By Michael H. Crawford, MD, Editor
Synopsis: A comparison of inclisiran therapy to placebo and ezetimibe therapy over six months in primary prevention patients at low risk of atherosclerotic cardiovascular disease and not taking lipid-lowering therapy has shown that inclisiran subcutaneously every six months reduces low-density lipoprotein cholesterol more than ezetimibe and is comparable to the reported results of high-dose statins taken daily.
Source: Taub PR, Gutierrez A, Wewers D, et al. Safety and lipid-lowering efficacy of inclisiran monotherapy in patients without ASCVD: The VICTORION-Mono randomized clinical trial. J Am Coll Cardiol 2025; Apr 26. doi.org/10.1016/j.jacc.2025.04.049. [Online ahead of print].
Inclisiran, a small interfering ribonucleic acid (RNA) that blocks proprotein convertase subtilisin/kexin type 9 (PCSK9) given subcutaneously every six months after a second dose at three months, currently is U.S. Food and Drug Administration (FDA)-approved as an adjunct treatment with statin therapy for patients with primary hypercholesterolemia. The purpose of the VICTORION-Mono (V-Mono) trial is to evaluate the effectiveness of inclisiran as monotherapy in patients with a low risk of atherosclerotic cardiovascular disease (ASCVD) who do not meet guideline criteria for cholesterol-lowering therapy (pooled equation < 7.5% 10-year risk) and low-density lipoprotein (LDL) cholesterol of 100 mg/dL to 190 mg/dL.
V-Mono was a six-month, randomized, double-blind, placebo and active comparator, multicenter, international, Phase III study that compared LDL-lowering with inclisiran monotherapy to placebo and ezetimibe for 150 days and the safety of these therapies for 30 additional days. Excluded were patients with prior ASCVD, diabetes, familial hypercholesterolemia, triglycerides > 400 mg/dL, or any cholesterol-lowering therapy in the last 90 days.
Inclisiran sodium 300 mg or matching placebo were injected subcutaneously on days 1 and 90. The primary endpoint was the percentage change in LDL from baseline to day 150. Seven secondary endpoints included changes in PCSK9 serum levels and other lipoproteins. The safety and tolerability of inclisiran also was assessed. Between 2023 and 2024, 350 patients were randomized 2:1:1 to inclisiran (174 patients), ezetimibe (89 patients), and placebo (87 patients). The mean age of the participants was 46 years, 63% were women, 79% were white, 40% were Hispanic, 11% were Black, and mean LDL cholesterol was 135 mg/dL. Overall, ≥ 94% completed the study. There was only one adverse event noted, in the inclisiran group.
In the subjects treated with medication compared to placebo, the mean change in LDL was -51% for inclisiran, -11% for ezetimibe, and -1% for placebo. The percent change in LDL vs. placebo was -64% and -47% vs. ezetimibe. The mean change in PCSK9 levels was -75% vs. placebo and -73% vs. ezetimibe. The mean change in lipoprotein(a) was -25% vs. placebo and -24% vs. ezetimibe. There were no differences in subgroups by age, sex, and other characteristics.
Adverse events were observed in 31% of the subjects taking inclisiran vs. 29% of those taking placebo and 30% of those taking ezetimibe (P = NS). Only four patients stopped therapy, three taking inclisiran and one taking placebo. New diabetes was diagnosed in four patients taking inclisiran, of which three patients had prediabetes at entry. There was no new diabetes in the ezetimibe or placebo groups. Adverse hepatic events occurred in 1% of both the inclisiran and ezetimibe groups. The authors concluded that inclisiran was superior to ezetimibe and placebo for reducing LDL and was well-tolerated.
Commentary
These results in primary prevention patients replicate the LDL cholesterol-lowering effects and safety of prior inclisiran studies in patients with known ASCVD. For patients who would rather have an injection every six months than take a pill every day, this is a game-changer, especially for statin-resistant patients. Low-risk patients with high (but not dangerously high) LDL levels often are statin-hesitant because of the fear of muscle symptoms and the induction of new diabetes. Also, statin adherence has been reported to be about 50% and statin intolerance has been reported to be up to 29% in ASCVD patients. In addition, almost all patients had a robust response to inclisiran. By contrast, there was more variability in the response to ezetimibe. Finally, inclisiran has a favorable safety profile.
In comparison to the reported efficacy of anti-PCSK9 monoclonal antibody agents, which also are subcutaneously injected, inclisiran appears competitive. Compared to placebo, biweekly alirocumab reduced LDL by 48% and biweekly evolocumab reduced LDL by 57%, whereas in V-Mono, inclisiran reduced LDL by 64% vs. placebo. Also, inclisiran can be administered every six months after an initial three-month injection.
A major strength of V-Mono is the diverse patient population recruited. There are limitations to consider. The follow-up was short (180 days). There was no comparison to statins, bempedoic acid, or anti-PCSK9 monoclonal antibody agents. There was a low response rate to ezeimibe of -11% compared to other reports of about -20%. The authors speculated that this may be the result of noncompliance with ezetimibe, but these data were not collected. If this new indication for inclisiran is approved by the FDA, it may be attractive to a wide range of patients.
Michael H. Crawford, MD, is Professor Emeritus of Medicine and Consulting Cardiologist, UCSF Health, San Francisco.
A comparison of inclisiran therapy to placebo and ezetimibe therapy over six months in primary prevention patients at low risk of atherosclerotic cardiovascular disease and not taking lipid-lowering therapy has shown that inclisiran subcutaneously every six months reduces low-density lipoprotein cholesterol more than ezetimibe and is comparable to the reported results of high-dose statins taken daily.
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