Physicians' Academy for Cardiovascular Education

Conventional lipid-lowering therapy is not effective enough for heFH patients

Achieved LDL Cholesterol Levels in Patients with Heterozygous Familial Hypercholesterolemia: a Model That Explores The Efficacy of Conventional and Novel Lipid Lowering Therapy

Literature - Hartgers ML, Besseling J, Stroes ES, et al., - J Clin Lipidol. 2018 Available online 18 April. DOI: 10.1016/j.jacl.2018.04.002

Introduction and methods

Current clinical guidelines recommend aiming for LDL-c levels below 70 mg/dL (1.8 mmol/L) or below 100 mg/dL (2.6 mmol/L) in patients with heterozygous familial hypercholesterolemia (heFH) with and without a history of coronary heart disease (CHD), respectively [1]. A large proportion of patients does not reach these levels, despite use of lipid-lowering therapy (LLT) consisting of statins with or without ezetimibe [2,3].

Several additional LDL-c lowering agents have been developed in recent years to address this unmet clinical need. Studies evaluating CETP inhibitors (CETPi) and PCSK9 inhibitors (PCSK9i) in heFH patients, have demonstrated additional LDL-c reduction on top of maximal tolerated LLT, and a press release on the REVEAL trial with anacetrapib reported a reduction of major coronary events [4-8].

HeFH patients enrolled in these trials do not necessarily represent general heFH patients, and LDL-c levels of the latter group may be lower than those eligible for trials, and treatment adherence is likely lower in real life than in trial setting. Also, trial populations are a genetically and clinically heterogeneous group.

This study aimed to determine which fraction of heFH patients identified in the Dutch FH cascade screening program [9,10], would reach the recommended LDL-c levels with maximally tolerated conventional LLT and additional CETPi or PCSK9i at different adherence rates. The study population consisted of 10479 heFH patients with a pathogenic mutation and full lipid profiles available, of whom 1059 (10.1%) had a history of CHD and 9420 (89.9%) did not.

Main results


These analyses of a large cohort of subjects with genetically defined heFH show that with conventional LLT consisting of maximal dose statin therapy and ezetimibe, even when assuming 100% adherence, about half of heFH patients with a history of CHD would reach guideline-recommended LDL-c target, and about 93% of those without CHD. If novel therapies are added to maximal LLT, the percentages increase to over 95% with CETPi and to over 99% with PCSK9i.

When recently published adherence rates are applied, the percentages for PCSK9i decrease to 87% reaching target in primary prevention, and to 40% in secondary prevention. Other novel therapies that overcome the problem of adherence may solve this issue, for instance PCSK9-specific RNA silencing with a long-lasting effect and consequently markedly reduced injection frequency.


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Find this article online at J Clin Lipidol