New Agents to Reduce Cholesterol Levels: Implications for Nephrologists

Lucia Del Vecchio; Ivano Baragetti; Francesco Locatelli

Disclosures

Nephrol Dial Transplant. 2020;35(2):213-218. 

In This Article

PCSK9 Inhibitors: Clinical use

The clinical development of PCSK9 inhibitors started in 2011 in patients with familial hypercholesterolaemia (FH) or high-risk CVD.

Evolocumab and alirocumab are approved now for clinical use. These two drugs are extremely effective in reducing serum cholesterol levels, but they are also very expensive.

In FH, they seem to be as effective as LDL apheresis, even if not necessarily overlapping.[40] The combined data of 10 trials (6699 patient-years of follow-up) of the ODYSSEY development programme with alirocumab showed that many more patients receiving the drug obtained average LDL-C <50 mg/dL than those treated with statins, ezetimibe or placebo; percentage reductions in LDL-C from baseline were inversely correlated with major adverse CV event rates.[41] Preliminary Phase II and III trials showed significant reductions of CV outcomes with PCSK9 inhibitors.[42,43]

A meta-analysis summarized the data from 35 trials comparing treatment with and without PCSK9 inhibitors in 45 539 patients.[44] The treatment was associated with a lower rate of myocardial infarction, stroke and coronary revascularization, but no effect was observed on all-cause or CV mortality, likely because of a relatively short follow-up (on average 85.5 weeks). Similarly, another meta-analysis was not capable of demonstrating a significant effect on patient mortality.[45] Again, the majority of the included studies had a relative short follow-up and the data of the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) study were not available yet.[46] This large trial enroled more than 27 000 patients with CVD and LDL-C ≥70 mg/dL despite statin therapy, who were randomized to receive evolocumab (140 mg every 2 weeks or 420 mg monthly subcutaneously) or placebo. Evolocumab significantly reduced the risk of the primary composite CV endpoint compared with placebo; despite maximized statin dose, evolocumab obtained a 59% decrease in LDL-C until median values of 30 mg/dL. According to a pre-specified analysis, the drug significantly reduced the CV risk also in diabetic patients.[47]

Similarly, the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes after an Acute Coronary Syndrome During Treatment with Alirocumab) showed that alirocumab was effective in comparison with placebo in reducing the risk of recurrent ischaemic CV events or death among nearly 18 000 patients receiving statin therapy who have had previous acute coronary syndrome.[48] The absolute benefit of alirocumab was greater for baseline LDL-C ≥100 mg/dL.

The clinical development of a third agent, bococizumab, was halted following the occurrence of anti-drug antibodies reducing efficacy in nearly one half of the patients.[49] Preliminary data showed good CV efficacy in higher risk patients with LDL ≥100 mg/dL.[50] The high immunogenicity is likely explained by the fact that bococizumab is a humanized antibody. The clinical development of other humanized, monoclonal antibodies targeting PCSK9 has been stopped as well.

In addition to immunogenicity, other safety issues are possibly linked to PCSK9 inhibitors. Given that the brain has a high cholesterol content, the first question is whether reducing LDL-C to extreme levels could affect cognitive functions. The available experience with PCSK9 inhibitors does not suggest negative effects from this point of view.[41] This is in line with the observation that patients who have very low cholesterol levels spontaneously are not at risk for dementia.[51] Moreover, lipoproteins do not cross the blood–brain barrier and brain cholesterol is synthesized de novo independently of circulating cholesterol levels.[52]

PCSK9 inhibitors may possibly increase cholesterol accumulation in pancreas beta cells and decrease insulin secretion.[53] Differing from statins, at present, PCSK9 inhibitor use does not seem to increase the risk of new-onset diabetes or worsen a pre-existing one.[38,44,54] They do not even increase myalgia or cause a rise in alanine or aspartate aminotransferase levels.[44] A role of PCSK9 inhibitors in septic shock, chronic viral infections and fatty liver is still unclear.[55]

Inclisiran is a chemically synthesized siRNA molecule that produces sustained hepatocyte-specific, PCSK9-specific RNA silencing. Data from a Phase II study showed good efficacy, with nearly half of the patients obtaining LDL-C levels <50 mg/dL with two doses of 300 mg.[56,57] This reduction is similar to that achieved with monoclonal antibodies targeting PCSK9. No major safety issues emerged, excepting reactions at the injection site in nearly 5% of the patients.

At present, the main limitation to wider use of this effective class of drug is its high cost in comparison with the degree of the obtained reduction in CV risk.[58]

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