University of Washington Diabetes Institute, Seattle, Washington 98195 (A.C.) and University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado 80045 (R.H.E.).
J Clin Endocrinol Metab. 2016 Mar;101(3):804-14. doi: 10.1210/jc.2015-3940. Epub 2016 Feb 23.
While substantial benefit has accrued with respect to prevention and treatment of atherosclerotic cardiovascular disease (ASCVD) since the advent of statin therapy, much remains unknown and there is considerable need to address residual risk beyond statins. Moreover, many individuals are unable to tolerate statins.
As a result of several recent clinical trials and publications describing early Phase 1-3 clinical trials, the authors briefly discuss the current situation regarding pharmacological management for the prevention and treatment of individuals with disorders of lipid and lipoprotein metabolism, outline some of the unanswered questions, and speculate on where we might expect to be in 5-10 years.
Fortunately, recent developments in drug therapy hold considerable promise of additional benefits. In addition, new drugs in the pipeline, ongoing clinical trials, and new approaches to treatment hold promise for further improvements in therapy in the foreseeable future. During the next 5-10 years, we expect to know whether the PCSK9 inhibitors indeed live up to their promise and result in the hoped-for reduction in ASCVD events, whether triglyceride lowering indeed adds additional benefit, how best to approach HDL, and the importance of lipoprotein (a). Advances in the use of molecular biological approaches such as anti-sense oligonucleotides and RNA silencing, and the use of biological agents such as PSCK9 antibodies, is likely to play an important role in these advances.
The advent of PCSK9 inhibitors is likely to provide a major breakthrough in the management of individuals with heterozygous familial hypercholesterolemia, patients with established ASCVD who are unable to reach targets with other therapies, and high-risk individuals with statin intolerance. The next 5-10 years should also clarify uncertainties concerning the pharmacological management of individuals with low levels of HDL-cholesterol, hypertriglyceridemia, and elevated lipoprotein (a).
自他汀类药物治疗问世以来，在预防和治疗动脉粥样硬化性心血管疾病（ASCVD）方面已经取得了实质性的收益，但仍有许多未知之处，并且需要解决他汀类药物以外的剩余风险。此外，许多人无法耐受他汀类药物。
由于最近的几项临床试验和出版物描述了早期的 1 期至 3 期临床试验，作者简要讨论了目前在预防和治疗脂质和脂蛋白代谢紊乱个体方面的药物管理情况，概述了一些尚未解决的问题，并推测在未来 5-10 年内我们可能会处于什么位置。
幸运的是，药物治疗的最新进展带来了额外的益处。此外，新的药物研发、正在进行的临床试验以及新的治疗方法有望在可预见的未来进一步改善治疗效果。在未来的 5-10 年内，我们预计将了解 PCSK9 抑制剂是否真的能实现其承诺，是否能降低 ASCVD 事件，降低甘油三酯是否真的能带来额外的益处，如何最好地处理 HDL，以及脂蛋白（a）的重要性。在使用分子生物学方法（如反义寡核苷酸和 RNA 沉默）和生物制剂（如 PCSK9 抗体）方面的进展可能在这些进展中发挥重要作用。
PCSK9 抑制剂的出现可能为治疗杂合子家族性高胆固醇血症患者、无法通过其他治疗方法达到目标的已确诊 ASCVD 患者以及他汀类药物不耐受的高危人群提供重大突破。未来的 5-10 年也应该阐明有关治疗低水平高密度脂蛋白胆固醇、高甘油三酯血症和升高的脂蛋白（a）患者的药物管理方面的不确定性。
