Strategies for lowering lipoprotein(a): a spotlight on novel pharmacological treatments

KEYWORDS:

• Lipoprotein(a)
• olpasiran
• pelacarsen
• SLN360
• cardiovascular disease

Lipoprotein (a) appears to play a causal role in the pathogenesis of cardiovascular disease (CVD) [1,2]. In a meta-analysis of 36 prospective studies in subjects without established CVD (n = 126,634), Lp(a) levels showed a continuous and independent association with coronary heart disease (CHD) and ischemic stroke during 1.3 million person-years of follow-up [3]. In a meta-analysis of 7 statin outcome trials (n = 29,069; 52% with established CVD), both baseline and on-statin Lp(a) levels showed a linear and independent association with cardiovascular events [4]. Genetic variants associated with increased levels of Lp(a) are also independently related to increased incidence of CHD [5,6].

Currently, no agents that specifically lower Lp(a) levels are commercially available [1,2]. Statins have no effect or might slightly increase Lp(a) levels [4]. Niacin lowers Lp(a) levels modestly (by approximately 20–25%) but had no effect on cardiovascular events in two large, randomized, controlled trials [7,8]. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors also lower Lp(a) levels by approximately 25% and this reduction was shown to contribute independently to the reduction in cardiovascular morbidity [9]. Mipomersen, an antisense oligonucleotide targeting apoB, lowers Lp(a) levels by 21–31% but is approved only by the FDA and only in patients with homozygous familial hypercholesterolemia [10]. Lp(a) apheresis substantially lowers Lp(a) levels (by > 60%) and is recommended in some European countries in patients with early-onset or progressive CVD [11]. Hormone replacement therapy also reduces Lp(a) levels by 25% in postmenopausal women [12]. Finally, several nutraceuticals, including flaxseed oil, phytosterols, l-carnitine and coenzyme Q10 were shown to lower Lp(a) levels [13–15].

Recently, several agents that specifically lower Lp(a) have been developed. In an early randomized, double-blind, placebo-controlled trial in healthy volunteers with Lp(a) levels ≥ 75 nmol/l, pelacarsen (formerly known as IONIS-APO(a)-L_Rx, AKCEA-APO(a)-L_Rx and TQJ230), an antisense oligonucleotide targeting apolipoprotein(a) that is conjugated with a triantennary N-acetylgalactosamine (GalNAc₃) moiety, a high-affinity ligand for the asialoglycoprotein receptor on the surface of hepatocytes, which increases its affinity to hepatocytes, administered as a single dose of 10–120 mg or as multiple doses of 10 mg, 20 mg, or 40 mg at day 1, 3, 5, 8, 15, and 22, reduced Lp(a) levels by 66–92% [16]. No adverse events were reported [10]. In a more recent randomized, double-blind, placebo-controlled, dose-ranging trial in 286 patients with established CVD and screening LP(a) levels ≥ 60 mg/dl (150 nmol/l), pelacarsen at a dose of 20, 40, or 60 mg every 4 weeks, 20 mg every 2 weeks, or 20 mg every week, induced dose-dependent reductions in Lp(a) levels (from 35 to 80%) at 6 months [17]. Notably, the 60 mg every 4 weeks regimen yielded the largest reduction in Lp(a) levels, which was comparable with the 20 mg every week regimen (72 and 80%, respectively) [17]. The reduction in Lp(a) levels appears to be independent of baseline Lp(a) levels, gene variants and isoform size [18]. The commonest adverse effect of pelacarsen was injection-site reaction whereas the rates of adverse effects on platelet count, liver and renal function did not differ from the placebo group [17]. The ongoing double-blind, placebo-controlled, randomized Lp(a)HORIZON trial (NCT04023552) is evaluating the effects of pelacarsen 80 mg every 4 weeks on cardiovascular events in 8,324 patients with Lp(a) levels ≥ 70 mg/dl and established CVD (history of myocardial infarction or ischemic stroke, or symptomatic peripheral arterial disease) [19]. The estimated study completion date is in May of 2025 [19].

