Advances in cardiovascular safety of SGLT-2 inhibitors and GLP-1 receptor agonists

LAI Yanlan; HUANG Aiwen; ZHANG Lili; LIAO Xiaolan; ZHAO Lijun; SONG Hongtao

doi:10.12206/j.issn.1006-0111.202006061

Volume 38 Issue 6

Nov. 2020

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Article Navigation > Journal of Pharmaceutical Practice and Service > 2020 > 38(6): 496-500, 567

LAI Yanlan, HUANG Aiwen, ZHANG Lili, LIAO Xiaolan, ZHAO Lijun, SONG Hongtao. Advances in cardiovascular safety of SGLT-2 inhibitors and GLP-1 receptor agonists[J]. Journal of Pharmaceutical Practice and Service, 2020, 38(6): 496-500, 567. doi: 10.12206/j.issn.1006-0111.202006061

Citation:

LAI Yanlan, HUANG Aiwen, ZHANG Lili, LIAO Xiaolan, ZHAO Lijun, SONG Hongtao. Advances in cardiovascular safety of SGLT-2 inhibitors and GLP-1 receptor agonists[J]. Journal of Pharmaceutical Practice and Service, 2020, 38(6): 496-500, 567. doi: 10.12206/j.issn.1006-0111.202006061

Advances in cardiovascular safety of SGLT-2 inhibitors and GLP-1 receptor agonists

doi: 10.12206/j.issn.1006-0111.202006061

LAI Yanlan^{1, 2
,},
HUANG Aiwen¹,
ZHANG Lili¹,
LIAO Xiaolan^{1, 2},
ZHAO Lijun^{1, 2},
SONG Hongtao^{1
,
,}

1.
Department of Pharmacy, No. 900 Hospital of Joint Logistics Support Force of the PLA, Fuzhou 350025, China
2.
Department of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China

Received Date: 2020-06-16
Rev Recd Date: 2020-09-07
Publish Date: 2020-11-25

Abstract

Type 2 diabetes is a high risk factor for atherosclerotic cardiovascular disease. Studies have found that SGLT-2 inhibitor and GLP-1 receptor agonists have cardiovascular protective effects in patients with type 2 diabetes and cardiovascular disease. Therefore, from the aspects of cardiovascular safety test and its Meta-analysis and net-like Meta-analysis, the research progress of cardiovascular safety of SGLT-2 inhibitors and GLP-1 receptor agonists is summarized.
- SGLT-2 inhibitors,
- GLP-1 receptor agonists,
- type 2 diabetes,
- cardiovascular safety

References

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据2019年国际糖尿病联盟发布的全球糖尿病地图，我国成人糖尿病患者数量位居世界第一，已达1.164亿人^[1]。与非糖尿病人群相比，2型糖尿病（T2DM）患者发生心血管疾病的风险可增加2～4倍，其中心肌梗死和卒中是T2DM患者死亡的主要原因^[2]。美国FDA和欧洲药品管理局要求加强对现有降糖药物的心血管安全性监测，同时所有新型降糖药物上市前必须通过心血管安全性研究（CVOT）^[3]。2015年EMPA-REG OUTCOME试验结果揭晓了恩格列净对T2DM患者有显著的心血管保护作用，随后LEADER、CANVAS试验相继证实了利拉鲁肽、卡格列净等的心血管益处。目前，国内外对钠-葡萄糖共转运蛋白2（SGLT-2）抑制剂、胰高血糖素样多肽-1（GLP-1）受体激动剂的心血管保护作用开展了广泛的研究，现就SGLT-2抑制剂、GLP-1受体激动剂的心血管安全性研究进展做一综述。

