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14-06-2024 | Dyslipidemia | Editor's Choice | News

Plozasiran reduces triglyeride levels in patients with mixed hyperlipidemia

Author: Cher Thornhill

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medwireNews: The hepatocyte-targeted apolipoprotein (APO)C3 small-interfering RNA plozasiran is a promising agent for the management of mixed hyperlipidemia, the MUIR trial suggests.

Christie Ballantyne, from the Baylor College of Medicine in Houston, Texas, USA, and colleagues assert: “A phase 3 trial of the effect of plozasiran on the risk of atherosclerotic cardiovascular disease is therefore warranted.”

Their 48-week, phase 2b, double-blind trial, reported in The New England Journal of Medicine, assessed the effect of subcutaneous plozasiran administered every 3 months at doses of 10 mg, 25 mg or 50 mg, or every 6 months at a dose of 50 mg, compared with placebo.

The study included 353 patients with mixed hyperlipidemia, defined as triglyceride levels of 150–499 mg/dL and either a low-density lipoprotein (LDL) cholesterol level of at least 70 mg/dL or a non-high-density-lipoprotein (non-HDL) cholesterol level of at least 100 mg/dL.

The mean baseline triglyceride levels were 253.2 mg/dL, 234.1 mg/dL, 250.3 mg/dL, and 248.0 mg/dL among patients taking plozasiran every 3 months at the 10 mg (n=67), 25 mg (n=67), or 50 mg (n=66) dose, and every 6 months at the 50 mg dose (n=66), respectively.

At 24 weeks, the reductions in triglyceride levels were significantly greater for the participants who were randomly assigned to receive plozasiran at any dose than those given placebo. By week 24, the least squares mean decrease in triglyceride levels was a significant 51.5% with plozasiran 10 mg, 57.7% with plozasiran 25 mg, and 64.1% and 45.9% with the 3-month and 6-month 50 mg doses, respectively. 

This compared with a least squares mean decrease of 1.7% for the 87 patients taking placebo, from a mean baseline value of 237 mg/dL.

Treatment benefit for patients taking plozaisran compared with placebo equated to 49.8 percentage points with the 10 mg dose, 56 percentage points with the 25 mg dose, 62.4 percentage points with 50 mg every 3 months, and 44.2 percentage points with 50 mg every 6 months.

The researchers note that the effect of plozasiran on triglyceride levels was “evident at 4 weeks after the initiation of treatment,” and by week 24 “the fasting triglyceride levels were below 150 mg per deciliter in most participants in the plozasiran groups.”

Reductions from baseline were also seen for APOC3, non-HDL cholesterol, and remnant cholesterol (total minus LDL and HDL cholesterol) and these changes were “commensurate” with those seen for triglyceride, say Ballentyne et al.

They point out that genetic modeling studies have suggested that “reductions in the remnant cholesterol level of 13 to 32 mg/dL could lead to 20% reductions in the incidence of recurrent major adverse cardiovascular events and that each 1-[standard deviation] reduction in the APOC3 level would be associated with a nearly 15% reduction in the lifetime risk of coronary artery disease,” highlighting that “[n]o currently approved pharmacologic treatments can consistently achieve this magnitude of reduction.”

Worsening glycemic control, measured according to factors such as glycated hemoglobin, new-onset diabetes, type 1 and 2 diabetes, hyperglycemia, and insulin resistance, occurred in 12%, 7%, and 20% of participants given plozasiran 10 mg, 25 mg, and 50 mg every 3 months, respectively, and in 21% of those given 50 mg every 6 months, as well as 10% of the placebo-treated controls.

The investigators observe that worsening of glycemic control has been described with other lipid-lowering treatments, such as statins, but is usually “manageable and offset by clinical benefit.”

In terms of the safety profile, “plozasiran generally performed similar to placebo,” say the authors. Serious adverse events occurred in 3–11% of patients given plozasiran and 6% of those given placebo, none of which were deemed to be related to the study drug.

Four deaths occurred – two in the 50 mg every 3 months dose group and one each in the 25 mg every 3 months and 50 mg every 6 months treatment groups.

Ballentyne and colleagues conclude: “This trial has helped in laying the groundwork for a more extensive outcomes trial, which would more rigorously test whether plozasiran reduces levels of non-HDL cholesterol and cholesterol remnants and the risk of atherosclerotic cardiovascular disease.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group

N Engl J Med 2024; doi:10.1056/NEJMoa2404143
61st ERA Congress; Stockholm, Sweden:  23–26 May 2024

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