I am an endocrinologist who specializes in lipids at Reims University Hospital, France, where I am the local expert in the field of dyslipidemia. This means that I frequently work with cardiologists who treat patients with MI, and it was in this context that I met Mr. Stéphane Favereaux. I am also a member of the Nouvelle Société Francophone d’Athérosclérose (NSFA), which brings together all the lipid specialists in France.

Dyslipidemias are diseases linked to elevated lipoproteins, some of them being genetically transmitted. Lp(a) has been described in the literature since the 1960s and was initially mentioned by the Norwegian Kare Berg in 1963 [1]. My interest in Lp(a) dates back to the 1990s, when Lp(a) was the subject of numerous studies. For about 10 years, we conducted research into this lipoprotein with Dr Eduardo Anglés-Cano, a thrombosis specialist who was working on Lp(a) in patients with coronary artery disease or diabetes. Because no treatment was able to lower it effectively, the scientific community seemed to lose interest in Lp(a) for around 20 years. Interest has been renewed over the last 5 years, thanks to new research and the prospect of new therapies that could significantly reduce the circulating concentration of Lp(a).

Lp(a) is the combination of an LDL-like particle and apoprotein(a) [apo(a)], which is composed of repeating structures called kringles (pretzel-shaped helical structures), similar to plasminogen. The molecular weight of apo(a) varies from 250 to 800 kDa, depending on the number of kringle domains and the extent of glycosylation [2], explaining 70–90% of the variability in Lp(a) levels between individuals [3, 4]. There is considerable genetic heterozygosity (> 95%), with most people carrying two differently sized apo(a) alleles [2]. The low-molecular-weight isoforms of apo(a) are associated with high Lp(a) levels (median of ~100 nmol/L or 0.40 g/L), whereas the high molecular weight forms are associated with lower levels (median ~25 nmol/L or 0.10 g/L) (Fig. 1) [2]. As apo(a) shares a high degree of structural homology with plasminogen, Lp(a) may interfere with fibrinolysis processes (Fig. 2) [2, 5,6,7]. Lp(a) has been associated with increased risk for atherosclerosis, thrombosis, and aortic valve calcification. Numerous longitudinal, and prospective clinical studies in primary and secondary prevention have demonstrated a link between elevated Lp(a) levels and the development of atherosclerotic CVD, particularly MI and ischemic stroke, in young patients and, more recently, aortic valve stenosis [8,9,10,11,12,13,14,15,16]. The relationship between the Lp(a) levels and the risk for major cardiovascular events is linear, meaning that the higher the Lp(a) level, the greater the cardiovascular risk [17, 18]. In clinical practice, the threshold of 125 nmol/L (0.50 g/L) is considered to translate to a clinically significant increase in cardiovascular risk [2, 17, 19].

Lipoprotein(a) [Lp(a)]: mechanistic insights. Pathophysiological pathways providing a causal link between high plasma concentrations of Lp(a) and atherosclerotic vascular disease and aortic stenosis. Clinical outcomes are related to atherosclerotic stenosis complicated by thrombosis (myocardial infarction, stroke), peripheral artery disease (PAD), or aortic valve replacement (AVR) caused by valve calcification and aortic stenosis [2]. Apo(a) apolipoprotein(a); LDL low-density lipoprotein; OxPL oxidized phospholipids. Used with permission of Elsevier, from Durlach V, et al. Lipoprotein(a): Pathophysiology, measurement, indication and treatment in cardiovascular disease. A consensus statement from the Nouvelle Société Francophone d’Athérosclérose (NSFA). Arch Cardiovasc Dis. 114, 2021. Permission conveyed through Copyright Clearance Center, Inc.

Contribution of apolipoprotein(a) [apo(a)] polymorphism to inhibition of fibrinolysis, a mechanism that may favor thrombus development. Lipoprotein(a) [Lp(a)] competes with plasminogen for binding to fibrin and cell plasminogen receptors. Inhibition of plasminogen binding and activation impairs fibrinolysis/pericellular proteolysis, and is related to high Lp(a) concentrations and small apo(a) isoforms (< 22 kringles [K]; 17 K in the figure), but not to large apo(a) isoforms (30 K in the figure) [2]. t-PA tissue plasminogen activator. Used with permission of Elsevier, from Durlach V, et al. Lipoprotein(a): Pathophysiology, measurement, indication and treatment in cardiovascular disease. A consensus statement from the Nouvelle Société Francophone d’Athérosclérose (NSFA). Arch Cardiovasc Dis. 114, 2021. Permission conveyed through Copyright Clearance Center, Inc.

