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Baseline lipoprotein a, or Lp(a), levels are strongly associated with major adverse cardiovascular events (MACE) in high-risk patients with elevated triglyceride levels receiving statin therapy, a new analysis suggested.

The report, a post hoc analysis of data from the REDUCE-IT trial, also showed icosapent ethyl (IPE; Vascepa, Amarin), a refined version of omega-3 fatty acid eicosapentaenoic acid (EPA), was associated with a reduction in this risk across a range of Lp(a) levels.

"The benefit of IPE is invariant to Lp(a) concentrations," lead study author Michael Szarek, PhD, research professor, Department of Cardiology, University of Colorado, Aurora, told theheart.org | Medscape Cardiology.

"If you're doing all the right things to lower your LDL [low-density lipoprotein] and other lipid parameters, including taking statins, but you still have high triglycerides and high residual risk due to high Lp(a), then IPE is a treatment that should be considered."

The findings were published online on March 25, 2024, in the Journal of the American College of Cardiology. They will also be presented at the upcoming annual American College of Cardiology (ACC) Scientific Session 2024, April 6-8.

The multicenter REDUCE-IT compared IPE with placebo in those with cardiovascular disease (CVD) or diabetes and other cardiovascular risk factors, as well as elevated triglycerides despite statin therapy.

The primary results showed IPE was associated with reduced MACE vs placebo. Although several mechanisms could be involved, "blunting" of Lp(a)-related oxidation likely plays some role, said Szarek.

Clinical trials testing a statin or proprotein convertase subtilisin/kexin type 9 inhibitor have shown Lp(a) is related to cardiovascular events, but the key criterion for inclusion in those studies was elevated LDL cholesterol, said Szarek. "The unique thing about REDUCE-IT is that at baseline, subjects had pretty well-controlled LDL but had to have elevated triglycerides."

This new analysis included 7026 patients from REDUCE-IT, mean age about 64 years, who had baseline Lp(a) assessments. The median baseline concentration was 11.6 mg/dL.

Szarek and colleagues wanted to know if the relationship between baseline Lp(a) concentrations and MACE held up in this "relatively unique patient population" and whether the treatment benefit of IPE was consistent across Lp(a) concentrations.

Participants were followed for a median of 4.9 years. The outcome of first and total MACE included death from CV disease, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization, and unstable angina.

The data showed significant relationships with first and total MACE (P < .0001). "The study shows your risk for MACE goes up and up and up as your baseline Lp(a) goes up," said Szarek. "So, this is establishing the fact that regardless of treatment assignment, baseline Lp(a) is prognostic for MACE."

Dispelling Threshold Effect

Researchers looked at subgroups of people with concentrations of 50 mg/dL and over and those with less than 50 mg/dL. As Szarek explained, 50 mg/dL has been considered to have something of a threshold effect.

The study showed the treatment effect of IPE is consistent across different Lp(a) concentrations. "Whether your baseline Lp(a) is low or high, the treatment has a benefit in terms of MACE," said Szarek.

This helps dispel the notion of a threshold level, he added. "It's probably not a threshold but a continuous relationship. I think people are moving away from the idea there's a threshold, and this is just another piece of the puzzle so to speak."

The bottom line, though, is that clinicians want to get Lp(a) levels as low as possible and several targeted drugs are being developed to do that, said Szarek.

In an accompanying editorial, Michael J. Blaha, MD, Johns Hopkins Ciccarone Center for the Prevention of Atherosclerotic Cardiovascular Disease, Baltimore, and Harpreet S. Bhatia, MD, Division of Cardiovascular Medicine, University of California San Diego, said this research "adds to a growing body of literature" showing "Lp(a) is closely associated with risk and should lead to further scrutiny of the arbitrary 50 mg/dL threshold."

They noted that while reduced CV risk associated with IPE is consistent across Lp(a) levels, the absolute event rates remained relatively high in those with Lp(a) ≥ 50 mg/dL compared with those with Lp(a) < 50 mg/dL.

This, they wrote, speaks to "continued residual risk and the need for further therapies that specifically target the inherent risk of Lp(a)."

The analysis "represents a nonrandom subset of the overall study population" as it included only 86% of REDUCE-IT participants, although those included and excluded were apparently similar, said the editorial writers.

They also pointed out Lp(a) levels in study participants were not significantly affected by either the treatment or placebo, and the association of Lp(a) with outcomes was not affected by EPA levels.

The study was supported by Amarin. Szarek served as a consultant for and/or has received research support from CiVi, Resverlogix, Lexicon, Baxter, Esperion, Amarin, NewAmsterdam, Silence, Sanofi, and Regeneron Pharmaceuticals. Blaha served on advisory boards for Novartis, Novo Nordisk, Bayer, Roche, Merck, Amgen, AstraZeneca, Agepha, Vectura, Boehringer Ingelheim, and Eli Lilly and has received grants from Amgen, Novo Nordisk, and Bayer. Bhatia received consulting fees from Kaneka Medical and Novartis Pharmaceuticals.