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Updates on management of lipoprotein(a) and familial hypercholesterolaemia

Prof. Henry Ginsberg
Columbia University
New York, US
Prof. Kathryn Tan
The University of Hong Kong
12 Mar 2020
Awareness of the importance of lipoprotein(a) [Lp(a)] in cardiovascular disease (CVD) is growing. Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, such as alirocumab (Praluent®, Sanofi), have been shown to reduce Lp(a), according to Professor Henry Ginsberg from the Columbia University, New York, US, who spoke at a Sanofi-sponsored symposium organized by the Hong Kong Society of Endocrinology, Metabolism and Reproduction (HKSEMR) recently. At the same symposium, Professor Kathryn Tan from the University of Hong Kong provided an update on familial hypercholesterolaemia (FH) management, including the role of PCSK9 inhibitors.

Clinical relevance of Lp(a)


Lp(a) consists of the glycoprotein apolipoprotein(a) covalently linked to an LDL-particle containing apolipoprotein B-100 (apoB). [Curr Opin Lipidol 2004;15:167-174; J Lipid Res 2016;56:1339-1359.]

There is extensive heterogeneity in apo(a) protein size, with more than 40 different isoforms, resulting in more than 40 different sizes of Lp(a) particles. Almost all individuals have apo(a) isoforms of two different sizes, each inherited from one parent. [J Am Coll Cardiol 2017;69:692-711] Therefore, a wide variation in Lp(a) levels may exist between individuals. [Eur Heart J 2010;31:2844-2853]

“Lp(a) levels are about 90 percent genetically determined,” said Ginsberg. “Studies have shown a continuous association between Lp(a) levels and risk of CV events, such as MI and stroke.” [JAMA 2009;302:412-423; JAMA 2003;301:2331-2339]

In addition, Lp(a) is shown to be a risk factor for calcific aortic stenosis. In particular, one single nucleotide polymorphism (SNP) in the lip(a) locus (rs10455872) reached genome-wide significance for the presence of aortic valve calcification (odds ratio per allele, 2.05; p=9.0x10-10). [N Engl J Med 2013;348:503-512]

Measuring Lp(a)

“Despite the clinical relevance, measurement of Lp(a) is problematic. Lp(a) levels are generally reported as mg/dL or nmol/L due to the use of different assays,” said Ginsberg. [J Am Coll Cardiol 2017;69:692-711] “The conversion factor for mg/dL to nmol/L is variable – ranging from about 1.8 to 2.5 – with an error of between 10 percent and 30 percent. Scientists in the field are trying to develop a new, single assay that would be in nmol/L.”

“Patients should be advised that two measurements for Lp(a) are being used, and that if they switch from a lab using nmol/L to a lab using mg/dl, their level will be lower by 50 percent and vice-versa,” he advised.

Clinical benefits of Lp(a) lowering

A 100 mg/dL difference in Lp(a) level has the same association with coronary heart disease (CHD) risk as a 1 mmol/L difference in LDL-cholesterol (LDL-C) level. [JAMA Cardiol 2018;3:619-627] As Ginsberg explained, this is based on the assumption that all the risk of Lp(a) is derived from its cholesterol content and Lp(a) is 30–40 percent cholesterol, but more research is needed into these areas.

According to Ginsberg, a 1 mmol/L lower lifetime LDL-C level is associated with a 50 percent reduction in the lifetime risk of CHD. “If all the risk of Lp(a) is from its cholesterol content, this same risk reduction can also be achieved with an 80–100 mg/dL reduction in Lp(a) over a lifetime.” [JAMA Cardiol 2018;3:619-627]

Treatment options for elevated Lp(a)


Treatment options for elevated Lp(a) include apheresis, which is time-consuming and expensive, and niacin, which has been shown to reduce Lp(a) levels by 30–40 percent. However, data on the effect of statins and fibrates on Lp(a) are limited and inconsistent. [J Lipid Res 2016;57:1751-1757; Eur Heart J 2010;t31:2844-2853]

Other agents have shown a minor decrease in Lp(a) levels of less than 10 percent. These include aspirin, L-carnitine, ascorbic acid plus L-lysine, calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, androgens, oestrogen, tamoxifen, and thyroxine replacement in hypothyroid subjects. [Eur Heart J 2010;31:2844-2853]

Role of PCSK9 inhibitors in Lp(a) lowering

“PCSK9 inhibitors, such as alirocumab, have been shown to reduce Lp(a) levels by up to 30 percent,” said Ginsberg. [Am J Cardiol 2014;114:711-5; J Am Coll Cardiol 2014;63:1278-1288]

In patients with established atherosclerotic CVD, elevated baseline Lp(a) concentration was independently associated with an increased risk of coronary events. [Circulation 2018;139:1483-1492]

“Patients with elevated baseline Lp(a) levels achieved greater absolute reduction in Lp(a) and tended to obtain greater clinical benefit from PCSK9 inhibition,” said Ginsberg. [Circulation 2018;139:1483-1492]

A post hoc analysis of a recent trial showed that patients in the highest quartile of baseline Lp(a) experienced the greatest reduction in risk of major adverse CV events (MACE) from PCSK9 inhibition. In patients in the 75th percentile of baseline Lp(a), the proportion of MACE reduction attributable to changes in Lp(a) was 27 percent. (Figure 1) [Bittner V, et al, ACC 2019, abstract 413-12] “The clinical benefit of Lp(a) lowering may occur predominantly in patients with elevated baseline levels,” noted Ginsberg.

