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Controversies on new lipid targets

  • Discovering new lipid targets: are genetics relevant? Presented by B G Nordestgaard (Copenhagen, DK)
  • Cholesteryl ester transfer protein-inhibition: pros and cons, presented by P J Barter (Sydney, AU) - Slides
  • Lipoprotein-associated phospholipase A(2): a mechanistic link to cardiovascular disease? Presented by E Di Angelantonio (Cambridge, GB)
  • High-density lipoprotein: quantity or quality? Presented by J Chapman (Paris, FR) - Slides

A joint symposium between the ESC and the European Atherosclerosis Society provided an opportunity to bring together a world class group of experts in the field of lipids and they did not disappoint.

Borge Nordestgaard from Denmark opened the session with challenging questions about the possible mechanisms of harm and relevance of the different lipid particles LDL, HDL, TG and Lp(a). He began by pointing out the fundamental fact that, unlike triglycerides, cholesterol is not degradable in the body and so creates a problem once it has infiltrated the vessel wall. He outlined the research steps for understanding whether lipid particles cause harm or are just markers. These include having concordant data from epidemiology, genetics, animal studies, mechanistic plausibility and finally evidence from large clinical outcome studies. Using LDL as the paradigm, where data from all these types of study indicating causality, he described the half-way position that we are in with regard to Lp(a) and HDL particles. Lp(a) has long standing epidemiological studies and more recent genetic studies suggesting causality but we currently lack evidence from randomized trials that lowering Lp(a) prevents CHD. For HDL the situation is even more uncertain. Genetic studies of people with mutations which affect HDL cholesterol levels do not correlate as you might expect with risk. Interventions that raise HDL levels, similarly have not yet shown benefit although there are several in the pipeline.

Professor Philip Barter from Sydney, Australia then updated us on one of the most important group of new HDL raising drugs, the cholesterol ester transfer protein (CETP) inhibitors. He admitted at the outset that we still don’t know whether inhibiting CETP will produce benefit and are not likely to know until the results of outcome trials are available in a few years time. With the demise of torceptrapib, the first CETP inhibitor to be tested in a large trial and found to increase rather than decrease cardiovascular events, attention has now turned to dalcetrapib (a Roche product) which is currently being assessed in a large outcome trial and anacetrapib (a MSD product) for which an large outcome trial has just started. These drugs raise HDL-cholesterol, in the case of dalcetrapib by about 30% but anacetrapib producing a more than doubling of HDL. Based on observational epidemiology these higher HDL levels should translate into less CHD but what is becoming clear is that the situation is much more complex than seen for LDL. Concerns have been expressed that the HDL cholesterol produced by CETP inhibition might be dysfunctional with respect to reverse cholesterol transport but Professor Barter reassured us that this is not supported by the evidence from several studies. He also reviewed data from the DEFINE study in 1600 high-risk patients which showed a good safety and tolerability profile of anacetrapib. This group of drugs holds real promise as an addition to the lipid-lowering armentarium but we will have to wait a few years for the results of the clinical outcome trials.

Dr Di Angelantonio from Cambridge University, UK told us about a less well known lipid marker known as lipoprotein-associated phospholipase (LpPLA2). This is a serine lipase produced by inflammatory cells which circulates in blood linked to LDL. As a marker it is of interest because it is associated with CVD risk although much of the association is lost with full adjustment for other lipid factors. In addition, there is a drug, darapladib which inhibits LpPLA2 activity and is being evaluated for its effects on cardiovascular disease. With already some promising results from imaging studies the results of clinical outcome trials are awaited.

For the final presentation, Dr John Chapman took us back to the interesting topic of HDL and talked about whether it is quality or quantity that matters. Simplistic ideas that HDL is mainly concerned with reverse cholesterol transport were dismissed and data presented showing the anti-oxidant and anti-inflammatory roles of HDL. The difficultly is knowing which of many potential roles of HDL is clinically relevant in man. A large number of proteins make the HDL proteome and several of these are now the focus of current research interest. Dr Chapman gave a comprehensive overview of the current state of knowledge but left us all feeling how much more we need to understand.




Controversies on new lipid targets

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.