ORIGINALLY PUBLISHED
04 June 2024
Dyslipidaemia, characterised as abnormally elevated levels of lipids and lipoproteins in the bloodstream, is a well-established contributor to cardiovascular (CV) disease.1 Elevated levels of a form of dyslipidaemia known as low-density lipoprotein cholesterol (LDL-C), often referred to as "bad cholesterol," significantly raises the risk of atherosclerotic CV events such as coronary artery disease, stroke, and heart failure.1-3 The global burden of dyslipidaemia is growing, contributing to approximately 4.4 million deaths annually worldwide.4
An Escalating Public Health Concern
Dyslipidaemia, or a dysregulation in the levels of circulating lipids in plasma, is one of the most modifiable risk factors for cardiovascular (CV) disease, yet this metabolic condition remains under-recognised and under-treated globally.4 Among the dyslipidaemia phenotypes, hypercholesterolaemia, which is characterised by high plasma levels of low-density lipoprotein cholesterol (LDL-C), stands out as the most prevalent.2 Over one-third of the world’s population is affected by elevated blood cholesterol,5 and the greater the lifetime exposure to high LDL-C levels, as seen with an ageing population, the greater the risk of adverse outcomes.6 Over recent decades, elevated LDL-C has become an increasingly prominent risk factor for mortality, jumping from 15th in 1990 to 11th in 2007 to 8th by 2019.7
Management of dyslipidaemia through lowering of LDL-C levels has proven effective in reducing the incidence of both initial (primary prevention) and recurrent (secondary prevention) CV events.3 Despite this progress, the continued prevalence of high LDL-C levels and the rise of comorbidities such as type 2 diabetes, hypertension, and obesity continues to pose serious CV risks.8
Today, one in three heart attacks or strokes can be directly attributed to high LDL-C7. Alarmingly, even among those people achieving target LDL-C levels, approximately 40% still experience major CV events, highlighting a significant residual risk that may not be fully addressed with current standard of care (SoC).8-10
The mainstay of cholesterol lowering: Inhibiting cholesterol synthesis with statins
Statin therapy, a class of lipid-lowering medicines which inhibit cholesterol biosynthesis in the liver, remain the recommended first-line therapy for LDL-C reduction and have become a cornerstone standard of clinical lipid management.11 These agents are typically well-tolerated, widely-used and effective, making them the mainstay of current SoC.12
However, despite the broad adoption of lipid-lowering therapies, only 20% of patients can reach their guideline-recommended LDL-C targets.13 Factors contributing to this shortfall include insufficient LDL-C response to statins, poor treatment adherence, and patient-specific limitations to single-agent therapy.8 High intensity statin therapy and maximal statin therapy represent the most aggressive approaches currently available, yet many patients still fail to achieve optimal LDL-C levels.13 Additionally, dyslipidaemia progresses silently, and rates of LDL-C testing and monitoring through routine blood tests are low.14
Despite strong cumulative evidence of the benefits of LDL-C lowering, many patients fail to reach their guideline recommended levels and remain at risk of further disease progression. Development of an easy-to-use novel therapy for hypercholesterolemia may help improve the gap between the current status of lipid treatment and what is possible through lower LDL-C levels in our patients.
Addressing complementary mechanisms: The potential of statins and PCSK9 inhibition
There are two well-understood and validated pathways in cholesterol metabolism that have been identified as targets for reducing LDL-C levels: intracellular cholesterol synthesis11,12 and LDL-receptor (LDL-R) degradation.15 Statins reduce intracellular LDL-C levels by inhibiting a key enzyme involved in cholesterol synthesis.12 While statins address one of the two modes of action involved in LDL-C regulation, their efficacy can vary,10 suggesting that statins alone may be insufficient to lower LDL-C levels to target levels in some patients.8
In addition to statin-targeted intracellular LDL-C synthesis, the process of LDL-R recycling and degradation by the protein, PCSK9 (proprotein convertase subtilisin/kexin type 9) is another well-validated mechanism that can be targeted to lower LDL-C levels.12,15,16
PCSK9 mechanism of action showing LDL receptor degradation and cholesterol metabolism in liver cells, illustrating how PCSK9 enhances LDL cholesterol clearance from blood vessels (Image: references 15,16)
PCSK9 is a protein that promotes the degradation of the LDL-C/LDL-R complex in the lysosome of hepatic cells, thereby reducing the liver's ability to remove LDL-C from the bloodstream.15 By inhibiting PCSK9, there is increased LDL-R availability at the cell surface, enabling enhanced LDL-C clearance.15,16 When used in combination with statins, which indirectly upregulate LDL-R expression, PCSK9 inhibitors offer a synergistic effect: suppressing cholesterol production while amplifying its clearance.8
Targeting Multiple Pathways
Statins work to reduce total LDL-C levels by inhibiting intracellular LDL-C synthesis, while inhibition of PCSK9 can reduce LDL-C levels by increasing LDL-C clearance.12,15,16 Statins also indirectly increase expression of LDL-R and PCSK9, further increasing the amount of LDL-R on cell surfaces and potential LDL-C clearance.12,17
A growing body of evidence shows that targeting these two potentially complementary pathways may lower LDL-C beyond what statins alone can achieve and can help reduce persistent residual risk.8
Statins are used by millions of people to help manage their LDL cholesterol, but many do not achieve control and remain at risk of serious cardiovascular events such as myocardial infarction, stroke or other life-threatening conditions. AstraZeneca is pioneering new ways to tackle disease, targeting underlying biology and optimising treatment through combination approaches that can prevent or slow disease progression more effectively. By embracing innovation and advances in science, we want to transform the future standard-of-care, enabling more patients to reliably achieve their LDL-C goals.
Future directions
Recent scientific advances suggest that optimising dyslipidaemia treatment will combine innovation and a shift towards optimising personalised, multi-modal strategies. These may include fixed-dose combinations, emerging oral PCSK9 inhibitors, siRNA-based therapies, and lipid-lowering agents targeting lipoprotein(a) and triglyceride-rich lipoproteins—all of which address diverse and complementary aspects of lipid metabolism.18-20
With the global burden of atherosclerotic CV disease on the rise, there's an urgent need to reevaluate what constitutes “optimal care.” Precision targeting of residual risk, especially in patients with coexisting cardiometabolic disorders, could redefine how clinicians approach prevention and risk reduction.
Over the past few decades, we have advanced our understanding and recognition of high LDL-cholesterol as a modifiable risk factor in cardiovascular disease. However, we need to continue innovating in this space to be able to improve outcomes in patients who are not meeting their LDL-cholesterol targets and who remain at risk of a major cardiovascular event.
At AstraZeneca, we are deepening our understanding of the interconnections between risk factors such as dyslipidaemia and CV diseases to help develop a new wave of solutions. We are pioneering novel ways to target well-known disease pathophysiology and taking a patient-centric approach to build upon the current SoC to address residual risk. Where current therapies have their limitations, we want to address these barriers and be able to meet the needs of patients who are not attaining guideline-directed LDL-C target levels and remain at risk of CV disease.
Topics:
