PCSK9 inhibition in statin-intolerant HeFH patients: What’s new?

Statin therapy reduces cardiovascular events in both primary and secondary prevention. In real life, however, adherence to chronic therapy is suboptimal, also because of the occurrence of side effects, the most common of which are the so-called statin-associated muscle symptoms (SAMS in short), which are reported in 5–15% of treated patients. Randomised controlled trials, however, have suggested a little effect of statin therapy on muscle pain (i.e. myalgia) or weakness. Furthermore, a recent analysis of the ASCOT trial clearly suggested a nocebo effect. Yet in clinical practice many high-risk patients, based on reported effects, are identified as statin-intolerant. These patients cannot benefit from the protective effects of statins, and are exposed to the cardiovascular sequelae of uncontrolled high low-density lipoprotein cholesterol (LDL-C) levels. Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder characterized by high levels of LDL-C from birth, resulting in a high risk of premature (<50 years for men and <60 years for women) cardiovascular events. An intensive, early treatment is needed in these patients because of the high burden of cholesterol, and statin intolerance may represent a major issue. Several clinical trials have shown a clear benefit and reassuring safety of therapy with monoclonal antibodies against circulating PCSK9 (alirocumab and evolocumab) in patients with HeFH. A recent pooled analysis of studies on alirocumab treatment in more than 800 patients with HeFH showed that the rates of treatment-emergent adverse events were similar in alirocumab group (regardless of the dose) and placebo group (80.5% and 83.0%, respectively). The incidence of myalgia was comparable in the two groups (5.1% versus 6.2%). Similar observations were reported also in the RUTHERFORD studies which evaluated the effect of evolocumab in HeFH. In the current issue of this journal, Sbrana et al. reported the efficacy of a 3-month therapy in real life with PCSK9 mAbs in 18 statin-intolerant HeFH patients, resulting in reductions of LDL-C and Lp(a) levels ( 51% and 20%, respectively) comparable with those achieved in other active arms of trials enrolling HeFH patients (Figure 1) and to those observed in other high risk patients. Adverse events were reported in two patients and were not linked to muscle-related disorders. Despite it being a very small group of patients with a short treatment time, these results support the effectiveness and safety of PCSK9 inhibition with monoclonal antibodies in statin-intolerant patients with HeFH, and extend the observation reported in the GAUSS trials. This is definitely an encouraging report from the real-life setting, however it should be remarked that the definition of statin intolerance adopted by the authors is more ‘relaxed’ if compared with the recommendations of the different guidelines/ consensus. This raises the question whether the patients selected in the study are all truly statin-intolerant. Finally, the small percentage of patients reaching the goal and the need for some of them to undergo lipid apheresis, show the other side of the coin: even with the availability of these powerful drugs, optimal treatment requires further intervention such as LDLapheresis. New therapeutic approaches are also at the horizon which can benefit patients not at goal and at high cardiovascular risk. In summary, it appears that