Inclisiran in combination with statin therapy achieves profound LDL-C and lipoprotein(a) reduction without acute cardiovascular events in high-risk patients with familial hypercholesterolemia

Background Patients with familial hypercholesterolemia (FH) and prior myocardial infarction are at extremely high cardiovascular risk. Despite maximally tolerated statin therapy, many fail to achieve guideline-recommended LDL-C targets. Inclisiran, a small interfering RNA targeting PCSK9, provides potent, durable LDL-C reduction and may also lower atherogenic lipoprotein(a) [Lp(a)], potentially mitigating residual cardiovascular risk. Objectives To assess the long-term efficacy and safety of inclisiran added to statin therapy in reducing LDL-C and Lp(a) in high-risk FH patients over two years. Methods In this prospective, multicenter study, 172 adults (mean age 62 ± 10 years; 68% male) with FH diagnosed ≥5 years, prior myocardial infarction, and on stable statin therapy were enrolled. Inclisiran 300 mg was administered subcutaneously at baseline, 3 months, and every 6 months thereafter for 24 months. Primary endpoints were percent change in LDL-C and Lp(a). Safety endpoints included hepatic enzyme and creatine kinase elevations, adverse events, and the incidence of acute cardiovascular events. Results Inclisiran plus statin therapy resulted in a mean LDL-C reduction of 51% (baseline 4.8 ± 0.5 → 2.3 ± 0.4 mmol/L, p<0.001) and Lp(a) reduction of 27% (baseline 70 ± 15 → 51 ± 12 mg/dL, p<0.001). At 24 months, 78% of patients achieved LDL-C <1.8 mmol/L and 42% reached <1.4 mmol/L. No patient experienced an acute cardiovascular event during follow-up. The regimen was well tolerated; mild transient liver enzyme elevations occurred in 6% of patients, CK remained stable, and no discontinuations due to adverse events were reported. Conclusions In high-risk patients with familial hypercholesterolemia and prior myocardial infarction, inclisiran added to statin therapy provides robust, durable LDL-C and clinically meaningful Lp(a) reductions. The absence of acute cardiovascular events over two years underscores the potential of mechanism-based combination therapy to reduce residual atherogenic risk. These findings support early implementation of inclisiran in statin-treated FH patients inadequately controlled with conventional therapy, highlighting its clinical and prognostic relevance.