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EAS 2017: Congress Prague highlights

15 May 2017   (0 Comments)
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EAS Congress Prague, held during 23-26 April, broke all previous records with almost 2,500 delegates attending this premier event. The Congress featured topical ‘state-of-the-art’ plenaries, novel therapeutic approaches in managing elevated cholesterol and triglycerides, as well as insights into how genetics impacts dietary approaches for preventing cardiometabolic disease. Here we provide a snapshot of some of the highlights.

What is the key driver of atherosclerotic cardiovascular disease: cholesterol or inflammation/immune response?

This question was one of the main underlying themes of the Congress, discussed in the Anitschkow lecture, given by Anitschkow Award recipient, Professor Alan Tall (Columbia University, New York, USA), plenary lectures, as well as one of the KeyNote lectures by Professor Göran Hansson (Karolinska Institutet, Karolinska University Hospital and the Center for Molecular Medicine, Stockholm, Sweden). Atherosclerosis is now well recognized as a chronic inflammatory disease that is initiated by the retention and, with persistent hypercholesterolaemia, accumulation of cholesterol-containing lipoproteins, particularly low-density lipoprotein (LDL), in the artery wall. These lipoprotein components have been shown to play a role in activation of innate immune cells, which contribute to vascular inflammation, modulation of the adaptive immune system and ultimately the initiation, progression, and (in)stability of atherosclerotic plaque. There is also evidence that cross-talk between cellular cholesterol and inflammatory/immune responses can impact haematopoiesis and thus contribute to atherothrombosis.1 As outlined by Professor Tall, novel genetic insights indicate that stimulation of haematopoietic stem cell proliferation, either with JAK2 gain of function variants or LINK loss of function variants, was associated with myeloproliferative neoplasms and atherothrombosis, underpinning common links between ASCVD and cancer.2

The plenary debate provided an ideal setting to discuss this question further. Professor Chris Packard (University of Glasgow, UK) made a watertight case for LDL as the main driver of ASCVD based on the Bradford Hill criteria for causality.3 Not only is there biological plausibility for LDL in the development and progression of ASCVD, but there is also consistent, coherent evidence from epidemiologic, genetic and randomized clinical studies for a dose-dependent, log-linear association between the absolute magnitude of exposure to LDL and the risk of ASCVD. Indeed, the temporal association between LDL and ASCVD is exemplified by familial hypercholesterolaemia (FH), predominantly due to mutations in the gene for the LDL receptor, in which exposure to high LDL levels from birth promotes accelerated ASCVD.4


The definitive case for LDL as a major driver of ASCVD is made in the new EAS Consensus Panel Statement, published during Congress.5 The conclusions of the EAS Consensus Panel, led by Professors Catapano, Chapman, and Ginsberg were based on analysis of data from over 200 studies involving more than 2 million people followed for over 20 million person-years and with over 150,000 cardiovascular events. LDL cholesterol, which is a reasonable marker of LDL particles in most instances, has been predominantly used to assess the risk of cardiovascular disease and as a target for therapies.

However, as noted by Professor Peter Libby (Brigham and Women’s Hospital, Harvard Medical School, Boston, USA) in his lecture, inflammation provides a mechanism that links risk factors for atherosclerosis, such as LDL cholesterol, with changes in the arterial wall and promotion of ASCVD. In particular, he emphasized the role of innate monocytes, precursors of macrophages, as key mediators connecting low-grade inflammation and altered lipid metabolism. As Professor Hansson concluded both proponents were right: atherosclerosis is a chronic inflammatory condition in which LDL acts as the driver of both innate and adaptive immunity, mechanisms critical in ASCVD.


EAS President Professor Lale Tokgozoglu (Hacettepe University, Ankara, Turkey) summarises the key message from this debate in this video.

New EAS Consensus Panel statement: LDL causes ASCVD

While LDL cholesterol is recognized as a major modifiable risk factor for ASCVD,6 is it casual in this process? As highlighted in the above debate, the totality of evidence – which refutes any possibility of study selection bias - discussed in this EAS Consensus Statement clearly negates any remaining doubts that LDL is causal for ASCVD.5 Moreover, findings from Mendelian randomization studies (a type of ‘natural clinical trial’) showing that rare genetic mutations that lead to lower LDL cholesterol levels are associated with a correspondingly lower risk of ASCVD are consistent with findings from clinical intervention studies. The EAS Consensus Panel also showed consistency in clinical benefit per mmol/L reduction in LDL cholesterol for any LDL lowering treatment in which the effects are principally mediated via the LDL receptor, which includes statins, PCSK9 inhibitors and ezetimibe. There was accrual of benefit from treatment over time, with an anticipated 10% reduction in risk of cardiovascular events expected in the first year of treatment, a 20% reduction in risk in the second year of treatment and a further 1.5% relative reduction in each subsequent year. These findings are remarkably consistent with the results of FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) with evolocumab and SPIRE-2 (Studies of PCSK9 Inhibition and the Reduction of Vascular Events) with the now terminated bococizumab.7,8

