p.32 抽出テキスト

............................................................................................................................................................................. The ODYSSEY Outcomes trial randomized 18924 patients after hospitalization for acute MI or unstable angina, treated with statins, and with LDL-C >_1.8 mmol/L (>_70 mg/dL), non-HDL cholesterol >_2.6 mmol/L (>_100 mg/dL), or ApoB >_80 mg/dL, to receive injections of alirocumab or matching placebo. Allocation to alirocumab reduced the mean baseline LDL-C from 2.38 mmol/L (92 mg/dL) to 1.24 mmol/L (48 mg/dL) at 12 months. There was a 15% relative reduction in the primary outcome (composite of CHD death, nonfatal MI, ischaemic stroke, or unstable angina requiring hospitalization) (HR 0.85, 95% CI 0.780.93) after a median follow-up of 2.8 years.120 Although there was a significant reduction in all-cause mortality in the ODYSSEY trial, this was an exploratory outcome and was not supported by a significant effect on CV death.

8.4.4 Adverse effects and interactions Anti-PCSK9 mAbs are injected subcutaneously, every other week or once a month, at different doses depending on the agent used. The potential for interaction with orally absorbed drugs is absent, as they will not interfere with pharmacokinetics or pharmacodynamics. Among the most frequently reported side effects are itching at the site of injection and flu-like symptoms.292 In some studies, an increase of patient-reported neurocognitive effects has been described.293 However, the EBBINGHAUS trial,231 which was specifically designed to detect neurocognitive function changes, was reassuring, as were the safety reports in both the FOURIER and ODYSSEY trials. Mendelian randomization studies have also suggested that PCSK9 inhibition may increase the risk of DM with an LDL-C-related effect, as apparently occurs for statins.294 To date, no signal has emerged from RCTs.295297 Although large long-term trials of PCSK9 inhibitors are needed to rule out these and other potential side effects of inhibition of PCSK9,298 7 year data from the IMPROVE-IT study have shown that prolonged low LDL-C concentrations are not associated with any clear adverse effects.299 A potential problem of long-term antibody treatment is the occurrence of autoantibodies. Evolocumab and alirocumab are fully human antibodies and, therefore, theoretically less likely to induce autoantibodies. To date, only very few cases of antidrug antibodies have been reported, and no reduction of LDL-C lowering has been observed, but long-term use needs to be monitored. Indeed, the development programme for a third PCSK9 inhibitor, bococizumab, a humanized antibody, was discontinued because of an increase of neutralizing antibodies, which resulted in the attenuation of the LDL-C-lowering effect over time, as well as a higher rate of injection site reactions.300 However, although PCSK9 inhibitors are very effective drugs that can reduce LDL-C and CV events on top of statin and/or ezetimibe treatment, considering the costs of the treatments and the limited data on long-term safety, these drugs are likely to be considered costeffective only in those patients at very high-risk of ASCVD, and their use may not be possible in some countries with limited healthcare resources.

8.5 Lomitapide

The microsomal TG transfer protein (MTP) transfers TGs and phospholipids from the endoplasmic reticulum to ApoB, as a necessary step in the formation of VLDL. MTP inhibition thus prevents the formation of VLDL in the liver and of chylomicrons in the intestine. Lomitapide is an MTP inhibitor designed for o.d. oral treatment of HoFH. In an open-label, single-arm titration study evaluating lomitapide as adjunct therapy to statins, with or without apheresis and a low-fat diet,301 LDL-C was reduced by 50% from baseline at 26 weeks and by 44% at 56 weeks. Lomitapide was also shown to decrease the frequency of apheresis in HoFH patients. It should be noted that the drug’s effect on CV outcomes has not yet been determined.

As a consequence of its mechanism of action, lomitapide has been shown to be associated with increased aminotransferase levels, which most likely reflects the increased fat in the liver, as well as poor GI tolerability.301,302 The GI side effects were the most frequent reasons preventing a further increase in the dose of lomitapide in clinical trials.301 However, it has been noted that the frequency and intensity of GI side effects generally decrease with time. Therefore, prescription of lomitapide requires careful patient education and liver function monitoring during therapy.

8.6 Mipomersen

Mipomersen is an antisense oligonucleotide able to bind the messenger RNA (mRNA) of ApoB-100, which triggers the selective degradation of mRNA molecules. After subcutaneous injection, the oligonucleotide is preferentially transported to the liver, where it binds to a specific mRNA preventing the translation of ApoB protein and, consequently, reducing the production of atherogenic lipids and lipoproteins, including LDL and Lp(a).303 An adjunct to lipid-lowering medications and diet, mipomersen is indicated to reduce LDL-C in patients with HoFH. Mipomersen is currently approved by the US Food and Drug Administration (FDA), but not by the European Medicines Agency (EMA). Reactions at the injection site are the most common adverse effects observed in patients treated with mipomersen.304 However, the main concerns regarding mipomersen’s safety are related to liver toxicity. Mipomersen may lead to the development of steatosis. Treated patients have shown a higher increase of liver fat from baseline compared with patients randomized to placebo.303 The efficacy and safety of long-term mipomersen treatment are currently under evaluation in patients with severe HeFH, and in statin-‘intolerant’ patients.

8.7 Fibrates

8.7.1 Mechanism of action Fibrates are agonists of peroxisome proliferator-activated receptora (PPAR-a), acting via transcription factors regulating, among other things, various steps in lipid and lipoprotein metabolism. As a consequence, fibrates have good efficacy in lowering fasting TG levels, as well as post-prandial TGs and TG-rich lipoprotein (TRL) remnant particles.

8.7.2 Effects on lipids Clinical impacts on lipid profiles vary among members of the fibrate class, but are estimated to reach a 50% reduction of the TG level, a <_20% reduction of the LDL-C level (but a paradoxical small LDL-C increase may be observed with high TG levels), and an increase of the HDL-C level of <_20%. The magnitude of effect is highly dependent on the baseline lipid levels.305 Both the HDL-raising and Downloaded from academic.oup.com/eurheartj/article/41/1/111/5556353 by guest on 07 October 2026