特泽帕肽治疗2型糖尿病患者疗效及安全性的meta分析

doi:10.3969/j.issn.1004-583X.2023.01.002

摘要/Abstract

摘要：

目的系统评价特泽帕肽治疗2型糖尿病(T2DM)患者的疗效及安全性。方法通过检索CNKI、万方、VIP、Pubmed、Embase及Cochrane library数据库获得符合纳入标准的随机对照研究(RCTs)。结果共纳入7篇RCTs,共7163名T2DM患者。Meta分析结果显示,5 mg、10 mg、15 mg 3种剂量的特泽帕肽降低糖化血红蛋白(HbA₁c)、减轻体重的疗效均明显优于所有对照组[胰高血糖素样肽1受体激动剂(GLP-1RA)、胰岛素、安慰剂],疗效呈剂量依赖性,随剂量增高,显示出更大的疗效,3种剂量下HbA₁c降低的幅度分别为[ $M D$ =-0.98, 95% $C I$ (-1.34, -0.62)]、[ $M D$ =-1.21, 95% $C I$ (-1.53, -0.89)]、[ $M D$ =-1.37, 95% $C I$ (-1.70, -1.03)];体重降低幅度分别为[ $M D$ =-6.05, 95% $C I$ (-8.58, -3.52)]、[ $M D$ =-8.56, 95% $C I$ (-11.14, -5.98)]、[ $M D$ =-10.60, 95% $C I$ (-13.24, -7.97)](均 $P$ <0.01)。在降低空腹血糖(FPG)方面,10 mg、15 mg两种剂量降低FPG的疗效均优于所有对照组(GLP-1RA、胰岛素、安慰剂),疗效呈剂量依赖性,FPG降低的幅度分别为[ $M D$ =-1.47, 95% $C I$ (-2.23, -0.70)]、[ $M D$ =-1.55, 95% $C I$ (-2.27,-0.83)](均 $P$ <0.01),5 mg剂量组降低FPG的疗效优于安慰剂,但5 mg特泽帕肽与对照组(GLP-1RA或胰岛素)相比,降低FPG的疗效无明显差异。在HbA₁c<7%、HbA₁c≤6.5%、HbA₁c<5.7%的达标率及体重减少≥5%、体重减轻≥10%、体重减少≥15%的比例方面也存在剂量依赖性,随剂量增加,HbA₁c达标率及体重减少的比例增加。安全性方面,特泽帕肽的低血糖发生率与GLP-1RA、安慰剂相似,但低于德谷/甘精胰岛素。在胃肠道不良反应方面,与安慰剂相比,3种剂量特泽帕肽治疗后出现胃肠道不良反应的比例均高于安慰剂。在特泽帕肽与对照组(GLP-1RA或胰岛素)的比较中,特泽帕肽10 mg、15 mg剂量治疗后出现胃肠道不良反应的比例均高于对照组(GLP-1RA或胰岛素),但是特泽帕肽5 mg与对照组相比,出现胃肠道不良反应的比例无明显差异。结论与安慰剂、GLP-1RA和胰岛素相比,特泽帕肽在降低HbA₁c、FPG、减轻体重方面具有明显的剂量依赖性优势,没有增加低血糖风险,但10 mg及15 mg特泽帕肽与胃肠道不良事件的发生率增加有关。

关键词: 糖尿病,2型, 特泽帕肽, meta分析

Abstract:

