scholarly journals LEGACY: Phase 2a Trial to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamic Effects of the Anti-EL (Endothelial Lipase) Antibody MEDI5884 in Patients With Stable Coronary Artery Disease

2021 ◽  
Author(s):  
Christian T. Ruff ◽  
Michael J. Koren ◽  
Joseph Grimsby ◽  
Anton I. Rosenbaum ◽  
Xiao Tu ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Statin Therapy ◽  
High Intensity ◽  
Cholesterol Efflux ◽  
Stable Coronary Artery Disease ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Endothelial Lipase ◽  
Artery Disease

Objective: Functional HDL (high-density lipoprotein) particles that facilitate cholesterol efflux may be cardioprotective. EL (endothelial lipase) hydrolyzes phospholipids promoting catabolism of HDL and subsequent renal excretion. MEDI5884 is a selective, humanized, monoclonal, EL-neutralizing antibody. We sought to determine the safety, pharmacokinetics, and pharmacodynamic effects of multiple doses of MEDI5884 in patients with stable coronary artery disease. Approach and Results: LEGACY was a phase 2a, double-blind, placebo-controlled, parallel-design trial that randomized 132 patients with stable coronary artery disease receiving high-intensity statin therapy to 3 monthly doses of 1 of 5 dose levels of MEDI5884 (50, 100, 200, 350, or 500 mg SC) or matching placebo. The primary end point was the safety and tolerability of MEDI5884 through the end of the study (day 151). Additional end points included change in HDL cholesterol and cholesterol efflux from baseline to day 91, hepatic uptake of cholesterol at day 91, changes in various other lipid parameters. The incidence of adverse events was similar between the placebo and MEDI5884 groups. In a dose-dependent manner, MEDI5884 increased HDL cholesterol up to 51.4% ( P <0.0001) and global cholesterol efflux up to 26.2% ([95% CI, 14.3–38.0] P <0.0001). MEDI5884 increased HDL particle number up to 14.4%. At the highest dose tested, an increase in LDL (low-density lipoprotein) cholesterol up to 28.7% ( P <0.0001) and apoB (apolipoprotein B) up to 13.1% ( P =0.04) was observed with MEDI5884. However, at the potential target doses for future studies, there was no meaningful increase in LDL cholesterol or apoB. Conclusions: Inhibition of EL by MEDI5884 increases the quantity and quality of functional HDL in patients with stable coronary artery disease on high-intensity statin therapy without an adverse safety signal at the likely dose to be used. These data support further clinical investigation. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03351738.

High-density lipoprotein cholesterol does not predict future cardiovascular events in patients treated with statins for secondary prevention: an observation from the REAL-CAD study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Nagai ◽  
I Yokota ◽  
K Omote ◽  
I Sakuma ◽  
Y Nakagawa ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Statin Therapy ◽  
Cardiovascular Events ◽  
Primary Outcome ◽  
Stable Coronary Artery Disease ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Artery Disease