There are important implications from this statement for clinical practice.
• The lower the LDL cholesterol level attained with treatments specifically targeting LDL, the greater the clinical benefit accrued. Indeed, this implication is reinforced by data from FOURIER, in which further reduction in LDL cholesterol (from ~2.3 mmol/L to 0.78 mmol/L, i.e. ~90 mg/dl to 30 mg/dl) with a PCSK9 inhibitor on top of statin therapy led to incremental reduction in cardiovascular events when compared with statin alone.
• Cumulative LDL exposure is an important determinant of ASCVD. Therefore, if elevated LDL cholesterol can be targeted earlier in high risk patients, there will be a greater decrease in the lifetime risk of a cardiovascular event. This point is highly relevant in the setting of FH, where diagnosing and treating children and adolescents with FH earlier could lead to decades of healthy life, a premise which underpins the EAS Consensus Panel statement on paediatric FH.9

PCSK9 inhibition again

EAS Congress Prague provided the first opportunity in Europe to discuss the results of FOURIER and to place these findings in context with GLAGOV, an intravascular ultrasound imaging study of the effects of PCSK9 inhibition.10

FOURIER clearly showed that the relationship between LDL cholesterol lowering and reduction in cardiovascular risk extends to very low LDL cholesterol levels with no suggestion of a threshold for benefit. Subgroup analyses of FOURIER also indicated that the magnitude of benefit was consistent across all subgroups studied, including men and women, as well as diabetes patients (not reported in the paper). However, as shown by FOURIER and GLAGOV, despite attainment of very low LDL cholesterol levels, some patients will still show ASCVD progression and experience clinical events. As explained by Professor Stephen Nicholls (South Australian Health and Medical Research Institute, Adelaide, Australia) this is because such patients are likely to have a number of risk factors that will persist despite LDL cholesterol reduction, and these contribute to an increased propensity for ASCVD progression.

The other concern for clinicians is the safety of very low LDL cholesterol levels; one in four of the FOURIER population treated with evolocumab attained an LDL cholesterol value <20 mg/dl (0.52 mmol/L). To date there is no evidence to suggest any adverse effects associated with these very low LDL cholesterol levels, although long-term data are still needed. Reassuringly, long-term data from IMPROVE-IT also showed no issues with very low LDL cholesterol levels.11 And, as added by Professor John Chapman (University of Pierre and Marie Curie, Pitié-Salpêtrière University Hospital, Paris, France) it has already been shown that the very low LDL cholesterol levels typical of newborns (0.5-1.0 mmol/L or 20-40 mg/dL) do not negatively impact physiological development, including brain development.12,13

Professor Nicholls addresses some of the questions arising from the discussion in these videos.

  • Why do patients in FOURIER progress despite very low LDL cholesterol levels on a PCSK9 inhibitor?
  • Following FOURIER, do we still need ezetimibe in the management of high risk patients?
  • Can we use imaging to define very high risk patients?
  • Are very low LDL cholesterol levels safe?
  • How do the different approaches to PCSK9 inhibition compare?








Novel approaches to managing triglycerides

As at previous EAS Congresses, there was news in the Late Breaker Clinical Sessions on novel approaches to managing rare inherited lipid disorders, including volanesorsen (formerly ISIS-APOCIIIRx) for the management of markedly elevated triglycerides in Familial Chylomicronaemia Syndrome (FCS), and evinacumab for the management of homozygous FH.

In the APPROACH study in 66 FCS patients, treatment with volanesorsen (an antisense inhibitor of apolipoprotein C-III) for 13 weeks led to 77% reduction in triglycerides (absolute reduction of 19 mmol/L) versus an increase of 18% on placebo (p<0.0001).14 At this time, 77% of volanesorsen-treated patients had triglycerides <8.5 mmol/l (750 mg/dl), the threshold for chylomicronaemia, and 50% had triglycerides <5.7 mmol/l (<500 mg/dl), the guideline threshold for severe hypertriglyceridaemia. Treatment response was sustained for 52 weeks. With a managed plan of surveillance, reduction in platelet count was not an issue for later patients included in the study. Given the lack of pharmacological therapeutic options for FCS, it is likely that volanesorsen will have a favourable benefit versus risk ratio for this patient group.

There was also an update to a proof-of-concept study with evinacumab, (REGN1500), a human monoclonal antibody to angiopoietin-like protein 3 (ANGPTL3), first reported at last year’s Congress.15 As an add-on treatment in nine patients with homozygous FH, evinacumab led to 49% reduction in LDL cholesterol (mean absolute reduction 4.1 mmol/L), and this response was sustained at 12 weeks (mean reduction 52%). As to why a monoclonal antibody to ANGPTL3 should be effective in a condition that is predominantly due to mutations in the LDL receptor is a key question meriting further study.

In a plenary session, Professor Anne Tybjaerg-Hansen (Rigshospitalet, Copenhagen, Denmark) discussed how expanded insights into the genetics of triglyceride heritability have led to the development of novel pharmacotherapeutic approaches, including antisense agents to apolipoprotein CIII, monoclonal antibodies to ANGPTL3 and ANGPTL4, and a first in class selective peroxisome proliferator alpha modulator (SPPARM-α). This SPPARM α (pemafibrate) is now being evaluated in a cardiovascular outcomes study in type 2 patients with diabetic dyslipidaemia (elevated triglycerides and low high-density lipoprotein cholesterol). After much deliberation, it now appears that we may be on the cusp of a new era in the management of hypertriglyceridaemia.

