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An action plan is needed to care for people with lipid disorders in Australia to reduce the burden of cardiovascular disease.
Cardiovascular disease (CVD) remains our nation’s biggest killer, with a frequency of one in four deaths due to CVD. In 2020, approximately 56 700 people aged 25 years and over had an acute coronary syndrome (ACS) event in Australia — that’s 155 ACS events every day. Furthermore, CVD imposes a substantial burden in health care expenditure, costing the Australian economy $5 billion each year, which is projected to grow.
CVD is a preventable condition, with high cholesterol being a common, yet often neglected, modifiable risk factor. There is compelling evidence that apolipoprotein B (apoB)-containing lipoproteins, particularly low-density lipoprotein (LDL), causes CVD. Cumulative exposure to LDL-cholesterol over time (“cholesterol-years”) leads to atherosclerosis; this concept is central to the care patients with familial hypercholesterolaemia (FH), a relatively common condition (affecting one in 250 people), is characterised by elevated plasma levels of LDL-cholesterol from birth and premature CVD.
Extensive clinical trial data show that lowering LDL-cholesterol can safely and effectively reduce atherosclerotic cardiovascular disease (ASCVD) risk; every 1 mmol/L lowering of LDL-cholesterol level is on average associated with a 20% reduction in the risk of ASCVD, with extra benefit accruing over time. Accordingly, the current therapeutic mantra is “the lower, the earlier, the longer the better”. Recognising this, recent European guidelines have recommended lower LDL-cholesterol goals in higher risk patients.
Current state of play in Australia
A heart-healthy lifestyle and statins are the cornerstone of lipid-lowering therapy for the prevention of CVD. However, data from Europe and Australia show that despite optimised statins, over half of patients are not attaining guideline-recommend LDL cholesterol goals.
In primary care in Australia, almost two-thirds of patients treated with statins are not attaining LDL cholesterol goals. Most high risk primary prevention patients are not prescribed lipid-lowering therapy. For example, approximately 100 000 people are living with FH in Australia, but most are undiagnosed and inadequately treated. In patients with ACS, the CONCORDANCE registry showed that almost half did not attain lipid goals after 12 months.
Globally, there is new emphasis on “high intensity lipid-lowering therapy” strategy, particularly in higher risk patients. Available therapies that can be added to statin include ezetimibe, bile acid sequestrants and the injectable proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies. Bile acid sequestrants are rarely used owing to their gastrointestinal side effects, the impact on fat-soluble vitamin absorption, and medication interactions, although tolerability is better with colesevelam than with traditional agents.
Alirocumab and evolocumab are PCSK9 monoclonal antibodies that have been shown to reduce CVD risk in the secondary prevention setting and are guideline-recommended. Both are available on the Pharmaceutical Benefits Scheme (PBS) to facilitate attainment of LDL-cholesterol goal in high risk patients, including FH. However, despite their long term efficacy and safety, uptake of PCSK9 monoclonal antibodies remains low, even in tertiary care.
The promise of novel therapies
Opportunely, we are entering a new era of lipid management. LDL-cholesterol remains the primary target in clinical practice. However, beyond LDL-cholesterol are other apoB-containing lipoproteins, such as triglyceride-rich lipoproteins (TRLs) and lipoprotein(a) [Lp(a)], which are causally associated with ASCVD and, accordingly, are new therapeutic targets.
Genetic studies and advances in drug development have led to several lipid-lowering therapies that promise attainment of lipid and lipoprotein levels previously unattainable. CVD outcome trials, as well as safety, acceptability and cost-effectiveness data will enable clinical utilisation and improvement in care.
Gene silencing by targeted delivery of ribonucleic acid (RNA)-based therapies has come to the forefront, enabling safe and effective regulation of multiple atherogenic lipoproteins. Their long duration of action, especially with small interfering RNAs, allows less frequent dosing regimens and hence greater patient convenience and adherence to essential therapy. For example, inclisiran, a small interfering RNA targeting PCSK9, lowers LDL-cholesterol by approximately 50% incremental to diet and statins (with or without ezetimibe) and is administered as a subcutaneous injection twice a year. In clinical trials, RNA-based therapies lower TRLs by targeting angiopoietin-like protein 3, or lower Lp(a) by more than 80–90% by targeting apolipoprotein(a) (eg, pelacarsen, olpasiran or zerlasiran).
Oral agents targeting PCSK9 or apolipoprotein(a) (eg, muvalaplin) are now possible with the development of small molecule therapies, but frequent pill taking may pose barriers to adherence. Also, vaccines and gene editing approaches (eg, CRISPR-Cas9) are on the horizon, offering exciting possibilities for sustained lipid management; further research is needed to resolve questions on safety, costs and, in the case of gene editing, bioethical issues.
Implications for clinical practice
The increasing armamentarium of lipid-lowering therapies will bring greater choice and flexibility to clinicians and patients, with the potential to offer more personalised treatment. However, many novel therapies are currently not available for clinical use in Australia (eg, bempedoic acid and icosapent ethyl), are not yet reimbursed on the PBS (eg, inclisiran), are accessed only under special schemes (eg, evinacumab) or are only available through clinical trials.
