Abstract Body: Introduction: Inclisiran is a novel drug that employs ribonucleic acid (RNA) interference to lower the levels of the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein. It has demonstrated a significant reduction in LDL cholesterol levels compared to placebo. We aim to comprehensively evaluate the safety of using inclisiran in patients with dyslipidemia and ASCVD or ASCVD risk equivalent.

Methods: Four electronic databases of Pubmed/MEDLINE, Web of Science, Embase and ClinicalTrials.gov were searched from inception to May 5th, 2024, to identify relevant randomized controlled trials (RCTs) comparing safety profiles of inclisiran and the control group. The outcomes investigated were all-cause mortality, major adverse cardiovascular events (MACE), injection site adverse events, new onset or worsening type 2 diabetes mellitus (T2DM), and nasopharyngitis. The effect estimates of outcomes were assessed using risk ratio (RR) with a 95% confidence interval (CI). Random-effects meta-analysis was conducted using the restricted maximum likelihood method. Subgroup analysis was performed based on different dosing regimens.

Results: The study included 7 RCTs enrolling 4790 patients (age 63.8 ± 9.7 years, 33.2 % females) who received inclisiran. Compared to the control group, inclisiran use did not yield a significant effect on all-cause mortality (RR, 0.92; 95% CI, 0.54 to 1.54; I² = 0%), MACE (RR, 0.98; 95% CI, 0.82 to 1.17; I² = 0%), nasopharyngitis (RR, 1.10; 95% CI, 0.83 to 1.45; I² = 0%) and T2DM (RR, 1.02; 95% CI, 0.85 to 1.21; I² = 0%). However, inclisiran use demonstrated a significant increase in injection site adverse events (RR, 7.08; 95% CI, 3.42 to 14.64; I² = 27%).

Conclusions: Inclisiran use significantly increased injection-site reaction, with no increase in mortality, T2DM, or nasopharyngitis. Further trials are required to assess the safety of inclisiran, particularly the association of the severity of injection site adverse events over longer treatment durations exceeding 540 days.