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Published on: August 28, 2018
Investigating the Lowest Threshold of Vascular Benefits from LDL Cholesterol Lowering with a PCSK9 mAb Inhibitor
Paul J Cacciottolo1, Michalis S Kostapanos2, Elena Hernan Sancho3
1Division of Experimental Medicine and Immunotherapeutics (EMIT), University of Cambridge, Cambridge, UK pjc99@medschl.cam.ac.uk.
Insights
This study investigates how lowering low-density lipoprotein cholesterol (LDL-C) with PCSK9 inhibitors impacts cardiovascular disease mechanisms. Findings explore endothelial function and vascular inflammation, crucial for cardiovascular event reduction.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Medical Imaging
Background:
- Elevated low-density lipoprotein cholesterol (LDL-C) is a key predictor of cardiovascular events.
- Reducing LDL-C is the primary strategy for decreasing cardiovascular morbidity and mortality.
- The optimal LDL-C threshold for maximal cardiovascular benefit remains undefined.
Purpose of the Study:
- To explore the physiological mechanisms behind the cardiovascular benefits of LDL-C reduction via PCSK9 inhibition.
- To assess changes in endothelial function and vascular inflammation in patients with established cardiovascular disease (CVD).
- To compare the effects of PCSK9 inhibition against standard care in CVD patients.
Main Methods:
- A single-centre, randomized, open-label, mechanistic study involving approximately 60 patients with established CVD on high-intensity statins.
- Baseline assessments included 18-fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) of the aorta and carotid arteries, and endothelial function tests.
- Participants were randomized 1:1 to receive either alirocumab (PCSK9 inhibitor) or ezetimibe, with repeat assessments after 8 weeks.
Main Results:
- Changes in FDG-PET/CT parameters and endothelial function will be correlated with lipid level and systemic inflammation biomarker changes.
- The study aims to elucidate the specific vascular effects of intensive LDL-C lowering.
- No results are available yet as this is a mechanistic study design.
Conclusions:
- The INTENSITY-HIGH study will provide insights into the direct vascular effects of PCSK9 inhibition in patients with established CVD.
- Understanding these mechanisms may help define lower LDL-C thresholds for cardiovascular event reduction.
- Results will contribute to optimizing lipid-lowering strategies for secondary cardiovascular prevention.
Introduction:
Elevated low-density lipoprotein cholesterol (LDL-C) is a strong independent risk predictor of cardiovascular (CV) events, while interventions to reduce it remain the only evidence-based approach to reduce CV morbidity and mortality. Secondary prevention statin trials in combination with ezetimibe and/or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors showed that there is no 'J shaped curve' in LDL-C levels with regard to CV outcomes. The lowest threshold beyond which reduction of LDL-C confers no further CV benefits has not been identified.The INTENSITY-HIGH study seeks to explore physiological mechanisms mediating CV benefits of LDL-C lowering by PCSK9 inhibition in patients with established cardiovascular disease (CVD). The study examines the changes in measures of endothelial function and vascular inflammation imaging following intervention with PCSK9 and against standard of care.
Methods And Analysis:
This is a single-centre, randomised, open label, parallel group, mechanistic physiological study. It will include approximately 60 subjects with established CVD, with LDL-C of <4.1 mmol/L on high-intensity statins. All eligible participants will undergo 18-fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) scanning of the aorta and carotid arteries, as well as baseline endothelial function assessment. Subsequently, they will be randomised on a 1:1 basis to either alirocumab 150 mg or ezetimibe 10 mg/day. Repeat FDG-PET/CT scan and vascular assessments will be undertaken after 8 weeks of treatment. Any changes in these parameters will be correlated with changes in lipid levels and systemic inflammation biomarkers.
Ethics And Dissemination:
The study received a favourable opinion from the Wales Research Ethics Committee 4, was registered on clinicaltrials.gov and conformed to International Conference for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice. The results of this study will be reported through peer-reviewed journals and conference presentations.
Trial Registration Number:
NCT03355027.
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