Efficacy and safety of inclisiran monotherapy in patients with hypercholesterolemia without background lipid-lowering therapy: a systematic review and meta-analysis

Abstract Background Inclisiran effectively reduces low-density lipoprotein cholesterol (LDL-C) by suppressing proprotein convertase subtilisin/kexin type 9 (PSCK9) in patients on maximally tolerated statins with atherosclerotic cardiovascular disease (ASCVD) or risk equivalent. However, less is known about the efficacy of inclisiran as a monotherapy strategy for LDL-C reduction in patients with elevated levels but who are not on statins, ezetimibe, or any other lipid-lowering therapy (LLT). Purpose To investigate whether the lipid-lowering efficacy of inclisiran in LDL-C reduction indicates a significant pharmacodynamic effect regardless of baseline cardiovascular risk in patients with hypercholesterolemia without any LLT. Methods We conducted a comprehensive search of PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) comparing inclisiran sodium at dose of 300 mg (equivalent to 284 mg inclisiran) with placebo in adults with hypercholesterolemia who were not on statin, ezetimibe, nor any other LLT at baseline for evaluating the lipid-lowering efficacy of inclisiran as monotherapy. Outcomes of interest were (1) primary efficacy endpoint as percentage change in LDL-C from baseline, in patients without any background LLT and in those without statin use, and (2) percentage change in PCSK9 levels from baseline. R software version 4.3.1 was used for statistical analysis to estimate pooled effects of mean difference (MD) and 95% confidence intervals (CI) under e random-effects model. Heterogeneity was examined with I² statistics. Results We included five RCTs comprising 540 patients, of whom 311 (58%) were treated with inclisiran monotherapy, and the remaining 229 (42%) received placebo. Median follow-up ranged from 6 to 18 months (or 183 to 540 days). When compared with placebo, patients treated with inclisiran monotherapy who were not on any LLT had a significant decrease in percentage change in LDL-C from baseline (MD −46.24%; 95% CI −51.35 to −41.12; p<0.01; Figure 1A), with no significant difference when stratified by low risk versus high-risk population (test for subgroup difference p=0.33; Figure 1A). Similarly, inclisiran monotherapy lowered the LDL-C from baseline in patients without statin at baseline by about 53% more compared with placebo (MD −52.57%; 95% CI −62.34 to −42.80; p<0.01; Figure 1B). Moreover, the inclisiran group showed a significant 77% reduction in PCSK9 levels compared with the placebo group (MD −77.29%; 95% CI −84.31 to −70.27; p<0.01; Figure 2A). Conclusion In this meta-analysis of RCTs evaluating patients with hypercholesterolemia without any background LLTs, inclisiran monotherapy significantly reduced percentage change in LDL-C from baseline, regardless of ASCVD risk. These findings were consistent in a sensitivity analysis only in patients without statin use at baseline, as well as in reduction of PSCK9 levels.Inclisiran Figure 1For image description, please refer to the figure legend and surrounding text.  Inclisiran Figure 2For image description, please refer to the figure legend and surrounding text.