EAS 2023
Lipids, and ASCVD risk at EAS 2023
Read highlights from the 2023 European Atherosclerosis Society (EAS) congress in Mannheim, Germany, and online. Discover the latest on:
- personalising the management of cardiovascular risk
- the important role of lipoprotein(a)
- genetic insights and management strategies for familial hypercholesterolaemia
Watch Professor Kosh Ray highlight what EAS has to offer for a practicing cardiologist.
Personalised prevention
By Eleanor McDermid
The EAS congress opened with the recipient of this year’s Anitschkow Prize – Professor Stephen Nicholls – giving an overview of his career researching lipids1.
He finished by outlining the many treatments now available or in development for reducing cardiometabolic risk, but cautioned that “we cannot give our patients every single one of these therapies – they won’t take them all and we can’t afford it.”
Nicholls therefore looks forward to an era of personalised prevention, with the optimal treatments targeted to patients according to their personal lipid profiles and comorbidities.
We cannot give our patients every single one of these therapies – they won’t take them all and we can’t afford it.
The plenary sessions of EAS outlined key factors beyond low-density lipoprotein (LDL) cholesterol that should be considered when assessing a person’s personal cardiovascular disease risk and making treatment decisions2. These included:
- fatty liver disease and non-alcoholic steatohepatitis
- type 2 diabetes
- obesity
- triglycerides
- lipoprotein(a)
- inflammation
Professor Kausik Ray explains why healthcare professionals need to think beyond the numbers to manage cardiovascular risk, and highlights the role of patient advocates.
Surprise ASCVD benefits of a diabetes medication
At times, a major risk factor can turn into a major opportunity for atherosclerotic cardiovascular disease (ASCVD) prevention. In a Sunday CME session, Professor Lale Tokgozoglu outlined how a class of medications designed purely to lower glucose levels – the glucagon-like peptide-1 receptor agonists – proved to also protect patients against ASCVD events3.
She highlighted that in secondary prevention patients the effects became apparent after about 1 year of use, whereas the benefit of this drug class in primary prevention was unclear until the publication of the REWIND trial4, which found a significant benefit over an extended follow-up of a median 5.4 years.
This shows “that you have to be cautious and wait for the positive effects of these agents”, said Tokgozoglu.
Glucagon-like peptide-1 receptor agonists reduced ASCVD risk in primary prevention populations, but this emerged only after a long follow-up
Professor Lale Tokgozoglu discusses epidemiological shifts in ASCVD and explains how its association with diabetes has presented solutions as well as problems.
ASCVD risk: test, and test some more
Among the original research studies presented were two that highlighted the need to be exhaustive when it comes to measuring risk factors.
A session focused on inflammation included research findings based on participants of the Copenhagen General Population Study5. This analysis revealed a high risk of events in people who had high levels of both remnant cholesterol and C-reactive protein (CRP).
Being in the highest versus the lowest tertile of remnant cholesterol and of CRP was associated with a significantly increased risk of myocardial infarction (MI) and of ASCVD, at hazard ratios of 2.2 and 1.9, respectively, whereas the corresponding hazard ratios were 1.6 and 1.4 for remnant cholesterol alone and 1.7 and 1.6 for CRP alone.
Presenter Dr Takahito Doi pointed to previous evidence that remnant cholesterol is causally associated with inflammation. Nevertheless, the results of his research indicate that healthcare professionals should measure both risk factors when evaluating ASCVD risk, he stressed.
In a session on genetic susceptibility, Dr Elena Olmastroni presented results that showed the value of measuring the same risk factor in two ways6.
In an analysis of UK Biobank participants, those with a high polygenic risk score who also had a family history of coronary heart disease (CHD) had a markedly higher CHD risk than people with either factor alone.
Specifically, the cumulative lifetime risk was 36% in people with both risk factors, 21% in those who only had a positive parental history and 22% in those with high polygenic risk score alone. By contrast, the cumulative risk was just 12% in people without either risk factor.
