Physicians' Academy for Cardiovascular Education

An impression of the controversies and hot issues discussed at the PACE SNAPSHOT meeting

Oct. 13, 2014 - news

Many international leading experts were invited by the PACE Foundation to provide the audience with a state of the art and comprehensive overview of different novel interventions in the future management of cardiovascular disease. A broad range of topics were covered, to update the audience on the latest developments in the field of cardiovascular medicine and diabetes. There was ample time for discussion and exchange of ideas and experiences. The SNAPSHOT meeting was co-chaired by Prof. John Kastelein, MD (Academic Medical Center, Amsterdam, The Netherlands) and Prof. John Deanfield, MD (University College London, London, United Kingdom).
In his overview of insights and options of LDL lowering by statins and cholesterol absorption inhibitors, Prof. Chris Packard, MD (Glasgow, United Kingdom) wondered whether we need anything new. When considering the residual risk that is still present after existing treatment, the answer is yes. Due to disappointing results with strategies to raise HDL, the pendulum is swinging back to LDL-lowering strategies. There does not appear to be a plateau phase to lowering risk reduction by lowering LDL. The ongoing IMPROVE-IT will show the effect of addressing low LDL-c levels as a primary target. Furthermore, add-on therapy, especially needed in patients with side-effects to the currently available treatment options, such as CETP-inhibition and PCSK9-inhibition are currently being tested in clinical trials, and the outcome data are eagerly anticipated.
Prof. Paul Ridker, MD (Boston, MA, USA) then discussed the promise of new interventions that target the inflammation seen in CVD. Different approaches to target the inflammatory biomarker or a more upstream factor have been employed, some of which suggest that the process of atherothrombosis can indeed be modified. A caveat is however that these hypotheses assume that we can safely affect the immune system long term. This remains to be established; the balance between risk and benefit needs to be carefully considered.
Prof. Bryan Williams, MD (London, United Kingdom) spoke about innovative opportunities to manage hypertension. He considered the positive findings of the PARADIGM-HF, in which an angiotensin receptor neprilysin inhibitor (ARNI) gave a large reduction in pulse pressure; it may give better blood pressure lowering than RAAS blockade alone or another monotherapy. Prof. Williams also discussed results of clinical trials that evaluate renal artery stenting, as well as device-based therapy. He concluded that there is an unmet need for treatment of systolic hypertension in the aging population, and other specific patient groups like people with true therapy resistance and hyperaldosteronism. Furthermore, target-organ protection should be improved.
Kees Hovingh, MD (Amsterdam, The Netherlands) shared the latest insights on and options for therapy of homozygous familial heterozygosity (HoFH). He was involved in a Dutch study that established a molecular diagnosis of HoFH in 1 in 300.000 people, and heterozygous FH was found in about 1 in 250. That means that the bad news is that more patients are affected by these disorders than previously estimated. Fortunately the good news is that there are more therapies available or in development, with which patients can be treated better.
Prof. Evan Stein, MD (Cincinnati, OH, USA) elaborated on the mechanisms and therapeutic options of inhibition of synthesis of PCSK9, to restore LDL receptor recycling. Questions that need answers are whether there is a limit to LDL reduction with monoclonal antibodies, and how long the effect lasts. The currently available data suggests that in FH, a higher dose does not give additional LDL reduction, but it does yield a longer effect, suggesting that maximally 60-65% of LDL can be bound. Current data suggest that PCSK9 inhibition is a promising therapy, potentially the most effective LDL-lowering strategy, without showing signs of adverse events.
Prof. Christie Ballantyne, MD (Huston TX, USA) proceeded to discuss small molecule-based therapeutic strategies for hypertriglyceridaemia. Carriers of a mutation in the ApoC3 allele have a favourable plasma lipid profile and apparent cardioprotection. Several agents are in development that are aimed at mimicking these observations, by inhibiting a factor in triglyceride metabolism, such as icosapent ethyl (EPA), DGAT1 and CAT2003, a SREBP inhibitor. Ongoing trials will shed light on what is the optimal therapy to treat hypertriglyceridaemia, beyond statins.
Prof. Philip Barter, MD (Sydney, Australia) then aimed to clarify why CETP inhibitors have not lived up to their promise to date. He explained why some studies evaluating CETP-inhibitors did not adequately test the hypothesis that effective CETP-inhibition reduces CV events. He shared promising results with another, more potent CETP-inhibitor, which does not show adverse effects like a previous agent. Its performance in outcome studies is eagerly awaited.
Prof. Kausik Ray, MD (London, UK) discussed what is new in HDL mimetics for treatment of acute coronary syndrome (ACS). Many patients experience recurrent CV events shortly after ACS. The multiple lesions responsible for this residual risk need systemic treatment rather than stenting. Several ApoA1-based strategies are being looked t for their potential to remove cholesterol from a plaque. Also, an approach involving reconstituted HDL (CSL-112) appears capable of increasing cholesterol efflux, and its safety is now being tested in ACS patients.
Prof. Naveed Sattar, MD (Glasgow, UK) explored whether novel interventions to reduce CVD risk in diabetes are living up to their promises. He appreciated that the CVD risk in T2DM goes beyond the effect of having high plasma glucose: there is a non-linear relationship between glucose levels and risk. Only mildly lowering LDL-c levels is unlikely to have an effect on outcomes. HbA1c is a difficult target; agents like SGLT2 inhibitors and GLP-1 agonists had unexpected effects like increasing LDL-c and heart rate, respectively, in addition to their glucose-lowering effects. Their net effect on CVD risk is unclear. Prof Sattar wondered whether maybe neutrality is as much as can be achieved with regard to limiting CVD risk in diabetes, as opposed to CV protection.
Prof. John Kastelein, MD (Amsterdam, The Netherlands) finished this edition of the PACE SNAPSHOT meeting with an overview of antisense drugs to lower LDL-c and TG levels that are in development, directed against apoB and apoCIII. While results with apoB-antagonists were considered unsuccessful, prof. Kastelein stressed that they give very variable results. Thus, very robust LDL-lowering is seen in some; this is not appreciated enough. Mean reduction is meaningless here.  ApoCIII antagonism strongly decreased TG levels in phase II studies, although there was a hint that LDL goes up. Thus, they may best be combined with statins. Outcome studies will need to confirm these hopeful observations. 

