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Office for Translational Research

 

Summary

The INTENSITY experimental medicine trial seeks to answer the following questions:

 What is the lowest LDL (‘bad’) cholesterol threshold beyond which we can still expect benefits on vascular biology markers of early or late atherosclerosis?

  • In low risk healthy individuals
  • In patients with established cardiovascular disease.

Is there a mechanistic basis explaining further cardiovascular benefits from more aggressive LDL reduction?

 

 

The study is being conducted in two separate cohorts of healthy volunteers (INTENSITY LOW) and stable cardiovascular patients (INTENSITY HIGH). It is funded by JP Moulton Charitable Foundation and is being conducted by Dr Joseph Cheriyan and Dr Paul Cacciottolo.

 

The Study

INvestigating the lowest Threshold of vascular bENefits from LDL cholesterol lowering with a PCSK9 mAb InhibiTor (alirocumab) INTENSITY

The INTENSITY LOW study aims to investigate if there are limits to LDL reduction in terms of vascular health from a mechanistic viewpoint and limitations to primary prevention in healthy volunteers by lowering LDL cholesterol using PCSK9 therapies. This research is being carried out because it is unclear what the lowest threshold of LDL cholesterol should be in order to attain significant reductions in CV risk in healthy individuals. It is unknown whether there is a true limit of LDL cholesterol below which there is no further improvement in endothelial function in healthy people and whether this is associated with a reduction in markers of both systemic and vascular inflammation. This study also aims to show that LDL cholesterol lowering via PCSK9 inhibition as a therapeutic intervention has effects that are comparable to those achieved with statins in terms of vascular function.

Defining this may help to identify individuals from the general population who may benefit from more aggressive lipid-lowering treatment than standard statin treatment, in terms of CV morbidity and mortality. This study will be conducted in healthy volunteers only; participants will be randomized to the Alirocumab arm (a therapy designed to lower cholesterol) or comparison arm.

Thirty healthy individuals will be recruited to this single-centre, randomized, single-blind, parallel-group, mechanistic-physiological study, which will be conducted at Cambridge University Hospitals NHS Foundation Trust. The study will be open to recruitment for one year and the total study duration for each participant will be approximately 10 weeks. A series of non-invasive haemodynamic assessments and minimally invasive procedures including blood tests and forearm blood flow measurements will be conducted to determine if there is an improvement of nitric oxide bioavailability and reduced systemic inflammation.

INTENSITY HIGH aims to answer if there are limits to LDL reduction in terms of vascular health, exploring the mechanisms by which secondary prevention in patients with established heart disease may benefit from even lower LDL levels. By using PCSK9 inhibitors such as Alirocumab, very low LDL cholesterol levels, not previously encountered in statin trials, can be achieved in patients with established heart disease on top of intensive statin treatment.

This research is being carried out because it is unclear what the lowest threshold of LDL cholesterol should be to attain significant reductions in CV risk in stable cardiovascular patients. It is unknown whether there is a true limit of LDL cholesterol below which there is no further improvement in endothelial function in stable cardiovascular patients and whether this is associated with a reduction in markers of both systemic and vascular inflammation.

Defining this may help identify individuals from the general population who may benefit from more aggressive lipid lowering treatment than standard statin treatment in terms of CV morbidity and mortality.

This study will be conducted in patients with stable cardiovascular disease; they will be randomized to receive either a combination of Alirocumab and statin, or Ezetimibe plus statin. Sixty patients will be recruited to this single-centre, randomized, open-label, parallel-group, mechanistic-physiological study, which will be conducted at Cambridge University Hospitals NHS Foundation Trust. The total study duration for each participant will be approximately 14 weeks. A series of non-invasive vascular studies and medical imaging assessments will be conducted to observe vascular and systemic inflammation and to assess endothelial vascular function.