between Hypertensive Disorders In First Pregnancy And Maternal Cardiovascular Disease

Introduction: Women with a history of hypertensive disorders in pregnancy (HDP; gestational hypertension [GHTN] or preeclampsia) have an increased risk of CVD risk factors and events compared to women with normotensive pregnancies. However, the extent to which the relationship between HDP and CVD events is mediated by established CVD risk factors is less clear. Hypothesis: We hypothesized that a large proportion of the HDP-CVD relationship would be mediated by subsequent CVD risk factors — chronic hypertension (CHTN), type 2 diabetes (T2D), hypercholesterolemia, and BMI. Methods: Parous women free of prior CVD events, CHTN, T2D, and hypercholesterolemia at first birth in the Nurses’ Health Study II comprised the analytic sample (n=57,974). Pregnancy history was retrospectively reported in 2009. Women were followed for confirmed CVD events (coronary heart disease [non-fatal or fatal MI, fatal CHD] or stroke [non-fatal or fatal]) from first birth through 2015. Potential mediators were self-reported on biennial questionnaires. We used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the relationship between HDP in first pregnancy (preeclampsia or GHTN vs. normotension [ref]) and CVD, adjusting for age, race/ethnicity, parental education, family history of CVD before age 60, and pre-pregnancy risk factors (e.g., smoking, diet, and BMI). To evaluate the proportion of the HDP-CVD association that was jointly mediated by the CVD risk factors we used the difference method, comparing a model including these four factors to a model without them. Results: Nine percent of women (n=5,306) had a history of HDP in first pregnancy (preeclampsia: 6.3%; GHTN: 2.9%). CVD events occurred in 650 women with normotension in first pregnancy, 30 with GHTN, and 81 with preeclampsia. Adjusting for pre-pregnancy confounders, women with HDP in first pregnancy had a 63% higher rate of incident CVD (CI: 1.33-2.00) compared to women with normotension in first pregnancy; in particular, the strongest association was observed between preeclampsia and CHD (HR=2.18, CI: 1.62-2.93). The overall HDP-CVD association was largely mediated by the group of four CVD risk factors (HDP: proportion mediation [PM]=65%, CI: 35-87; preeclampsia: PM=57%, CI: 21-87; GHTN: PM=99%, CI: inestimable). All CVD risk factors contributed to mediation, but chronic hypertension accounted for the largest proportion. Conclusions: While approximately 40% of the association between preeclampsia and CVD remained unexplained, almost all the increased risk of CVD conferred by a history of GHTN was jointly accounted for by the development of established risk factors postpartum. Screening for CHTN, T2D, hypercholesterolemia, and overweight/obesity after pregnancy may be especially helpful in CVD prevention among women with a history of HDP.

Sex differences in the association of risk factors for heart failure incidence and mortality

BackgroundThere are known risk factors associated with the development of heart failure (HF), but it is not fully understood whether these differ by sex.ObjectivesTo investigate sex differences in risk factors...

1472-P: Association between Triglycerides and Residual Cardiovascular (CVD) Risk in Patients with Type 2 Diabetes and Established CVD: An Analysis of the BARI2D Trial

Background: While hypertriglyceridemia is a known risk factor for developing CVD, whether it poses residual risk in patients with type 2 diabetes mellitus (T2DM) and established CVD is under-studied. Methods: Using data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, we examined 2,307 patients with T2DM and CVD to determine the association of baseline fasting triglyceride (TG) levels with MACE (time to CV death, myocardial infarction (MI), or stroke) or CV death over a mean follow-up of 5.0 years. Results: At baseline, the mean fasting TG was 181 mg/dl with a median (Q1, Q3) of 148 (104, 219) mg/dl. Overall, 49.3% had TG≥ 150 mg/dl (N=1,167). Compared with those with TG&amp;lt;150 mg/dl, they were younger, more frequently Caucasian and with higher BMI. In unadjusted models, TGs were significantly associated with MACE and CV death (Table). This association did not remain after adjustment for multiple factors, including nonHDLc. Conclusions: In this analysis of patients with T2DM and known CVD, TGs were relatively high and were associated with CV outcomes, but not when other risk factors were taken into account. Thus, while TGs are clearly a marker of those with residual high risk for CV events in T2DM, whether they specifically need to be lowered awaits well conducted clinical trials. Disclosure N. Pagidipati: Research Support; Self; Amarin Corporation, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Regenerative Medical Solutions, Sanofi. A. Navar: Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc. Research Support; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; Amarin Corporation, Amgen Inc., Regeneron Pharmaceuticals, Sanofi. H. Mulder: None. D.M. Wojdyla: None. S. Philip: Employee; Self; Amarin Corporation. Stock/Shareholder; Self; Amarin Corporation. C.B. Granowitz: Employee; Self; Amarin Pharma Inc. Stock/Shareholder; Self; Amarin Pharma Inc. Funding Amarin Corporation

A15456 Efficacy of Cilnidipin vs. Amlodipin on microalbuminuria in hypertensive patients- clinical experience

Objectives: 1. To find the efficacy of cilnidipin vs. amlodipin on microalbuminuria in hypertensive patients 2. To evaluate changes in hypertension, s. uric acid level and presence of ankle edema on patients on cilnidipin vs. amlodipin. Methods: A retrospective analysis of our clinical data from jan-2017 till feb-2018 was carried out. Inclusion criteria: Ø Hypertension 3–5 years Ø age: 50–70 years Ø no monotherapy – either cilnidipin or amlodipin Exclusion criteria: established CVD, acute illness. Patients were analyzed & grouped according to the inclusion criteria and statically evaluated to find the objectives. Patient who were detected with microalbuminuria & were on amlodipin were shifted to cilnidipin and followed up after 1 month. Results: 476 patient were found who matched the inclusion criteria (M = 261 F = 215) Patients on cilnidipin at baseline = 290 (F = 143; F = 147) Patients on amlodipin at baseline = 186 (F = 79; M = 107) Patients with microalbuminuria shifted from amlodipin to cilnidipin = 113 (F = 39; M = 74) These patients (n = 91- F = 17; M = 42) when followed up further after 1 month for microalbuminuria showed improvement (n = 59) or absence (n = 32) of albuminuria. Patients on amlodipin also had s/e of ankle edema (n = 41) vs. those on cilnidipin (n = 27). S.uric acid was evaluated in the patients shifted from amlodipin to cilnidipin & it showed non-significant improvement. Improvement in blood pressure values is almost the same in both groups of patient. Conclusion: Based on our clinical experience, we could affirm the fact that although amlodipin is an effective hypertensive agent. Cilnidipin has an additional benefit of improvement in microalbuminuria, which makes it the preferred choice in patients.