Icosapent Ethyl Lowers CV Risk Across Lp(a) Range: REDUCE-IT

Icosapent ethyl (Vascepa; Amarin) remains effective at reducing cardiovascular events in patients with elevated triglycerides but relatively well-controlled LDL cholesterol on a statin irrespective of their baseline lipoprotein(a) concentration, according to a post hoc analysis of the REDUCE-IT trial.

The study, published online Monday in the Journal of the American College of Cardiology, also confirmed that MACE risk increases along with Lp(a) levels in this type of population.

The findings, taken together, indicate that “any potential benefit of Lp(a)-lowering from drugs currently being tested in clinical trials might be expected to be complementary to the CV risk reduction benefits of icosapent ethyl,” researchers led by Michael Szarek, PhD (CPC Clinical Research, Aurora, CO, and SUNY Downstate School of Public Health, Brooklyn, NY), report.

In discussing the clinical implications of the findings with TCTMD, Szarek—who will present the findings as a moderated poster at the upcoming American College of Cardiology 2024 Scientific Session—noted that there are no approved therapies specifically targeting Lp(a)-related risks, although there are several in the pipeline.

In that context, what these finding indicate “is that if you have a patient with pretty well-controlled LDL because they’re taking a statin or other therapeutics for that and they still have high triglycerides and they have elevated lipoprotein(a), then [icosapent ethyl] seems to be a particularly beneficial treatment for that.”

Interplay Between Lp(a) and Icosapent Ethyl

Numerous prior studies have established that elevated Lp(a) is a risk factor for cardiovascular events. Trials of statins and PCSK9 inhibitors have shown that lowering LDL cholesterol reduces CV risks among patients with high Lp(a) levels, but it remains unclear whether the effects of other therapies that lower CVD risk through mechanisms other than LDL cholesterol-lowering may be influenced by Lp(a).

Szarek and colleagues note that “the oxidized lipids associated with Lp(a) increase inflammation and are atherogenic” and that eicosapentaenoic acid (EPA)—contained in icosapent ethyl—“may  inhibit the oxidation of these lipoproteins.”

Thus, they say, “a treatment that increases EPA concentrations may provide a different path to reduce CV events in a setting where high Lp(a) is a significant contributor to risk.”

To explore some of these issues, the investigators performed a post hoc analysis of the REDUCE-IT trial, in which icosapent ethyl reduced cardiovascular events by a relative 25% in statin-treated patients with high triglyceride levels, relatively well-controlled LDL cholesterol, and either established cardiovascular disease or diabetes plus risk factors.

The current analysis included 7,026 participants (median age 64 years; 28% women) who had baseline Lp(a) measurements. The median concentration was 11.6 mg/dL, with 20.4% of patients having a value of 50 mg/dL or greater. Over the first year of follow-up, Lp(a) concentrations changed very little in both arms of the trial.

We should still in 2024 continue to lower risk as much as possible through other mechanisms in a patient that has high Lp(a). Michael Blaha

As seen in prior studies, baseline Lp(a) levels were positively related to risks of first and total MACE (CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina)—P < 0.0001 for both.

The beneficial effect of icosapent ethyl in terms of reducing first or total CV events was not significantly influenced by Lp(a) level on continuous basis (P > 0.10 for interactions). Similarly, treatment reduced first MACE in patients with Lp(a) levels below 50 mg/dL and in those with higher levels (P = 0.68 for interaction).

The researchers note that PCSK9 inhibitors have been shown to reduce CV risk in patients with high Lp(a) levels while slightly lowering levels of the biomarkers, whereas icosapent ethyl provided risk reduction while having only a minimal effect on Lp(a) concentrations.

“Although further research is needed to describe the mechanism, a preliminary report suggests that this effect could be related to the significant inhibition of Lp(a)-related oxidation by EPA, similar to its inhibition of small dense low-density lipoprotein oxidation. As it markedly increases EPA concentrations, this might explain the observed efficacy of icosapent ethyl in the higher range of Lp(a),” they write.

“At a minimum,” they add, “the present findings indicate that the efficacy of icosapent ethyl is maintained in settings in which Lp(a) concentrations are a significant determinant of risk.”

Eyeing Personalized Treatment

Commenting for TCTMD, Michael Blaha, MD (Johns Hopkins Ciccarone Center for the Prevention of Atherosclerotic Cardiovascular Disease, Baltimore, MD), who wrote an accompanying editorial with Harpreet Bhatia, MD (University of California, San Diego), said that elevated Lp(a) is a common problem that physicians struggle to treat due to the lack of targeted therapies.

Regarding the finding that icosapent ethyl has beneficial effects that are independent of Lp(a), Blaha said: “In this climate where you don’t have any specific treatments, even that’s worth knowing.”

This places icosapent ethyl into a group with other therapies that have been shown to reduce CV risks without interacting with Lp(a), including statins and antihypertensives, he added. “They’re all options to lower risk in a patient with high Lp(a). They just probably don’t target the risk inherent to high Lp(a),” he said. “That’s where we are clinically right now—find a patient that’s high risk perhaps because of their high Lp(a) and then treat all the other things that you can to lower that patient’s risk, even though we can’t really offer Lp(a)-specific therapies.”

Lp(a)-specific therapies may be coming, with promising results already seen with agents like pelacarsen (Novartis), an antisense oligonucleotide, and olpasiran (Amgen), a small-interfering RNA (siRNA) molecule. Pelacarsen is currently being evaluated in the phase III Lp(a)HORIZON trial, which is expected to be completed in 2025.

The “Holy Grail” for reducing a patient’s cardiovascular risks in the future, Blaha said, will be treatment that involves delivery of therapies that target the factors specifically driving the risk—using a statin to lower LDL cholesterol and then providing an Lp(a)-lowering agent to address residual risk if levels are high, for instance.

If Lp(a)HORIZON shows that lower Lp(a) works, “that would be a step in the right direction towards personalizing our decisions,” Blaha said.

But in the meantime, he said, “we should still in 2024 continue to lower risk as much as possible through other mechanisms in a patient that has high Lp(a).”