Inclisiran-induced LDL-cholesterol reduction with and without concomitant statin therapy: a real-world analysis

Inclisiran lowers LDL-cholesterol (LDL-C) by inhibiting hepatic PCSK9 synthesis. Whether concomitant statin therapy modifies the magnitude of inclisiran-associated LDL-C reduction in routine clinical practice remains uncertain. In this retrospective single-center observational study, 67 patients treated with inclisiran for at least 9 months were analyzed. Patients previously treated with PCSK9 monoclonal antibodies were excluded. LDL-C values were assessed longitudinally and stratified by concomitant statin therapy. Multivariable linear mixed-effects models were used to evaluate inclisiran-associated percentage LDL-C reduction over time. Thirty-seven patients received concomitant statin therapy and 30 patients did not. Median follow-up was 18 months (IQR 12.5-28). Median LDL-C reduction ranged from approximately - 25% to - 40% across follow-up visits. At 9 months, 10 of 59 patients (16.9%) achieved a ≥ 50% LDL-C reduction. In the primary multivariable longitudinal mixed-effects model, concomitant statin use was not significantly associated with percentage LDL-C reduction (β for no statin vs. statin: 33.1% points; 95% CI - 4.6 to 70.7; p = 0.085). Statin intensity was also not significantly associated with LDL-C reduction (β - 0.11 per percentage point of maximum approved dose; 95% CI - 0.60 to 0.37; p = 0.644). In an exploratory responder analysis, concomitant statin therapy was associated with higher odds of achieving ≥ 50% LDL-C reduction at 9 months (OR 7.69; 95% CI 1.28-45.45; p = 0.026). During follow-up, 18 patients (26.9%) discontinued inclisiran, predominantly due to insufficient LDL-C reduction. In routine clinical practice, neither concomitant statin use nor statin intensity was significantly associated with the magnitude of LDL-C reduction observed during inclisiran therapy. However, responder and attrition sensitivity analyses suggested a possible association between concomitant statin therapy and a more pronounced inclisiran-associated LDL-C response. These findings support the clinical use of inclisiran in heterogeneous real-world populations, while highlighting the potential benefit of maintaining concomitant statin therapy whenever tolerated.