New LDL-cholesterol lowering therapies: pharmacology, clinical trials, and relevance to acute coronary syndromes.

Reduction in plasma low-density lipoprotein cholesterol (LDL-C) is a fundamental treatment for the prevention of acute coronary syndromes (ACS). Although statin therapy confers significant protection against ACS in both primary and secondary prevention, a considerable residual risk remains after intensive therapy. In addition, a significant proportion of high-risk patients do not achieve the optimal LDL-C goal recommended in the current guidelines (<1.8 mmol/L). Hence, novel LDL-C-lowering agents that act via mechanisms distinct from HMG-CoA reductase inhibition are under investigation. We reviewed the recent literature on the development of novel LDL-C-lowering agents that could potentially be used as an alternative or adjunct to statin therapy in high-risk coronary patients. PubMed and Scopus databases were searched to retrieve studies on the efficacy and/or tolerability of novel LDL-C-lowering agents in animals and humans. Agents that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein (apo) B, and microsomal triglyceride transfer protein (MTTP) are the most promising therapies. Inhibition of PCSK9, apoB, and MTTP has been achieved mostly via fully humanized monoclonal antibodies (mAbs), antisense oligonucleotides, and synthetic compounds, respectively. PCSK9 inhibitors increase the hepatic uptake of LDL-C, while apoB and MTTP inhibitors decrease the synthesis and secretion of apoB-containing lipoproteins. These 3 mechanisms lead to marked reductions in plasma LDL-C in patients with hypercholesterolemia at risk for ACS, particularly those with familial hypercholesterolemia. Moreover, these agents can exert additional benefits by decreasing plasma levels of apoB, triglycerides, and lipoprotein(a). Mipomersen and lomitapide have been approved by the United States Food and Drug Administration (US FDA) for use in patients with homozygous familial hypercholesterolemia. PCSK9 inhibitors are currently under final evaluation in clinical outcomes studies and are anticipated to find wide application either as monotherapy or as an adjunct to statins. A main safety concern is the risk for hepatic steatosis with apoB and MTTP inhibitors, which needs to be explored in prospective, long-term trials. PCSK9, apoB, and MTTP inhibitors can exert potent reductions in plasma LDL-C and apoB concentrations, either as monotherapy or in combination with statins. These effects are particularly relevant to high-risk individuals with marked hypercholesterolemia, such as those with familial hypercholesterolemia. Although the use of mipomersen and lomitapide is limited to severe familial hypercholesterolemia as a replacement for LDL-apheresis, PCSK9 inhibitors are likely to be more widely prescribed in patients at high risk for CVD, especially those who are resistant to or intolerant of high-intensity statin therapy. PCSK9 mAbs are efficacious and have an excellent safety profile, but their long-term impact on cardiovascular events is currently under investigation. Whether PCSK9 mAbs decrease the rates of recurrent cardiovascular events within 3 months following ACS is questionable; however, these agents, unlike statins, may not have pleiotropic benefits on the unstable plaque.

Sahebkar A ，Watts GF 《-》

Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial.

Following acute coronary syndrome (ACS), the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol (LDL-C) even within the setting of intensive statin treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab, a fully human monoclonal antibody to PCSK9, improves cardiovascular outcomes after ACS. This Phase 3 study will randomize approximately 18,000 patients to receive biweekly injections of alirocumab (75-150 mg) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infarction or unstable angina. Qualifying patients are treated with atorvastatin 40 or 80 mg daily, rosuvastatin 20 or 40 mg daily, or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria: LDL-C ≥ 70 mg/dL, non-high-density lipoprotein cholesterol ≥ 100 mg/dL, or apolipoprotein B ≥ 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years, providing 90% power to detect a 15% hazard reduction. Adverse events of special interest include allergic events and injection site reactions. Interim analyses are planned when approximately 50% and 75% of the targeted number of primary end points have occurred. ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS.

Schwartz GG ，Bessac L ，Berdan LG ，Bhatt DL ，Bittner V ，Diaz R ，Goodman SG ，Hanotin C ，Harrington RA ，Jukema JW ，Mahaffey KW ，Moryusef A ，Pordy R ，Roe MT ，Rorick T ，Sasiela WJ ，Shirodaria C ，Szarek M ，Tamby JF ，Tricoci P ，White H ，Zeiher A ，Steg PG ... -  《-》

Management of Hypercholesterolemia, Appropriateness of Therapeutic Approaches and New Drugs in Patients with High Cardiovascular Risk.

Agabiti Rosei E ，Salvetti M 《-》

Promising new therapies for the treatment of hypercholesterolemia.

Valerio MG ，Velayati A ，Jain D ，Aronow WS ... -  《-》

New therapies targeting apoB metabolism for high-risk patients with inherited dyslipidaemias: what can the clinician expect?

Sahebkar A ，Watts GF 《-》