1751

Screening for elevated Lp(a)
Because Lp(a) level is predominantly genetically determined and does not change over a lifetime, an individual would only need to be tested once. “Individuals at intermediate or high risk of CVD/CHD should be screened for Lp(a),” recommended Ginsberg. (Table) [Eur Heart J 2010;31:2844-2853]

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“The time for Lp(a) has come. We should all be aware of it and look for it in our patients,” he concluded.

FH: An underdiagnosed condition 

FH is an autosomal dominant disorder and a common genetic cause of premature CHD. [Eur Heart J 2015;36:2425-2437]

“FH is not a rare genetic disorder,” stressed Tan. “It is present in about five in every 1,000 births, compared with 0.5 in every 1,000 births for genetic disorders such as sickle cell disease and Fragile X syndrome.” [Eur Heart J 2015;36:2425-2437]

However, except for the Netherlands and Norway, the majority of patients with FH worldwide remain undiagnosed. In Asia, it is estimated that less than 1 percent are diagnosed, and diagnosis is mainly based on the phenotype of elevated LDL-C as genetic testing is not widely available. [Eur Heart J 2017;38:1580-1583]

“Individuals with homozygous FH who do not receive any treatment usually die of CHD before their 20th birthday. Individuals with heterozygous FH are likely to develop premature CHD in their 30s or 40s,” said Tan. “However, if identified and treated early, these individuals could have a similar life expectancy to individuals without FH. It is therefore very important to identify these patients early and start treatment in a timely manner.” (Figure 2) [Eur Heart J 2013;34:3478-3490]

1753  

In a recent study, Tan and colleagues identified 42 distinct mutations in 67 percent of index FH cases. The majority of causative mutations were in the LDL-receptor (LDLR) gene, while 6 percent of patients had mutations in the APOB gene. When validated against genetic testing, the Dutch Lipid Clinic Network diagnostic criteria demonstrated a sensitivity of 82.8 percent and a specificity of 53.3 percent. [Mol Genet Genomic Med 2019;7:e00520]

“Once an index patient is identified, cascade screening of their family members should be performed, including screening the parents of a child with FH,” Tan advised.

The place of PCSK inhibitors in FH

High-intensity statins and ezetimibe are the first-line and second-line therapies in FH, respectively. Prior to the introduction of PCSK9 inhibitors, bile acid-binding resin was advised as a third-line drug. [Eur Heart J 2013;34:3478-3490]

In the ODYSSEY FH I and FH II trials, alirocumab treatment significantly lowered LDL-C in patients who failed to achieve adequate LDL-C control with other maximally tolerated lipid-lowering therapies (LLT). (Figure 3) [Eur Heart J 2015;36:2996-3003]

1754
 
Alirocumab was well tolerated in the ODYSSEY FH trials, with comparable rates of treatment-emergent adverse effects (TEAEs), serious adverse effects and TEAEs leading to treatment discontinuation vs placebo. A higher proportion of patients experienced injection site reactions with alirocumab vs placebo, but these reactions were usually mild and self-limiting. [Eur Heart J 2015;36:2996-3003]

“According to the latest recommendations on FH management, LDL-C goals should be <2.6 mmol/L, or <1.8 mmol/L in the presence of CVD. High-intensity statins and ezetimibe remain as first- and second-line therapies. PCSK9 inhibitors are now likely to be the third drug of choice, if cost is not an issue,” said Tan. [Nat Rev Cardiol 2015;12:565-575] “With PCSK inhibitors, we can get FH patients’ LDL-C levels down to what we have never been able to achieve in the past.”  

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Most Read Articles
01 Apr 2020
Being overweight or obese in adolescence appears to increase the risk of papillary thyroid cancer in adulthood, a recent study has shown.
3 days ago
A recent study reports a mean growth rate of proximal aorta of about 0.1 mm/year in hypertensive patients with known aortic dilatation. In addition, those with increased rather than normal aortic z score have slower dilatation over time.
01 Apr 2020
Higher intakes of tofu, soy protein and soy isoflavones, but not total legumes or total soy, appear to reduce the risk of developing type 2 diabetes (T2D), suggests a study.
Tristan Manalac, Yesterday
A new reusable auto-injector e-device allows for the safe and effective self-injection of certolizumab pegol (CZP), according to a new study.