Estimation of the major cardiovascular events prevention with Inclisiran

Background and aims: The ORION 10-11 trials have reported the efficacy of Inclisiran on low-density lipoprotein cholesterol (LDLc) reduction, and also suggested prevention of major cardiovascular events (MACE) incidence. Methods: We have performed a meta-analysis of the available studies, involving PCSK9 inhibitors or Inclisiran for >6 months, that reported the incidence of MACE. The primary endpoint was MACE incidence, as reported in outcomes-based randomized clinical trials (OB-RCT) and non OB-RCT. Analyses were performed using fixed effect models and fractional polynomial regression. Results: The meta-analysis included a total of 57,431 patients, 1592 treated with Inclisiran and 28,259 with PSCK9 inhibitors (17,244 with evolocumab and 11,015 with alirocumab). Baseline mean LDLc was 104.1 (12.9) mg globally. On-treatment mean LDLc was 40.1 (7.8) mg/dl and mean absolute LDLc reduction was 60.6 (10.3) mg/dl. A total of 5389 MACE were reported, 2482 in patients receiving the study drug and 2907 in patients assigned to placebo. Treatment was associated with OB-RCT and no heterogeneity was observed. The estimation of MACE reduction associated with LDLc reduction, adjusted by age, diabetes, hypertension and baseline LDLc, provided a linear trend in the risk of MACE and LDLc reduction that was linear and all studies fitted properly. Conclusions: The results of the ORION 10-11 trials are in concordance with results of trials involving treatment with PCSK9 inhibitors. The results of the ORION-4 trial will provide definite evidence on the effects of Inclisiran on MACE reduction.