The old adage that prevention is better than cure holds strong for cardiovascular disease (CVD). Accounting for 25% of all Australian deaths, CVD costs the Australian health system $12.7 billion annually, placing an enormous burden on individuals, their family and the economy.
Traditional risk factors include modifiable causes (e.g. dyslipidaemia, hypertension, smoking, diabetes and lifestyle). Non-modifiable causes include genetics and gender.
Genetics has potential to be modifiable utilising techniques such as CRISPR. Female gender is not “protective” as such with CVD remaining a major cause of death for Australian females, and gender at best delaying onset. Females have lower rates of goal-directed medical therapy, lower rates of coronary intervention and are underrepresented in clinical trials, potentially worsening CVD outcomes.
Dyslipidaemia in 2024
It is established that while elevated LDL levels increase the risk of plaque build-up, atherosclerosis is an inflammatory process as demonstrated by the LoDoCo2 trial. There are patients with high LDL levels at lower risk of CVD and half of patients with MI will have ‘normal’ cholesterol levels. More nuance is needed to determine actual risk.
LDL is the major target for lipid lowering with evidence-based therapies to reduce major cardiovascular events (MACE). Increasing HDL with pharmacotherapies has not shown benefit and trials are unlikely to demonstrate this. TG (definite causative factor) has limited evidence-based pharmacotherapies.
Lipoprotein(a) (Lp(a)) is a genetically determined lipid particle related to LDL. It is highly atherogenic with levels determined by SNPs effecting K-IV region. About 20% of the population is considered to have elevated Lp(a), with levels higher in black people and in females, increasing in the post-menopausal period. No therapies exist to reduce Lp(a) with clinical trials continuing.
Current management of LDL cholesterol
Dietary modification and lifestyle change are recommended for all patients.
Statins remain the mainstay for therapy with robust evidence of their efficacy. LDL reduction with high potency agents at mod-high dose is >50%. Perceived and real side effects are common. Despite maximal tolerated statin therapy, many patients will not get to LDL target. Eztimibe is added to statins and confers an additional 20% LDL reduction and a modest relative reduction of MACE of 7% in secondary prevention patients.
For patients meeting PBS criteria, PCSK9-I (twice weekly self-administered injection) confers a further 50-60% reduction of LDL (on top of statin and ezetimibe) and a 15% reduction in MACE.
Inclisiran, an mRNA therapy targeting PCSK9-I (initially 3/12 then 6/12ly nurse administered injection) is available via a patient familiarisation program and 50% LDL reduction is achieved. The major CV outcome trial result is still pending.
Future therapies
Bempedoic acid (not available in Australia), a statin alternative, lowers LDL by 20% and MACE by 13% in statin intolerant patients.
Lp(a) therapies will potentially confer enormous benefit to patients with elevated levels. Lp(a) is considered to contribute to the residual risk of a future CVD event and therefore treatment is anticipated to reduce risk significantly particularly in the highest 20% of Lp(a) levels.
Phase 3 clinical trials are under way with RNA therapies lowering Lp(a) by 95% in patients with high Lp(a) and a history of CVD. Results of these trials will be available over the next few years.
APOCIII is a TG and ANGPTL3 a TG/LDL lipid target therapy with multiple trials utilising RNA therapies planned or ongoing.
The case for lipid clinics
Managing dyslipidaemia can be difficult. Debunking social media conspiracy theories, managing patient side effects, choosing optimal lipid lowering agents, and negotiating the PBS and when to commence newer therapies such as the injectables (mAb PCSK9-I and siRNA Inclisiran) as well as future agents (e.g. Bempedoic acid, Lp(a) therapies) can be daunting.
Lipid clinics are well established, providing up titration of evidence-based goal directed therapies, genetic assessment, and patient access to research programs (e.g. for currently untreatable conditions such as elevated Lp(a)). They integrate dietary, exercise physiology, pharmacology and rehabilitation services.
Up to 50% of patients are not on statin therapy 12 months after admission for an MI, despite evidence they should be. The ‘why’ is not fully understood and requires more research. Lipid clinics can ensure patients continue therapies clearly demonstrated to reduce risk. This requires education, engagement, support and understanding patient circumstances.
Clinical trials are very important to get new therapies approved, with access facilitated through research units. Public hospital-based and private research groups have links with lipid clinics providing patient access. Clinitrials is currently recruiting to the Acclaim Lp(a) trial and has many patients in follow-up in the Ocean A study and participated in the now completed Clear Outcomes study of Bempedoic acid.
It is also correct that not all patients will benefit from lipid-lowering therapies and the use of imaging such as CTCA and Ca scores is providing more nuance in our assessment of risk. The AusCVD risk calculator now incorporates Ca score as a reclassification factor.
Lipid clinics can support patients and GPs to optimise lipid management, assessing risk to determine optimal pharmacotherapies, providing patients with reassurance that their condition is treatable, that genetic risk can be screened for and managed appropriately. They can ensure patients get the best management available in an increasingly subspecialised area.
Key messages
- CVD remains the number one killer in Australia
- Risk factor management is often suboptimal
- Lipid clinics can optimise treatment.
Author competing interests – the author is principal investigator on lipid and heart failure studies, and medical director of cardiology studies at Clinitrial