PCSK9 therapeutics and cholesterol optimisation: on the the edge of an era?

Jorge Plutzky and Erik Stroes took up the challenge to present together, by having a dialogue on various aspects of cholesterol-modifying therapy. In particular, they explored to what extent we might be at the edge of an era, considering the advent of PCSK9 inhibiting therapy and how this may change clinical practice. By current lack of outcome data of PCSK9 antibody treatment, the speakers recognised that the current situation should still be considered as the pre-PCSK9 era.

Early signals in some of the PCSK9-trials are encouraging, but the longer-term outcome data remain to be published. Still, the rationale of LDL-c lowering is backed up by genetic data. The preliminary observations are good news when comparing them with previous investigative therapeutic strategies, such as HDL-increasing approaches. The CETP-inhibitor evacetrapib increased HDL by 120% and it reduced LDL-c by 37%, but did not yield CV benefit (Nicholls S et al., presented at ACC 2016). The HDL story underscores the importance of waiting for long-term outcome RCT data.

American data on prescription of the now available PCSK9 antibodies suggests that long-term RCT data is also needed to convince physicians to use the agents. Naturally, reimbursement rules also affect treatment decisions. It is an interesting thought that the novel PCSK9 inhibitors would probably be used a lot more if they were much cheaper, as most physicians are already convinced by their efficacy.

The obvious answer to the question of who should receive PCSK9-inhibiting therapy, is those with inadequate LDL-c lowering. This raises some additional questions though, for instance is the aim to reach an absolute target, or to obtain a certain percentage of LDL-c lowering? The largest reduction in absolute CV risk can be achieved at higher baseline LDL-c; at a lower concentration, a smaller additional absolute risk reduction is seen with further LDL-c lowering.18 The ‘expected benefit’ of PCSK9 inhibitors is largest in those with a high absolute 10-year CVD risk and with high expected LDL-c reduction; in this patient category, the number needed to treat is obviously lower than if either of these conditions are lower.19

In the United States, specific target LDL levels have been removed from the lipid guidelines. Stroes shares that Europe may move to the use of cut-off point for residual LDL-c level on statin therapy, which will raise the bar of LDL-c burden before a PCSK9 inhibitor may be given. In cases of familial hypercholesterolemia (FH), CV risk is higher at a given LDL-c concentration than in those without an FH-causing mutation, due to live-long exposure to elevated LDL-c levels. A concept parallel to ‘pack-years’ for smoking may be helpful to better assess the impact of LDL-c burden in an individual. It is reassuring that trials thus far have not suggested that there may be a risk associated with having very low LDL-c levels, but again the awaited outcome trials will need to confirm this.

The last topic they covered was statin ‘intolerance’. Stroes stressed that also recent literature has shown no difference in the amount of side-effects seen with statins and placebo. So, when a patient presents with myalgia, it is important to rechallenge and change the dose, as symptoms may disappear.20 The GAUSS-3 trial was set up with two double-blind phases to investigate whether there is any reality to the phenomenon. Of 511 patients with a history of intolerance to multiple statins due to muscle-related adverse effect, 42.6% experienced intolerable muscle symptoms on atorvastatin treatment, but not on placebo. 26.5% reported the reverse situation: muscle complaints on placebo, but not on statin therapy.21 Thus, it is a complex phenomenon. Stroes shared that unpublished data suggest that genetic loci are associated with statin-associated muscle symptoms (presented at AHA 2016). Hence, there appears to be more to it than psychological factors. Still, it remains important to motivate patients to keep taking statins or trying another one. At Brigham and Women’s Hospital, a study documented that rechallenging with a statin pays off, as over 90% of those who were rechallenged were still taking a statin 12 months later.22

Plutzky concluded the session by saying that to him, PCSK9-inhibiting therapy does not so much represent a new era in medicine. Rather, for now he sees it as an amazing chapter in the ongoing cholesterol era. Stroes added that, even if the outcome data show that PCSK9 inhibition makes it feasible to eradicate the LDL-c burden, a big challenge remains in identifying those at high risk and starting treatment early enough.

Disclosures

Jorge Plutzky, MD – Director of the Vascular Disease Prevention Program, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Erik SG Stroes, MD – Professor of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands