BACKGROUND Individuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778). METHODS In DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C ≥ 100 mg/dL; n = 413) were randomized to open-label alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C ≥ 70 mg/dL; n = 441) were randomized in a double-blind fashion to alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin < 9% (DM-DYSLIPIDEMIA) or < 10% (DM-INSULIN). Alirocumab dose was increased to 150 mg Q2W at week 12 if week 8 LDL-C was ≥ 70 mg/dL (DM-INSULIN) or non-HDL-C was ≥ 100 mg/dL (DM-DYSLIPIDEMIA). Lipid reductions and safety were assessed in patients with ASCVD from these studies. RESULTS This analysis included 142 DM-DYSLIPIDEMIA and 177 DM-INSULIN participants with ASCVD, including 95.1% and 86.4% with coronary heart disease, and 32.4% and 49.7% with microvascular diabetes complications, respectively. At week 24, alirocumab significantly reduced LDL-C, non-HDL-C, ApoB, and LDL-PN from baseline versus control. This translated into a greater proportion of individuals achieving non-HDL-C < 100 mg/dL (64.6% alirocumab/23.8% UC [DM-DYSLIPIDEMIA]; 65.4% alirocumab/14.9% placebo [DM-INSULIN]) and ApoB < 80 mg/dL (75.1% alirocumab/35.4% UC and 76.8% alirocumab/24.8% placebo, respectively) versus control at week 24 (all P < 0.0001). In pooling these studies, 66.4% (alirocumab) and 67.0% (control) of individuals reported treatment-emergent adverse events. The adverse event pattern was similar with alirocumab versus controls. CONCLUSIONS Among individuals with T2DM and ASCVD who had high non-HDL-C/LDL-C levels despite maximally tolerated statin, alirocumab significantly reduced atherogenic cholesterol and LDL-PN versus control. Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov. NCT02642159. Registered 30 December 2015 and Clinicaltrials.gov. NCT02585778. Registered 23 October 2015.

中文翻译：

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Alirocumab 治疗 2 型糖尿病和动脉粥样硬化性心血管疾病患者：ODYSSEY DM-血脂异常和 DM-胰岛素研究分析。


背景 糖尿病患者的致动脉粥样硬化脂蛋白和胆固醇水平通常较高，表现为低密度脂蛋白胆固醇 (LDL-C)、非高密度脂蛋白胆固醇 (non-HDL-C)、载脂蛋白 B (ApoB) 和 LDL 升高颗粒数（LDL-PN）。动脉粥样硬化性心血管疾病（ASCVD）的存在会增加未来心血管事件的风险。我们评估了前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型 (PCSK9) 抑制剂 alirocumab 在 2 型糖尿病 (T2DM)、高 LDL-C 或非 HDL-C 患者中的疗效和安全性，并确定接受最大耐受他汀类药物的 ASCVD ODYSSEY DM-血脂异常 (NCT02642159) 和 DM-胰岛素 (NCT02585778)。方法 在 DM-血脂异常中，患有 T2DM 和混合性血脂异常（非 HDL-C ≥ 100 mg/dL；n = 413）的个体被随机分配接受开放标签 alirocumab 75 mg 每 2 周 (Q2W) 或常规治疗 (UC) 治疗组24 周，在分层随机化之前选择 UC 选项。在 DM-INSULIN 试验中，接受胰岛素治疗的 T2DM 患者（LDL-C ≥ 70 mg/dL；n = 441）以双盲方式随机接受 alirocumab 75 mg Q2W 或安慰剂组，为期 24 周。研究参与者的糖化血红蛋白也为 < 9%（DM-血脂异常）或 < 10%（DM-胰岛素）。如果第 8 周 LDL-C ≥ 70 mg/dL（DM-胰岛素）或非 HDL-C ≥ 100 mg/dL（DM-血脂异常），Alirocumab 剂量在第 12 周增加至 150 mg Q2W。这些研究对 ASCVD 患者的降脂效果和安全性进行了评估。结果该分析包括 142 名患有 ASCVD 的 DM-血脂异常和 177 名 DM-INSULIN 参与者，其中分别有 95.1% 和 86.4% 患有冠心病，32.4% 和 49.7% 患有微血管糖尿病并发症。 第 24 周时，与对照相比，alirocumab 显着降低了基线 LDL-C、非 HDL-C、ApoB 和 LDL-PN。这意味着达到非 HDL-C < 100 mg/dL 的个体比例更高（64.6% alirocumab/23.8% UC [DM-血脂异常]；65.4% alirocumab/14.9% 安慰剂 [DM-胰岛素]）和 ApoB %第 24 周时与对照相比，3C 80 mg/dL（分别为 75.1% alirocumab/35.4% UC 和 76.8% alirocumab/24.8% 安慰剂）（所有 P < 0.0001）。汇总这些研究后，66.4%（alirocumab）和 67.0%（对照）的个体报告了治疗引起的不良事件。 alirocumab 与对照组的不良事件模式相似。结论 在患有 T2DM 和 ASCVD 的个体中，尽管他汀类药物具有最大耐受性，但非 HDL-C/LDL-C 水平仍较高，alirocumab 与对照组相比显着降低了致动脉粥样硬化胆固醇和 LDL-PN。 Alirocumab 通常耐受性良好。试验注册 ClinicalTrials.gov。 NCT02642159。于 2015 年 12 月 30 日在 ClinicalTrials.gov 注册。 NCT02585778。注册日期：2015 年 10 月 23 日。