Arterial wall inflammation measured with 18F-FDG PET/CT in patients with statin intolerance before and after treatment with a PCSK-9 inhibitor

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are relatively
novel therapeutic agents to treat dyslipidaemia. It prevents degradation of
low-density lipoprotein cholesterol (LDL-C) receptors in the liver, thereby
promoting uptake of LDL-C from the circulation into the liver, resulting in
lower plasma LDL-C levels. Phase II/III studies showed strong LDL-C lowering
after PCSK-9 inhibition (i.e. 50-75%) without clinically relevant adverse
events. Therefore, PCSK-9 inhibitors are promising agents for use in patients
with elevated LDL-C levels and increased cardiovascular (CV) risk.
Besides LDL-C, inflammation is a critical pathway contributing to
destabilisation of atherosclerotic lesions. Consequently, inhibiting
inflammatory activity has emerged as potential therapeutic target in patients
at increased cardiovascular risk. In contrast to statins which decrease both
LDL-c as well as the acute phase reactant C-reactive protein (CRP), PCSK-9
inhibition does not lower CRP levels. The latter has fueled the question
whether PCSK9-inhibition may lack the ability to lower inflammatory activity,
which may theoretically limit the clinical efficacy of PCSK-9 inhibition in
high-risk CV patients.

In the present study, we set out to evaluate arterial wall inflammation in
patients at increased CV-risk with statin-associated muscle symptoms (SAMS),
precluding effective statin therapy. Following twelve weeks of treatment with
PCSK9-Ab, the change in both lipid levels as well as arterial wall inflammation
is assessed. The results of this study will help unravel whether PCSK9-Ab
induced LDL-c lowering reduces inflammatory activity in patients with SAMS, in
absence of significant changes in CRP.

This is a multi-center, double-blind, placebo-controlled, intervention study
using PCSK9 inhibition (alirocumab).

Treatment with Alirocumab (or placebo) for 3 months.

Awaiting the outcome studies for PCSK9-Ab, individual patients will not gain
direct *health* benefit from this study. The results are expected to provide
insight into the relation between LDL-C changes and inflammatory activity in
atherosclerotic arteries. The burden and risk of participating in this study
are estimated to be intermediate. The study requires a maximum of 4 study
visits and 1 phone consultation. The exposure to radiation related to 18F-FDG
PET/CT is 8.2 mSv for 2 consecutive PET/CT scans in this study. Maximal blood
withdrawal including clinical laboratory assessment will be 144 ml.