Pathways to LDL goal
Professor Lale Tokgozoglu discusses approaches to getting patients to their cholesterol goals, and emphasises the importance of patient-centred care.
The focus on other lipid and non-lipid risk factors does not diminish the importance of achieving LDL targets, and two presentations in the late-breaker session showcased the most recent and upcoming therapies to reduce LDL.
In the CLEAR Outcomes randomised controlled trial7, use of bempedoic acid resulted in a significantly reduced risk for major adverse cardiovascular events in patients who were unable or unwilling to take a statin8, which presenter Professor Stephen Nicholls described as a “significant and a frustrating challenge for all of us and our patients in particular.”
The trial results show that use of bempedoic acid in this group for a median of 40.6 months reduced participants’ risk of having a primary endpoint event (nonfatal MI or stroke, coronary revascularisation or cardiovascular death) by a significant 13%, with rates of 11.7% versus 13.3% in the bempedoic acid and placebo group, respectively.
The lipid-lowering ability of bempedoic acid translated into cardioprotective benefits in the CLEAR Outcomes trial
Bempedoic acid is already approved on the basis of its lipid-lowering ability; the 13,970 CLEAR Outcomes participants experienced an average 21.7% reduction in LDL cholesterol over the first 6 months of use. In addition, they had an average 22.2% reduction in CRP levels.
Nicholls highlighted that the cardioprotective effect of bempedoic acid was similar to that of other non-statin therapies such as ezetimibe, evolocumab and alirocumab.
The last two of these medications are both proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and are both administered by subcutaneous injection, potentially presenting a barrier to treatment.
But a phase 2b trial presented9,10 in the same session showed promising results for a novel oral PCSK9 inhibitor, currently termed MK-0616, in 380 patients with hypercholesterolaemia and a wide range of ASCVD risk.
Presenter Professor Alberico Catapano reported a dose–response effect of MK-0616, with the average LDL cholesterol reductions versus placebo at week 16 being 41.2%, 55.7%, 59.2% and 60.9% with doses of 6, 12, 18 and 30 mg/day, respectively. There were similar reductions in apolipoprotein B and non-high-density lipoprotein cholesterol.
There were no notable safety issues during this relatively short trial, so Catapano concluded that “these data obviously are supportive” of the further development of MK-0616 for this indication.
Finally, findings from the SANTORINI registry provided a reminder of the value of optimising existing treatments. The registry includes 9,136 patients with high and very high CVD risk enrolled at 623 sites across 14 European countries11.
LDL cholesterol measurements at baseline and 1 year were available in 7,210 participants (average age 65 years; 72% men). Over the course of the year, their average LDL cholesterol level fell from 2.42 to 1.98 mmol/L, with a corresponding increase in those achieving their personal LDL cholesterol goal, from 21.2% to 31.2%.
Professor Kausik Ray, who presented the results, emphasised that a population shift of approximately 0.4 mmol/L resulted in only about an extra 10% of people achieving their goal.
Looking at medication changes over time, he highlighted an increased use of combination therapy, from 27.5% to 41.7%, mostly in the form of ezetimibe added to a statin, most strikingly in the subgroup of patients at the very highest CVD risk.
Irrespective of risk level, a greater proportion of patients given combination therapy achieved their LDL cholesterol goal than those give monotherapy.
“However, at a population level we’re not getting our population to goal because we’re not putting enough of our patients onto combination therapy”, said Ray.
He concluded: “The mantra has to be: move to combination therapy rather than monotherapy, and that starts with your assessment of risk. If you don’t know what the risk is, you don’t know how well you need to treat.”
The mantra has to be: move to combination therapy rather than monotherapy, and that starts with your assessment of risk.
Spotlight on lipoprotein(a)
By Eleanor McDermid
The conference featured discussion of lipoprotein(a), following on from last year’s publication of the EAS consensus statement12 on Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis.
Professor Christie Ballantyne gives his view of the EAS consensus statement on Lp(a) and the changes healthcare professionals should be making to their practice.
