Efficacy of inclisiran in patients affected by familial hypercholesterolemia: data from CHOLINET Registry

Background/Introduction Previous randomized controlled trials reported that inclisiran effectively reduce low-density lipoprotein cholesterol (LDL-C) by 50%. However, in trials including patients with familial hypercholesterolemia (FH), LDL-C reduction was lower in patients with FH, compared to placebo. Currently, real-life data about LDL-C reduction in patients with FH treated with inclisiran are poor and contradictory. Purpose CHOLINET (Cholesterol inclisiran Italian network) is a single country, multicenter, observational, prospective, phase IV registry of Italian patients, initiating inclisiran as part of routine clinical management of hyperlipidaemia. Purpose of this analysis was to evaluate the efficacy of inclisiran in patients with and without FH. Methods The CHOLINET registry enrolled patients receiving inclisiran according to standard clinical practice. Clinical and demographic characteristics, concomitant therapies, blood chemistry, were recorded at the time of first prescription and at subsequent follow-ups. Analyses were stratified by the presence or absence of FH. FH was diagnosed using the Dutch Lipid Clinical Network Score (DLCNS). Results This subgroup analysis included 513 patients enrolled in the CHOLINET registry, who reached at least the 3-month dose. Of them, 78 (15.2%) patients had FH. At baseline, median LDL-C was 160 mg/dL in patients with FH and 100 mg/dL in those without. The percentage of patients receiving a concomitant lipid lowering therapy (LLT) was higher in patients without FH than in patients with FH (89.2% vs 74.4%). At three-months follow-up, median LDL-C percentage reduction was significantly lower in patients with FH than in patients without FH (46.3% vs 53.3%; p<0.001); similarly, the percentage of patients achieving LDL-C target according to CV risk class was significantly lower in patients with FH (24.4% vs 63.4%, p<0.001). Similarly, of 171 patients who completed nine-months follow-up, median LDL-C percentage reduction was significantly lower in 27 patients with FH compared to 144 patients without FH (47.6% vs 40.5%, p=0.004). Moreover, at the 9-month follow-up, 22.2% of patients with FH achieved the LDL-C target, compared to 73.6% in those without (p<0.001). At multi-variable analysis, FH (OR: 0.47; 95% CI: 0.23-0.95; p=0.036) was predictor of failure to achieve LDL-C target. Conclusions Further pathophysiological mechanisms could be involved in FH, such as genotype, LDL-C receptors residual function and multiple mutations, which might explain the variability in response to inclisiran in patients with FH. However, further studies are needed to better characterize patient with FH and to understand the reasons for high interindividual variations in LDL-C reduction in this population.