The understanding of the causal association between elevated Lp(a) and atherosclerotic cardiovascular disease (ASCVD) risk continues to grow, and recommendations to test for elevated Lp(a) are now embedded into most international cardiovascular guidelines, with a number of guidelines recommending that everyone should be tested at least once in their lifetime.

The limbic spoke with cardiologist Professor David Hare about the current understanding of the role of Lp(a) in ASCVD risk and how elevated levels inform management decisions.

Lp(a): an inherited risk factor for CVD

Lp(a) is an LDL-like particle in which ApoB is covalently bound to a plasminogen-like molecule called apolipoprotein(a).^1,2 Plasma levels of Lp(a) are largely genetically determined and vary significantly among individuals² In each individual, levels remain generally stable throughout life and are not influenced by age, sex, fasting state, or lifestyle factors.³

It is estimated that around 20–30% of the global population have elevated Lp(a) in the atherothrombotic range, generally defined as a concentration greater than 0.3 to 0.5 g/L.¹ “The differing Lp(a) assays – and the units used – can be a bit confusing,” noted Professor Hare. “There are a number of Lp(a) isoforms, so the assays need to be isoform-independent,” he explained. “The measurements are generally expressed in molar units, such as nmol/L, or mass units, such as g/L,” he noted.

Patients with relatively early-onset coronary artery disease (CAD) are more likely to have elevated Lp(a) compared to the general population. “A consecutive series of CAD patients 70 years of age and below at the Austin Hospital in Melbourne showed that one in three had a very high serum Lp(a) level above 0.5g/L and one in six had extremely high levels above 1.0g/L,”² reported Professor Hare.

Epidemiological and genetic studies have shown Lp(a) to be an independent, causal risk factor for cardiovascular disease and calcific aortic valve disease.⁵ Outcomes studies investigating statins and PCSK9 inhibitors have also shown that when Lp(a) is elevated, cardiovascular event rates are higher at any achieved LDL-C level.¹

The impact of elevated Lp(a) on ASCVD risk occurs over time, and is thought to be mediated through mechanisms including atherogenesis, inflammation and thrombosis.⁴ “The structural homology of Lp(a) and plasminogen could potentially result in some impairment in thrombolysis, independent of the atherosclerotic effects,” explained Professor Hare.

In a recently published analysis⁴ the authors found that elevated Lp(a) and coronary artery score are independently associated with ASCVD risk, which they say suggests that elevated Lp(a) increases ASCVD risk independently of the subclinical coronary atherosclerosis burden captured by CAC score. “This is perhaps related to the unique pathways of inflammation and thrombosis that are triggered by elevated Lp(a) and oxidized phospholipid levels,” the authors suggest. “These findings highlight the potential limitation of CAC score for capturing the totality of ASCVD risk in asymptomatic individuals,” they say. Notably, the analysis found that individuals with an elevated Lp(a) but a CAC=0 remained at a low 10-year risk of ASCVD regardless of Lp(a) level, which the authors say supports the approach of using CAC scores as a decision-making aid, whereby those with very low or CAC scores of 0 can be ‘de-risked,’ even in the presence of an elevated Lp(a).“It is important to remember that in younger patients with heterozygous familial hypercholesterolaemia – and for which a genetic panel is now reimbursed in Australia – soft plaque can still be present in the absence of coronary calcification,” noted Professor Hare.

Testing recommendations

The accumulating evidence of its significance to cardiovascular risk has led to Lp(a) testing recommendations in international guidelines in an effort to identify patients who would benefit from further intensification of therapy.

The 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidaemia for the Prevention of Cardiovascular Disease in Adults³ also recommend measuring Lp(a) once in a person’s lifetime as a part of initial lipid screening. “The high prevalence of elevated Lp(a) level, the strength of the association with incident and recurrent ASCVD events, and the potential to improve CV risk stratification, strongly justify universal screening to identify very high levels,” the guidelines authors say.³

In the United States, the 2020 American Association of Clinical Endocrinologists/American College of Endocrinologist algorithm⁸ for management of dyslipidemia and prevention of CVD⁷ recommends that Lp(a) measurement should be considered in patients with a family history of premature ASCVD and/or increased Lp(a) and in all patients with premature or recurrent ASCVD despite LDL-C lowering.

Professor Hare explained that an Australian Atherosclerosis Society working group is currently working on a consensus paper on Lp(a). “My personal view is that everyone should be measured once in their lives, since Lp(a) is a major risk enhancer,” he said.

Once tested, what next?

While there is no treatment currently available to selectively lower serum Lp(a),⁵ guidelines recommend that individuals found to have elevated Lp(a) should receive earlier and more intensive management of other ASCVD risk factors, including high-intensity lipid lowering therapy, behaviour modification, and counselling.^3,6,7 Additionally, it’s recommended that patients with elevated Lp(a) are formally screened for familial hypercholesterolaemia (FH), since they commonly co-exist.²

On the future horizon are novel therapies to selectively lower elevated Lp(a), with a number now in early stages of clinical trials and showing promising results.⁵ “The most promising agents are small interfering RNA and oligonucleotide antisense therapies that alter the ability of hepatic cells to produce Lp(a),” said Professor Hare. “These can reduce the circulating Lp(a) levels by as much as 90%, with clinical outcome trials now well underway,” he said. “Then rather than just being a ‘risk-enhancer’, elevated Lp(a) levels will be an actual ‘target’ for intervention,” he explained. “We are going to find that Lp(a) is way more important than is currently recognised,” he said.

Disclosure

This article was sponsored by Novartis. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review Australian product information for all related products via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.

References

1. Tsimikas S et al. NHLBI Working Group Recommendations to reduce lipoprotein(a)-mediated risk of cardiovascular disease and aortic stenosis. J Am Coll Cardiol 2018;71: 177–192.
2. Oo HP et al. The prevalence of elevated lipoprotein(a) in patients presenting with coronary artery disease. Heart Lung Circ 2020;29: 1682–1687
3. Pearson GJ et al. Canadian Cardiovascular Society Guidelines for the management of dyslipidaemia for the prevention of cardiovascular disease in adults. Can J Cardiol 2021; 37:1129–1150.
4. Mehta A et al. Independent association of lipoprotein(a) and coronary artery calcification with atherosclerotic cardiovascular risk. J Am Coll Cardiol 2022;79:757–768.
5. Nicholls SJ The riskier lipid: what is on the HORIZON for lipoprotein (a) and should there be Lp(a) screening for all? Curr Cardiol Rep 2021;23:97
6. Mach F et al. 2019 ESC/EAS guidelines for the management of dyslipidaemia: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111–188.
7. Handelsman Y et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Management of Dyslipidaemia and Prevention of Cardiovascular Disease Algorithm – 2020. Endocr Pract 2020; 26:1196–1224.
8. Witzturn JL & Ginsberg HN. Lipoprotein (a): coming of age at last. J Lipid Res 2016;57:336–339.