1. SGLT-2抑制剂的心血管保护作用

肾脏重吸收葡萄糖主要依赖SGLT-2，其主要分布于近曲小管S1、S2段管腔侧细胞膜上，介导90%葡萄糖的重吸收^[4]。SGLT-2抑制剂通过抑制肾脏肾小管中的SGLT-2，抑制葡萄糖重吸收，降低肾糖阈，促进尿葡萄糖排泄，起降低血液循环中葡萄糖水平的作用。目前，FDA批准上市的SGLT-2抑制剂有：恩格列净、卡格列净、达格列净、埃格列净。在我国被批准上市的有：恩格列净、卡格列净和达格列净。

1.1. SGLT-2抑制剂的心血管安全性试验

恩格列净、卡格列净、达格列净、埃格列净的心血管安全性试验分别称为EMPA-REG OUTCOME、CANVAS、DECLARE-TIMI 58、VERTIS-CV试验，均为大型、双盲、随机、安慰剂对照的前瞻性试验。试验均以心血管死亡、非致死性心肌梗死和非致死性卒中的主要心血管事件（MACE）为终点，评价SGLT-2抑制剂对T2DM患者的心血管作用。试验结果（见表1）显示，与安慰剂相比，恩格列净、卡格列净均可降低T2DM患者心血管事件的发生风险（P=0.038和0.02），而达格列净在心血管事件的风险与安慰剂相比无统计学差异；同时研究显示，恩格列净可降低T2DM患者的心血管死亡、全因死亡及心力衰竭住院风险（P<0.001、P<0.001、P=0.002），卡格列净、达格列净可降低T2DM患者心衰住院风险^[5-7]。在心肌梗死和卒中风险事件，恩格列净与安慰剂相比无统计学差异；卡格列净与安慰剂相比在心血管死亡、非致死性心肌梗死或非致死性卒中事件无统计学差异。VERTIS-CV试验结果未发布，埃格列净对T2DM患者的心血管作用尚不明确。

试验项目	EMPA-REG OUTCOME	CANVAS	DECLARE-TIMI 58
干预措施	恩格列净(10～25 mg/d)	卡格列净(100～300 mg/d)	达格列净(10 mg/d)
样本量（例，T/C^①）	4687/2333	5795/4347	8582/ 8578
平均年龄（年）	63.1	63.3	64.0
中位随访期（年）	3.1	2.4	4.2
合并ASCVD（例，%）	7020(100%)	6656(65.6%)	6974(40.6%)
主要事件（HR，95%CI）	0.86(0.74～0.99)	0.86(0.75～0.97)	0.93(0.84～1.03)
心肌梗死	0.87(0.70～1.09)	0.85(0.69～1.05)	NA
缺血性卒中	1.18(0.89～1.56)	0.90(0.71～1.15)	1.01(0.84～1.21)
心血管死亡	0.62(0.49～0.77)	0.87(0.72～1.06)	0.98(0.82～1.17)
全因死亡	0.68(0.57～0.82)	0.87(0.74～1.01)	0.93(0.82～1.04)
心力衰竭住院	0.65(0.50～0.85)	0.67(0.52～0.87)	0.73(0.61～0.88)
注：T/C：试验组/对照组；ASCVD，动脉粥样硬化性心血管疾病；NA，无数据。

