Department of Pharmacology and Toxicology, College of Pharmacy, University of Sulaimani, Sulaimani, Federal Region of Kurdistan, Iraq.
Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom; Centre for Diabetes, Endocrinology and Metabolism, Manchester University NHS Foundation Trust, Manchester, United Kingdom.
Clin Ther. 2022 Feb;44(2):331-348. doi: 10.1016/j.clinthera.2021.12.005. Epub 2022 Mar 1.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that have proven efficacy in improving cardiovascular outcomes. Roles for the PCSK9 molecule in metabolic pathways beyond LDL receptor processing and cholesterol homeostasis are well established. PCSK9 genetic variants associated with lower LDL-C levels correlate with a higher incidence of type 2 diabetes (T2DM), calling into question the appropriateness of these drugs in patients with T2DM and those at high risk of developing diabetes, and whether cardiovascular benefit seen with PCSK9 inhibitors might be offset by resultant dysglycemia. The purpose of this review was to examine the role of PCSK9 protein in glucose homeostasis, the impact of PCSK9 inhibition in relation to glucose homeostasis, and whether some of the cardiovascular benefit seen with PCSK9 inhibitors and statins might be offset by resultant dysglycemia.
Comprehensive literature searches of electronic databases of PubMed, EMBASE, and OVID were conducted by using the search terms hyperlipidaemia, PCSK9, diabetes, and glucose as well as other relevant papers of interest collected by the authors. The retrieved papers were reviewed and shortlisted most relevant ones.
Genetically determined lower circulating LDL-C and PCSK9 concentrations may have an incremental effect in increasing T2DM incidence, but any perceived harm is outweighed by the reduced risk of atherosclerotic cardiovascular disease achieved through lower lifetime exposure to LDL-C. PCSK9 monoclonal antibodies are effective and safe in patients with T2DM and those at high risk of developing it. The number-needed-to-treat to prevent one atherosclerotic cardiovascular disease event in the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) study in the subgroup with diabetes is significantly lower than for those without. Therefore, T2DM or being at high risk to develop it should not be a reason to avoid these agents. The safety of PCSK9 inhibition in relation to glucose homeostasis may depend on the method of inhibition and whether it occurs in circulation or the cells. Data from experimental studies and randomized controlled trials suggest no detrimental effect of PCSK9 monoclonal antibodies on glucose homeostasis. More data and large randomized controlled studies are needed to assess the impact of other methods of PCSK9 inhibition on glucose homeostasis.
PCSK9monoclonal antibodies markedly reduce LDL-C and consistently reduce cardiovascular mortality in patients with and without diabetes. Current evidence does not suggest an adverse effect of PCSK9 monoclonal antibodies on glycemic parameters.
前蛋白转化酶枯草溶菌素 9（PCSK9）抑制剂是一种新型药物，已被证实能有效改善心血管结局。PCSK9 分子在 LDL 受体加工和胆固醇稳态以外的代谢途径中的作用已得到充分证实。与 LDL-C 水平降低相关的 PCSK9 遗传变异与 2 型糖尿病（T2DM）的发生率较高有关，这使得这些药物在 T2DM 患者和发生糖尿病风险较高的患者中的适用性以及 PCSK9 抑制剂带来的心血管获益是否可能被由此产生的血糖异常所抵消受到质疑。本综述的目的是研究 PCSK9 蛋白在血糖稳态中的作用、PCSK9 抑制对血糖稳态的影响，以及 PCSK9 抑制剂和他汀类药物带来的部分心血管获益是否可能被由此产生的血糖异常所抵消。
使用电子数据库 PubMed、EMBASE 和 OVID 进行了全面的文献检索，使用的检索词包括高脂血症、PCSK9、糖尿病和葡萄糖，以及作者收集的其他相关论文。对检索到的论文进行了审查，并对最相关的论文进行了筛选。
循环中较低的 LDL-C 和 PCSK9 浓度可能与 T2DM 发生率的增加有增量关系，但通过降低 LDL-C 的终生暴露来降低动脉粥样硬化性心血管疾病的风险，超过了由此产生的血糖异常带来的潜在危害。PCSK9 单克隆抗体在 T2DM 患者和发生糖尿病风险较高的患者中安全有效。在 FOURIER（用 PCSK9 抑制剂治疗高危人群的进一步心血管结局研究）研究中，糖尿病亚组每治疗 26 例患者即可预防一例动脉粥样硬化性心血管疾病事件，这一数字明显低于无糖尿病患者。因此，T2DM 或发生糖尿病的高风险不应成为避免使用这些药物的理由。PCSK9 抑制与血糖稳态的安全性可能取决于抑制的方法以及抑制发生在循环中还是细胞中。来自实验研究和随机对照试验的数据表明，PCSK9 单克隆抗体对血糖稳态没有不良影响。需要更多的数据和大型随机对照试验来评估其他 PCSK9 抑制方法对血糖稳态的影响。
PCSK9 单克隆抗体可显著降低 LDL-C，并一致降低有或无糖尿病患者的心血管死亡率。目前的证据并未表明 PCSK9 单克隆抗体对血糖参数有不良影响。
