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

  • In a model in which patients would not use any LLT, 0.4% of patients with and 3.1% of patients without CHD would meet recommended LDL-c goals.
  • Assuming 100% adherence and 50% LDL-c reduction based on maximal dose statin, 8.3% and 48.1% of patients with and without CHD would meet the LDL-c target.
  • Addition of ezetimibe, assuming an additional 20% LDL-c lowering, would lead to goal attainment in 54.3% and 93.2% respectively.
  • Mimicking the anticipated effect of CETPi, assuming an additional 40% LDL-c reduction, would result in 95.7% and 99.7% of patients with and without CHD reaching target, respectively.
  • With an anticipated additional 60% LDL-c lowering with PCSK9i, the percentages of patients reaching target would be 99.8% and 100% for those with and without CHD.
  • Assuming 80% adherence for conventional maximal LLT and CETPi and 62% for PCSK9i, LDL-c reductions are lower, and consequently the proportion of patients reaching LDL-c target, up to 31.4% and 81.2% with CETPi (32% LDL-c reduction), and 40.3% and 87.1% with PCSK9i (37.2% LDL-c reduction).


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.


1. Catapano, A. L. et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J 37, 2999-3058, doi:10.1093/eurheartj/ehw272 (2016).

2. Pijlman, A. H. et al. Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands. Atherosclerosis 209, 189-194, doi:10.1016/j.atherosclerosis.2009.09.014 (2010).

3. Beliard, S. et al. Improvement in LDL-cholesterol levels of patients with familial hypercholesterolemia: can we do better? Analysis of results obtained during the past two decades in 1669 French subjects. Atherosclerosis 234, 136-141, doi:10.1016/j.atherosclerosis.2014.02.021 (2014).

4. Kastelein, J. J. et al. Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study.

Lancet 385, 2153-2161, doi:10.1016/S0140-6736(14)62115-2 (2015).

5. Kenilworh, N. J. (Kenilworth, N.J., 2017).

6. Raal, F. et al. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation 126, 2408-2417, doi:10.1161/CIRCULATIONAHA.112.144055 (2012).

7. Raal, F. J. et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 385, 331-340, doi:10.1016/S0140-6736(14)61399-4 (2015).

8. Kastelein, J. J. et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J 36, 2996-3003, doi:10.1093/eurheartj/ehv370 (2015).

9 Umans-Eckenhausen, M. A., Defesche, J. C., Sijbrands, E. J., Scheerder, R. L. & Kastelein, J. J. Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands. Lancet 357, 165-168, doi:10.1016/S0140-6736(00)03587-X (2001).

10 Besseling, J., Kastelein, J. J., Defesche, J. C., Hutten, B. A. & Hovingh, G. K. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA 313, 1029-1036, doi:10.1001/jama.2015.1206 (2015)

Find this article online at J Clin Lipidol

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