阿利西尤单抗对 2 型糖尿病、高甘油三酯和低高密度脂蛋白胆固醇患者的影响。
Effect of alirocumab on individuals with type 2 diabetes, high triglycerides, and low high-density lipoprotein cholesterol.
机构信息
The Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
出版信息
Cardiovasc Diabetol. 2020 Feb 8;19(1):14. doi: 10.1186/s12933-020-0991-1.
BACKGROUND
Mixed dyslipidemia [elevated non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides (TGs), and decreased HDL-C] is common in type 2 diabetes mellitus (T2DM) and is associated with increased cardiovascular risk. Non-HDL-C and apolipoprotein B (ApoB) are the preferred therapeutic targets for mixed dyslipidemia. Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) that effectively reduces low-density lipoprotein cholesterol (LDL-C), non-HDL-C, ApoB, and lipoprotein(a) (Lp[a]), and is well-tolerated in individuals with T2DM.
METHODS
The previously reported open-label ODYSSEY DM-DYSLIPIDEMIA trial data demonstrated the effects of alirocumab on individuals with non-HDL-C ≥ 100 mg/dL and TGs ≥ 150 and < 500 mg/dL receiving stable maximally tolerated statin (n = 413). This post hoc subgroup analysis of the primary trial investigated the effects of alirocumab [75 mg every 2 weeks (Q2W) with possible increase to 150 mg Q2W at Week 12] versus usual care [ezetimibe, fenofibrate, or no additional lipid-lowering therapy (LLT)] on non-HDL-C and other lipids in individuals with T2DM and baseline TGs ≥ 200 mg/dL and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women).
RESULTS
Alirocumab significantly reduced non-HDL-C [LS mean difference (standard error (SE)), - 35.0% (3.9)], ApoB [LS mean difference (SE), - 34.7% (3.6)], LDL-C [LS mean difference (SE), - 47.3% (5.2)], LDL particle number [LS mean difference (SE), - 40.8% (4.1)], and Lp(a) [LS mean difference (SE), - 29.9% (5.4)] versus usual care from baseline to Week 24 (all P < 0.0001). Results were similar for alirocumab versus usual care. TG reductions were similar between alirocumab and usual care (no significant difference), but greater with fenofibrate versus alirocumab (P = 0.3371). Overall, alirocumab significantly increased HDL-C versus usual care [LS mean difference (SE), 7.9% (3.6); P < 0.05], although differences with alirocumab versus ezetimibe or fenofibrate were non-significant. Most individuals receiving alirocumab achieved ApoB < 80 mg/dL (67.9%) and non-HDL-C < 100 mg/dL (60.9%). Adverse event frequency was similar between alirocumab (67.2%) and usual care (70.7%). Additionally, no clinically relevant effect of alirocumab on change in glycemic parameters or use of antihyperglycemic agents was observed.
CONCLUSIONS
Alirocumab is an effective therapeutic option for individuals with T2DM, TGs ≥ 200 mg/dL, and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women). Atherogenic lipid (ApoB and non-HDL) reductions were greater with alirocumab than ezetimibe, fenofibrate, or no LLT. Consistent with previous studies, alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov, NCT02642159. Registered December 24, 2015, https://clinicaltrials.gov/ct2/show/NCT02642159.
背景
2 型糖尿病（T2DM）患者常合并混合性血脂异常（即非高密度脂蛋白胆固醇（non-HDL-C）和甘油三酯（TGs）升高，高密度脂蛋白胆固醇（HDL-C）降低），并伴有心血管风险增加。非-HDL-C 和载脂蛋白 B（ApoB）是非混合性血脂异常的首选治疗靶点。Alirocumab 是一种针对前蛋白转化酶枯草溶菌素 9（PCSK9）的单克隆抗体，可有效降低 LDL-C、非-HDL-C、ApoB 和脂蛋白（a）（Lp[a]），在 T2DM 患者中耐受性良好。
方法
先前报告的开放标签 ODYSSEY DM-DYSLIPIDEMIA 试验数据显示，Alirocumab 可使非-HDL-C≥100mg/dL 和 TGs≥150mg/dL 且<500mg/dL 的患者受益[接受最大耐受剂量他汀治疗（n=413）]。本研究对主要试验进行了事后亚组分析，旨在探讨 Alirocumab（每 2 周 75mg，12 周时可能增至 150mg Q2W）与常规治疗（依折麦布、非诺贝特或无其他降脂治疗（LLT））相比，对 T2DM 患者、基线 TGs≥200mg/dL 和 HDL-C<40mg/dL（男性）或<50mg/dL（女性）的非-HDL-C 和其他血脂的影响。
结果
与常规治疗相比，Alirocumab 可显著降低非-HDL-C[LS 平均差值（标准误差（SE）），-35.0%（3.9）]、ApoB[LS 平均差值（SE），-34.7%（3.6）]、LDL-C[LS 平均差值（SE），-47.3%（5.2）]、LDL 颗粒数[LS 平均差值（SE），-40.8%（4.1）]和 Lp(a)[LS 平均差值（SE），-29.9%（5.4）]，差异均具有统计学意义（所有 P<0.0001）。与常规治疗相比，Alirocumab 也有类似的结果。与常规治疗相比，Alirocumab 组和常规治疗组的 TG 降低幅度相似（无显著差异），但与非诺贝特相比，Alirocumab 组的 TG 降低幅度更大（P=0.3371）。总的来说，与常规治疗相比，Alirocumab 可显著增加 HDL-C[LS 平均差值（SE），7.9%（3.6）；P<0.05]，尽管与 Alirocumab 相比，ApoB<80mg/dL 的比例（67.9%）和非-HDL-C<100mg/dL 的比例（60.9%）无显著差异。接受 Alirocumab 治疗的大多数患者可达到 ApoB<80mg/dL（67.9%）和非-HDL-C<100mg/dL（60.9%）。Alirocumab 组和常规治疗组的不良事件发生率相似（67.2% vs. 70.7%）。此外，Alirocumab 对血糖参数变化或抗高血糖药物使用无临床相关影响。
结论
Alirocumab 是 T2DM 患者、TGs≥200mg/dL 和 HDL-C<40mg/dL（男性）或<50mg/dL（女性）的有效治疗选择。与依折麦布、非诺贝特或无 LLT 相比，Alirocumab 可降低致动脉粥样硬化的脂质（ApoB 和非-HDL-C）。与既往研究一致，Alirocumab 通常具有良好的耐受性。临床试验注册信息 Clinicaltrials.gov，NCT02642159。注册日期 2015 年 12 月 24 日，https://clinicaltrials.gov/ct2/show/NCT02642159。
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