A significant number of people have high or very high levels of Lp(a). It is estimated that 20% of the European population has Lp(a) levels above 125 nmol/L (0.50 g/L) [20]. In France, this means about 10 million people. Between 13% and 35% of patients with CVD have Lp(a) levels above 125 nmol/L (0.50 g/L) [18, 21,22,23]. Lp(a) levels are predominantly determined by genetics, which means that the risk associated with this factor is largely unmodifiable. Lifestyle factors, such as diet and physical activity, have minimal or no influence on Lp(a) levels [17]. Mr. S. Favereaux is a perfect example of this: even though he led an exemplary lifestyle, he experienced his first MI before he was 40 years of age. Lp(a) levels vary with ethnicity, with Black individuals and South Asian populations having higher median Lp(a) levels than white or East Asian populations [18, 24].

To determine which patients should be screened for Lp(a), we follow the 2019 European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guidelines [25]. Mr. S. Favereaux had almost all of the criteria set out in the recommendations: a family history of CVD (his grandmother had undergone limb amputation due to peripheral arteriopathy); a premature cardiovascular event (he had an MI before the age of 40 years); and recurrent CVD despite optimal treatment (he had three stents placed and received standard post-MI treatment with the combination of a statin, beta-blocker, ACE inhibitor, and aspirin, but subsequently required a further two stents). These were all indications that an additional risk factor was at play. At around 330 nmol/L (1.50 g/L), Mr. S. Favereaux’s Lp(a) levels are considered to be very high [2, 26]. Mr. S. Favereaux’s diagnosis led to a recommendation for familial cascade screening, involving his children, sister, nephew, and niece, as recommended in the ESC/EAS consensus statement for familial hypercholesterolemia (FH) [25].

According to the ESC/EAS guidelines, Lp(a) assessment should be considered at least once in a lifetime to identify very high inherited Lp(a) levels [25]. Currently, French and European populations are insufficiently tested for Lp(a); less than 0.5% of the general population are tested and less than 5% of patients with CVD [23, 26]. Two reasons may explain this low testing rate. The first is simply the cost of testing. Even though it is a simple blood test, Lp(a) testing is not reimbursed in most European countries, including France. Second, there is a clear lack of knowledge about Lp(a) among practitioners, although this seems to be changing with new treatments on the horizon and changes in the recommendations in the last 5 years [2, 17, 25]. I am convinced that detecting an increase in Lp(a) as early as possible is the best thing to do: we have the resources to reassure families, and the screening consists of a simple blood test.

Ongoing debate surrounds the standardization of the Lp(a) assay because of inherent challenges including the lack of a definitive reference method, and the reporting of Lp(a) values as molar (nanomoles per liter [nmol/L]) or mass concentrations (grams per liter [g/L]) by different assays [27].

If Lp(a) testing reveals an elevated level, the first step is to explain the importance of this cardiovascular risk factor to the patient without causing them excessive concern. Of course, the same applies for other risk factors, such as hypertension, type 2 diabetes, or smoking. I give my patients with moderate to very high Lp(a) levels information on Lp(a) from the French patient association, Association Nationale des Hypercholestérolémies familiales et Lipoprotéines (a) (ANHET). Since its creation, I have been one of the scientific advisers of the association and I am very involved in many of their projects. The patient association plays an extremely important role as the interface between patients, doctors, and scientists, allowing us to learn from one another and move forward hand in hand. I also invite my patients to contact ANHET directly and follow the webinars that are regularly held with learned societies or other associations. These are excellent sources of accessible information. I know that Mr. S. Favereaux was able to attend some of them.

Secondly, it is important to explain to patients that risk factors are multiplicative, so other risk factors will have to be strictly managed to prevent the occurrence of an early cardiovascular event. Management of LDL-C, blood pressure, glucose, and lifestyle factors is recommended [17]. As Mr. S. Favereaux had an excellent lifestyle—he was a slim, physically active, non-smoker—I did not give him any specific recommendations on this point. My only advice was yoga to reduce his stress levels, because he has a stressful job as a prison guard.

