15289-s-bos

106 | Chapter 7 secretion of chylomicrons from the intestine. Inhibiting the activity of this protein prevents the formation of chylomicrons and lipoproteins including Lp(a). The effect of the MTP inhibitor, Lomitapide (Aegerion Pharmaceuticals, Cambridge, Massachusetts, USA) in combination with a low-fat diet and maximum statin therapy, was studied in patients with homozygous FH. Following a 26 week open label study, a long-term extension study showed that 56 weeks of treatment led to a reduction of LDL-C (44%), and a reduction in Lp(a) of 19%. However, after 78 weeks Lp(a) had returned to baseline levels [32]. The most frequent encountered side effects were gastrointestinal complaints (93%), and elevated liver enzymes >3x upper limit normal (34%) and >5x upper limit normal (14%) [32]. In 2013, Lomotapide was approved by the FDA and EMA, for the treatment of homozygous FH patients. The safety profile makes it likely that lomitapide will remain solely registered for this indication. As with mipomersen, this implies that the decrease in Lp(a) will remain an additional beneficial effect for those homozygous FH patients who use the drug for LDL-C lowering. Furthermore, the long-termextension study showed that the effect of lomitapide on Lp(a) is temporary so it is questionable whether this effect is clinically relevant. CETP inhibition Cholesterol ester transfer protein (CETP) transfers cholesterol esters and TG between HDL-C and Apo-B containing lipoproteins. CETP inhibition decreases Apo-B containing lipoproteins and increases cholesterol enrichment in HDL-C. The first two CETP inhibitors were terminated because of respectively safety concerns (ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerosis Events) with torcetrapib) and futility (dal-OUTCOMES with dalcetrapib) [33]. Currently a third CETP inhibitor, anacetrapib was investigated in two phase 3 safety trials. The DEFINE (Determining the EFficacy and tolerability of CETP INhibition with AnacEtrapib) showed a reduction in LDL-C (45%), TG (7%), an increase in HDL-C (169%), but no data on Lp(a) was available[34]. Furthermore, an CVD outcome trial with anacetrapib REVEAL (Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification)) is underway, results are expected in 2017. A phase 2 trial of anacetrapib in Japanese dyslipidaemic patients showed an increases in HDL-C of 160%, a decrease in LDL-C of 32%, and a decrease in Lp(a) cholesterol of 50% [33]., Furthermore a phase 3 trial in heterozygous FH patients (REALIZE (Study to Assess the Tolerability and Efficacy of Anacetrapib Co-administered With Statin in Participants With Heterozygous Familial Hypercholesterolemia)) was completed in February 2014. However, the data have not