Commentary on EAS 2016

Looking back at EAS 2016 Innsbruck –
Highlights of the 84th Annual Congress, May – June 01, 2016

EAS Congress, held during 29 May-1 June, in Innsbruck, Austria welcomed over 2,000 delegates from across five continents. The Congress featured illuminating ‘state-of-the-art’ plenaries, news about novel therapeutic approaches in dyslipidaemia, as well as the latest updates to guidelines and EAS initiatives. This overview provides a snapshot of some of the highlights.

Overcoming obesity with lifestyle and beyond: do novel targets offer promise?

As highlighted by all guidelines in cardiovascular disease (CVD) prevention, including the 2016 Sixth Joint Task Force on Cardiovascular Disease Prevention in Clinical Practice guidelines,¹ lifestyle is the first fundamental step for preventing obesity and associated cardiometabolic disease. Indeed, in the Joint International Chair on Cardiometabolic Risk (ICCR) and EAS session, Professor Jean Pierre Després (Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, and Université Laval, Québec City, Québec, Canada), highlighted four common lifestyle risk factors – smoking, excessive alcohol intake, poor diet and lack of physical activity – which together account for about 80% of deaths from non-communicable disease.² It therefore makes clear socioeconomic sense that lifestyle should be at the forefront for cardiovascular health.

With respect to diet, fat is once more back on the agenda for debate. The problem is how the message has been translated for public health. Despite overwhelming evidence that replacing saturated fat in the diet with polyunsaturated fat reduces low-density lipoprotein (LDL) cholesterol levels and subsequently CVD, current thinking places emphasis on a diet low in total fat. Professor Alice H. Lichtenstein (Tufts University, USA) reinforced the need to change thinking and focus on diet quality, with a Mediterranean type diet that avoids refined grains, starch, added sugars, salt, and trans fats, seen as a prime example, very much in line with current guideline thinking.¹

Beyond lifestyle, state of the art lectures suggested novel targets that may offer promise for the management of metabolic disease. These may include adipose triglyceride lipase (ATGL), browning of white adipose tissue (WAT), and fibroblast growth factor-21 (FGF21), an endocrine growth factor. There is clear evidence that activation of brown adipose tissue (BAT), the primary organ for heat production, confers beneficial effects on adiposity, insulin resistance and hyperlipidaemia, at least in animal models.³ The ‘re-discovery’ of beige adipocytes, which can be induced to form brown adipocytes (collectively referred to as thermogenic adipocytes) after exposure to environmental stimuli, such as cold, has been a major driver for understanding the underlying mechanisms involved in this process. Given that thermogenic activation is associated with increased uptake and internalization of triglyceride rich lipoproteins, increased uptake of cholesterol, stimulation of insulin release, promotion of bile acid synthesis and excretion via the alternative pathway, as well as potentially favourable effects on the gut microbiome, this may offer new therapeutic potential for the treatment of metabolic disease. Additionally, FGF21 plays a critical role in regulation of energy homeostasis, as well as central effects that influence nutrient intake and reward behaviours, suggesting that targeting FGF21 may offer future therapeutic potential.^4,5

Novel insights into angiogenesis

Anitschkow Award recipient Professor Peter Carmeliet (Katholieke Universiteit Leuven, Belgium) discussed how metabolism in endothelial cells, key players in angiogenesis, may offer new directions for therapy, not only in oncology but also atherosclerosis. Studies have shown that endothelial cells rely mainly on glycolysis, one of the major metabolic pathways that convert glucose to pyruvate, for ATP production, and that glycolysis is further enhanced in angiogenic endothelial cells. The key glycolytic regulator PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3) is an important determinant of angiogenesis influencing the balance of tip versus stalk cells. Pharmacological blockade of PFKFB3 causes a transient, partial reduction in glycolysis, and reduces pathological angiogenesis with minimal systemic harm.

Novel insights from Professor Carmeliet’s laboratory have also shown two different functions for fatty acid oxidation, both in proliferation of vascular endothelial cells, and in differentiation of venous to lymphatic endothelial cells. While endothelial cells take up fatty acids such as palmitate via the enzyme CPT1a into the mitochondria, this is not used for generation of ATP. Instead, inhibition of CPT1a resulted in loss of deoxyribonucleotides, indicating that carbon from fatty acids is critical for sustaining deoxyribonucleotide production and DNA synthesis in endothelial cells. As to why this is the case, Professor Carmeliet explained that as proliferating stalk cells need carbon for biosynthesis, fatty acids are a much richer carbon source than glucose or glutamine. Additionally, fatty acids and derived acetyl CoA have a metabolic signalling function. The transcription factor PROX1 plays a key role in this process, as it ‘hijacks’ fatty acid oxidation. Binding of PROX1 to the promoter of the CPT1a gene results in upregulation of CPT1a, increased fatty acid oxidation and increased acetyl coA production, which acts at the mitochondria to promote differentiation of venous endothelial cells to lymphatic endothelial cells. Thus PROX1 can be regarded as a ‘smart’ transcription factor, as not only does it increase production of acetyl coA, a substrate for acetylation of histones, but it also recruits histone acetylators to these sites specifically for lymphatic genes. Such insights may offer future possibilities for therapeutic angiogenesis, as well as potential for the treatment of lymph oedema.