Objective To systematically evaluate the efficacy and safety of tirzepatide in the treatment of type 2 diabetes mellitus (T2DM). Methods CNKI, Wanfang, VIP, Pubmed, Embase and Cochrane Library were retrieved to collect randomized controlled trails (RCTs), which met inclusion criteria. Results Seven RCTs representing 7163 T2DM patients were included. Meta-analysis results showed that the tirzepatide 5 mg, 10 mg and 15 mg was superior to the control groups (glucagon-like peptide-1 receptor agonist [GLP-1RA], insulin and placebo) in reducing glycosylated hemoglobin A1c (HbA₁c) and weight loss. The curative effect appeared to be highly dose-dependent, it showed greater efficacy with increasing dose. The decrease of HbA₁c in the tirzepatide 5 mg, 10 mg and 15 mg was ( $M D$ =-0.98, 95% $C I$ [-1.34, -0.62], ( $M D$ =-1.21, 95% $C I$ [-1.53,-0.89]) and ( $M D$ =-1.37, 95% $C I$ [-1.70,-1.03]), respectively. The weight loss ranges were ( $M D$ =-6.05, 95% $C I$ [-8.58,-3.52]), ( $M D$ =-8.56, 95% $C I$ [-11.14, -5.98]) and ( $M D$ =-10.60, 95% $C I$ [-13.24, -7.97]) (all $P$ <0.01), respectively. The tirzepatide 10 mg and 15 mg was superior to the control groups (GLP-1RA, insulin and placebo) in reducing fasting plasma glucose (FPG). The curative effect appeared to be dose-dependent, and the extent of FPG reduction with the tirzepatide 10 mg and 15 mg was ( $M D$ =-1.47, 95% $C I$ [-2.23, -0.70]) and ( $M D$ =-1.55, 95% $C I$ [-2.27, -0.83]), (all $P$ <0.01), respectively. The tirzepatide 5 mg was more effective in reducing FPG than placebo. No difference was significant in reducing FPG between tirzepatide 5 mg and the control group (GLP-1RA or insulin). There was also a dose dependence on the compliance rate of HbA₁c<7%, HbA₁c≤6.5%, HbA₁c<5.7% and the proportion of weight loss≥5%, weight loss≥10%, weight loss≥15%. However, there was no significant in compliance rate of HbA₁c and the proportion of weight loss increased. The safety of tirzepatide in incidence of hypoglycemia was similar to that of GLP-1RA and placebo, but lower than that of degludec/glargine insulin. The proportion of gastrointestinal adverse reactions of tirzepatide 5 mg, 10 mg and 15 mg was higher than that of placebo, the proportion of gastrointestinal adverse reactions of tirzepatide 10 mg and 15 mg was higher than that of the control group (GLP-1RA or insulin), but there was no significant difference in gastrointestinal adverse reactions between the control group and tirzepatide 5 mg. Conclusion Compared with placebo, GLP-1RA and insulin, tirzepatide has significant dose-dependent advantages in reducing HbA₁c, FPG and weight loss, and does not increase the risk of hypoglycemia, but tirzepatide 10 mg and 15 mg are associated with increased incidence of gastrointestinal adverse events.

Key words: diabetes mellitus, type 2, tirzepatide, meta-analysis

中图分类号:

R587.1

谢飞飞, 张维健. 特泽帕肽治疗2型糖尿病患者疗效及安全性的meta分析[J]. 临床荟萃, 2023, 38(1): 20-36.

Xie Feifei, Zhang Weijian. Efficacy and safety of tirzepatide in patients with type 2 diabetes mellitus: A meta-analysis[J]. Clinical Focus, 2023, 38(1): 20-36.

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https://lchc.magtechjournal.com/CN/Y2023/V38/I1/20

图/表 31

图1 文献筛选流程图

Fig. 1 Flow chart of literature screening

表1 纳入研究基本信息

Tab. 1 Basic information of included studies

纳入研究	干预措施	样本量(例)	年龄(岁)	HbA₁c(%)	疗程(周)	质量等级
Frias 2018^[2]	Tirzepatide 5 mg	55	57.9±8.2	8.2±1.0
	Tirzepatide 10 mg	51	56.5±9.9	8.2±1.1
	Tirzepatide 15 mg	53	56.0±7.6	8.1±1.1	26	B
	Dulaglutide 1.5 mg	54	58.7±7.8	8.1±1.0
	Placebo	51	56.6±8.9	8.0±0.9
Rosenstock 2021^[4]	Tirzepatide 5 mg	121	54.1±11.9	8.0±0.8
	Tirzepatide 10 mg	121	55.8±10.4	7.9±0.8	40	A
	Tirzepatide 15 mg	121	52.9±12.3	7.9±1.0
	Placebo	115	53.6±12.8	8.1±0.8
Frías 2021^[5]	Tirzepatide 5 mg	470	56.3±10.0	8.3±1.1
	Tirzepatide 10 mg	469	57.2±10.5	8.3±1.0	40	B
	Tirzepatide 15 mg	470	55.9±10.4	8.3±1.0
	Semaglutide 1 mg	469	56.9±10.8	8.3±1.0
Ludvik 2021^[6]	Tirzepatide 5 mg	358	57.2±10.1	8.2±0.9
	Tirzepatide 10 mg	360	57.4±9.7	8.2±0.9	52	B
	Tirzepatide 15 mg	359	57.5±10.2	8.2±0.9
	Insulin degludec	360	57.5±10.1	8.1±0.9
Del Prato 2021^[7]	Tirzepatide 5 mg	329	62.9±8.6	8.5±0.8
	Tirzepatide 10 mg	328	63.7±8.7	8.6±0.9	52	B
	Tirzepatide 15 mg	338	63.7±8.6	8.5±1.0
	Insulin glargine	1 000	63.8±8.5	8.5±0.9
Dahl 2022^[8]	Tirzepatide 5 mg	116	62±10	8.3±0.9
	Tirzepatide 10 mg	119	60±10	8.4±0.8	40	A
	Tirzepatide 15 mg	120	61±10	8.2±0.9
	Placebo	120	60±10	8.4±0.8
Inagaki 2022^[9]	Tirzepatide 5 mg	159	56.8±10.1	8.2±0.9
	Tirzepatide 10 mg	158	56.2±10.3	8.2±0.9	52	A
	Tirzepatide 15 mg	160	56.0±10.7	8.2±0.9
	Dulaglutide 0.75 mg	159	57.5±10.2	8.2±0.9

