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
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 . 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.
- 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.