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PCSK9 inhibitors may not be sufficient to curb atherosclerotic cardiovascular disease

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Journal of the American College of Cardiology
Reuters Health - 13/09/2021 - PCSK9 inhibitors may only partly address the portion of atherosclerotic cardiovascular disease risk mediated through the lipoprotein a Lp(a)/oxidized phospholipids (OxPLs) pathway, researchers say. They suggest that a targeted therapy such as pelacarsen may also be needed.

"Our study showed, in an analysis of two small randomized clinical trials of different PCSK9 inhibitors, that OxPLs on apoB-containing lipoproteins were unchanged, despite expected reductions in low-density lipoprotein cholesterol (LDL-C) and Lp(a)," Dr. Sotirios Tsimikas of the University of California San Diego told Reuters Health by email. "Our finding may explain prior findings of persistent vascular inflammation in patients treated with PCSK9 inhibitors."

"While secondary analyses of randomized clinical trials with PCSK9 inhibitors demonstrated risk reduction in patients with elevated Lp(a), likely due to a combination of LDL and Lp(a) lowering, persistently elevated levels of OxPLs in these patients may explain residual cardiovascular risk," he said.

As reported in the Journal of the American College of Cardiology, Dr. Tsimikas and colleagues measured OxPL-apoB and OxPL-apo(a) in patients enrolled in the ANITSCHKOW (https://bit.ly/3A8iVhP) and EQUATOR (https://bit.ly/3z29a3C) PCSK9 inhibitor studies. ANITSCHKOW assessed evolocumab 420 mg subcutaneous monthly and EQUATOR evaluated RG7652 400 mg subcutaneous monthly or 800 mg every two months.

The team's secondary analysis included 32 participants in the ANITSCHKOW study with LDL-C >100 mg/dL and Lp(a) >50 mg/dL at entry, and 78 participants in EQUATOR with baseline LDL-C 90 to 250 mg/dL but no entry criteria for Lp(a). Dose cohorts from EQUATOR were analyzed together because the cumulative doses were the same.

In EQUATOR, median Lp(a) was 37.2 mg/dL; OxPL-apoB, 10.8 nmol/L; and OxPL-apo(a), 33.4 nmol/L. The corresponding values in ANITSCHKOW were 221.0 nmol/L; 12.5 nmol/L; and 23.8 nmol/L.

PCSK9 inhibitors resulted in no significant difference in the mean percent change in OxPL-apoB in both trials compared with placebo; no significant difference in OxPL-apo(a) in ANITSCHKOW; and a small statistically significant difference in EQUATOR.

The authors conclude, "Lp(a)- and OxPL-mediated atherothrombotic and inflammatory risk may require more potent and specifically targeted therapies, such as pelacarsen or other drugs targeting Lp(a) or OxPLs."

Dr. Tsimikas said, "More studies in larger populations are needed before findings such as these change clinical practice. The HORIZON trial (https://bit.ly/2VzeP3y) will help answer the question of whether therapy that specifically and potently lowers Lp(a) and its associated oxidized phospholipids improves cardiovascular outcomes."

Dr. Richard Becker, Director, Physician-in-Chief at the UC College of Medicine's Heart, Lung and Vascular Institute in Cincinnati, commented on the study in an email to Reuters Health. "PCSK9 inhibitors have been shown to reduce LDL levels and reduce cardiovascular events in patients at risk for, and those with, cardiovascular disease. The benefit includes patients with modestly elevated LDL in whom there is an elevated level of Lp(a)."

"The benefit of PCSK9 inhibition is multifactorial and includes LDL lowering, inhibition of monocyte/macrophage migration and activation (major components of plaque formation and stability), and possibly upregulation of scavenger receptors," he said. "Other mechanisms of benefit are likely. A benefit is achieved without a direct effect on inflammation - potentially opening the door to add-on therapies or precision-based drug target selection."

"Because only 10% to 15% of adults have an elevated LP(a) (above 50 mg/dL), targeted treatments like the anti-sense drug pelacarsen would apply to this particular group of individuals," he noted. "By contrast, according to the Centers for Disease Control and Prevention, nearly 75 million adults in the United States have an elevated LDL cholesterol, representing 1 in 3 adults."

"Evidence for the benefit of LP(a) reduction must first be convincingly shown in large-scale clinical trials," he said. "In the future, there will likely be options to address the needs of individual patients with precision, according to a comprehensive lipid panel that includes LP(a), OxPL, LDL cholesterol and other important measures."

Dr. Tsimikas is a co-inventor of and has received royalties from patents owned by the University of California San Diego on oxidation-specific antibodies and of biomarkers related to oxidized lipoproteins; is a co-founder of and has an equity interest in Oxitope and its affiliates as well as in Kleanthi Diagnostics; and has a dual appointment at University of California San Diego and Ionis Pharmaceuticals.

SOURCE: https://bit.ly/3z3p9hH Journal of the American College of Cardiology, online September 13, 2021.

By Marilynn Larkin



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