1.2. SGLT-2抑制剂心血管安全性研究(CVOT)的Meta分析

纳入SGLT-2抑制剂的EMPA-REG OUTCOME、CANVAS、DECLARE-TIMI 58试验进行Meta分析，共34322例患者，其中60.2%合并动脉粥样硬化性心血管疾病（ASCVD），疗效包括：心血管事件，心血管死亡、心力衰竭住院和肾病进展的复合事件^[8]。研究表明，SGLT-2抑制剂可降低T2DM患者发生心血管事件的风险（HR 0.89, 95% CI 0.83～0.96, P=0.0014），但结果仅在合并ASCVD的T2DM人群中具有统计学差异（HR 0.86, 95% CI 0.80～0.93），对伴有ASCVD高危因素的T2DM患者，SGLT-2抑制剂与安慰剂相比在主要结果无统计学差异（HR 1.00, 95% CI 0.87～1.16）。同时研究显示，在合并或伴有ASCVD高危因素，以及合并/无心力衰竭T2DM人群中，SGLT-2抑制剂均可降低心血管死亡或心力衰竭住院风险（HR 0.77, 95% CI 0.71～0.84, P<0.0001）^[8]。另一项纳入了上述四项试验的Meta分析结果显示，SGLT-2抑制剂可降低合并或伴有ASCVD高危因素的T2DM患者心血管事件的发生风险（HR 0.88, 95% CI 0.82～0.94, P<0.001）^[9]。此外，另一项Meta分析提示SGLT-2抑制剂可降低T2DM合并慢性肾脏病（CKD）患者心血管死亡、非致死性心肌梗死、非致死性卒中的复合事件发生风险（RR 0.81, 95% CI 0.70～0.94），心力衰竭住院风险可降低39%（95% CI 0.48～0.78）^[10]。

1.3. SGLT-2抑制剂的心血管安全性研究

CVD-REAL是一项研究SGLT-2抑制剂对T2DM患者的心血管益处，共纳入309 056名T2DM患者，其中87%的患者无心血管疾病史。结果显示，SGLT-2抑制剂可降低T2DM患者的心衰住院风险（HR 0.61, 95% CI 0.51～0.73, P<0.001），降低全因死亡风险（HR 0.49, 95% CI 0.41～0.57, P<0.001），心衰住院和全因死亡事件的复合事件风险降低46%（95% CI 0.48～0.60, P<0.001）^[11]。同时CVD-REAL试验的亚组分析提示，与其他降糖药物相比，SGLT-2抑制剂可降低T2DM患者的心肌梗死和卒中风险（HR 0.85, 95% CI 0.72～1.00, P=0.05; HR 0.83, 95% CI 0.71～0.97, P =0.02）^[12]。OBSERVE-4D研究纳入了来自4个美国大型医保报销数据库的1 060 449例T2DM患者，头对头地比较卡格列净与其他SGLT-2抑制剂或其他非SGLT-2抑制剂，对T2DM患者心力衰竭住院的影响。研究结果显示，与非SGLT-2抑制剂的降糖药相比，卡格列净降低T2DM患者因心力衰竭住院的风险（HR 0.39, 95% CI 0.26～0.60），卡格列净与其他SGLT-2抑制剂对T2DM患者心力衰竭住院风险的影响无统计学差异（HR 0.90, 95% CI 0.71～1.13）；对于合并心血管疾病的T2DM人群，卡格列净可降低心力衰竭住院风险（HR 0.44, 95% CI 0.36～0.54），但与其他SGLT-2抑制剂相比，研究结果无统计学差异（HR 0.70, 95% CI 0.30～1.63）^[13]。恩格列净的EMPRISE试验结果显示，与西格列汀相比，恩格列净可降低T2DM患者心力衰竭风险（HR 0.50, 95% CI 0.28～0.91）^[14]。

2. GLP-1受体激动剂的心血管保护作用

GLP-1是一种肠促胰素，分布于胰腺、心脏、肺、脑和胃肠道等区域，通过葡萄糖浓度依赖性的方式促进胰岛β细胞分泌胰岛素，抑制胰岛α细胞释放胰高血糖素^[15-16]。GLP-1受体激动剂通过提高T2DM患者体内GLP-1受体活性，促进胰岛素分泌，抑制胰高血糖素释放，延缓胃排空，中枢性食欲抑制等多种机制调控机体血糖稳态。目前FDA批准上市的GLP-1受体激动剂有利拉鲁肽、索马鲁肽、艾塞那肽、利司那肽、度拉糖肽、阿必鲁肽。中国食品药品监督管理总局批准上市的GLP-1受体激动剂有利拉鲁肽、艾塞那肽、度拉糖肽、贝那鲁肽和洛塞那肽。

