Background

Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) significantly lower the levels of low-density lipoprotein and very-low-density lipoproteins (VLDL), but their effect on postprandial lipoprotein metabolism in dyslipidemic subjects is unclear.

Objective

This study aimed to investigate the effects of evolocumab on postprandial lipid responses, ectopic fat depots, whole-body cholesterol synthesis, hepatic lipogenesis, and fat oxidation in patients with type II diabetes.

Methods

The trial was a single-phase, nonrandomized study of 12-week treatment with evolocumab 140 mg subcutaneously every 2 weeks in 15 patients with type II diabetes on background statin therapy. Cardiometabolic responses to a high-fat mixed meal were assessed before and at the end of the intervention period.

Results

Evolocumab treatment reduced significantly postprandial rises in plasma total triglyceride (by 21%; P < .0001) and VLDL₁ triglyceride (by 15%; P = .018), but the increase in chylomicron triglyceride after the meal was not significantly perturbed (P = .053). There were reduced postprandial responses in plasma total apolipoprotein C-III (by 14%; P < .0001) and apolipoprotein B-48 concentration (by 17%; P = .0046) and in “remnant-like particles” cholesterol (by 29%; P < .0001) on the PCSK9 inhibitor. Treatment reduced the steady-state (ie, fasting and postprandial) concentrations of VLDL₂ cholesterol by 50% (P < .0001) and VLDL₂ triglyceride by 29% (P < .0001), in addition to the 78% reduction of low-density lipoprotein cholesterol (P < .001). The changes in apolipoprotein C-III associated significantly with reduction in postprandial responses of remnant-like particles cholesterol and triglyceride-rich lipoprotein cholesterol. Evolocumab therapy did not influence liver fat accumulation, hepatic de novo lipogenesis, or fasting β-hydroxybutyrate but did increase total body cholesterol synthesis (P < .01).

Conclusion

Evolocumab treatment improved postprandial responses of triglyceride-rich lipoproteins and measures of cholesterol-enriched remnant particles in type II diabetic subjects. These results indicate that postprandial phenomena need to be taken into account in assessing the full range of actions of PCSK9 inhibitors in dyslipidemic individuals.

中文翻译：

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evolocumab抑制前蛋白转化酶枯草杆菌蛋白酶/ kexin 9型对II型糖尿病受试者餐后富含甘油三酸酯的脂蛋白的反应。

背景

原蛋白转化酶枯草杆菌蛋白酶/ kexin型9（PCSK9）的单克隆抗体显着降低了低密度脂蛋白和极低密度脂蛋白（VLDL）的水平，但它们对血脂异常受试者的餐后脂蛋白代谢的影响尚不清楚。

客观的

这项研究的目的是研究依伏洛单抗对II型糖尿病患者餐后脂质反应，异位脂肪贮库，全身胆固醇合成，肝脂肪生成和脂肪氧化的影响。

方法

该试验是对15例II型糖尿病患者进行他汀类药物背景治疗后，每2周皮下注射evolocumab 140 mg每12周治疗12周的非随机研究。在干预期之前和结束时评估对高脂混合餐的心脏代谢反应。

结果

Evolocumab治疗可显着降低餐后血浆总甘油三酯（降低21％; P  <.0001）和VLDL ₁甘油三酸酯（降低15％; P  = .018），但餐后乳糜微粒甘油三酸酯的增加并未受到明显干扰（P  = .053）。血浆总载脂蛋白C-III（降低14％；P  <.0001）和载脂蛋白B-48浓度（降低17％；P  = .0046）和“残留样颗粒”胆固醇（降低29）的餐后反应均降低％；P  <.0001）在PCSK9抑制剂上。治疗使VLDL ₂胆固醇的稳态（即空腹和餐后）浓度降低了50％（P 除了低密度脂蛋白胆固醇降低了78％（P  <.001） ，VLDL ₂甘油三酯降低了29％（P <.0001 ）。载脂蛋白C-III的变化与残余样颗粒胆固醇和富含甘油三酸酯的脂蛋白胆固醇的餐后反应减少显着相关。Evolocumab治疗不影响肝脏脂肪积聚，肝新生脂肪形成或禁食β-羟基丁酸酯，但确实增加了体内总胆固醇的合成（P  <.01）。

结论

Evolocumab治疗改善了II型糖尿病患者的富含甘油三酸酯的脂蛋白的餐后反应，并测定了富含胆固醇的残余颗粒。这些结果表明，在评估血脂异常人群中PCSK9抑制剂的全部作用时，应考虑餐后现象。