图2 研究的偏倚风险图

Fig. 2 Risk of bias plot of the studies

图3 研究的偏倚风险总结图

Fig. 3 Risk of bias summary chart of the studies

图4 HbA1c的meta分析结果

Fig. 4 Meta-analysis results of HbA1c

图5a HbA1c的亚组meta分析结果

Fig. 5a Meta-analysis results of HbA1c in subgroups

图5b Tirzepatide vs (GLP-1RA 或 Insulin)亚组meta分析结果

Fig. 5b Meta-analysis results of Tirzepatide vs GLP-1RA or Insulin in subgroup

图5c Tirzepatide vs Placebo亚组meta分析结果

Fig. 5c Meta-analysis results of Tirzepatide vs Placebo in subgroup

图6 FPG的meta分析结果

Fig. 6 Meta-analysis results of FPG

图7a FPG的亚组meta分析结果

Fig. 7a Meta-analysis results of FPG in subgroup

图7b Tirzepatide vs (GLP-1RA 或 Insulin)亚组meta分析结果

Fig. 7b Meta-analysis results of Tirzepatide vs GLP-1RA or Insulin in subgroup

图7c Tirzepatide vs Placebo亚组meta分析结果

Fig. 7c Meta-analysis results of Tirzepatide vs Placebo in subgroup

图8 体重的meta分析结果

Fig. 8 Meta-analysis results of body weight

图9a 体重的亚组meta分析结果

Fig. 9a Meta-analysis results of body weight in subgroup

图9b Tirzepatide vs (GLP-1RA或 Insulin)体重亚组meta分析结果

Fig. 9b Meta-analysis results of Tirzepatide vs GLP-1RA in body weight subgroup

图9c Tirzepatide vs Placebo体重亚组meta分析结果

Fig. 9c Meta-analysis results of Tirzepatide vs Placebo in body weight subgroup

图10a HbA1c<7%达标率的meta分析结果

Fig. 10a Meta-analysis results of HbA1c<7% compliance rate

图10b HbA1c<7%达标率的亚组meta分析结果

Fig. 10b Meta-analysis results of HbA1c<7% compliance rate in subgroup

图11a HbA1c≤6.5%达标率的meta分析结果

Fig. 11a Meta-analysis results of HbA1c<6.5% compliance rate

图11b HbA1c≤6.5%达标率的亚组meta分析结果

Fig. 11b Meta-analysis results of HbA1c<6.5% compliance rate in subgroup

图12a HbA1c<5.7%达标率的meta分析结果

Fig. 12a Meta-analysis results of HbA1c<5.7% compliance rate

图12b HbA1c<5.7%达标率的亚组meta分析结果

Fig. 12b Meta-analysis results of HbA1c<5.7% compliance rate

图13 体重减少≥5%的meta分析结果

Fig. 13 Meta-analysis results of body weight loss >5%

图14 体重减少≥10%的meta分析结果

Fig. 14 Meta-analysis results of weight loss >10%

图15 体重减少≥15%的meta分析结果

Fig. 15 Meta-analysis results of body weight loss >15%

图16 低血糖事件的meta分析结果

Fig. 16 Meta-analysis results of hypoglycemia events

图17 胃肠道不良反应的meta分析结果

Fig. 17 Meta-analysis results of gastrointestinal adverse reactions

图18a 胃肠道不良反应的亚组meta分析结果

Fig. 18a Meta-analysis results of gastrointestinal adverse reactions in subgroup

图18b Tirzepatide vs (GLP-1RA 或 Insulin) 胃肠道不良反应亚组meta分析结果

Fig. 18b Meta-analysis results of gastrointestinal adverse reactions in Tirzepatide vs GLP-1RA or Insulin in subgroup