2.1. GLP-1受体激动剂的心血管安全性试验

GLP-1受体激动剂相关的大型心血管安全性试验有LEADER、SUSTAIN-6、EXSCEL、ELIXA试验，分别研究了利拉鲁肽、索马鲁肽、艾塞那肽和利司那肽对T2DM患者心血管疾病的影响，其中LEADER、SUSTAIN-6、EXSCEL均以心血管事件为主要结局，ELIXA以心血管死亡、非致死性心肌梗死、非致死性卒中和不稳定性心绞痛住院的复合终点为主要结局^[17-20]。试验结果（见表2）显示，利拉鲁肽、索马鲁肽可降低心血管事件发生风险（P=0.01、P=0.02）；此外，利拉鲁肽可降低T2DM患者发生心血管死亡和全因死亡的风险（P=0.007、P=0.02），索马鲁肽可降低非致死性卒中风险（P=0.04）；利拉鲁肽与安慰剂在非致死性心肌梗死、非致死性卒中和心力衰竭住院事件方面无统计学差异；在心肌梗死、全因死亡、心血管死亡及心衰住院终点方面，索马鲁肽与安慰剂无明显统计学差异^[17-18]。与安慰剂相比，艾塞那肽和利司那肽对T2DM合并心血管疾病的患者具有非劣效性，两者在主要终点处均无统计学差异(P=0.81、P=0.06)^[19-20]。

试验项目	EXSCEL	SUSTAIN-6	LEADER	ELIXA
干预措施	艾塞那肽(2 mg/w)	索马鲁肽(0.5～1.0 mg/w)	利拉鲁肽(0.6～1.8 mg/d)	利司那肽(10～20 μg/d)
样本量（例，T/C^①）	7256/7396	1648/1649	4668/4672	3034/3034
中位随访期（年）	3.2	2.1	3.5	2.1
合并ASCVD（例，%）	10782(73.1%)	2735(83%)	6764(72.4%)	6068(100%)
主要终点（HR，95%CI）	0.91 (0.83～1.00)	0.74(0.58～0.95)	0.87 (0.78～0.97)	1.02 (0.89～1.17)
心肌梗死	0.97 (0.85～1.10)	0.74 (0.51～1.08)	0.86 (0.73～1.00)	1.03 (0.87～1.22)
缺血性卒中	0.85 (0.70～1.03)	0.61 (0.38～0.99)	0.86 (0.71～1.06)	1.11 (0.47～2.62)
心血管死亡	0.88 (0.76～1.02)	0.98 (0.65～1.48)	0.78 (0.66～0.93)	0.98 (0.78～1.22)
全因死亡	0.86 (0.77～0.97)	1.05 (0.74～1.50)	0.85 (0.74～0.97)	0.94 (0.78～1.13)
心力衰竭住院	0.94 (0.78～1.13)	1.11 (0.77～1.61)	0.87 (0.73～1.05)	0.96 (0.75～1.23)
注：T/C：试验组/对照组。

2.2. GLP-1受体激动剂心血管安全性研究的Meta分析

GLP-1受体激动剂的心血管安全性试验结果不一，为验证GLP-1受体激动剂对心血管的保护作用，Bethel等^[21]将上述四项大型CVOT试验纳入Meta分析，结果显示，GLP-1受体激动剂可降低心血管事件发生风险（HR 0.90, 95%CI 0.82～0.99, P=0.033），同时心血管死亡风险降低13%（95%CI 0.76～0.96, P=0.007），全因死亡风险降低12%（95%CI 0.81～0.95, P=0.002）；但在心肌梗死、卒中、不稳定性心绞痛住院或心力衰竭住院方面，GLP-1受体激动剂与安慰剂相比均无统计学差异。Kristensen等^[22]根据现有临床试验证据进行Meta分析和系统回顾，结果显示，GLP-1受体激动剂可降低T2DM患者心血管事件的发生风险(HR 0.88, 95% CI 0.82～0.94, P<0.0001)，其中，心血管死亡风险降低12%(95% CI 0.81～0.96, P=0.003)，卒中风险降低12%（95% CI 0.83～0.95, P=0.001），心力衰竭住院风险可降低9%（95% CI 0.83～0.99, P=0.028）。

