Real-world efficacy and safety of Inclisiran: a prospective cohort study

Background: Inclisiran is a small interfering RNA (siRNA) therapeutic agent that reduces hepatic synthesis of PCSK9. In Phase III clinical trials, Inclisiran has shown the ability to reduce LDL cholesterol levels by about 50% with a good safety profile, and with the advantage of infrequent administration, which could promote therapeutic adherence. Inclisiran received reimbursement from Italian Drug Agency (AIFA) only in October 2022; but our dyslipidemia Centre, relating to the LIPIGEN NETWORK, had the opportunity to give it early to patients as early as the summer of 2022. We therefore carried out a prospective cohort study to evaluate the efficacy and safety of Inclisiran in real life. Methods: The inclusion criteria were essentially those provided by AIFA for the prescribability of the drug. Enrollment began in July 2022 and preliminary analysis was conducted in April 2023. For all patients included in the study, Inclisiran was administered at time 0, after 90 days and every 180 days thereafter, according to drug administration protocol. The main parameter examined to verify the drug effectiveness was the average percentage reduction of LDL cholesterol at the same time intervals. Secondly, we also evaluated the average percentage changes of the other components of the lipid profile (total cholesterol, HDL cholesterol and triglycerides). The safety profile assessment was performed by comparing the liver (AST, ALT, GGT) and renal (creatinine, uricemia) function values recorded at baseline with those observed during therapy (both at days 90 and 270). In addition, injection site reactions were verified by monitoring patients within 15 minutes following subcutaneous administration of Inclisiran. Results: 14 patients were enrolled from July 2022 to April 2023 (5 females and 9 males) with a mean age at the start of therapy of 57.35 years. All patients had a high or very high cardiovascular risk, defined according to the latest ESC/EAS guidelines (2021). The mean percentage reduction in LDLC values was 29.3% at 90 days and 38% at 270 days (-41.43mg/dl and -73.7 mg/dl respectively). Using the T-test for paired samples, these variations were statistically significant between T0 and T1 and between T0 and T2 (p value 0.013 and 0.028, respectively). The reduction, on the other hand, was not statistically significant between T1 and T2 (p value = 0.699). This last data, although it may be the result of the sample smallness, is in accordance with the mechanism of action of the drug, which immediately determines a reduction in LDL-C levels, subsequently undergoing a plateau phase with stabilization of its effectiveness. Total cholesterol values showed an average percentage reduction of about 20% at 90 days and about 26.1% at 270 days (-46 mg/dl and -69.67 mg/dl respectively). Also in this case the variations were statistically significant between T0 and T1 and between T0 and T2 (p value respectively 0.018 and 0.027), while they were not statistically significant between T1 and T2. As for HDL cholesterol values, there was an average percentage increase of 6.14% after 90 days and 2.6% after 270 days. These variations were not statistically significant between T0 and T1 or between T0 and T2, but between T1 and T2 (p value 0.032). This indicates the existence of a tendency to increase over time the HDL cholesterol levels, which will be interesting to analyze again when the sample will be more numerous and the follow-up longer. About the average values of triglycerides, there was an average percentage reduction of 28.56% at 90 days and 2.6% at 270 days. In any case, these changes were not statistically significant, although in our population there were no patients suffering from hypertriglyceridemia. Regarding the safety profile, almost all patients showed a reaction at the injection site, when the drug was administered at the deltoid level, characterized by painless muscle fasciculations, lasting about two minutes, which subsequently resolved without sequelae. In all phases of treatment, there was no change in liver or kidney function indices, indicating a good safety profile of Inclisiran, according to what has been reported in the literature. Moreover, since the drug was administered in an intra-hospital environment and by medical staff, it was easy to evaluate the adherence to the therapy which turned out to be 100%, favoured by infrequent administration. Conclusions: Our data represent a first analysis of the efficacy and safety of Inclisiran in real life. According to the literature, even in our sample of patients, the therapy with Inclisiran was effective in reducing LDL-C and TOTC levels, with a good safety profile and an optimal patient adherence. Further studies are needed to evaluate the impact of therapy on HDL-C and triglyceride values.