Lp(a) genetics, risk, measurement and management
A Monday plenary session included a talk from consensus statement co-Chair Professor Florian Kronenberg on what he referred to as “the mysterious brother of LDL [low-density lipoprotein]”13.
He outlined the “bumpy ride” of Lp(a) to cardiovascular relevance, with initial epidemiological studies providing conflicting evidence of its association with risk, but cohorts such as the Copenhagen Study and the UK Biobank finally providing convincing evidence of a link with:
- coronary artery disease
- aortic stenosis
- heart failure
- ischaemic stroke
- peripheral arterial disease
- cardiovascular and all-cause mortality
Kronenberg stressed that both high Lp(a) and the associated adverse outcomes are frequent, making Lp(a) an important risk factor from a public health perspective.
The presenter then gave an overview of Lp(a) genetics, explaining that there are a large number of Lp(a) isoforms, and people who have the small isoforms have a twofold increased ASCVD risk compared with people who have larger isoforms. In addition to isoform, a number of genetic variants also have a large impact on Lp(a) levels14-16.
Overall, Lp(a)-increasing variants result in increased ASCVD, whereas those that reduce levels are cardioprotective17.
Moving on from genetics, Kronenberg highlighted the advice in the EAS consensus statement to measure Lp(a) at least once in each adult during their lifetime12.
All adults should have Lp(a) measured at least once during their lifetime
“Keep it simple: otherwise it’s not followed”, Kronenberg commented, noting that recommendations from other guidelines are more complex and will often result in people being tested too late, when they have already had a major ASCVD event.
But he stressed that the adverse effect of Lp(a) increases as people accumulate more additional ASCVD risk factors and therefore Lp(a) should not be considered in isolation. Conversely, it should not be overlooked, even in people with multiple risk factors, because doing so could cause healthcare professionals to underestimate a patient’s ASCVD risk.
Professor Florian Kronenberg talks about risk management in patients with high Lp(a) levels and the potential for new medications specifically targeting this risk factor in the near future.
Kronenberg highlighted a risk calculator, created by Professor Brian Ference to accompany the EAS consensus statement, to help patients and healthcare professionals understand the impact of Lp(a) on risk18.
There are as yet no medications specifically targeting Lp(a), making it critically important to employ early and intensive management of general risk factors in patients with high Lp(a) levels.
Early, intensive risk management is key in patients with high Lp(a) levels
Lipoprotein apheresis may also be an option “in certain countries under certain conditions” such as progressive cardiovascular disease despite optimal management of risk factors, noted Kronenberg.
However, several therapies based on antisense oligonucleotide and small interfering RNA technologies that specifically target Lp(a) are in the pipeline, he said, with the first phase 3 results expected in 2025.
Kronenberg’s take-home messages.
Lp(a) is:
- a causal risk factor
- a common risk factor
- helpful for risk assessment
He concluded that “it’s time to give Lp(a) a place in clinical practice”.
Lp(a): Latest research findings
A number of research studies presented at EAS focused on Lp(a), including one underlining the frequency of this risk factor in patients with high ASCVD risk.
In this study of 110 hospitalised patients with high cardiovascular risk, Paulina Gorzelak-Pabiś and team identified elevated Lp(a) levels in 33.3% of those hospitalised for cardiac causes and 22% of those hospitalised for other reasons19. The difference between the two groups was not significant, despite the average Lp(a) level being significantly higher in the cardiovascular causes group.
In the light of their findings, the researchers stressed the need to check Lp(a) levels in hospitalised patients with high ASCVD risk – even if they are being treated for other conditions.
Also presented at the conference was an analysis involving 70,317 people from the Copenhagen General Population Study20.
Confirming previous findings, presenter Dr Peter Thomas reported a dose–response association between Lp(a) levels and the risk of peripheral artery disease and abdominal aortic aneurysm, with hazard ratios of 2.99 and 2.22, respectively, for people in the fifth versus the first quintiles.
