Abstract
Background
Clinical trial results suggest inclisiran lowers low-density lipoprotein-cholesterol (LDL-C), but long-term real-world data in Japanese coronary artery disease (CAD) patients are limited.
Methods and Results
We retrospectively studied 40 CAD patients treated with inclisiran and followed for 12 months, assessing LDL-C levels at baseline and every 3 months; endpoints were within-patient LDL-C change, MACE (exploratory), and safety. Mean LDL-C fell by 59%, 56%, and 57% at 3, 6, and 12 months, respectively (all P<0.05). Adverse reactions comprised 1 case of MACE and 1 of injection-site reaction over the 12 months.
Conclusions
In this single-center cohort, inclisiran was associated with sustained LDL-C reductions and acceptable tolerability over 1 year.
Key Words: Coronary artery disease, Inclisiran, Lipid lowering, PCSK9 inhibitors
Central Figure.
Coronary artery disease (CAD) is a leading cause of morbidity and mortality. Low-density lipoprotein cholesterol (LDL-C) is a key modifiable risk factor and its reduction is central to CAD management. Inclisiran offers sustained LDL-C reduction with biannual dosing after initial and 3-month doses. Although large-scale clinical trials, such as the ORION series, have demonstrated its efficacy, real-world data over an extended period for patients with CAD are still unknown.1 This study aimed to evaluate the 1-year efficacy and tolerability of inclisiran in Japanese patients with CAD.
Methods
Study Design and Population
A retrospective single-center study was conducted in 40 patients with CAD who received inclisiran. The inclusion criteria were a diagnosis of CAD and an LDL-C level >70 mg/dL despite maximally tolerated statin therapy. The exclusion criteria were severe liver disease, dialysis, and active cancer.
Treatment and Follow-up
The patients received inclisiran at baseline, 3 months, and 9 months. Lipid profiles were assessed at baseline and 3, 6, 9, and 12 months. Safety was monitored on the basis of adverse events and clinical assessments.
Primary Outcomes
• Percent change in LDL-C levels from baseline to 12 months.
• Incidence of major adverse cardiovascular events (MACE: myocardial infarction, stroke, hospitalization for heart failure, and cardiovascular death).
Secondary Outcomes
• Safety and tolerability, including adverse event profiles.
• Elevated liver enzymes (AST/ALT) and creatine phosphokinase (CPK).
Statistical Analysis
Statistical analyses were performed using STATA software, version 16.
Results
Inclisiran led to significant LDL-C reduction at 3 months (59%, P<0.05), which was sustained at 6, 9, and 12 months (56%, 58%, and 57%, respectively; P<0.05). Furthermore, inclisiran decreased lipoprotein(a) (Lp(a)) which is a LDL-like particle with an additional apolipoprotein(a) moiety covalently attached to apolipoprotein B-100.2 ApoB, including LDL, very-low-density lipoprotein, intermediate-density lipoprotein, and Lp(a),3 also significantly decreased 1-year after administration of inclisiran. Moreover, inclisiran significantly reduced the total cholesterol and ApoB levels compared to baseline, but not triglycerides (TG), ApoB or ApoAI (Table). During the observation period, MACE occurred in 1/40 (2.5%) of patients (sudden death). Two patients developed injection-site redness that resolved within a few days without intervention. The 7 patients who switched from evolocumab to inclisiran had no apparent events during the observation period. The percentage achievement of LDL-C <70 mg/dL was 85% (34/40) and LDL-C <55 mg/dL was 78% (31/40).
Table.
Effects of Inclisiran Over 12 Months
| Laboratory data | Baseline | 12 months | P value |
|---|---|---|---|
| TC (mg/dL) | 171.1±36.1 | 131.3±39.8 | <0.05 |
| HDL-C (mg/dL) | 56.1±11.5 | 57.7±11.9 | 0.51 |
| LDL-C (mg/dL) | 109.8±21.1 | 47.2±19.4 | <0.05 |
| TG (mg/dL) | 105.7±29.2 | 95.1±28 | 0.32 |
| HbA1c (%) | 6.5±0.9 | 6.3±0.8 | 0.67 |
| Lipoprotein(a) (mg/dL) | 30.8±13.2 | 19.1±12.4 | <0.05 |
| Alb (g/dL) | 3.6±0.6 | 3.5±0.7 | 0.47 |
| ApoAI (mg/dL) | 132.6±31.8 | 135.2±29.2 | 0.28 |
| ApoB (mg/dL) | 106.3±28.7 | 67.7±23.7 | <0.05 |
| Hb (g/dL) | 11.9±1.6 | 11.8±1.8 | 0.74 |
| AST (U/L) | 28.1±11.8 | 27.4±12.1 | 0.42 |
| ALT (U/L) | 26.6±13.2 | 27.1±13 | 0.32 |
| CPK (U/L) | 167.3±59.5 | 178.1±61.3 | 0.19 |
Data are mean±SD. Alb, albumin; Apo, apolipoprotein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; Hb, hemoglobin; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; TC, total cholesterol; TG, triglycerides.
Discussion
The results of this study showed a durable and significant reduction in LDL-C levels over 12 months in Japanese patients with CAD administered inclisiran. A key advantage of inclisiran is its biannual dosing regimen, which may improve adherence compared with daily oral statins and PCSK9 monoclonal antibodies, which require more frequent administration.4 In this study, the percentage achievement of LDL-C <70 mg/dL was 85% and LDL-C <55 mg/dL was 78%, which are acceptable results compared to FOURIER and ODYSSEY (percentage achievement of LDL-C <70 mg/dL was 87% and 79%, respectively).5 One patient died suddenly at 3 months after the second dose of inclisiran, but the event was deemed unrelated to treatment. All other adverse events were non-serious and did not result in discontinuation. However, the study was limited by its small sample size; confirmation in larger, randomized, adequately powered trials is warranted.
Conclusions
Inclisiran achieved a sustained reduction in LDL-C with a favorable safety outcome in patients with CAD. Our findings suggest that inclisiran can be effectively incorporated into lipid-lowering therapies for high cardiovascular-risk populations, but further studies are warranted to confirm its long-term cardiovascular benefits.
Conflicts of Interest
The authors state that there are no conflicts of interest to disclosure.
IRB Information
This study was approved by the Institutional Review Board of Kita-Harima Medical Center (20180822-2). All procedures were conducted in accordance with the ethical standards of the responsible committee on human experimentation and the 1975 Declaration of Helsinki.
Author Contributions
S.T. designed the study. S.Y. and A.Y. take responsibility for the integrity of the data and accuracy of the data analysis. S.T. wrote the manuscript and analyzed the data.
Funding Statement
Funding: None.
References
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