The FH Australasia Network held a virtual summit over two weekends in October that brought together a host of international experts in the field of familial hypercholesterolaemia (FH). The purpose of the FH Summit was to initiate processes for the implementation of FH clinical recommendations that the network had recently published;1 the recommendations were developed with the input of contributors from diverse disciplines, and were endorsed by major national and international organisations. Here, the limbic reports on updates in paediatric and adult FH from presenters Dr Shubha Srinivasan (Paediatric endocrinologist and clinical lead of the lipid service in the Sydney Children’s Hospital and Clinical Associate Professor at The University of Sydney) and Associate Professor Karam Kostner (Associate Professor of Medicine at the University of Queensland and Director of Cardiology at Mater Hospital Brisbane).
New evidence in paediatric FH
“Despite estimates putting prevalence of heterozygous FH at 1 in 300, affecting around 16,000 children, we’re not treating anywhere near that number of children right now,” said Dr Srinivasan. She explained that untreated patients have a 20-fold increased risk of premature coronary heart disease, leading to the current focus on awareness, earlier identification and treatment. These goals are captured in a quote from Dr Albert Wiegeman, a paediatric cardiologist from the Netherlands: “We owe it to our patients to identify and treat children with familial hypercholesterolaemia early, so that they can lead a long and healthy life.”
Does treating children and adolescents with FH make a difference? Dr Srinivasan said that research confirms that it does. A study by Luirink and colleagues published in 2019,2 with 20-year follow-up of children treated with statins, showed a 32% reduction in LDL levels, carotid intima-media thickness (CIMT) progression similar to unaffected siblings, and a reduction in CV events and death from CV causes – lower than parents who had not been started on statins as children (1% vs 26% for CV events and 0% vs 7% for death from CV causes).2
Early identification and treatment in FH: what do the guidelines say?
Heart UK published a statement of care in 2019 that suggests detecting FH through opportunistic screening and identification from family members.3
Dr Srinivasan considered an alternative approach: “What if we did universal screening?”.
A study from Wald and colleagues4 showed that for every 1000 children screened at the time of immunisation, four children and four parents were detected with FH. Using a similar model in Australia, Martin and colleagues4 recently published data showing that one child is detected for every 150 screened at immunisation (when children are aged 1-2 years old). However, the data also showed that if you add on reverse cascade screening of the parents, detection rates rise to one person for every 56 children screened.5
“The UK guidance also has clear protocols for treatment of children and adolescents with FH,” said Dr Srinivasan. Treatment goals are listed as follows:3
- For children <10 years old: aim for a 30-50% reduction in LDL-C (target <3.5 mmol/L)
- Children ≥ 10 years old: aim to achieve a 50% reduction (target <3.5 mmol/L)
- Children ≥ 14 years old: aim for a target of <2.5 mmol/L
Recently, Australian guidance has been published that includes paediatric FH.1 The guidance has clear parameters for suspecting FH based on LDL levels in addition to the following points for diagnosing FH in children and adolescents:1
- Identification of homozygous FH should be done as early as possible (by the age of 2 years)
- Testing of all children suspected of heterozygous FH should be done between the ages of 5 and 10 years so that treatment can begin early
- The Dutch Lipid Clinical Network (DLCN) criteria should not be used in children and adolescents
- Highly probable phenotypic diagnosis of FH if LDL-C levels are:
- >5.0 mmol/L in the absence of parental history
- 0 – 5.0 mmol/L in presence of parental history
- >3.5 mmol/L in family with known pathogenic variant
When it comes to management of children and adolescents diagnosed with FH, Dr Srinivasan highlighted the importance of lifestyle modifications including diet and psychological issues and other lifestyle measure.
The guidelines also recommend:1
- Statin treatment for heterozygous FH be initiated at age 8-10 years (irrespective of gender)
- Plasma LDL-C targets do not need to be as intensive as in adults:
- Children between 8-10 years on a suitable diet: <4.0 mmol/L or a 30-40% reduction in LDL-C levels
- Children ≥10 years on a suitable diet: <3.5 mmol/L or 50% reduction in LDL-C levels
Treatment options for paediatric FH
Dr Srinivasan showcased data from an audit of the Children’s Westmead Hospital lipid clinic. She noted the attendance in clinic, refusal of statin treatment and poor adherence to treatment in teenagers as barriers to treatment. However, Dr Srinivasan also pointed out that treatment can achieve a reduction in LDL-C levels of 31-38%.
Dr Srinivasan explained that dietary modifications can achieve a 10-20% reduction in LDL-C levels. Treatment options include statins, ezetimibe in children older than 10 years, and newer therapies such as PCSK9 inhibitors, inclisiran and ANGPTL3 inhibitors are under investigation. The PCSK9 inhibitor evolocumab has been approved by the TGA for use in patients with homozygous FH aged 12 years and older in combination with other lipid lowering therapies,8 though it is not yet approved for use in paediatric heterozygous FH patients.
