Inclisiran, PCSK9s Elicits Sustained LDL-C Reductions in Familial Hypercholestrolemia

According to a new systematic review and meta-analysis published in Open Heart, proprotein convertase subtilisin/kexin type 9 (PCSK9) targeting therapies—especially inclisiran (Leqvio; Novartis)—demonstrate significant and sustained reductions in low-density lipoprotein cholesterol (LDL-C), apoprotein B (ApoB), lipoprotein A [Lp(a)], and triglyceride levels (TGL) in patients with familial hypercholesterolemia (FH), especially heterozygous patients. The results affirm the efficacy of this novel class of cholesterol-targeting drugs.¹

PCSK9 Inhibitors and Their Efficacy in Hypercholesterolemia

PCSK9s have been shown in numerous research initiatives to help patients attain their LDL-C goals. Most recently, results from the V-DIFFERENCE trial (NCT05192941)² presented at the European Society of Cardiology 2025 Congress highlighted the efficacy of inclisiran in combination with lipid-lowering therapy among patients with hypercholesterolemia, with no muscle-related adverse events. The monoclonal antibody class has demonstrated efficacy across multiple medications, including established treatments like evolocumab (Repatha; Amgen) and alirocumab (Praluent; Regeneron, Sanofi) and investigational drugs such as recaticimab.^2-5

For patients with hypercholesterolemia, effective treatment options are essential to optimal LDL-C control and reduced cardiovascular risk. FH presents a particular concern given its genetic nature, significantly heightening the risk of premature atherosclerotic cardiovascular disease and making it difficult to reduce cholesterol with lifestyle modifications alone. Patients with the disease have mutations in genes, including the LDL-C receptor and PCSK9, which makes it difficult to clear LDL-C from the bloodstream. The complicated yet severe nature of FH requires early diagnosis and treatment initiation to reduce cardiovascular risk.^1,6

Investigators of the current meta-analysis sought to evaluate the safety and efficacy of PCSK9 inhibitors and small-interfering RNA therapies such as inclisiran in both adults and pediatric patients with FH. They focused on the impact of key lipid biomarkers, including LDL-C, TGL, ApoB, and Lp(a), with their goal to support clinical decision-making in FH management.¹

A Series of PCSK9s Induce Significant Lowering of Lipid Biomarkers

The investigators collected 23 randomized controlled trials (RCTs) that were included in the systematic review. Three studies specifically investigated patients with homozygous FH (HoFH), while the rest were conducted exclusively in patients with heterozygous FH (HeFH). In total, 4282 patients with FH were enrolled, receiving 5 types of PCSK9-targeting therapies: alirocumab, bococizumab (Pfizer), evolocumab, tafolecimab (Sintbilo; Innovent), and inclisiran. Follow-up periods ranged from 12 weeks to 78 weeks.¹

Across the 23 RCTs, PCSK9-targeting therapies demonstrated a statistically significant LDL-C reduction (–46.64% [95% CI, –50.77 to –42.52]; P < .00001) compared with placebo. There were also notable reductions in ApoB levels (–34.94 [95% CI, –40.89% to –28.99%]; P < .00001), Lp(a) (–22.70% [95% CI, –25.95% to –19.44%]; P < .00001), and TGL (–15.18% [95% CI, –19.34 to –11.03%]; P < .00001).¹

For pediatric patients, they too presented a substantial reduction in LDL-C levels (–38.15% [95% CI, –43.57% to –32.73%]; P < .00001), ApoB (–33.66% [95% CI, –38.16% to –29.15%]; P < .00001), and Lp(a) (–17.1% [95% CI, –26.43% to –7.78%]; P < .0003).¹

Patients with HeFH demonstrated significantly greater responses to treatment compared with patients with HoFH regarding LDL-C, ApoB, and TGL reductions. For the studies exclusively reporting on HeFH, PCSK9 therapies led to significant mean reductions in LDL-C. Contrastingly, for the studies focusing on HoFH, there was a smaller observed reduction in LDL-C. This was also the case for ApoB and TGL, although Lp(a) levels were comparable between both populations. These differences signify the importance of proper distinction between HeFH and HoFH when prescribing PCSK9 inhibitors.¹

Importantly, there was a significant presence of injection site adverse effects in PCSK9-targeting therapies versus the control group (odds ratio [OR] = 4.67 [95% CI, 3.76 to 5.8]; P < .00001). However, there was no significant difference between either group regarding the rate of serious adverse effects (OR = 0.99 [95% CI, 0.8 to 1.23]; P = .93). There were also no major differences between the groups on adverse effects leading to treatment discontinuation (OR = 1.31 [95% CI, 0.93 to 1.85]; P = .12).¹

“These therapies have a favorable safety profile, with minimal significant adverse events reported, making them a well-tolerated and promising treatment option for patients with persistently high LDL-C levels despite standard lipid-lowering therapies,” the authors concluded. “Long-term follow-up, especially with siRNA therapy, is necessary for a better understanding of this new and revolutionary drug class in the HF population.”¹

REFERENCES

1. Ho VQT, Tran NB, Nguyen N, et al. PCSK9 targeting therapies for familial hypercholesterolaemia: a meta-analysis of efficacy on lipid biomarkers and safety in adults and children across 23 RCTs. OpenHeart. 2025;12(2):e003490. doi.org/10.1136/openhrt-2025-003490

2. Study of Efficacy, Safety, Tolerability and Quality of Life of Inclisiran (KJX839) vs Placebo, on Top of Ongoing Individually Optimized Lipid-lowering Therapy, in Participants With Hypercholesterolemia (V-DIFFERENCE). ClinicalTrials.gov identifier: NCT05192941. Updated June 11, 2025. Accessed September 22, 2025. https://clinicaltrials.gov/study/NCT05192941

3. Halpern L. Inclisiran With LLT Reduces LDL-C in Hypercholesterolemia Without Inducing Muscle Pain. Pharmacy Times. Published September 9, 2025. Accessed September 22, 2025. https://www.pharmacytimes.com/view/inclisiran-with-llt-reduces-ldl-c-in-hypercholesterolemia-without-inducing-muscle-pain

4. Robinson JG, Farnier M, Krempf M, et al. Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events. N Engl J Med. 2015;372(16):1489-1499. doi:10.1056/NEJMoa150103

5. Halpern L. Novel PCSK9 Inhibitor Recaticimab Lowers LDL-C in Adult Heterozygous Familial Hypercholesterolemia. Pharmacy Times. Published September 12, 2025. Accessed September 22, 2025. https://www.pharmacytimes.com/view/novel-pcsk9-inhibitor-recaticimab-lowers-ldl-c-in-adult-heterozygous-familial-hypercholesterolemia

6. Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Euro H Journ. 2025;35(32):2146-2157. doi:10.1093/eurheartj/ehu274