PCSK9 inhibitors: where are we now?

Atherosclerotic cardiovascular disease remains a major cause of death and disability, especially for high-risk familial hypercholesterolaemia individuals. Proprotein convertase subtilisin kexin type 9 inhibitors (PCSK9i) reduce low-density lipoprotein cholesterol levels and cardiovascular event rates [1]. PCSK9i represent a new group of lipid-lowering drugs, which have generated a substantial change in lipid management. Multiple studies were published evaluating the lipid-lowering efficacy and safety of these drugs. In addition, large randomised clinical trials have demonstrated that the decrease in LDL-C levels achieved with these agents were associated with lower incidence of cardiovascular events [1,2].

According to K.C. Koskinas et al., the 2019 ESC/EAS guidelines rendered half of all post-acute coronary syndrome patients potentially eligible for PCSK9i treatment, as compared to a three-fold lower eligibility rate based on the 2018 ACC/AHA guidelines [3]. W. Masson et al. suggested to be accurate when selecting patients eligible for PCSK9i in daily practice, maximising conventional regimens and strictly identifying statin intolerant patients [2].

While PCSK9i improve clinical prognosis in secondary prevention, high market prices have limited their widespread adoption. As previously experienced with statins, evidence of clinical benefit along with population-based estimations of treatment eligibility is required to assess whether healthcare savings accrued from the reduction of cardiovascular events might counterbalance treatment costs. K.C. Koskinas et al.’s study provides new insights on treatment eligibility that will be useful to inform cost-effectiveness analyses according to transatlantic guideline criteria, also taking into account different drug prices and reimbursement policies in different countries [3]. Of 2,521 patients, 93.2% were treated with statins (53% high-intensity statins) and 7.3% with ezetimibe at 1 year, and 54.9% had very high-risk atherosclerotic cardiovascular disease. Low-density lipoprotein-cholesterol (LDL-C) levels less than 1.8 mmol/l and less than 1.4 mmol/l at 1 year were observed in 37.5% and 15.7% of patients, respectively. After modelling the statin intensification and ezetimibe effects, these numbers increased to 76.1% and 49%, respectively. The proportion of patients eligible for PCSK9i was 51% according to ESC/EAS criteria versus 14% according to ACC/AHA criteria [3]. Otherwise, compared with no treatment with a PCSK9i, treatment with a PCSK9i was not associated with a statistically significant change in congestive heart failure exacerbations requiring hospitalisation [4] but there are no data about the outcomes of PCSK9i in patients supported with mechanical circulatory support (MCS).

Moreover, dyslipidaemia is common in recipients after heart transplantation (HTx) [5,6]. Monoclonal antibodies that inhibit PCSK9 reduce LDL-C levels and subsequently the risk of cardiovascular events in patients with dyslipidaemia. There is a lack of data on the effect of this medication class on cholesterol levels in patients after HTx [6]. Nowadays, PCSK9i were not generally recommended to manage transplanted patients but there are a few publications higlighting this off-label experience. M. Kuhl et al. observed a non-significant increase of everolimus and tacrolimus levels as well as a non significant decrease of the ciclosporin levels [6].

However, the effect of these drugs on clinical outcomes is unclear because prior reviews showed a number of limitations. Reviews have focused on the composite outcome ‘major adverse cardiovascular events’. The substantial heterogeneity in this endpoint between trials makes it hard to interpret the results of reviews and efficacy may be overestimated because patients with high blood cholesterol might receive revascularisation procedures more often [7]. However, in clinical outcomes studies, alirocumab decreased the risk of all-cause serious adverse events and evolocumab probably increased the risk of mortality [7].

Treatment with PCSK9i is well tolerated and improves cardiovascular outcomes. Although no overall benefit was noted in all-cause or cardiovascular mortality, such benefit may be achievable in patients with higher LDL-C [4]. K.C. Koskinas et al. promoted PCSK9i as an effective secondary prevention and dyslipidaemia treatment but future perspectives should cover the following topics: guidance with PCSK9i patients in end-stage heart failure, including supported with MCS,  heart transplanted recipients and children with dyslipidemia.

Note: The content of this article reflects the personal opinion of the author and is not necessarily the official position of the European Society of Cardiology.