LDL cholesterol lowering: Sixth Task Force guidelines and Key Note lecture

In a special workshop, EAS President, Professor Alberico Catapano (University of Milan, Italy) overviewed what was new in the very recently published Sixth Joint Task Force guidelines.¹ In terms of lipids, LDL cholesterol goals remain essentially unchanged, although the alternative goal of at least 50% reduction from baseline LDL cholesterol levels has been refined for high risk and very high risk patients. Statins remain the first line therapy for lowering LDL cholesterol. Although the Task Force recognizes the efficacy of the PCSK9 inhibitors in lowering LDL cholesterol by more than 50%, recommendations for these treatments await the results from long-term outcomes studies, the first of which is expected early in 2017.

Much of the focus in drug development has been on novel therapies that are able to lower LDL cholesterol substantially, allowing patients to attain levels below those recommended in guidelines. However, in the Key Note Lecture, Nobel Laureate Professor Michael S. Brown (Jonsson Center for Molecular Genetics, University of Texas Southwestern, Dallas, USA) questioned whether instead the focus should be on targeting treatment earlier rather than later so as to reduce the cumulative burden of LDL cholesterol. Such an approach is supported by studies which showed that exposure to genetically mediated lower LDL cholesterol levels from early life is associated with an even greater reduction in coronary heart disease risk, implying a cumulative effect on the burden of LDL cholesterol exposure.^6,7 Such an approach underlies the recommendations of the EAS Consensus Panel statement focusing on the care of children and adolescents with familial hypercholesterolaemia (FH).⁸

Cardiovascular risk: is it the same in men and women?

Clinicians need to recognize that the profile of cardiovascular risk differs between men and women, as highlighted in the Joint European Society of Cardiology/EAS session. Despite well recognized differences in the prevalence of risk factors between the sexes,⁹ which evolve over age, further work is needed to investigate how and why cardiovascular disease presentations differ. Indeed, Professor Georgios Kararigas (German Center for Cardiovascular Research, Charite University Hospital, Berlin, Germany) made the case during this session for investigation of the mechanisms that influence left ventricular modelling in men and women, including modulation of oestrogen receptor β activity,¹⁰ which will be critical for better defining the role of non-invasive markers and biomarkers in risk assessment, clinical management and prognosis. Ultimately, such findings may lead to the development of personalized clinical care for men and women, which despite therapeutic advances, remains an overlooked priority in the 21st century.

Novel therapeutic approaches in homozygous FH

EAS Congress also offered tantalizing insights into novel therapies. Of note, the Late Breaker Clinical Session showcased new treatments with potential for the management of homozygous FH, which although rare, is associated with markedly elevated LDL cholesterol and accelerated atherosclerotic cardiovascular disease. Even with maximal LDL cholesterol lowering treatments, these patients rarely if ever attain LDL cholesterol goal, highlighting the need for additional approaches.¹¹

This session included a proof-of-concept study with evinacumab (REGN1500), a human monoclonal antibody to angiopoietin-like protein 3 (ANGPTL3). Treatment with evinacumab for 4 weeks led to a mean reduction in LDL cholesterol of 55% (range 25-90%), representing an absolute reduction of 4.5 mmol/l (0.4 to 10.1 mmol/L).¹² These encouraging results merit further investigation of this novel therapeutic approach. Additionally, there was interest in an affitope-based anti-PCSK9 vaccine (AT04A) tested in an animal model. Immunization with this vaccine was associated with substantial reduction in cholesterol (by more than 50%) and other atherogenic lipoproteins, inflammatory markers, as well as the severity of atherosclerotic lesions.¹³ This anti-PCSK9 vaccine has now progressed to Phase I clinical development.14 Results with MBX-8025, an oral peroxisome proliferator-activated receptor delta agonist, were more intriguing. While treatment with this agent reduced LDL cholesterol concentration (by <50%), it was also associated with a substantial increase in plasma PCSK9 levels, which would be expected to abrogate the efficacy of this therapy.¹⁵

Beyond lowering LDL cholesterol levels substantially, the key question is whether the introduction of novel treatments for homozygous FH offer the possibility of reducing the risk of cardiovascular events. While it may be too premature to answer this, initial data from the TAUSSIG study, an ongoing study with the PCSK9 inhibitor evolocumab in patients with homozygous FH, are encouraging. Not only did this study show that the LDL cholesterol lowering response was maintained over 12 months, but the annualized cardiovascular event rate was 2.1% (over <2 years follow-up), substantially lower than that reported for patients on statin and ezetimibe but not apheresis (3.5%).^16-18 Only four patients had cardiovascular events, none of whom died. Thus, despite the limitations of few absolute events, limited follow-up duration and lack of historical cohort data for homozygous FH for comparison, the data augur for possible long-term benefit on patient prognosis in this severely debilitated patient group.

