Filippatos Theodosios D, Panagiotopoulou Thalia, Tzavella Eleftheria, Elisaf Moses S
1 Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina, Greece.
J Cardiovasc Pharmacol Ther. 2018 May;23(3):187-191. doi: 10.1177/1074248418757011. Epub 2018 Feb 7.
Clinical trials and meta-analyses have shown that statins can dose dependently increase the incidence of new-onset diabetes mellitus (DM) especially in patients with underlying abnormalities of carbohydrate homeostasis. Mendelian randomization studies support these findings since genetic variants in the gene encoding the target of statins, the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, are associated with increased incidence of new-onset DM, suggesting that the so-called diabetogenic effect of statins is an "on-target effect" possibly related to their main mechanism of action, that is the increased low-density lipoprotein (LDL) receptor expression. Additionally, Mendelian randomization studies have shown that genetic variants as proxies of other drugs that increase LDL receptor expression (ezetimibe and proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) also increase the risk of new-onset DM. This concept is supported by the fact of decreased DM prevalence in patients with familial hypercholesterolemia who have decreased LDL receptor expression. In contrast, hypolipidemic drugs, such as the cholesteryl ester transfer protein inhibitors, that decrease LDL cholesterol without directly interfering with the LDL receptor expression do not seem to detrimentally affect carbohydrate homeostasis. However, the clinical trials of ezetimibe and PCSK9 inhibitors have not shown an increased DM risk, possibly suggesting that other potential non-well-defined "off-target effects" of hypolipidemic drugs may affect carbohydrate homeostasis. Thus, the long-term effect of hypolipidemic drugs on DM risk depends not only on their final mechanism of hypolipidemic action but also on other "on-target" and "off-target" effects of these drugs.
临床试验和荟萃分析表明，他汀类药物可剂量依赖性地增加新发糖尿病（DM）的发病率，尤其是在碳水化合物稳态存在潜在异常的患者中。孟德尔随机化研究支持这些发现，因为编码他汀类药物靶点的基因（即3-羟基-3-甲基戊二酰辅酶A还原酶）中的遗传变异与新发DM的发病率增加相关，这表明他汀类药物所谓的致糖尿病作用是一种“靶向效应”，可能与其主要作用机制有关，即低密度脂蛋白（LDL）受体表达增加。此外，孟德尔随机化研究表明，作为增加LDL受体表达的其他药物（依泽替米贝和前蛋白转化酶枯草溶菌素/kexin 9型[PCSK9]抑制剂）替代物的遗传变异也会增加新发DM的风险。家族性高胆固醇血症患者LDL受体表达降低，其DM患病率下降这一事实支持了这一概念。相比之下，降低LDL胆固醇但不直接干扰LDL受体表达的降血脂药物，如胆固醇酯转移蛋白抑制剂，似乎不会对碳水化合物稳态产生不利影响。然而，依泽替米贝和PCSK9抑制剂的临床试验并未显示DM风险增加，这可能表明降血脂药物的其他潜在未明确的“非靶向效应”可能会影响碳水化合物稳态。因此，降血脂药物对DM风险的长期影响不仅取决于其降血脂作用的最终机制，还取决于这些药物的其他“靶向”和“非靶向”效应。