Lifestyle: novel genetic insights

Precision medicine takes into account individual variability in pharmacotherapeutic strategies for prevention of cardiovascular disease. However, can the same approach also apply to dietary strategies to cardiovascular prevention? Such an approach has been suggested for the management of obesity, based on observational data showing that the effect of common variants on body mass index can be influenced by physical activity and diet, as well as the biology of eating behaviour.16 Does such a pharmacogenomic approach also apply to the management of metabolic disease?

Professor Qi Sun (Harvard T.H. Chan School of Public Health, Boson, USA) discussed this possibility during his plenary lecture. There is already evidence that the glycaemic response to metformin is heritable: could the effects of nutritional interventions on glycaemic response also be under genomic control? Findings from the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial, which used a genetic risk score based on 14 fasting glucose-associated variants to investigate changes in fasting glucose and insulin levels, and insulin resistance and insulin would support this.17 This study showed an interaction between a high genetic risk score and high fat diet. This may suggest that a low-fat diet may be more beneficial for glucose control in individuals with a high genetic risk score.


Furthermore, the interaction between diet and pharmacogenomic effects on the gut microbiome are also relevant, as discussed by Professor Fredrik Bäckhed (The Wallenberg Laboratory, University of Gothenburg, Sweden). The impact of this crosstalk on microbial diversity in the gut could offer promise in the prevention and management of metabolic disorders in the future, although much remains to be done to translate findings in experimental models to the clinical setting.

EAS President Professor Lale Tokgozoglu (Hacettepe University, Ankara, Turkey) highlights the future potential of this approach.


What’s New in EAS FH Studies Collaboration?

Finally, there was an update from Professor Kausik Ray (Imperial College, UK), on the FHSC. To date, 74 lead investigators from 62 countries (but excluding the USA), have agreed to take part in this initiative; data from more than 4000 patients in 10 countries have been entered. And as part of this collaboration, the Homozygous FH (HoFH) International Clinical Collaboration (HICC) registry has received data from nearly 200 of the planned 500-600 patients.

Save the date:
EAS 2018 will be in Lisbon, Portugal, May 5-8

Join us there for the latest news and views in ASCVD and prevention of ASCVD



References

1. Murphy AJ, Tall AR. Disordered haematopoiesis and athero-thrombosis. Eur Heart J 2016;37:1113-21.
2. Tall AR, Levine RL. Cardiovascular disease: Commonality with cancer. Nature 2017;543:45-7.
3. Hill AB. The environment and disease. Association or causation? Proc R Soc Med 1965;58:295-300.
4. Nordestgaard BG, Chapman MJ, Humphries SE et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease. Consensus Statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478-90.
5. Ference BA, Ginsberg HN, Graham I et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017 Apr 24. doi: 10.1093/eurheartj/ehx144. [Epub ahead of print]
6. Yusuf S, Hawken S, Ounpuu S et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937-52.
7. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
8. Ridker PM, Revkin J, Amarenco P et al. Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients. N Engl J Med 2017;376:1527-39.
9. Wiegman A, Gidding SS, Watts GF et al. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J 2015;36:2425-37.
10. Nicholls SJ, Puri R, Anderson T et al. Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA 2016;316:2373-84.
11. Giugliano RP, Wiviott SD, Blazing MA et al. Long-term safety and efficacy of achieving very low levels of low-density lipoprotein cholesterol : a prespecified analysis of the IMPROVE-IT trial. JAMA Cardiol 2017 Mar 14. doi: 10.1001/jamacardio.2017.0083. [Epub ahead of print]
12. Descamps OS, Bruniaux M, Guilmot PF, Tonglet R, Heller FR. Lipoprotein concentrations in newborns are associated with allelic variations in their mothers. Atherosclerosis 2004;172:287-98.
13. Dietschy JM, Turley SD. Thematic review series: brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res 2004;45:1375-97.
14. Gaudet D, Digenio A, Alexander V et al. The APPROACH Study: A randomized, double-blind, placebo-controlled, Phase 3 study of volvanesorsen administered subcutaneously to patients with familial chylomicronaemia syndrome (FCS). Presented at EAS Congress Prague.
15. Gaudet D, Gipe D, Hovingh GK et al. Safety and efficacy of evinacumab, a monoclonal antibody to ANGPTL3, in patients with homozygous familial hypercholesterolaemia; a single arm, open-label, proof of concept study. Presented at EAS Congress Prague.
16. Bray MS, Loos RJ, McCaffery JM et al. NIH working group report-using genomic information to guide weight management: From universal to precision treatment. Obesity 2016;24:14-22.
17. Wang T, Huang T, Zheng Y et al. Genetic variation of fasting glucose and changes in glycemia in response to 2-year weight-loss diet intervention: the POUNDS LOST trial. Int J Obes (Lond) 2016;40:1164-9.


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