HEART UK – Hypercholesterolaemia: familial or not?

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Reflecting the times, HEART UK held its 34th Annual Medical and Scientific Conference virtually this year with sessions taking place over a number of days in July. Covering the latest developments within the lipid community, this year’s conference had a particular focus on how to reduce uncertainty surrounding the diagnosis of familial hypercholesterolaemia (FH), including taking a look at current NHS initiatives working to speed up FH identification. In addition, the importance of lipoprotein (a) was revisited, including early data on some promising therapeutics to target this molecule. Dr Andreas Tridimas reports the highlights from the virtual meeting.

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HEART UK

Familial hypercholesterolaemia or not?

The importance of considering polygenic hypercholesterolaemia in those with no monogenic cause for familial hypercholesterolaemia (FH), was outlined by Professor Steve Humphries (UCL Institute of Cardiovascular Science, London).1 By looking for the presence of specific high low-density lipoprotein cholesterol (LDL-C), single nucleotide polymorphisms (SNPs) and combining these to generate a SNP-score, those with the most variants can be identified.

Professor Steve Humphries
Professor Steve Humphries

Individuals who are in the top five deciles of the SNP-score are highly likely to have a polygenic explanation for their high LDL-C and this presents clinicians and patients with a genetic explanation for this. While future risk of early heart disease is lower in the polygenic than the monogenic patients, both groups will need robust cholesterol-lowering management. At present, this polygenic LDL-C SNP score is not universally available across the seven UK Genomic Laboratory hubs where FH tests are carried out.

Medication adherence

Non-adherence to prescribed medication is a well-recognised issue with Hippocrates first identifying the issue in the 5th century BC. Dr Pankaj Gupta (University Hospitals of Leicester) outlined an assay used at the National Centre for Drug Adherence Testing, where is a director, which is able to detect 140 commonly prescribed drugs, such as beta blockers, statins and ACE inhibitors, from a urine sample.

Dr Pankaj Gupta
Dr Pankaj Gupta

A study he and colleagues carried out showed that non-adherence increases in a near linear fashion with increasing numbers of prescribed medications – being around 30–40% in those on three anti-hypertensive medications, for example. An observational study they carried out found that there was a significant improvement in blood pressure and adherence, in a cohort of previously non-adherent hypertensive patients, who underwent urine testing.2 The European Society of Cardiology and European Society Hypertension are now recommending chemical adherence testing in their latest guidelines.

SAMSON study demonstrates the placebo effect

Dr James Howard (Imperial College London), a co-author of the SAMSON (Symptom Burden of Statins Compared with Placebo) trial, presented data looking at statin side effects in a cohort of statin-intolerant patients. In the study, 60 patients were allocated to either placebo, no therapy or a statin. Their side effects were then recorded using a smart phone app. As expected, those in the no treatment group had minimal symptoms and those in the statins group had widespread side effects. Interestingly, those in the placebo group reported symptoms, which were ‘90% as bad’ as when taking statins.

This study provides further evidence of the ‘nocebo effect’ with statins, whereby a patient’s perception of taking the treatment are able to influence the side effects encountered. Importantly, following completion of the trial, after the patients were able to see their results, 50% of those previously untreated statin-intolerant patients, were now taking statins.

Lipoprotein (a) moves centre stage

Lipoprotein (a) (Lp [a]) is now well established as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD),3 Dr Mike France (Manchester Royal Infirmary) reiterated at the conference. Measurement bias caused by molecular weight heterogeneity and the use of polyclonal antibodies in assays has led to underestimation of this risk in the past, he said.

Acceptable accuracy of assays has now been achieved, he said, by the use of calibrants allowing correction for the effect of isoform size and also the use of a calibration protocol, which assigns values determined by an isoform insensitive assay under the aegis of the International Federation of Clinical Chemistry. In the absence of truly isoform insensitive commercial assays, this methodology should now be adopted in clinical trials and clinically.

