Real-world lipid outcomes after switching PCSK9-targeting therapies in heterozygous familial hypercholesterolemia: the SHIFT-FH study

Abstract Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition represents a cornerstone of lipid-lowering therapy in heterozygous familial hypercholesterolemia (HeFH). Monoclonal antibodies (mAbs) and small interfering RNA (siRNA) targeting PCSK9 provide complementary therapeutic strategies; however, real-world data comparing lipid outcomes and target achievement after switching between these treatments remain limited. The SHIFT-FH study was a retrospective real-world cohort study including genetically confirmed HeFH patients receiving maximally tolerated lipid-lowering therapy and stable PCSK9 monoclonal antibody treatment for ≥ 6 months. According to routine clinical practice, patients either switched to siRNA therapy (inclisiran; Group 1) or continued monoclonal antibody therapy (Group 2). The primary outcome was achievement of guideline-recommended LDL-C targets at 6 and 12 months. Secondary outcomes included changes in lipid parameters and hepatic safety. Forty-eight patients were included (22 in Group 1 and 26 in Group 2; mean age 59.3 ± 12.8 years). At baseline, LDL-C target achievement was lower in patients subsequently switched to siRNA therapy (36.4% vs 80.8%; p = 0.002). At 12 months, target attainment remained lower in Group 1 (22.7% vs 53.8%). Switching to siRNA therapy was associated with a moderate increase in LDL-C levels (Δ + 29.6 ± 37.4 mg/dL; p = 0.003), whereas lipid levels remained stable in patients continuing monoclonal antibody therapy. Exploratory analysis suggested a trend toward an inverse association between baseline LDL-C levels and target achievement at follow-up. Liver enzymes remained within the normal range in both groups. In this real-world cohort of genetically confirmed HeFH patients, LDL-C target achievement was strongly influenced by baseline lipid burden and differed across therapeutic pathways. Switching between PCSK9-targeting strategies may influence long-term lipid control, highlighting the importance of individualized, target-oriented lipid management.