To our knowledge, there are very few reports on real-world data regarding the efficacy and safety of inclisiran.

Our key findings were: significant LDL-C reduction and high target achievement rates; real-world results consistent with prior RCTs and registries; enhanced efficacy of inclisiran when used alongside statin therapy; superior performance among patients with diabetes; a trend toward lower LDL-C reduction and a significantly lower target achievement in FH patients; favorable safety profile; high adherence rates.

Despite recent guidelines recommendations for lower LDL-C targets, real-world evidence highlights persistent undertreatment of high-risk patients. In the SANTORINI study, 80% of high and very high cardiovascular risk patients in Europe failed to meet the 2019 ESC/EAS LDL-C goals [9]. Similarly, in the Italian cohort 80% of patients did not reach these targets [19]. This may reflect factors such as risk underestimation, underuse of combination therapies, drug intolerance, and poor adherence [19]. Overcoming these obstacles to optimal lipid management requires a comprehensive and multifaceted approach that addresses knowledge, attitude, and behaviour barriers at the provider, patient, and healthcare delivery level [20, 21].

New pharmacological advancements, including inclisiran, offer promising tools to enhance LDL-C management. Inclisiran’s twice-yearly administration improves adherence and allows healthcare providers to closely monitor patients, ensuring compliance and addressing adverse events.

Our real-world, multicenter study assessed inclisiran’s efficacy and safety over 9 months in high and very high cardiovascular risk patients across 12 lipid clinics in Veneto region (Italy). The results show that inclisiran treatment on top of maximum tolerated LLTs is effective in reducing LDL-C levels, achieving mean reductions of 52.3% at 3 months, 50.0% at 9 months. The changes observed in our study are concordant with those seen in ORION-10 and ORION-11 trials, which showed a placebo-corrected reduction in mean LDL-C levels by approximately 50% over 18 months [14]. Regarding LDL-C target achievement, the proportion of patients who achieved the personal LDL-C target according to ESC/EAS 2019 guidelines was 64.7% at 3 months and 62.3% at 9 months. These findings are consistent with those reported in ORION-8 trial, an open-label extension of inclisiran phase II and III trials, where 66.3% of patients at very high cardiovascular risk reached the LDL-C target < 55 mg/dl at the end-of study [14, 22].

The baseline clinical and biochemical characteristics of our patients concerning age and sex were comparable to those reported in a pooled analysis of ORION-9, ORION-10, and ORION-11 trials. However, in our cohort, we noticed a lower prevalence of arterial hypertension (68.3% vs 79.4%), diabetes mellitus (25.0% vs 37.5%), and familial hypercholesterolemia (12.5% vs 19.3%). Moreover, the baseline mean LDL-C levels of our population were 118.7 ± 48.7 mg/dl, slightly higher than what has been observed in phase III clinical trials (111.9 ± 44.9 mg/dl). Also, the baseline mean LDL-C levels in the patient affected by FH in our study was higher than reported in the ORION-9 trial (173.8 ± 59.6 vs 151.4 ± 50.4 mg/dl). Finally, regarding background lipid-modifying therapy, it was interesting to note in our patients a lower use of statin (70.0% vs 92.0%), but far greater use of ezetimibe (83.8% vs 13.7%) [14, 23].

Our results aligned and sometimes exceed also to the data from the few real-world studies already published. In a UK study by Padam et al. with 80 patients, a single subcutaneous inclisiran injection was effective in reducing LDL-C by 48.6% at 2 months, with more prominent results in patients with a background statin therapy (−56.0% vs −44.9%) [24]. In a German study by Makhmudova et al. with 153 patients, the median LDL-C reduction was 35% at 3 months and 26% at 9 months, with a more pronounced reduction in statin users (−42.2% vs −31.9%) and patients naïve to PCSK9 inhibitors (−41.1% vs −23.6%) [25]. In a Dutch study by Mulder et al. with 65 patients, the median LDL reduction was 34.0% at 3 months and 23.6% at 9 months, and better results were obtained in statin users (−35.8% vs −32.4%) and patients naïve to PCSK9 inhibitors (−37.9% vs + 38.0%) [26]. In an Israeli study by Naoum et al. with 503 patients, the median LDL-C reduction from pre-injection levels was 42% at > 2 months, higher in those with concomitant lipid-lowering therapies (46%) than in the inclisiran-only patients (40%), and also higher in those not previously treated with PCSK9 monoclonal antibodies (48%). LDL-C target < 55 mg/dL was attained by only 21.9% of patients, and this could be explained by the lower rate (36%) of use of oral lipid-lowering therapy post-inclisiran initiation.[27] Finally, in an Italian study by Gargiulo et al., median LDL-C reduction was 51% at 3 months in 513 patients and 56% at 9 months in 171 patients. LDL-C < 55 mg/dl was reached in 57% of patients at 3 months, increasing to 67% at 9 months. Patients receiving statin ± ezetimibe (71%) showed greater LDL-C reduction compared to those not on combination therapy, both at 3 (58% vs 42%) and 9 months (61% vs 47%).[28].

Patients on statins experienced greater LDL-C reductions at 3 months compared to statin-intolerant patients (54.5% vs. 47.2%), highlighting the synergistic effect of statins and PCSK9 inhibitors via SREBP-2-mediated LDL-R upregulation [29]. This effect diminished at 9 months, potentially due to declining adherence or reduced statin dosing. However, statin users consistently achieved higher LDL-C targets at both time points.

Multivariable analysis identified statin use and diabetes mellitus as independent predictors of greater LDL-C reduction. The latter finding aligns with a recent post hoc analyses from the ORION trials, which reported LDL-C reductions with inclisiran ranging from 46.8% to 52.0% across different baseline glycemic status (normoglycemia, pre-DM, DM) [30]. Enhanced LDL-C reduction in patients with diabetes may be linked to a greater expression of asialoglycoprotein receptor (ASGPR) in obesity (and by association in DM), facilitating inclisiran uptake into the liver [31,32,33].

In FH patients was observed a lower LDL-C reduction trend (44.8% vs. 53.4% at 3 months), consistent with ORION-9, and a significantly lower target achievement both at 3 months (36.7% vs 68.8%) and 9 months (30.4% vs 68.7%) [13]. This may reflect the limited contribution of dysfunctional LDL receptors to LDL-C clearance in FH patients [3, 34].

Inclisiran demonstrated a favorable safety profile, with only 1.3% of patients experiencing mild and self-resolving injection-site reactions. Adherence was high, with only 1.7% of patients discontinuing treatment for personal reasons. These findings further support inclisiran as an effective, well-tolerated option for managing hypercholesterolemia in high and very high cardiovascular risk patients.

Our study presented limitations too. First, we included a small, predominantly Caucasian cohort from the Veneto region of Italy, limiting generalizability. Secondly, blood samples were analyzed in multiple laboratories rather than a centralized facility. Additionally, due to the low number of patients reaching the 9-months follow-up, the inference at this time-point should be cautious. Additional and more complete data about longer follow-up are expected from further analysis.