Statin intolerance remains an important issue. Nutraceutical regimens or bempedoic acid (when available in Australia), may be alternative therapies in patients with hypercholesterolaemia who are intolerant to statins. Furthermore, if Lp(a)-lowering is shown to reduce CVD risk in ongoing clinical trials in high risk patients, this will provide a powerful rationale for the use of gene silencing agents targeted at the apolipoprotein(a) gene.
The management of hypertriglyceridemia is challenging, as fibrates, niacin and mixed omega-3 fatty acids have not been shown to reduce CVD risk when added to statin in many clinical trials. Icosapent ethyl, however, is a highly purified eicosapentaenoic acid ethyl ester that can reduce CVD risk in high risk patients with hypertriglyceridemia on statin therapy. Icosapent ethyl is cost-effective, recommended by the guidelines for hypertriglyceridemia of the American College of Cardiology and is now approved by the Therapeutic Goods Administration. The increased risk of atrial fibrillation and bleeding with icosapent ethyl requires noting and monitoring, but these potential adverse events are far outweighed by the benefits of treatment on total CVD events.
However, before moving to new lipid-lowering therapies, we need to correctly use and make the most of currently available treatments. Addressing adherence to lifestyle and medications remains a concern. It is recognised that many patients with hypertension require a combination of therapies to achieve effective blood pressure lowering. The same for lipid-lowering needs to be acknowledged, especially in high risk patients with ACS or FH. The combination of high intensity statin plus ezetimibe plus PCSK9 monoclonal antibody can lower LDL cholesterol by approximately 85%, so that the LDL cholesterol goal can now be attained by most patients. Although effective therapies are already available, too few patients are receiving them.
What needs to change
To address these treatment gaps, a comprehensive, multifaceted and interdisciplinary approach is required. Lipid-lowering therapies need to be used on a background of optimal lifestyle management, including diet and exercise, which should be incentivised by public health interventions. Secondary causes of dyslipidaemia, such as obesity, must be addressed. Obesity is a rising global health problem requiring lifestyle and behavioural counselling and access to pharmacological (eg, glucagon-like peptide-1 analogues) or surgical approaches for weight control where indicated.
The reasons for suboptimal LDL-cholesterol goal attainment are multifactorial and must be addressed at the clinician, patient, and health care system level. For clinicians, gaps in knowledge, competing priorities and therapeutic inertia are potential reasons. For patients, there may be lack of awareness, misinformation, costs, non-adherence and side effects. Health care system-level reasons include inequitable access, fragmentation of care and strict PBS reimbursement criteria.
Australia needs greater awareness and education among both patients and health care professionals, as well as in the wider population, on the importance of lipid testing and management. The last Australian guideline on overall care of lipid disorders in 2005 needs updating. The FH Australasia Network recently developed guidance for enhancing the care of FH in 2020, followed by an Australian Atherosclerosis Society 2022 position statement on elevated Lp(a). However, we are nearing 2024 and broader national guidelines for lipid management that reflect contemporary evidence are needed. This was identified as a priority in Australia’s National Roundtable on Cholesterol in 2022. We also need an updated hypertension guideline, which together with a new lipid management guideline will enhance the impact of the new Australian CVD risk calculator.
Effective implementation of guidelines for CVD risk assessment and lipid-lowering will require an integrated health system approach with shared models of care spanning across primary care, specialist clinics, hospitals and allied health. Training of health care providers needs to be strengthened, with support for the central role of general practitioners and the increasing role of nurse practitioners and pharmacists. Digital tools for clinicians to support best practice (eg, decision-support systems) and patients to improve adherence to lifestyle changes and medications (eg, mobile applications) should be implemented. Before new therapies can be introduced, there is a need for implementation strategies to bridge the gap between evidence and clinical practice.
There needs to be a shift towards preventive strategies earlier in life. With further stakeholder consultation, a clear action plan for the care of lipid disorders in Australia needs to be developed and implemented nationally with key policy makers to further reduce the burden of CVD in the population.
Dr Nick S R Lan is a Cardiology Senior Registrar in the Department of Cardiology, Fiona Stanley Hospital, and a Clinical Senior Lecturer in the School of Medicine, University of Western Australia, Perth, Western Australia.
Professor Gerald F Watts is Senior Consultant Physician in the Departments of Internal Medicine and Cardiology, Royal Perth Hospital, and Winthrop Professor of Cardiometabolic and Internal Medicine at the University of Western Australia, Perth, Western Australia.
Dr Lan has received research funding from Sanofi as part of a Clinical Fellowship in Endocrinology and Diabetes; education support from Amgen, Bayer, Boehringer Ingelheim, Eli Lilly and Novartis; speaker honoraria from Boehringer Ingelheim, Eli Lilly, Novartis and Sanofi; and has participated in advisory boards for Eli Lilly.
Professor Watts has received honoraria related to consulting, research and speaker activities from Amgen, Arrowhead, AstraZeneca, CRISPR Therapeutics, Esperion, Novartis and Sanofi.
The statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of the AMA, the MJA or InSight+ unless so stated.
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