Real-World Data Show Efficacy of PCSK9 Inhibitors in Lowering LDL-C in HeFH Patients with Statin Intolerance

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Real world data demonstrated the efficacy of PCSK9 inhibitors in reducing low-density lipoprotein (LDL-C) cholesterol in patients with heterozygous familial hypercholesterolemia (HeFH).¹ The results of a retrospective cohort study published by Pharmacotherapy found that among patients with HeFH, most of whom have intolerance to statins, a high majority experienced a ≥50% decrease in LDL-C after 12 months of treatment with a PCSK9 inhibitor (mean reduction of approximately 59%), which is similar to data from clinical trials of patients with atherosclerotic cardiovascular disease (ASCVD).

“In clinical trials, PCSK9 inhibitors have been shown to reduce LDL-C levels by approximately 50–60% in addition to statin therapy, and have also been demonstrated to reduce other atherogenic lipoproteins,” the study authors wrote. “In large-scale randomized controlled trials, PCSK9 inhibitors have been shown to reduce the risk of major adverse cardiovascular events (MACE) (e.g., myocardial infarction [MI] and stroke), but not cardiovascular or all-cause death, in patients with ASCVD. Real-world cohort studies have demonstrated that PCSK9 inhibitors reduce LDL-C by approximately 60% over 1–2 years in patients with (familial hypercholesterolemia [FH]). Yet, there are limited data regarding the effect of PCSK9 inhibitors on novel atherogenic lipoproteins, such as apolipoprotein B (ApoB) and lipoprotein(a) (Lp[a]), as well as in patients with statin intolerance.”¹

PCSK9 attaches to LDL receptors on hepatocytes, which causes the breakdown of LDL receptors in the liver. PCSK9 inhibitors, such as Praluent (alirocumab) and Repatha (evolocumab), stop this process from occurring, leading to an increase in the amount of LDL receptors that clear LDL from the blood, subsequently lowering LDL-C levels. Both Praluent and Repatha are indicated to treat patients with established cardiovascular disease or primary hyperlipidemia.^2,3

The authors of the current retrospective, observational cohort study sought to analyze the efficacy of PCSK9 inhibitors in reducing atherogenic lipoproteins, including ApoB and Lp(a), in a real-world cohort of patients with HeFH at a specialized ambulatory lipid clinic and to identify challenges to PCSK9 inhibitor use in clinical practice.

The study’s primary objective was achieving a ≥50% decrease in serum LDL-C concentration from baseline to after 12 months of PCSK9 inhibitor therapy. Secondary objectives included achieving a ≥40% drop in serum LDL-C concentration from baseline to after 12 months of therapy; absolute and percentage change in serum lipid parameters from baseline to three–11 months, 12–23 months, and ≥24 months of therapy; absolute and percent decrease in Lp(a) from baseline to ≥three months of therapy; and documented challenges that prevent the use of PCSK9 inhibitors, such as cost, adverse effects, and intolerance.

A total of 95 patients were included in the analysis, with a mean age of 63 years, of whom 51% were female and the mean baseline LDL-C level was 4.0 mmol/L (155 mg/dL). Most patients (60%) had statin intolerance, with 73% on ezetimibe.

Investigators found that 74% of patients achieved a ≥50% decrease in LDL-C following 12 months of treatment with a PCSK9 inhibitor. Mean LDL-C concentration dropped 59% from baseline to 1.7 mmol/L (66 mg/dL) after 12 months of follow-up but increased to 1.9 mmol/L (73 mg/dL) after ≥24 months of follow-up.

Investigators observed similar trends in non-high-density lipoprotein cholesterol and apolipoprotein B. Meanwhile, lipoprotein(a) dropped by 45% over 12 months.

Investigators found that 12% of patients permanently discontinued therapy. The primary barrier to use of a PCSK9 inhibitor was mostly related to cost, according to the study.

“This study evaluated the real-world effectiveness of PCSK9 inhibitors in a cohort of patients with HeFH, most of which had statin intolerance,” the study authors wrote. “Almost 75% of patients were able to attain a ≥50% reduction (mean 59%) in their serum LDL-C concentration from baseline to about 12 months of therapy, which is consistent with data from landmark clinical trials of patients with ASCVD. Therefore, PCSK9 inhibitors should be considered in patients with HeFH who are unable to achieve a ≥50% reduction in lipid parameters with standard lipid-lowering therapy to mitigate cardiovascular risk.”¹

References

1. Siemens R, Pryjma M, Buchkowsky S, Barry AR. Real-world effectiveness of monoclonal antibody inhibitors of PCSK9 in patients with heterozygous familial hypercholesterolemia: A retrospective cohort study. Pharmacotherapy. 2024; 00: 1-8. doi:10.1002/phar.4609

2. Praluent. Prescribing information. Sanofi-Aventis U.S. LLC; 2015. Accessed September 6, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125559orig1s000lbledt.pdf

3. Repatha. Prescribing information. Amgen Inc; 2015. Accessed September 6, 2024. https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Repatha/repatha_pi_hcp_english.pdf