The third message for patients is that, while there are currently few therapeutic options for reducing Lp(a), we are going to offer them all that can be done based on the current state of knowledge and treatments. Treatments should be optimized, e.g., lipid-lowering treatments should be intensified in patients with Lp(a) > 250 nmol/L (1.10 g/L) [2]. At the time of discovering Mr. S. Favereaux’s elevated Lp(a), he was already taking the maximum tolerated doses of secondary preventive therapies. Despite his pharmacologic treatment and interventional procedures, his coronary artery disease was always one step ahead of us. For this reason, I offered him two choices: enter a 5-year clinical trial of a drug designed to reduce Lp(a) levels, with a 50/50 chance of receiving the drug because the study was placebo-controlled; or undergo lipoprotein apheresis. This was not an easy decision, and while he was considering these options, he suffered a third coronary event, requiring emergency quadruple bypass surgery. It was a clear demonstration of the aggressiveness of his disease.

This did not prevent the start of lipoprotein apheresis, his chosen option, which has now been underway for almost 1 year. Lipoprotein apheresis remains an exceptional solution for purifying the blood of Lp(a) in patients with very high Lp(a) levels that are not sufficiently reduced by conventional treatments. With reductions of 60–75% after a single session, lipoprotein apheresis is an effective method for lowering Lp(a) levels [28]. However, this solution is expensive (€1400 per session, reimbursed by the health insurance system in France) and time-consuming for the patient, with a 2-h session every 2 weeks. In France, fewer than 150 people receive LDL or lipoprotein apheresis.

Novel treatments for elevated Lp(a) levels are based on modern techniques, such as antisense oligonucleotides (ASO) and small interfering RNAs (siRNAs), which target apo(a) production in the liver [29,30,31,32]. On the basis of a single injection per month, or even every 3 months, these molecules can reduce Lp(a) levels by 80–90% [29,30,31,32]. We are impatiently awaiting the results of the first international phase 3 study with an ASO, the HORIZON study of pelacarsen [33], which will be published in 2026. The HORIZON study (NCT04023552) is being conducted in patients with CVD and Lp(a) levels ≥ 150 nmol/L (0.7 g/L) [33]. If the results show a reduction in cardiovascular events associated with the targeted reduction in Lp(a) levels achieved with pelacarsen, we will have a new treatment option to propose to our patients between 2026 and 2030. For Mr. S. Favereaux, this would mean stopping lipoprotein apheresis, and no longer having to suffer the constraints associated with this procedure. By controlling this risk factor, we might be able to slow the natural history of coronary artery disease and reduce the severity of future cardiovascular events. In the slightly more distant future, we could also imagine these new treatments being offered as primary prevention to Mr. S. Favereaux’s children to prevent them from developing CVD. Other ongoing phase 3 studies of novel Lp(a)-lowering treatments include the OCEAN(a) and ACCLAIM-Lp(a) studies (NCT05581303 and NCT06292013) of the siRNAs olpasiran and lepodisiran, respectively, in patients with atherosclerotic CVD and elevated Lp(a) levels [34, 35]. Additionally, the ongoing BROADWAY and BROOKLYN studies (NCT05142722 and NCT05425745) are evaluating the selective cholesteryl ester transfer protein inhibitor obicetrapib in patients with atherosclerotic CVD and/or heterozygous FH with elevated LDL-C [36]. Recently completed phase 2 studies with the oral inhibitor of Lp(a) formation muvalaplin [37] and the siRNA zerlasiran [29] have demonstrated good tolerability and persistent reductions in Lp(a) levels of over 80% after 12 and 48 weeks of treatment, respectively. All these advances are very promising for our patients.

Beyond the recommendations of learned societies published over the last 5 years, it is also up to us, medical specialists and scientists, to raise awareness of Lp(a) so that all our colleagues—endocrinologists, cardiologists, and general practitioners—become aware of the importance of this risk factor. Physicians need to know that elevated levels of Lp(a) are common and have a real impact on people’s health.