Olpasiran (formerly AMG890) is a N-acetylgalactosamine-conjugated, small interfering RNA that inhibits apolipoprotein(a) messenger RNA translation in hepatocytes [20,21]. In phase 1 studies, a single 3, 9, 75, or 225 mg dose of olparisan reduced Lp(a) levels by 56–99% and was well-tolerated [20,21]. The effects of olpasiran on major CHD events (myocardial infarction, urgent coronary revascularization or death due to CHD) will be evaluated in the The Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction (OCEAN(a)) – Outcomes Trial, a randomized, double-blind, placebo-controlled study, that will enroll 6,000 patients with Lp(a) levels ≥ 200 nmol/l and established CHD (history of myocardial infarction or history of percutaneous coronary intervention with stenting and at least 1 additional risk factor) [22]. The estimated study completion date is in December of 2026 [22].

SLN360 is another small interfering RNA that inhibits apolipoprotein(a) messenger RNA translation in hepatocytes [23]. In a single ascending dose study in adults with Lp(a) plasma levels ≥150 nmol/L and without established CVD, SLN360 (30, 100, 300 and 600 mg) induced dose-dependent reductions in Lp(a) levels by 46–96%, which persisted for at least 150 days after administration, and was well-tolerated [23].

Despite the strong association between elevated Lp(a) levels and cardiovascular risk, several questions remain unanswered regarding the benefit of Lp(a) lowering with these novel agents. First, which degree of Lp(a) lowering is necessary for a reduction in cardiovascular events? Second, will all patients benefit from Lp(a) lowering, as is the case with statins, or only patients with Lp(a) levels above a yet unknown threshold? Third, will these novel treatments be cost-effective? The results of ongoing (Lp(a)HORIZON) and future trials will hopefully address these questions.

1. Expert opinion

Even though preclinical, epidemiological and genetic data strongly suggest that Lp(a) is a causal risk factor for atherosclerosis [1–6], it is still unknown whether lowering Lp(a) will translate into a reduction in cardiovascular events. Even if this is the case, a large absolute reduction in Lp(a) levels (by approximately 50–100 mg/dl) appears to be needed for a substantial reduction in cardiovascular morbidity. However, this means that only patients with very high baseline Lp(a) levels will benefit from a treatment that reduces Lp(a) levels. Therefore, these novel treatments might be beneficial not to all patients with established CVD, as is the case for agents that lower low-density lipoprotein cholesterol (LDL-C) levels, but only in a small, selected group of patients. This in turn casts doubt on the cost-effectiveness profile of agents that target Lp(a), since it might result in a higher cost that will limit its availability in low-income countries. Overall, the cost of these novel treatments is a major issue, given the high cost of other agents that are also used in patients with very high cardiovascular risk, particularly PCSK9 inhibitors. Even though both studies that will evaluate the effects of pelacarsen and olpasiran on cardiovascular events will be performed in patients with established CVD [19,22], it might be useful to assess the benefit of these agents in patients without established CVD but with major additional cardiovascular risk factors, e.g. with diabetes or in smokers. On the other hand, patients with established CVD and without elevated Lp(a) levels but with very high-risk characteristics, e.g. recurrent cardiovascular events, inability to reach LDL-C targets, and/or presence of comorbidities, particularly diabetes or smoking, might also benefit from Lp(a) lowering, but this should be evaluated in appropriately designed trials. In case ongoing trials fail to show a benefit from Lp(a) lowering, one of the main focuses should be to achieve low-density lipoprotein cholesterol (LDL-C) targets with the wider use of high-potency statins in combination with ezetimibe and, if needed, PCSK9 inhibitors [24]. Novel agents that reduce LDL-C levels, including bempedoic acid and, in selected patients, evinacumab, might also be useful [25,26]. To further reduce cardiovascular morbidity, refinement of risk stratification, potentially with the wider use of genetic or imaging markers, will also be essential. The other cornerstone of preventive strategies should be individualization of treatment, including more aggressive lipid-, glucose- or blood-pressure-lowering treatment, combined antithrombotic treatment using antiplatelet and low-dose anticoagulants, and/or the use anti-inflammatory agents in appropriately selected patients [24,27–30]. It is reasonable to expect that a paradigm shift from ‘one size fits all’ to more personalized strategies will be more effective and cost-saving.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.