Efficacy and safety of inclisiran in patients with and without type 2 diabetes mellitus: a subgroup analysis from the CHOLINET Registry

Background/Introduction Patients with diabetes and dyslipidaemia have high prevalence of cardiovascular disease. Inclisiran has proven to be effective in lowering low-density lipoprotein cholesterol (LDL-C) in real-world setting. A previous post hoc pooled analyses of the ORION-9, ORION-10 and ORION-11 Phase 3 trials has shown that inclisiran can induce greater LDL-C percentage reductions among individuals with diabetes and prediabetes compared to those without. However, the effect of inclisiran in individuals with type 2 diabetes mellitus (T2DM) in real-world has not been fully characterized. Purpose CHOLINET (Cholesterol inclisiran Italian network) is an Italian multicenter prospective phase 4 registry including 44 Italian centers, designed to assess efficacy, safety, adherence and persistence of inclisiran treatment. Purpose of this subgroup analysis was to evaluate percentage change in LDL-C from baseline and the proportion of patients achieving LDL-C targets according to cardiovascular risk class, stratified by the presence or absence of T2DM. 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 T2DM. Results This subgroup analysis included 659 patients enrolled in the CHOLINET registry (20% with T2DM, 69% male, mean age 63 years). Among them, 529 patients reached the 3-month milestone, with 513 (97%) receiving their second dose, while 178 patients reached the 9-month milestone, of whom 171 (96%) received the third dose. Patients with T2DM were 110 (21.4%) at the 3-month follow-up and 38 (22.2%) at the 9-month follow-up. Median percentage reduction in LDL-C from baseline to 3 months was 56.2% in patients with T2DM compared to 50% in those without (p=0.015), while median percentage reduction in LDL-C from baseline to 9 months was 69.5% in patients with T2DM compared to 51.4% in those without (p=0.005). In addition, among patients evaluated at the 3-month follow-up, 65.5% of patients with T2DM achieved the LDL-C target, compared to 55.3% in the group without T2DM. Similarly, at the 9-month follow-up, 81.6% of patients with T2DM achieved the LDL-C target, compared to 60.9% in those without (p=0.03). Conclusions This subgroup analysis from the CHOLINET registry confirms inclisiran efficacy in reducing LDL-C, with a greater reduction and higher target achievement in T2DM patients. These findings highlight inclisiran potential role in optimizing lipid management in individuals with T2DM and could be partially explained by the modulation of the asialoglycoprotein receptor, responsible for the uptake of inclisiran into hepatocytes.