Key Points:
- Most patients with atherosclerotic cardiovascular disease (ASCVD) do not achieve sufficiently reduced low-density lipoprotein cholesterol (LDL-C) levels despite maximum-tolerated lipid-lowering therapy (LLT) to improve cardiovascular outcomes.
- Twice-yearly inclisiran therapy added to maximum-tolerated statin therapy reduces LDL levels by an additional 50% compared to maximum-tolerated statin therapy alone.
- The investigators randomized 450 participants to either inclisiran 284 mg at day 0, day 90, and day 270 plus usual LLT versus usual LLT alone.
- The “inclisiran-first” strategy resulted in greater reductions in LDL and more patients reaching goal LDL reduction with minimal and comparable adverse effects.
Despite evidence that lowering LDL cholesterol promotes improved cardiovascular outcomes, studies demonstrate that up to 80% of patients with atherosclerotic cardiovascular disease (ASCVD) do not achieve goal LDL-C reduction. Factors thought to contribute to this failure in reduction include clinical inertia from providers, medication non-adherence, and side effects. Despite the safety and effectiveness of high-intensity statin therapy, which can reduce LDL-C by about 50% compared with no pharmacotherapy, real-world data demonstrates under-utilization during both initiation and up-titration of statin therapy. Current studies demonstrate that even among high-risk ASCVD patients, fewer than 50% are treated with guideline-directed statin therapy or remain on statins after the first year. Other non-statin lipid lowering therapies (LLTs), including ezetimibe, bempedoic acid, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, are often required among high-risk ASCVD patients, but unfortunately also show substantial under-utilization based on real-world data.
A first-in-class small interfering ribonucleic acid (siRNA), inclisiran inhibits hepatic PCSK9 production, thereby promoting LDL-C clearance. Previous studies (ORION-3, -8, -9, -10, and –11) have shown the safety and efficacy of adding inclisiran to background LLT twice yearly after initial doses at baseline and day 90. Given the ease of and effectiveness of inclisiran therapy, the investigators here present the VICTORION-INITIATE trial, evaluating an “inclisiran-first” strategy (adding inclisiran immediately upon failure to reduce LDL-C to < 70 mg/dL despite maximum tolerated statin theapy) versus usual care among patients with ASCVD in American clinical practice.
Study participants were adults with ASCVD history and LDL-C ≥70 or non-HDL-C ≥ 100 and fasting triglycerides < 500, on maximally tolerated statin therapy determined at the discretion of the investigator. Statin-intolerant patients were eligible if they had documented side effects on ≥ 2 different statins, including one at the lowest dose. Participants were randomized to either an “inclisiran-first” approach – inclisiran 284mg subcutaneously at baseline, day 90, and day 270 in addition to usual care – versus usual care alone. PCSK9-inhibitors were excluded from the inclisiran-first arm, but other LLT besides statins could be used. Co-primary endpoints were percentage change in LDL-C from baseline to day 330 and discontinuation of statin therapy (defined as no statin use >= 30 days before end of study visit). Secondary endpoints included treatment-emergent adverse effects.
In total, 450 patients were randomized to either inclisiran-first or usual care, with 243 patients receiving inclisiran. Both arms were well-balanced, with median age 67 years old, 31% female, 12% Black race, and 15% Hispanic or Latino ethnicity. Most patients (97%) had health insurance at baseline, 58% self-reported annual income ≤ $50,000, and 48% reported education beyond high school. Mean baseline LDL-C was 97.4 mg/dL (SD: 32.8), and 90% of patients took statins at baseline with 25% reporting history of statin intolerance.
At study completion (day 330), mean LDL-C was significantly more reduced with an inclisiran-first strategy versus usual care alone (–60.0% vs –7.0%, p<0.001). Among patients with no history of statin intolerance, statin discontinuation rates with inclisiran-first were non-inferior to those of usual care alone (-10.6% [97.5% CI: -18.3, -3.0%]), predefined at 15%. Regarding adverse events, more patients in the inclisiran-first arm experienced treatment-related treatment-emergent adverse events (TEAEs) predominantly due to injection-site reactions (14.5% vs 0.5%), and there were not significant differences in treatment-emergent serious adverse effects (11.5% in inclisiran-first, 13.4% in usual care).
Ultimately, VICTORION-INITIATE is the first prospective randomized study to investigate the efficacy and safety of earlier inclisiran therapy in lipid-lowering therapy for ASCVD patients not at goal LDL-C despite maximum-tolerated statin therapy. Earlier inclisiran demonstrated greater reduction in LDL-C compared to usual care alone with non-inferior rates of statin therapy discontinuation. Furthermore, inclisiran therapy demonstrated non-significant differences in treatment-emergent adverse effects, save for injection-site reactions. The usual care arm demonstrated lower rates of intensified LLT therapy and under-utilization of non-statin LLT, demonstrating the real-world barrier to optimal LLT for improved ASCVD outcomes. The study findings suggest the value of earlier inclisiran therapy for ASCVD treatment and secondary prevention, and suggest further studies are needed to investigate effects on major adverse cardiovascular outcomes.