Future drugs in atherosclerotic cardiovascular disease

Poelgeest, E.P. van (2018)

Doctoral Thesis

The most important risk factor for atherosclerotic cardiovascular disease is increased levels of LDL-C. Statins have long been the most potent LDL-C
lowering drugs on the market. However, statin treatment is complicated by the
fact that a considerable number of patients is unable to tolerate full therapeutic doses, or can be classified as statin low or non-responders. In >25% of patients at (very) high risk
for cardiovascular disease, statin efficacy is too limited to achieve current guideline-mandated LDL-C target goals, and aggressive statin therapy decreases relative risk for ASCD by only 30-35%, leaving an unacceptable residual relative risk of 65-70% for life-threatening events. It is clear that on-treatment LDL-C levels and on-treatment measures of systemic inflammation are of equal importance in this residual risk. Both for residual cholesterol risk and residual inflammatory risk, effective drug therapy has been lacking for decades.
In this thesis, we describe the first clinical studies with novel compounds based on increased LDL-C levels and inflammation (including the required
methodology), and present the methodology that may be useful to develop future compounds based on dysfunctional endothelial barrier function resulting in subendothelial cholesterol accumulation and subsequent atheroma formation.

• Atherosclerosis
• Systemic inflammation
• Hypercholesterolemia
• PCSK9 inhibitor
• TLR4 signaling
• Acute kidney injury
• Endothelial dysfunction
• Human endotoxemia model
• Ex vivo LPS challenge test
• Invivo LPS challenge test

• All authors: Poelgeest, E.P. van
• Supervisor: Burggraaf, J.; Cohen, A.F.
• Co-supervisor: Moerland, M.
• Committee: Eikenboom, H.C.J.; Fijter, J.W. de; Kaasjager, H.A.H.; Middeldorp, S. der; Velde, N. van der
• Qualification: Doctor (dr.)
• Awarding Institution: Center for Human Drug Research, Medicine / Leiden University Medical Center (LUMC), Leiden University
• Date: 2018-04-10