2.3. GLP-1受体激动剂的心血管安全性研究

一项为期36个月的利拉鲁肽研究^[23]共纳入307例患者，其中19.9%的患者合并心血管疾病，研究显示心血管事件的发生率低于LEADER试验（2.59比3.4 /100人·年），但合并心血管疾病的T2DM患者再发心血管不良事件的风险明显增高。另一项基于人群的开放性队列研究^[24]显示，接受GLP-1治疗的T2DM患者较未经GLP-1受体激动剂治疗的T2DM患者全因病死率降低（RR 0.64, 95%CI 0.56～0.74, P<0.0001）。

3. 新型降糖药物心血管安全性的间接比较

EMPA-REG OUTCOME、CANVAS、LEADER、SUSTAIN-6试验，分别为恩格列净、卡格列净、利拉鲁肽、索马鲁肽具有心血管保护作用提供了可靠的临床证据。因此《2020ADA/EASD糖尿病诊疗标准》推荐，无论糖化血红蛋白水平如何，对于合并ASCVD、伴有ASCVD高危因素、合并糖尿病肾病或合并心力衰竭的T2DM患者，建议将具有明确心血管益处的SGLT-2抑制剂作为降糖治疗方案的药物之一，同时推荐具有明确心血管益处的GLP-1受体激动剂作为合并或伴有ASCVD高危因素的T2DM患者治疗药物之一^[25]。但指南未明确推荐SGLT-2抑制剂和GLP-1受体激动剂的具体药品和用法用量，同时具有心血管保护作用的新型降糖药物之间缺乏头对头的随机对照试验，治疗方案之间的有效性和安全性差异尚不明确。因此，有研究通过网状Meta分析，间接比较T2DM患者应用SGLT-2抑制剂和GLP-1受体激动剂的心血管益处。

3.1. SGLT-2抑制剂心血管安全性研究的网状Meta分析

Täger等^[26]根据卡格列净、达格列净、恩格列净和埃格列净的大型临床随机对照试验，以全因死亡为主要终点，心血管死亡和心力衰竭恶化为次要终点，通过网状Meta分析研究，间接比较了4种SGLT-2抑制剂对T2DM患者的心血管安全性。试验结果显示，与安慰剂相比，卡格列净和恩格列净可改善T2DM患者的全因死亡风险（RR 0.85, 95% CI 0.75～0.97; RR 0.67, 95% CI 0.55～0.80），降低心血管死亡风险（RR 0.85, 95% CI 0.73～0.99; RR 0.61, 95% CI 0.49～0.77），减少心力衰竭恶化的风险（RR 0.62, 95% CI 0.52～0.75; RR 0.66, 95% CI 0.50～0.86）。达格列净可降低T2DM患者心力衰竭恶化的风险(RR 0.75, 95% CI 0.62～0.88)，与卡格列净和达格列净相比，恩格列净对降低T2DM患者的全因死亡和心血管死亡风险有明显优势。埃格列净与安慰剂或其他SGLT-2抑制剂相比，在主要结果和次要结果方面均无统计学差异。

3.2. GLP-1受体激动剂心血管安全性研究的网状Meta分析

一项纳入了LEADER、SUSTAIN-6、EXSCEL、ELIXA试验的网状Meta分析^[27]比较了GLP-1受体激动剂利拉鲁肽、索马鲁肽、艾塞那肽和利司那肽对T2DM患者的心血管安全性。试验结果显示，与安慰剂相比，GLP-1受体激动剂可降低T2DM患者的心血管死亡风险（RR 0.87, 95% CI 0.78～0.96），其中利拉鲁肽可减少T2DM患者心血管死亡风险21%。在心血管死亡、心力衰竭住院、非致死性心肌梗死、非致死性卒中方面，利拉鲁肽、索马鲁肽、艾塞那肽和利司那肽分别与其他3种GLP-1受体激动剂相比均无统计学差异。但研究显示，与其他3种GLP-1受体激动剂相比，利拉鲁肽是降低T2DM患者心血管死亡和心衰住院风险的首选药物，索马鲁肽对降低T2DM患者的非致死性卒中和非致死性心肌梗死具有明显优势。