图18c Tirzepatide vs Placebo胃肠道不良反应亚组meta分析结果

Fig. 18c Meta-analysis results of gastrointestinal adverse reactions in Tirzepatide vs Placebo in subgroup

图19 注射部位不良反应的meta分析结果

Fig. 19 Meta-analysis results of adverse reactions at the injection site

参考文献 20

[1]	Aroda VR, Bain SC, Cariou B, et al. Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): A randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial[J]. Lancet Diabetes Endocrinol, 2017, 5(5):355-366. doi: 10.1016/S2213-8587(17)30085-2 URL
[2]	Frias JP, Nauck MA, Van J, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: A randomised, placebo-controlled and active comparator-controlled phase 2 trial[J]. Lancet, 2018, 392(10160):2180-2193.
[3]	Higgins JP, Thomas J, Chandler J, et al. Cochrane handbook for systematic reviews of interventions[M]. John Wiley & Sons, Ltd, 2019.
[4]	Rosenstock J, Wysham C, Frías JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): A double-blind, randomised, phase 3 trial[J]. Lancet, 2021, 398(10295):143-155.
[5]	Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes[J]. N Engl J Med, 2021, 385(6):503-515. doi: 10.1056/NEJMoa2107519 URL
[6]	Ludvik B, Giorgino F, Jódar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): A randomised, open-label, parallel-group, phase 3 trial [J]. Lancet, 2021, 398(10300):583-598. doi: 10.1016/S0140-6736(21)01443-4 pmid: 34370970
[7]	Del Prato S, Kahn SE, Pavo I, et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): A randomised, open-label, parallel-group, multicentre, phase 3 trial[J]. Lancet, 2021, 398(10313):1811-1824. doi: 10.1016/S0140-6736(21)02188-7 pmid: 34672967
[8]	Dahl D, Onishi Y, Norwood P, et al. Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: The SURPASS-5 randomized clinical trial[J]. JAMA, 2022, 327(6):534-545. doi: 10.1001/jama.2022.0078 pmid: 35133415
[9]	Inagaki N, Takeuchi M, Oura T, et al. Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): A double-blind, multicentre, randomised, phase 3 trial[J]. Lancet Diabetes Endocrinol, 2022, 10(9):623-633. doi: 10.1016/S2213-8587(22)00188-7 URL
[10]	Zhao FH, Zhou QT, Cong ZT, et al. Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors[J]. Nat Commun, 2022, 13(1): 1057. doi: 10.1038/s41467-022-28683-0 pmid: 35217653
[11]	Gribble FM, Reimann F. metabolic Messengers: Glucagon-like peptide 1[J]. Nat metab, 2021, 3(2): 142-148. doi: 10.1038/s42255-020-00327-x pmid: 33432200
[12]	Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept[J]. Mol metab, 2018, 18:3-14. doi: S2212-8778(18)30900-1 pmid: 30473097
[13]	Samms RJ, Coghlan MP, Sloop KW. How may GIP enhance the therapeutic efficacy of GLP-1?[J]. Trends Endocrinol metab, 2020, 31(6): 410-421. doi: 10.1016/j.tem.2020.02.006 URL
[14]	Samms RJ, Christe ME, Collins KA, et al. GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice[J]. J Clin Invest, 2021, 131(12):e146353. doi: 10.1172/JCI146353 URL
[15]	Thomas MK, Nikooienejad A, Bray R, et al. Dual GIP and GLP-1 receptor agonist tirzepatide improves beta-cell function and insulin sensitivity in type 2 diabetes[J]. J Clin Endocrinol Metab, 2021, 106(2):388-396. doi: 10.1210/clinem/dgaa863 pmid: 33236115
[16]	Heise T, Mari A, DeVries JH, et al. Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: A multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial[J]. Lancet Diabetes Endocrinol, 2022, 10(6):418-429. doi: 10.1016/S2213-8587(22)00085-7 URL
[17]	Finan B, Ma T, Ottaway N, et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans[J]. Sci Transl Med, 2013, 5(209):209ra151.
[18]	Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity[J]. N Engl J Med, 2022, 387(3):205-216. doi: 10.1056/NEJMoa2206038 URL
[19]	Tanday N, Flatt PR, Irwin N. metabolic responses and benefits of glucagon-like peptide-1(GLP-1) receptor ligands[J]. Br J Pharmacol, 2022, 179(4):526-541. doi: 10.1111/bph.15485 URL
[20]	Tan TM, Khoo B. Tirzepatide and the new era of twincretins for diabetes[J]. Lancet, 2021, 398(10295): 95-97. doi: 10.1016/S0140-6736(21)01390-8 URL