Chinese Expert Consensus on the use of GLP-1RAs in patients with type 2 diabetes mellitus complicated by arteriosclerotic cardiovascular disease
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摘要: 胰高糖素样肽-1受体激动剂(GLP-1RAs)除具有很强的降糖作用外，也具有很强的心血管保护作用。随着心血管结局研究结果的公布，GLP-1RAs也被证实可显著改善2型糖尿病患者合并动脉粥样硬化性心脏病的远期风险。本共识针对GLP-1RAs药理学、心血管保护机制、循证医学证据、临床应用建议、不良反应及注意事项等临床问题给出具体的推荐意见。
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关键词:
- 胰高血糖素样肽-1受体激动剂 /
- 2型糖尿病 /
- 动脉粥样硬化性心血管疾病
Abstract: Glucagon like peptide-1 receptor agonists (GLP-1RAs) not only have strong hypoglycemic effects, but also have strong cardiovascular protective effects. With the announcement of cardiovascular outcomes, GLP-1RAs have been proved to improve the long-term risk of type 2 diabetes patients with atherosclerotic heart disease significantly.This consensus provides specific recommendations on clinical issues such as GLP-1RAs pharmacology, cardiovascular protection mechanisms, evidence-based medical evidence, clinical application recommendations, adverse reactions, and precautions. -
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图 1 GLP-1RAs治疗ASCVD的药理作用
Figure 1. Pharmacological effects of GLP-1RAs in the treatment of ASCVD
表 1 GLP-1RAs分子结构和药代动力学特点
Table 1. Molecular structure and pharmacokinetic characteristics of GLP-1RAs
药物 分子结构 与人GLP-1
同源性/%作用时间 半衰期 给药频率 艾塞那肽 exendin-4 53 短效 2.4 h 每日2次 贝那鲁肽 重组人GLP-1 100 短效 11 min 每日3次 利司那肽 改良的exendin-4 50 短效 2~5 h 每日1次 利拉鲁肽 改良的人GLP-1 97 长效 13 h 每日1次 艾塞那肽周制剂 exendin-4 53 长效 2.4 h(缓释剂) 每周1次 阿必鲁肽 改良的人GLP-1 97 长效 4~5 d 每周1次 度拉糖肽 改良的人GLP-1 90 长效 4.7 d 每周1次 司美格鲁肽 改良的人GLP-1 94 长效 165 h 每周1次 
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表 2 GLP-1RAs在T2DM合并ASCVD中应用的主要随机临床试验汇总(一)
Table 2. Summary of CVOT on the cardiovascular application of GLP-1RAs
药物 主要心血管事件 全因死亡 心血管死亡 非致死性卒中 心力衰竭住院率 肾脏复合结局 阿必鲁肽 Harmony Outcomes 利司那肽 ELIXA 度拉糖肽 REWIND REWIND REWIND 艾塞那肽 EXSCEL 利拉鲁肽 LEADER LEADER LEADER LEADER 司美格鲁肽 SUSTAIN6-13 PIONEER 6 PIONEER 6 SUSTAIN-6 SUSTAIN-6 Efpeglenatide AMPLITUDE-O AMPLITUDE-O AMPLITUDE-O
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表 3 GLP-1RAs在T2DM合并ASCVD中应用的主要随机临床试验汇总(二)
Table 3. Summary of CVOT on the cardiovascular application of GLP-1RAs