Precision medicine: now and the future

Precision medicine, i.e. taking an individualized, molecular approach to risk assessment and clinical care, is not a new concept. The final plenary discussed the application of this approach in cardiometabolic disease. In an illuminating discussion, Professor Tschöp (Helmholtz Diabetes Center & Technische Universität München, Munich, Germany) provided a rationale for metabolic precision medicine in the development of new treatments for obesity and related metabolic disorders. Glucagon-like peptide-1 (GLP-1) analogs are considered the best therapeutic agents for type 2 diabetes and obesity due to their actions in lowering blood glucose and body weight. Recent focus has been on incorporation of metabolically-related peptide hormone receptors within one peptide, given that the individual activities of each receptor harmonize resulting in better overall metabolic activity. A monomeric peptide triagonist incorporating GLP-1, glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors within a single peptide, has shown unprecedented activity in rodent models, with synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect.19 Such novel approaches offer new possibilities for tailoring treatment to the high risk individual, and ultimately, a paradigm shift in the management of obesity and metabolic disease.

All in all, this year’s Congress shows that the EAS continues to be at the forefront of research in atherosclerosis and cardiovascular disease; consistent with its mission to “advance and exchange knowledge concerning the causes, natural history, treatment and prevention of atherosclerotic disease”.

References

1. Piepoli MF, Hoes AW, Agewall S et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2016; DOI: http://dx.doi.org/10.1093/eurheartj/ehw106 ehw106 First published online: 23 May 2016.
2. Hunter DJ, Reddy KS. Noncommunicable diseases. N Engl J Med 2013;369:1336-43.
3. Bartlet A, Heeren J. Adipose tissue browning and metabolic health. J Nat Rev Endocrinol 2014;10:24-36.
4. Chu AY, Workalemahu T, Paynter NP et al. Novel locus including FGF21 is associated with dietary macronutrient intake. Hum Mol Genet 2013;22:1895-902.
5. Talukdar S, Owen BM, Song P et al. FGF21 regulates sweet and alcohol preference. Cell Metab 2016;23:344-9
6. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264-72.
7. Ference BA, Yoo W, Alesh I et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol 2012;60:2631-9.
8. 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.
9. De Smedt D, De Bacquer D, De Sutter J et al. The gender gap in risk factor control: Effects of age and education on the control of cardiovascular risk factors in male and female coronary patients. The EUROASPIRE IV study by the European Society of Cardiology. Int J Cardiol 2016;209:284-90.
10. Kararigas G, Fliegner D, Forler S et al. Comparative proteomic analysis reveals sex and estrogen receptor β effects in the pressure overloaded heart. J Proteome Res 2014;13:5829-36.
11. Cuchel M, Bruckert E, Ginsberg HN et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014;35:2146-57,
12. Gaudet D, Gipe DA, Khoury É et al. Safety and efficacy of evinacumab, a monoclonal antibody to ANGPTL3, in patients with homozygous familial hypercholesterolemia: a single arm, open-label, proof of concept study. Abstract EAS16-0677, EAS Congress, 29 May-1 June, Innsbruck, Austria.
13. Galabova G, Juno C, van der Hoorn JWA et al. Affitope-based anti-PCSK9 (PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9) vaccine (AT04A) reduces atherosclerosis in APOE*3LEIDEN.CETP mice. Abstract EAS16-0577 08, EAS Congress, 29 May-1 June, Innsbruck, Austria.
14. Study Assessing Safety, Immunogenicity and LDLc -Lowering Activity of 2 PCSK9 Targeting AFFITOPE Vaccines in Healthy Subjects (AFF012). ClinicalTrials.gov Identifier: NCT02508896. https://clinicaltrials.gov/ct2/show/NCT02508896
15. Gaudet D, Saheb S, Bruckert E et al. A pilot study of MBX-8025 in the treatment of Homozygous Familial Hypercholesterolemia (HoFH). Abstract EAS16-1024 LB43 43, EAS Congress, 29 May-1 June, Innsbruck, Austria.
16. Raal FJ, Kurtz C, Honarpour N et al. Cardiovascular event rates in homozygous familial hypercholesterolemia (HoFH): Trial Assessing Long-Term Use of PCSK9 Inhibition in Subjects With Genetic LDL Disorders (TAUSSIG) Study Interim Results. Abstract EAS16-0688 25, EAS Congress, 29 May-1 June, Innsbruck, Austria.
17. Stein EA, Sampietro T, Santos R et al. Long-term treatment with evolocumab homozygous familial hypercholesterolemia patients: Results from the Trial Assessing Long-Term Use of PCSK9 Inhibition in Subjects With Genetic LDL Disorders (TAUSSIG). Abstract EAS16-0682 25, EAS Congress, 29 May-1 June, Innsbruck, Austria.
18. Raal FJ, Pilcher GJ, Panz VR et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation 2011;124:2202-7.
19. Finan B, Yang B, Ottaway N et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med 2015;21:27-36.