Concluding remarks on paediatric FH
“Thanks to opportunistic, selective and universal screening, we are identifying a greater number of children with FH, and international and Australian guidelines provide clear diagnosis thresholds for LDL-C levels. However, as more children are identified we need to establish shared care models to deliver optimised paediatric appropriate diet and lifestyle measures. Early introduction of statins are safe and effective, but LDL-C targets can still be difficult to achieve due to barriers such as treatment hesitancy and adherence issues. Newer therapies such as PCSK9 inhibitors are beginning to receive TGA approval, while research into ANGPTL3 inhibitors is looking promising,” said Dr Srinivasan
Current and future FH therapies for adult patients
Guidelines in recent years, largely propose to remove LDL-C targets.9 A/Prof Karam Kostner outlined his overarching treatment goals in FH:
- Lower LDL-C to the lowest possible levels – initially with statins, then by adding ezetimibe and if LDL-C levels not to target adding on PSCK9 inhibitors
- Aggressive treatment of other risk factors
- Cascade screening for affected family members
A/Prof. Kostner reviewed current treatment options for FH in adults. “Statin therapy is at the start of treatment. Statins have been shown to prevent progression to CV disease,” he noted.10 For further LDL-C lowering ezetimibe should be added to maximally tolerated statin therapy.11
“PCSK9 inhibitors revolutionised therapy in patients who do not achieve the desired LDL-C targets in both primary and secondary lines of prevention,” said A/Prof Kostner. The first two PCSK9 inhibitors approved for use in Australia are monoclonal antibodies (evolocumab and alirocumab),8,12 while the third is inclisiran, a small interfering (si) RNA that mimics the body’s process of RNA interference, thus increasing the LDL receptors on the liver13
Data supporting the benefits of evolocumab and alirocumab come from the FOURIER14 and ODYSSEY Outcomes15 trials, respectively. Both trials were large, CV outcomes trials in high risk populations assessing the respective monoclonal antibody in addition to maximal statin therapy (n=27,500 for FOURIER and 18,000 for ODYSSEY Outcomes).14,15
The primary endpoint for the FOURIER trial was a composite of CV death, MI, stroke, hospitalisation for unstable angina or coronary revascularisation. A/Prof. Kostner presented data showing evolocumab resulted in a mean reduction in LDL-C of 59% at 48 weeks. The composite CV primary endpoint was 14.6% with placebo compared to 12.6% with evolocumab.14
A/Prof. Kostner outlined the data behind the second registered PCSK9 inhibitor in Australia, alirocumab. ODYSSEY Outcomes15 showed approximately 60% reduction in LDL-C with alirocumab vs placebo. The primary endpoint (a composite of CHD death, non-fatal MI, ischaemic stroke and hospitalisation for unstable angina) was 14.5% with placebo and 12.5% with alirocumab.
“Inclisiran has been registered by the TGA but is not yet reimbursed,” explained A/Prof Kostner. He presented key data from the ORION-9 study,16 a phase III randomised, double-blind, placebo-controlled trial in patients with heterozygous FH on maximally tolerated statin with or without ezetimibe.16 The study showed a reduction of LDL-C levels between 40 and 50% and a greater proportion of patients achieving LDL-C targets with inclirisan added to therapy compared to placebo.16 “This is encouraging as an injectable therapy in high risk patients can achieve their LDL-C targets to a higher degree than if they are not on PCSK9 inhibitor,” said A/Prof Kostner.
A/Prof. Kostner briefly discussed research into ANGPTL3 inhibitors. He highlighted the first drug of this kind, evinacumab, that has shown a 47% reduction in LDL-C (versus a 2% increase in LDL-C with placebo) in 65 patients with homozygous FH, and on other lipid lowering therapies.17
These ANGPTL3 inhibitors are being explored as an adjunct therapy for patients who do not respond very well to statins or PCSK9 inhibitors.
Concluding remarks in adult FH
“FH is a high risk, atherosclerotic disease. Treatment should start early, usually with statins then with the addition of ezetimibe and, if this is not enough to get LDL-C levels to target, then with the addition of PSCK9 inhibitor – two of which are currently reimbursed on the PBS in Australia,” concluded A/Prof Kostner.
CHD=coronary heart disease; CI=confidence interval; CIMT=Carotid Intima-Media Thickness; CV=cardiovascular; HR=hazard ratio; LDL-C=low density lipoprotein cholesterol; MI=myocardial infarction; PBS=Pharmaceutical Benefits Scheme; siRNA=small interfering RNA; TGA=Therapeutic Goods Administration.
- Watts GF et al. Heart Lung Circ 2021;30:324-349.
- Luirink I, et al. N Engl J Med 2019;381:1547-1556.
- Ramaswami U, et al. Atheroscler 2019;290:1-8.
- Wald DS, et al. N Engl J Med 2016;375:1628-1637.
- Martin AC, et. al J Paediatr Child Health 2021; doi: 10.1111/jpc.15700. Online ahead of print.
- Yeung J, et al. J Paediatr Child Health 2021;57(8):1201-1207.
- Vuoria A, et al. Cochrane Database Syst Rev. 2017 Jul; 2017(7): CD006401.
- Repatha (evolocumab) Approved Product information, August 2021.
- Kostner K, et al. Heart, Lung Circ 2016;25:1051-1054.
- Packard CJ, et al. Vasc Pharmacol 2015;71:37-9.
- Pisciotta L, et al. Atherosclerosis 2007;194(2):e116-22.
- Praluent (alirocumab) Approved Product Information, January 2020.
- Leqvio (inclisiran) Approved Product information, September 2021.
- Sabatine MS, et al. N Engl J Med 2017;376:1713-22.
- Schwartz GG, et al. N Engl J Med 2018;379:2097-107.
- Raal FJ, et al. N Engl J Med 2020a; 382:1520-1530.
- Raal FJ, et al. N Engl J Med 2020b;383:711-20.
This article was written by the limbic in collaboration with the FH Australia Network.
Thank you to Amgen Australia Pty Ltd for providing the non-restrictive educational sponsorship that made it possible.