Finally, a revealed a strong association between Lp(a) levels and the presence and progression of coronary plaque measured on computed tomography angiography21.
Among 272 patients (average age 57 years, 42% women), each interquartile range (103 nmol/L) increase in Lp(a) levels was associated with a 1.17 percentage point higher percent atheroma volume at baseline and a 0.65 percentage point larger increase during follow-up averaging 10.2 years.
All about familial hypercholesterolaemia
By Eleanor McDermid
Familial hypercholesterolaemia (FH) was a major topic of discussion at the EAS congress, with three sessions devoted to the condition and original research also being presented in other sessions, including the late breakers.
Screening: the key to prevention
A session on screening included a talk from Ms Magdalena Daccord, chief executive of the FH Europe Foundation22.
She highlighted that despite years of advocacy and strong backing from the scientific community, paediatric FH screening has not yet been widely implemented in Europe. However, she described a few successes, such as Germany beginning to roll out screening in some areas, Portugal making a firm commitment to doing so and Bulgaria now measuring cholesterol levels in all 10-year-olds.
Daccord expressed the hope that with continuing advocacy and collaboration “we will be able to move the needle, prevent unnecessary deaths, and give those kids a chance to live a happy and fulfilling life”.
Her point was underlined by study findings presented in a poster session, based on patients in the homozygous FH International Clinical Collaborators database23. Of the 751 patients in this registry, 37 (49% women) were deceased at the time of inclusion.
These patients were a median age of 12 years at the time of diagnosis and just 32 years at the time of death. Almost all died of atherosclerotic cardiovascular disease (ASCVD), with just nine dying of other causes.
Nine patients died of ASCVD while still childhood, and most of those who died in adulthood had experienced multiple ASCVD events prior to their death, including several of the patients who eventually died of non-ASCVD causes.
Presenter Ms Janneke Mulder and team therefore concluded that “early diagnosis and initiation of treatment is crucial”.
Patients with FH are at high risk of dying from ASCVD in young adulthood, or even in childhood, so early detection is vital
Two oral presentations assessed different approaches to identifying FH patients. One, presented in the late-breakers session by Dr Federica Brucato, explored whether the Dutch Lipid Clinic Network (DLCN) score could accurately identify patients with genetically confirmed FH24.
The DLCN is based on family and clinical history, physical examination and low-density lipoprotein (LDL) cholesterol levels. However, the researchers found it to be no more accurate than LDL cholesterol levels alone for distinguishing between 449 patients with hypercholesterolaemia who carried mutations in genes with a role in FH and 387 who did not.
The intention for the DLCN score is that it is used to identify patients who should undergo genetic testing for FH. However, in this study, 23% of patients with relevant genetic variants would not have undergone testing had the researchers relied on the DLCN score.
By contrast, an explorative analysis presented by Dr Andrea Baragetti in one of the dedicated FH sessions showcased a plasma biomarker with potentially near-perfect accuracy for the identification of FH25.
The researchers measured 368 plasma proteins in 704 patients with FH and 586 controls without hypercholesterolaemia. The blood samples were taken at the time of diagnosis, when most patients were not yet taking statins.
Fibroblast growth factor (FGF)-5 stood out as being most strongly associated with FH, with 99.5% accuracy for distinguishing between FH patients and controls in area under the receiver operating characteristic curve analysis.
Moreover, FGF-5 had excellent accuracy for distinguishing between 133 patients with genetically confirmed FH and 55 who had clinically defined FH but no relevant genetic variant, even when restricted to 55 and 64, respectively, who were matched for LDL cholesterol levels.
Baragetti stressed that their findings need to be validated in external cohorts.
Lipoprotein(a) and FH
Another presentation in the late-breakers session tied together two conference themes, with research from the UK’s 100,000 Genomes Project suggesting that mutations in the gene encoding lipoprotein(a) (LPA) could underlie some unexplained cases of FH.