Professor Sam Tsimikas
Professor Sam Tsimikas

Current and emerging therapies to lower Lp(a) were discussed by Professor Sam Tsimikas (San Diego, USA).4–6 Current options include lipid apheresis, which has a 70% acute and 35% timed-average reduction in Lp(a), with evidence from longitudinal prospective studies of a reduction in cardiovascular events. Other more accessible treatment options include PCSK9 inhibitors, which lead to a 14–30% reduction in Lp(a). Trial data from ODYSSEY OUTCOMES (Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome) suggested that a substantial proportion of the benefit of alirocumab was derived from this Lp(a) lowering ability.

Multiple RNA therapeutics are currently undergoing evaluation with the principal target being to inhibit hepatic production of Apo(a), meaning that Lp(a) particles cannot be assembled. Pelacarsen is currently undergoing a phase 3 trial, after the phase 2 trial showed an 80% reduction in Lp(a) on the highest dose examined, with it appearing to be well tolerated. Outcome data for pelacarsen is expected in 2024.

Ms Victoria Spellacy
Ms Victoria Spellacy

Cardiovascular disease and the NHS Long Term Plan

Cardiovascular disease (CVD) has been identified as a clinical priority by the NHS Long Term Plan.7 It is the single biggest area where lives can be saved over the next 10 years. Ms Victoria Spellacy (NHS Accelerated Access Collaborative) discussed their strategy to speed up the uptake of clinical and cost-effective innovations, such as PCSK9 inhibitors, for example, by developing a National Institute for Health and Care Excellence-endorsed clinical pathway.

Breaking barriers in lipid management

Dr Joe Chidanyika
Dr Joe Chidanyika

One in 250 of the UK population is thought to have FH, of whom only 8% are currently identified. Dr Joe Chidanyika from the Academic Health Science Network (AHSN) described the AHSN lipid management and FH programme. Through approaches such as expanding access to genetic testing for FH and piloting child-parent screening, the AHSN hopes to accelerate FH identification and reduce national inequalities in lipid management.8

This renewed national focus on lipid and CVD management looks set to improve patient care in this area.

Dr Andreas Tridimas
ST7 in Chemical Pathology & Metabolic Medicine
Countess of Chester Hospital, Chester

References

1. Trinder M, Francis GA, Brunham LR. Association of monogenic vs polygenic hypercholesterolemia with risk of atherosclerotic cardiovascular disease. JAMA Cardiol 2020;5:390–9. https://doi.org/10.1001/jamacardio.2019.5954

2. Gupta P, Patel P, Štrauch B, et al. Biochemical screening for nonadherence Is associated with blood pressure reduction and improvement in adherence. Hypertension 2017 Nov;70(5):1042–1048. https://doi.org/10.1161/HYPERTENSIONAHA.117.09631

3. Cegla J, Neely RDG, France M, et al. HEART UK Medical, Scientific and Research Committee. HEART UK consensus statement on Lipoprotein(a): a call to action. Atherosclerosis 2019;291:62–70. https://doi.org/10.1016/j.atherosclerosis.2019.10.011

4. Tsimikas S, Moriarty PM, Stroes ES. Emerging RNA therapeutics to lower blood levels of Lp(a). J Am Coll Cardiol. 2021 Mar 30;77(12):1576–1589. https://doi.org/10.1016/j.jacc.2021.01.051

5. Szarek M, Bittner VA, Aylward P et al. Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial. Eur Heart J 2021;41:4245–4255. https://doi.org/10.1093/eurheartj/ehaa649

6. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I et al. Lipoprotein(a) reduction in persons with cardiovascular cisease. N Engl J Med 2020;382:244–55. https://doi.org/10.1056/NEJMoa1905239

7. NHS. NHS Long Term Plan, January 2019. https://www.longtermplan.nhs.uk/wp-content/uploads/2019/08/nhs-long-term-plan-version-1.2.pdf (last accessed 4th November 2021)

8. The Academic Health Science Network (AHSN). Lipid management and familial hypercholesterolaemia. https://www.ahsnnetwork.com/about-academic-health-science-networks/national-programmes-priorities/lipid-management-and-fh (last accessed 4th November 2021)

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