试验 ELIXA LEADER SUSTAIN-6 EXSCEL REWIND PIONEER-6 Hamony AMPLITUDE-O 药物 利司那肽 利拉鲁肽 司美格鲁肽皮下 艾塞那肽 度拉糖肽 司美格鲁肽口服 阿必鲁肽 Efpeglenatide 入组受试者/例 6 068 9 340 3 297 1 4752 9 901 3 183 9 463 4 076 随访时间/年 2.1 3.8 2.1 3.2 5.4 1.3 2.3 2 合并ASCVD/% 100 81 72 73 31 85 70 89.6 基线心力衰竭/% 22 18 24 16 9 未报道 20 18.1 糖尿病病史/年 9.3 12.8 13.9 12.0 9.5 14.9 14.2 15.4 基线HbA1c/% 7.7 8.7 8.7 8.0 7.2 8.2 8.4 8.91 他汀应用率/% 93 72 73 74 66 85 84 80.8 主要终点事件/HR(95%CI) 1.02
(0.89~1.17)0.87
(0.78~0.97)0.74
(0.58~0.95)0.91
(0.83~1.00)0.88
(0.79~0.99)0.79
(0.57~1.11)0.78
(0.68~0.90)0.73
(0.58~0.92)主要终点事件发生数量 844例 1 302例 254例 839例 2.35例/100例 136例 766例 314例 心血管死亡率/HR(95%CI) 0.98
(0.78~1.22)0.78
(0.66~0.93)0.98
(0.65~1.48)0.88
(0.76~1.02)0.91
(0.87~1.06)0.49
(0.27~0.92)0.93
(0.73~1.19)0.71
(0.59~0.87)心肌梗死发生率/HR(95%CI) 1.03
(0.87~1.22)0.86
(0.73~1.00)0.74
(0.51~1.08)0.97
(0.85~1.10)0.96
(0.79~1.15)1.18
(0.73~1.90)0.75
(0.61~0.90)0.75
(0.54~1.05)卒中发生率/HR(95%CI) 1.12
(0.79~1.58)0.86
(0.71~1.06)0.61
(0.38~0.99)0.85
(0.70~1.03)0.76
(0.62~0.94)0.74
(0.35~1.57)0.86
(0.66~1.14)0.74
(0.47~1.17)全因死亡率/HR(95%CI) 0.94
(0.78~1.13)0.85
(0.74~0.97)1.05
(0.74~1.50)0.86
(0.77~0.97)0.90
(0.80~1.01)0.51
(0.31~0.84)0.95
(0.79~1.16)0.78
(0.58~1.06)心力衰竭住院率/HR(95%CI) 0.96
(0.75~1.23)0.87
(0.73~1.05)0.86
(0.48~1.55)0.94
(0.78~1.13)0.93
(0.77~1.12)1.11
(0.77~1.61)0.85
(0.70~1.04)0.61
(0.380.98)
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表 4 GLP-1RAs治疗CVD的临床应用建议
Table 4. Clinical application recommendations for GLP-1RAs in the treatment of ASCVD
建议 推荐级别 证据等级 T2DM合并ASCVD患者推荐起始使用具有明确心血管获益的GLP-1RAs，不需考虑患者HbA1c水平和二甲双胍是否正在使用 Ⅰ A T2DM合并ASCVD高危因素但未确诊ASCVD患者推荐应用具有明确心血管获益的GLP-1RAs，其中度拉糖肽可用于主要心血管病变的一级预防 Ⅱa B 推荐级别：Ⅰ级指已证实和(或)一致公认有益、有用和有效的操作或治疗，推荐使用；Ⅱ级指有用和(或)有效的证据尚有矛盾或存在不同观点的操作或治疗；Ⅱa级指有关证据/观点倾向于有用和(或)有效，应用这些操作或治疗是合理的，应当考虑使用；Ⅱb级指有关证据/观点尚不能被充分证明有用和(或)有效，可以考虑使用；Ⅲ级指已证实和(或)一致公认无用和(或)无效，并对一些病例可能有害的操作或治疗，不推荐使用。证据水平：A级资料来源于多项随机对照研究或荟萃分析；B级资料来源于单项随机对照研究或大型非随机对照研究；C级资料来源于专家共识和(或)小型研究、回顾性分析、注册研究。
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表 5 GLP-1RAs的用法与用量
Table 5. Usage and dosage of GLP-1RAs
药物 规格 初始剂量 剂量调整/目标剂量 药物的供应形式 是否配
有针头利拉鲁肽 3 mL：18 mg 0.6 mg每日1次(可在任何时间给药) 可每周增加1次剂量，1周后增至1.2 mg每日1次。如需进一步控制血糖，可继续增至1.8 mg每日1次 1支注射笔有3个不同的可程序化调节剂量(0.6、1.2和1.8 mg)。注射笔可多次使用，针头为一次性 否 注射用司美格鲁肽 1.34 mg/mL，1.5 mL
1.34 mg/mL，3 mL0.25 mg每周1次(可在任何时间给药) 可每4周增加1次剂量，4周后增至0.5 mg每周1次。如需进一步控制血糖，可继续增至1.0 mg每周1次 提供2种不同的注射笔，每支笔有2个可程序化调节的剂量：一支笔允许使用0.25和0.5 mg的剂量，另一支笔允许使用1.0 mg的剂量。注射笔可多次使用，针头为一次性 否 度拉糖肽 1.5 mg：0.5 mL 1.5 mg每周1次 注射笔为一次性 是
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