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
K Dyankov, V Dimitrova, K KaramfiloffAbstract
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.