Slides of the preparations in the SNAPSHOT meeting have been prepared and shared for educational purposes by the presenters.

Slides • 8-9-2014

HDL mimetics for ACS treatment: What’s new?

Presentation by prof. Kausik Ray held during the PACE 2014 SNAPSHOT session on August 30, 2014 in Barcelona

Slides • 8-9-2014

Innovating hypertension management beyond current therapies: What are the opportunities?

Presentation by prof. Bryan Williams, London during the PACE 2014 SNAPSHOT session on August 30, 2014 in Barcelona

Slides • 8-9-2014

PCSK9 Inhibition: The final step in cholesterol lowering?

Presentation by prof. Evan Stein, Cincinnati, OH, USA, during the PACE 2014 SNAPSHOT session on August 30, 2014 in Barcelona

Slides • 8-9-2014

Hypertriglyceridemia: New small-molecule based strategies

Presentation by prof. Christie Ballantyne, MD, Huston TX, USA, during the PACE 2014 SNAPSHOT session on August 30, 2014 in Barcelona

Slides • 8-9-2014

Diabetes and reducing CVD: Are novel interventions living up to their promise?

Presentation by prof. Naveed Sattar, MD, Glasgow, United Kingdom, held during the PACE 2014 SNAPSHOT session on August 30, 2014 in Barcelona

Slides • 8-9-2014

LDL-c lowering by statins & cholesterol absorption inhibitors: Do we need anything new?

Presentation by prof. Chris Packard during the PACE 2014 SNAPSHOT session on August 30, 2014 in Barcelona

Slides • 8-9-2014

CETP inhibition: Close to a better understanding of the promise?

Presentation by prof. Philip Barter, MD, Sydney, Australia held during the PACE 2014 SNAPSHOT session on August 30, 2014 in Barcelona

Slides • 8-9-2014

Antisense drugs to lower LDL-c & TGs: Where are we now?

Presentation by prof. John Kastelein, MD, Amsterdam, the Netherlands, held during the PACE 2014 SNAPSHOT session on August 30, 2014 in Barcelona