Replacing statins with PCSK9-inhibitors and delaying treatment until 18 years of age in patients with familial hypercholesterolaemia is not a good idea

Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new, powerful, and very promising therapeutic option for reducing low-density lipoprotein (LDL)-cholesterol (LDL-C).1 Alirocumab and evolocumab are fully human monoclonal antibodies (mAbs) against PCSK9. The drugs have just been marketed and are in the process of being adopted in the treatment of high-risk patients, mainly as add-on to conventional lipid-lowering therapy or in those who cannot tolerate an effective dose of statins. In this issue of the European Heart Journal, Vuorio et al.2 present an idea for a new therapeutic option in treating young patients with familial hypercholesterolaemia (FH), i.e. delay of treatment until 18 years of age and then initiating lifelong PCSK9-inhibiting treatment. The reasoning being that the lifelong LDL-C burden will be considerably lower compared with initiating low-dose statin therapy at age 10 years and high-dose statin from age 18 years. For a number of reasons, outlined below, I disagree with this idea. The approval of alirocumab and evolocumab is based on results from randomized trials involving <4000 persons for each drug.3,4 Almost all patients in the trials, including the FH patients, were middle-aged5 and almost all FH-patients received PCSK9 mAbs in addition to maximally tolerated statin ± ezetimibe, i.e. not in monotherapy.6,7 Apart from two post hoc analyses of cardiovascular (CV) events,8,9 no results from CV endpoint trials are yet available, although the first results from such trials are expected in less than a year from now. Using these drugs as monotherapy in young, disease-free FH-subjects will not be on the label in the near future. Even if the CV endpoint trials should come out with substantial benefit, these trials will not provide evidence for such use due to the fact that the drugs are mainly being used on top of maximally tolerated statin therapy and mainly in secondary prevention.1 Also, so far, little is known about the long-term effects of PCSK9-inhibition, one concern being development of anti-drug antibodies which could cause injection site reactions and reduced efficacy of the drug.1,10 In contrast, statin therapy is probably the best documented drug therapy overall.11,12 Statins have been used in children and adolescents with FH in clinical trials and in clinical practice since the early 1990s. Over the years, a considerable amount of documentation and clinical experience has been gathered.13–20 Statin therapy is cheap, safe, and efficient when used in sufficient doses and with adequate compliance. However, maybe 5–10% of patients are unable to tolerate an effective dose of statins due mainly to muscle symptoms.21 Also, neither statins nor PCSK9 mAbs are approved for use during pregnancy. Early initiation of statin treatment in disease-free adult FH subjects, even with moderate doses and suboptimal LDL-levels, reduces the incidence of CV events to nearly the same level as in the general population.22,23 Recently, in a Norwegian genetic registry-based study of mortality among patients with FH, it was shown that the mean age at inclusion in the genetic registry was 54.8 years for those who died, compared with 33.6 years for the registry in total, indicating that delayed diagnosis and statin treatment is a major issue in those who died.24 Therefore, the most important issue in FH is to diagnose and treat early with statins. Also, there has been a tradition to add ezetimibe when needed, supported recently by the results from the IMPROVE-IT trial.25 A greater carotid intima media thickness (cIMT), considered to be a surrogate marker of atherosclerosis,26 has been found before the age of 10 in children with FH, compared with their unaffected siblings.27,28 Markers of vascular inflammation and endothelial dysfunction are also elevated in children with FH, indicating early atherosclerosis.29 Early initiation of pravastatin treatment in children with FH was associated with a subsequently smaller cIMT after an average treatment period of 4.5 years, and at 10-year follow-up.30,31 Furthermore, at 10-year follow-up, normalization of cIMT progression was found, but cIMT was still greater in children with FH than in their unaffected siblings.30 In this same cohort of young FH-patients, having initiated statin therapy during childhood, none had CV events up to age 30, while among their FH-parents ∼10% experienced events before age 30.20 Recently, rosuvastatin treatment over 3 years showed slowing of cIMT progression in FH-children aged 6–17 years compared with unaffected siblings.32 As outlined in the Consensus Panel on FH in children and adolescents from 2015, to prevent these changes from developing, it is reasonable to initiate statin treatment in childhood,33 rather than delaying treatment for many years, anticipating that the arterial wall changes are reversible. A strategy to delay treatment for some and not for others, presupposes an ability to sort out, at the age of 10, those who will be at high risk, from those who will be at lower risk. Clinically, this will be a difficult task. For women, an additional reason to start treatment early is that lipid-lowering therapy should be stopped when trying to conceive and during pregnancy, which can sum up to several years without treatment. Treatment with alirocumab and evolocumab reduces LDL-C by an average of 50–60%, but there is great variability in the individual response to treatment. With evolocumab, LDL-C reduction varied between 20 and 80% in individual FH-patients.34 Treating with PCSK9 mAbs in monotherapy, assuming a mean LDL-C reduction of 60%, an LDL goal of 1.8 mmol/L or lower, as assumed by Vourio et al. would only be achieved in those with a pretreatment LDL-C at or <4.5 mmol/L. However, in untreated FH, LDL-C levels >4.5 mmol/L are common.35 Therefore, treatment with statins and/or ezetimibe will be necessary in addition to PCSK9-inhibition for many patients. Moreover, treatment with high-dose statins and ezetimibe will reduce LDL-C by the same amount, as monotherapy with PCSK9 mAbs, ∼60%.36,37 The LDL-C load will be equal with these two regimens, but at current European prices, treatment cost for PCSK9 mAbs is ∼10-fold the cost for atorvastatin 80 mg plus ezetimibe. At a cost of ∼7500 € per year for PCSK9 mAbs, lifelong treatment of a large number of young FH-patients will incur prohibitive costs, and when used in monotherapy, probably with no additional benefit in reducing CV events. If more resources are to be used in the FH-population, it will be far better to use these resources to intensify early diagnostic activities and initiate statin treatment at a young age. The place for PCSK9-inhibtors will be as add-on therapy for those high-risk patients who do not achieve treatment goals with statins and ezetimibe, and for those, maybe 5–10% of patients who cannot tolerate statins. Compliance of statin therapy in young FH-patients can be low.15 PCSK9 mAbs are to be injected every second or fourth week, or possibly even more seldom with drugs in development.38 As PCSK9 mAbs till now mainly have been used in clinical trials with motivated patients, we do not know, in clinical practice, whether compliance will be better with fortnightly or monthly injections, compared with tablets to be taken every day. If so, it could be a reason for PCSK9-inhibiting treatment in selected patients. In the future, if prices come down, with the possible advent of biosimilars, other modes of PCSK9-inhibition, and proven substantial CV benefit and long-term safety, the cost–benefit balance for widespread use of PCSK9-inhibiton may well be positive, but from here it is a long way to go. In conclusion, at present, the idea of replacing statins with PCSK9 mAbs and delaying treatment to 18 years of age in patients with FH is not supported by current evidence and cost–benefit is far from being proven. G.L. drafted the manuscript and made critical revision of the manuscript for key intellectual content. Conflict of interest: G.L. has received advisory board and lecture fees from Amgen and Sanofi.