Abstract Background The relation between high-density lipoprotein cholesterol (HDL-C) level after statin therapy and cardiovascular events in patients with stable coronary artery disease remains unclear. Purpose We sought to determine the association of the HDL-C level after statin therapy with cardiovascular events in stable coronary artery disease patients. Methods This study was a post-hoc analysis of the Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study, which is randomised, open-label, blinded endpoint, physician-initiated, superiority clinical trial. Enrollment was from January 2010 to March 2013, and follow-up was through January 2016. From the main study, we excluded the patients without either HDL-C data at baseline or 6 months, with occurrence of the primary outcome at 6 months and reported poor adherence for pitavastatin. The primary outcome of interest was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission after 6 months from randomisation, consistent with the primary analysis of the trial. We constructed landmark Cox proportional hazards regression models with the 18 selected clinically relevant risk-adjusting variables during the entire follow-up period starting at 6 months after randomisation. Absolute and relative changes of HDL-C level were defined as (6 months value – baseline value) and (absolute change / baseline value) × 100, respectively. Results Among 14,774 participants in the REAL-CAD study, 9,221 patients were included in this analysis (7652 [83.0%] male; median [IQR] age, 70 [63–75] years; median [IQR] HDL-C, 49 [42–57] mg/dL; median [IQR] low-density lipoprotein cholesterol [LDL-C], 88 [75–101] mg/dL). During a median follow-up period of 4.0 (IQR 3.2–4.7) years, the primary outcome occurred in 417 (4.5%) patients. There was no significant difference in crude and adjusted cumulative incidence of the primary outcome among the quartiles of HDL-C level at 6 months (Figure 1). The adjusted risks of all the HDL-C related variables (baseline value, 6 months value, absolute and relative changes) for the primary outcome were not significant (Figure 2). Furthermore, the adjusted hazard ratio (HR) as HDL-C level at 6 months increased by 10 mg/dL remained non-significant for the primary outcome for each on-treatment LDL-C level at 6 months (&lt;70 mg/dL [HR 0.97, 95% CI 0.82–1.15], 70–100 mg/dL [HR 1.10, 95% CI 0.98–1.24], and ≥100 mg/dL [HR 0.94, 95% CI 0.78–1.13]). There was also no significant association between HDL-C level at 6 months and the primary outcome both in the low (1 mg/day [HR 1.02, 95% CI 0.91–1.14], increased by 10 mg/dL) dose and high (4 mg/day [HR 1.04, 95% CI 0.91–1.19]) dose pitavastatin groups Conclusion After statin therapy with modestly controlled LDL-C, HDL-C level has little prognostic value in patients with stable coronary artery disease. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): The Comprehensive Support Project for Clinical Research of Lifestyle-Related Disease of the Public Health Research Foundation

scholarly journals Assessing HDL Metabolism in Subjects with Elevated Levels of HDL Cholesterol and Coronary Artery Disease

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 6862
Author(s):  
William Hancock-Cerutti ◽  
John S. Millar ◽  
Silvia Valentini ◽  
Jason Liu ◽  
Jeffrey T. Billheimer ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Cholesterol Efflux ◽  
Ex Vivo ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Fractional Clearance ◽  
Artery Disease ◽  
Pool Sizes

High-density lipoprotein cholesterol (HDL-C) is thought to be atheroprotective yet some patients with elevated HDL-C levels develop cardiovascular disease, possibly due to the presence of dysfunctional HDL. We aimed to assess the metabolic fate of circulating HDL particles in patients with high HDL-C with and without coronary artery disease (CAD) using in vivo dual labeling of its cholesterol and protein moieties. We measured HDL apolipoprotein (apo) A-I, apoA-II, free cholesterol (FC), and cholesteryl ester (CE) kinetics using stable isotope-labeled tracers (D3-leucine and 13C2-acetate) as well as ex vivo cholesterol efflux to HDL in subjects with (n = 6) and without (n = 6) CAD that had HDL-C levels >90th percentile. Healthy controls with HDL-C within the normal range (n = 6) who underwent the same procedures were used as the reference. Subjects with high HDL-C with and without CAD had similar plasma lipid levels and similar apoA-I, apoA-II, HDL FC, and CE pool sizes with no significant differences in fractional clearance rates (FCRs) or production rates (PRs) of these components between groups. Subjects with high HDL-C with and without CAD also had similar basal and cAMP-stimulated ex vivo cholesterol efflux to HDL. When all subjects were considered (n = 18), unstimulated non-ABCA1-mediated efflux (but not ABCA1-specific efflux) was correlated positively with apoA-I production (r = 0.552, p = 0.017) and HDL FC and CE pool sizes, and negatively with the fractional clearance rate of FC (r = −0.759, p = 4.1 × 10−4) and CE (r = −0.652, p = 4.57 × 10−3). Our data are consistent with the concept that ex vivo non-ABCA1 efflux capacity may correlate with slower in vivo turnover of HDL cholesterol moieties. The use of a dual labeling protocol provided for the first time the opportunity to assess the association of ex vivo cholesterol efflux capacity with in vivo HDL cholesterol metabolic parameters.

scholarly journals Critical aspects of the management of stable coronary artery disease in primary care practice or how to increase the efficacy of evidence-based pharmacological therapy?