Presenter Dr Marta Futema stressed that around 60% of people with FH according to clinical criteria do not have a pathogenic variant in the known FH-causing genes26.
This was the case for 404 patients included in this study, but the team identified a rare noncoding variant (rs140570886) in LPA that was significantly associated with FH in these people when compared with 50,791 controls.
Two patients were homozygous for the mutation and 33 were heterozygous, comprising 8.7% of those with unexplained FH. And in an analysis involving 308,585 participants of the UK Biobank, the variant was strongly associated with levels of both lipoprotein(a) and of LDL cholesterol.
Expanding FH medication options
Also in the late-breakers session, Professor Luis Masana reported that lomitapide significantly reduced LDL cholesterol levels in children with homozygous FH27.
The open-label phase 3 APH-19 study involved 43 patients (average age 10.7 years; 55.8% girls) who were given 24 weeks of treatment with lomitapide at a dose of 20, 40 or 60 mg/day (escalated from 2, 2 and 5 mg/day, respectively).
Overall, the participants achieved an average 53.5% reduction in LDL cholesterol levels, falling from an average of 435.8 to 176.5 mg/dL. The safety profile was in line with expectations from adults' studies. Gastrointestinal events occurred in 67% of patients and the presenter explained that these were largely associated with poor adherence to the low-fat diet.
In one of the oral FH sessions, Professor Frederick Raal reported pooled data from three open-label studies of evolocumab treatment in a total of 39 children with FH28. This showed only a small, nonsignificant average reduction in LDL cholesterol levels, despite a large reduction in free proprotein convertase subtilisin/kexin type 9 (PCSK9) levels.
Nevertheless, 43% of children achieved at least a 15% reduction in LDL cholesterol over 12 weeks of treatment and 20% achieved at least a 25% reduction.
Raal therefore concluded that “at least a trial of PCSK9 inhibitor therapy” is worthwhile in paediatric FH patients who are not meeting LDL cholesterol targets with other therapies.
More promising, Raal also presented phase 2 data for a medication – ARO-ANG3 – that inhibits the expression of angiopoietin-like protein 3, thus reducing lipid levels via pathways that do not involve the LDL receptor.
Eighteen adults with FH took the medication at a dose of 200 or 300 mg/day for 20 weeks, resulting in average LDL cholesterol reductions of 4.4–5.0 mmol/L (44.0–48.1%), and similar reductions in other lipid measures.
The safety profile was favourable, with no adverse events of concern, and Raal reported that a phase 3 trial is being planned.
Combination therapy for FH
For all the promising new and upcoming lipid-lowering medications, the results from a Canadian registry study, involving 1602 patients with probable or definite FH (average age 44.8 years; 48.5% women), highlighted the continuing need to optimise existing treatments29.
Dr Iulia Iatan reported that over an average 11.9 years of follow-up, LDL cholesterol decreased by an average of 48.6%, from 7.0 to 3.6 mmol/L. In parallel, the proportion of patients taking lipid-lowering therapy rose from 16.7% to 83.5%.
This resulted in 28.6% of patients achieving a reduction of at least 2.5 mmol/L, with rates of 15.0%, 39.6% and 77.6% in those taking one, two and three lipid-lowering therapies, respectively.
This finding “emphasises the importance of taking combination lipid-lowering therapy to get these patients to lipid target”, concluded Iatan.
Combination therapy remains underused in patients with FH, despite greatly increasing the likelihood of them achieving their LDL cholesterol targets
Watch Professor Florian Kronenberg discuss lipoprotein(a) testing and management and hear his key take-home messages from the conference.
Professor Christie Ballantyne gives his view of the EAS lipoprotein(a) consensus statement and his key conference takeaways.
In her conference highlights, Professor Lale Tokgozoglu discusses the impact of diabetes medications on cardiovascular risk, arterial imaging for risk assessment and management, shared decision making and medication adherence.
Professor Kausik Ray discusses EAS 2023, cardiovascular risk management and the promise of small interfering RNA medications.
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