DOI: 10.6084/m9.figshare.24772600.v1
title: A systematic review and meta-analysis of tolerability, cardiac safety and efficacy of inclisiran for the therapy of hypercholesterolemic patients

description: Dyslipidaemia is a crucial risk factor for cardiovascular morbidity and mortality. A short interfering RNA called inclisiran diminishes circulating levels of PCSK9 and LDL-C by hindering PCSK9 translation in the liver. RCTs were electronically searched on PubMed, Cochrane Central, and Clinicaltrials.gov to assess the safety and efficacy of inclisiran. Cochrane Review Manager 5 was used to conduct the pooled analysis. Risk of bias was assessed and GRADE pro-GDT was utilized, respectively, to estimate the methodological quality and overall quality of evidence. Of 218 records screened, four studies were included with 2203 participants in inclisiran and 1949 participants in the placebo group. Inclisiran was related to non-significant elevated risk of total adverse events[RR = 1.05(0.98,1.12), <i>p</i> = 0.16; I<sup>2</sup> = 53%], non-serious adverse events[RR = 1.09(0.97,1.22),<i>p</i> = 0.15;I<sup>2</sup> = 61%] and all-cause mortality[RR = 1.01(0.60,1.70),<i>p</i> = 0.97;I<sup>2</sup> = 0%] whereas a lower risk of serious adverse events[RR = 0.94(0.70,1.25),<i>p</i> = 0.67;I<sup>2</sup> = 73%], cardiac disorders [RR = 0.87(0.66,1.15),<i>p</i> = 0.33;I<sup>2</sup> = 42%] and Major adverse cardiovascular events(MACE)[RR = 0.79(0.62,1.00),<i>p</i> = 0.05; I<sup>2</sup> = 0%] as compared to placebo. Inclisiran was also linked to a substantial decline in the percentage of LDL-C, PCSK9, total cholesterol, and Apo B. The pooled analysis of the existing evidence shows that inclisiran showed reduced risk of MACE along with excellent efficacy in managing dyslipidemia. Elevated cholesterol levels have been found to be associated with a high risk of heart disease and associated deaths. There are various classes of drugs used to control high low-density lipoprotein cholesterol (LDL-C) levels in blood yet appropriate control and patient compliance, to regular cholesterol-lowering drugs have been an issue. Inclisiran, a novel drug for reducing the LDL-C levels in serum can be given every six months as an effective therapy to minimize the levels of LDL-C in serum. This study was designed to assess the safety and effectiveness of inclisiran in patients with hypercholesterolemia. Inclisiran was found to have a non-significant elevated risk of total adverse events, non-serious adverse events, and all-cause mortality. The majority of the adverse events seem to be non-serious and tolerable. There was an observed non-significant lower risk of serious adverse events, cardiac disorders and significant reduced risk of major adverse cardiovascular events when compared to placebo. Inclisiran was also linked to a significant decline in the percentage of LDL-C, PCSK9, total cholesterol, and Apo B in patients with hypercholesterolemia. With the evidence available at present, inclisiran seems an efficacious and well-tolerated therapeutic strategy to manage elevated cholesterol and LDL-C levels. However, long-term, large cardiovascular outcome trials are required to conclude on the drug’s cardiovascular and overall safety.