Reducing cholesterol levels to decrease cardiovascular events: The role of new proprotein convertase subtilisin/kexin type 9 inhibitors

The need for new drugs to treat severe hypercholesterolemia is relevant because there are patients with genetic defects of cholesterol metabolism in whom current therapies are not effective enough or because there are patients at high risk for cardiovascular events necessitating extremely ambitious cholesterol targets and, finally, because in some patients the standard therapy is not well tolerated. Even under optimal therapeutic conditions, maximal therapy with statin also in association with a second lipid-lowering agent (ezetimibe, ionic exchange resin, fibrates etc.) may not be sufficient to reach the therapeutic target. This situation is evident in patients with familial hypercholesterolemia the prevalence of which was initially estimated in 1/500 patients for the heterozygous form and 1/1000 000 for the homozygous form. More recent analyses, on a large population cohort, estimated the prevalence of the heterozygous form to be 1/200–300 and for the homozygous 1/300 000–400 000.1 Another group of patients in whom the therapeutic target could be difficult to reach are those intolerant to statins. The prevalence of this condition is about 5–10%.2 For all those patients, new classes of drugs are being introduced that are able to act through different mechanisms of action than statins. New cholesterol-lowering drugs Four new classes of drugs designed to reduce LDL cholesterol (LDL-C) levels are currently in advanced phase of study. In patients with high or very high cardiovascular risk, those drugs are currently utilized in association with currently available lipid-lowering agents. For the inhibitors of the protein proprotein convertase subtilisin/kexin type 9 (PCSK9), studies testing efficacy with clinical cardiovascular endpoints are currently under way. Results of these trials should be available in 2–3 years. 1) A first drug is the antisense oligonucleotide, mipomersen acting by decreasing the hepatic synthesis of apolipoprotein B (ApoB) through degradation of its mRNA with a reduction of assembly and production of all atherogenic lipoproteins. In heterozygote patients for familial hypercholesterolemia, cardiovascular disease and on maximal statin treatment, mipomersen decreased LDL-C by 28%, Lp(a) by 21% and ApoB by 26%. Mipomersen has been approved only for treatment of patients with homozygous familial hypercholesterolemia by the Food and Drug Administration, because relevant side effects such as hepatic steatosis, inflammatory reactions at the site of injection and flu-like symptoms are commonly reported. 2) Lomitapide inhibits microsomal triglyceride transfer protein (MTP) impairing hepatic production and secretion of Very Low Density Lipoproteins (VLDL), MTP is the key protein in the transfer of triglycerides on the apoprotein B. In patients with homozygous familial hypercholesterolemia being treated with diet only, the maximum reduction with lomitapide was of 51% for LDL-C, 79% for VLDL cholesterol, 65% for triglycerides, 56% for ApoB and 15% for Lp(a); unfortunately, hepatic steatosis was frequent as well as gastrointestinal side effects. (3) The third class of drugs under investigation are the inhibitors of cholesterol ester transfer protein: anacetrapib reduces the exchange of cholesterol ester from HDL to ApoB lipoprotein (chilomicrons, VLDL and LDL), and the reverse transfer of triglycerides from ApoB-containing lipoproteins to HDL. Anacetrapib is the only drug in this class still under study; it can decrease LDL-C and Lp(a) by 40% if used in patients treated with statin and not affected by familial hypercholesterolemia, whereas it increases the HDL cholesterol by 140%. (4) A new very promising class of cholesterol-lowering drugs are the monoclonal antibodies against PCSK9. PCSK9 significantlymodulates the biologic cycle of the LDL receptors (LDLRs). This protein is synthesized and released by the hepatocytes (also by the intestine, the kidney and central nervous system), where it binds to the complex LDL–LDLR on the surface of the hepatocytes. Once bound to the LDL–LDLR complex and internalized in the hepatocytes, it prevents the intracellular recycling of the LDLR favoring its degradation and thus reducing the number of receptor on the cellular membrane. The monoclonal antibody interacting with PCSK9 prevents its binding to the LDL–LDLR complex favoring the recycling (rather than the degradation) of the latter on the surface of the hepatocytes. This mechanism allows more LDLRs on the cellular surface to be available to bind lipoproteins. The monoclonal antibodies anti-PCSK9 reduce LDLC by 60–70% and Lp(a) by 20–25% in heterozygous patients for familial hypercholesterolemia treated with statins.