3.3. SGLT-2抑制剂和GLP-1受体激动剂心血管安全性研究的网状Meta分析

对SGLT-2抑制剂和GLP-1受体激动剂的14个双盲、随机对照试验进行网状Meta分析，比较两者对T2DM患者发生心血管不良事件的影响^[28]。试验共纳入121 047例患者，主要结果为MACE，次要结果为非致死性卒中、非致死性心肌梗死、心血管死亡、全因死亡、心衰住院等^[28]。结果显示，SGLT-2抑制剂与安慰剂相比可降低T2DM患者的心血管死亡风险（OR 0.82, 95% CI 0.73～0.93）和全因死亡风险（OR 0.84, 95% CI 0.77～0.92），SGLT-2抑制剂和GLP-1受体激动剂均可降低MACE的发生风险（OR 0.88, 95% CI 0.82～0.95; OR 0.87, 95% CI 0.82～0.93），降低心衰住院风险（OR 0.68, 95% CI 0.61～0.77; OR 0.87, 95% CI 0.82～0.93），SGLT-2抑制剂降低T2DM患者心衰住院风险的优势高于GLP-1受体激动剂（OR 0.79, 95% CI 0.69～0.90），而GLP-1受体激动剂可降低T2DM患者的非致死性卒中风险（OR 0.88, 95% CI 0.77～0.99），SGLT-2抑制剂在非致死性卒中风险方面与安慰剂相比无统计学差异^[28]。

一项以全因死亡率为主要结果的网状Meta分析^[29]提示，SGLT-2抑制剂和GLP-1受体激动剂均可降低T2DM患者的全因病死率（HR 0.80, 95% CI 0.71～0.89; HR 0.88, 95% CI 0.81～0.94），减少T2DM患者的心血管死亡风险（HR 0.79, 95% CI 0.69～0.91; HR 0.85, 95% CI 0.74～0.94）。与对照组相比，SGLT-2抑制剂可减少T2DM患者的心衰住院风险（HR 0.62, 95% CI 0.54～0.72）和卒中风险（HR 0.86, 95% CI 0.77～0.97）。

4. 结语

2型糖尿病患者心血管事件发生率明显高于普通人群，与微血管并发症不同，研究显示严格控制血糖对其降低动脉粥样硬化性心血管疾病发生风险的效果一般^[30]。自2008年以来，多项心血管安全性试验逐渐证实了SGLT-2抑制剂、GLP-1受体激动剂不增加2型糖尿病患者发生心血管事件的风险，其中研究证实恩格列净、卡格列净、利拉鲁肽、索马鲁肽对T2DM患者具有心血管获益，为2型糖尿病治疗策略提供了新的方向。对现有的临床证据进行Meta分析，结果提示，SGLT-2抑制剂可降低心血管事件的发生风险，在合并或伴有ASCVD高危因素的T2DM人群中结果一致；GLP-1受体激动剂对于合并或伴有ASCVD高危因素的T2DM患者也具有一定的心血管保护作用。但达格列净、艾塞那肽和利司那肽在CVOT中未显示有心血管益处，具有心血管保护作用的恩格列净、卡格列净、利拉鲁肽和索马鲁肽也缺乏头对头的研究，SGLT-2抑制剂和GLP-1受体激动剂的疗效优势尚不明确，需要进一步研究。目前，多种新型降糖药物正在进行心血管安全性试验，其研究结果将陆续公布，相信未来有更多降糖药物对2型糖尿病患者具有心血管保护作用。

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