2020 ◽  
Vol 6 (3) ◽  
pp. 15-20
Author(s):  
Sergey K. Zyryanov ◽  
Sergey B. Fitilev ◽  
Alexander V. Vozzhaev ◽  
Irina I. Shkrebniova ◽  
Dmitry A. Klyuev
Keyword(s):  
Primary Care ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Medication Adherence ◽  
Stable Coronary Artery Disease ◽  
Density Lipoprotein ◽  
Pharmacological Therapy ◽  
Care Practice ◽  
Cross Sectional ◽  
Artery Disease

Introduction: The publication describes a fragment of the pharmacoepidemiologic study conducted to review the quality of management of patients with stable coronary artery disease (SCAD) in primary care over a 12-year period. The aim of the study was to justify the application of standard operating procedures (SOPs). Such determinants of pharmacotherapy as non-pharmacological modification of cardiovascular risk factors (RFs) and medication adherence were analyzed. Material and methods: A retrospective, cross-sectional, 3-stage (2006, 2011, 2018) study was conducted in a primary care setting of Moscow. As many as 3027, 1834, 805 patients with verified diagnosis of SCAD were included. Demographics, medical history, data on modifiable RFs and prescribed drug therapies were collected. At the third stage, medication adherence was measured, using the 8-item Morisky scale. Results and discussion: Over a 7-year period, better control of modifiable RFs in coronary patients was revealed. The target levels of blood pressure were reached in 58.3% (+20.7%; p &lt; 0.05) of the patients, total cholesterol – in 33.0% (+16.0%; p &lt; 0.05), and low-density lipoprotein cholesterol – in 23.3% (+12.2%; p &lt; 0.05). Two critical problems that determined still inadequate RFs control were identified. The attention of physicians to RFs and rates of non-pharmacological interventions remained low throughout the study. Information on lifestyle RFs was recorded in fewer than one-third of the subjects. The lipid profile was registered only in half of patients’ histories. Non-adherence to pharmacotherapy was identified in 51.3% of patients. Conclusion: Further increase in efficacy of pharmacotherapy might be provided by application of SOPs regarding the registration and correction of modifiable cardiovascular RFs, identification of non-adherent patients and promotion of medication adherence.

scholarly journals AGE RELATED DIFFERENCE IN THE LIPID PROFILE IN NORMAL HEALTHY WOMEN

2014 ◽  
Vol 04 (02) ◽  
pp. 094-097
Author(s):  
Deepti G. I. ◽  
Sukanya Shetty ◽  
Ashalatha V. Rao ◽  
Sarfraz Ahmad
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Lipid Profile ◽  
Density Lipoprotein ◽  
Premenopausal Women ◽  
Hdl Cholesterol ◽  
Cvd Risk ◽  
Lipid Disorder ◽  
Age Related ◽  
Artery Disease

Abstract: Background and objectives: Lipid disorder is a major risk factor for the progression of coronary artery disease. Age alone is a significant predictor of CVD risk in men and women. Before menopause, women have a much lower risk for cardiovascular events compared with men of their age. Reasons for protection from CVD in premenopausal women are complex, but a significant contribution can be assigned to the greater high-density lipoprotein (HDL) levels in younger women, which is an effect of estrogen. Methods: Fasting blood samples were collected from 40 healthy individuals (40 females divided into 2 groups according to age). Serum total cholesterol, triglycerides, and HDL- Cholesterol were estimated by enzymatic methods and LDL was calculated by Friedewald's equation. Results: The result showed increase in jyounger age group. Conclusion: It can be concluded that serum lipid profile changes can possibly be mediated by changing hormonal profile, especially estrogen which has role in lipid metabolism and indirectly on coronary artery disease.

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