Efficacy and safety of different doses of tirzepatide in patients with type 2 diabetes mellitus: a systematic review and network meta-analysis

doi:10.21203/rs.3.rs-3894429/v1

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Efficacy and safety of different doses of tirzepatide in patients with type 2 diabetes mellitus: a systematic review and network meta-analysis

https://doi.org/10.21203/rs.3.rs-3894429/v1

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Introduction: This study aims to evaluate the effectiveness and safety of different doses of tirzepatide on hypoglycemic, weight-loss, improvement of beta-cell function and insulin resistance in patients with type 2 diabetes mellitus compared with other glucose-lowering drugs or placebo.

Research Design and Methods: Searches were conducted for PubMed, Cochrane Library, Web of Science and Embase for randomized controlled trials (RCTs) of tirzepatide from their inception to 2023. The network meta-analysis followed the PRISMA guidelines. Based on the Cochrane risk of bias tool, we analyzed the included RCTs using Stata 15.1. The standardized mean difference and surface under the cumulative ranking curve were presented for each result. An evaluation of publication bias was conducted using funnel plots.

Results: Data from 17 studies involving 10405 patients was analyzed. Tirzepatide 10 mg and 15 mg were more effective at hypoglycemic control and weight loss than basal insulin (glargine or degludec) or GLP-1RAs (dulaglutide or semaglutide). Tirzepatide 15mg plays a leading role in lowering body weight (SCURA probability: 98.3%), fasting insulin (95.4%), fasting C-Peptide (91.8%), fasting blood glucose (88.2%) and glycated hemoglobin (85.7%). As for safety, 7407 (72%) had at least one treatment-emergent adverse events and most of that were gastrointestinal adverse events.

Conclusions: Tirzepatide 15 mg, not only exhibited a favorable hypoglycemic and weight-loss efficacy, but also achieve a reduction of fasting insulin and fasting C-Peptide by comparison with insulin and GLP1-RAs. It is need of more well-designed RCTs to evaluate potential benefits on insulin resistance and pancreatic beta cell function of tirzepatide.

tirzepatide

type 2 diabetes mellitus

network meta-analysis

beta-cell function

systematic review

Diabetes Mellitus Type 2 (T2DM) is characterized by elevated levels of blood glucose attribute to insulin resistance and pancreatic beta-cell dysfunction, triggering substantial social, health, and economic consequences^[1–2]. Diabetes global prevalence was estimated to be 10.5% (536.6 million people) in 2021, rising to 12.2% (783.2 million) in 2045, according to the 10th edition of the IDF. It is estimated that worldwide health expenditures on diabetes will reach USD 1054 billion by 2045, up from USD 966 billion in 2021^[3]. Globalization, ageing populations, sedentary lifestyles, especially obesity, are all contributing factors to this increase in cases^[4].

Tirzepatide is a novel, subcutaneously-administered, once-weekly incretin-based therapies that combines dual agonism of glucose-dependent insulinotropic polypeptide (GIPR) and glucagon-like peptide-1 receptors (GLP-1R)^[5]. As an assistant measure to diet and exercise to improve glycaemic control in adults with T2DM, the Food and Drug Administration (FDA) approved it on 13 May 2022^[6].

GLP-1R exists in the pancreatic beta and alpha cells, gastrointestinal tract, brain, heart, kidneys and immune cells^[7–8]. It not only reduces body weight, stimulates insulin secretion and inhibits glucagon secretion in a glucose-dependent mode, but it also delays gastric emptying, reduces appetite, improves satiety, and indirectly reduces peripheral insulin resistance^[9–11]. Besides being located in the same tissues as GLP-1R, a significant expression of GIPR is also detected in adipose tissues and bone cells, having the function of insulin secretion, glucagon secretion, lipidoses in the adipose tissue, bone formation^{[7, 12–14]}. There is evidence that GLP-1R-GIPR co-agonists can be therapeutically beneficial for patients with T2DM, leading to increased insulin secretion and improved beta cell function^[15–19].

Presently, it has been proved that tirzepatide not only can achieve effective hypoglycemic and weight loss effects compared to selective GLP-1 RAs with dose-dependent, but it also can improve pancreatic beta-cell function, improve insulin sensitivity in patients with T2DM ^[20–22]. For all that, up to now, comparing different doses of tirzepatide with other glucose-lowering treatments in terms of glycaemic control, weight loss, beta-cell function and insulin resistance in network meta-analysis is missing. Accordingly, the purpose of this study was to collect all RCTs that compared tirzepatide with other antihyperglycemic agents or placebo among T2DM patients and perform a network meta-analysis so as to assess the comparative effects of different doses of tirzepatide on glucose lowering and weight loss, more importantly, on function of islet beta cell and insulin resistance to provide a basis for its future use.

Our study was conducted in accordance with the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” guidelines^[23] and the “Cochrane handbook for systematic reviews of interventions”^[24]. This study have been registered on PROSPERO (registration no. CRD42023462087).

2.1 Search strategy

Searches were conducted for PubMed, Cochrane Library, Web of Science and Embase till Jul 2023 for relevant RCTs comparing different does of tirzepatide with any other antihyperglycemic agents or placebo. The following search terms were used: “tirzepatide” or “ly3298176” or “dual GIP/GLP-1 receptor agonist” or “dual GIP and GLP-1 receptor agonist” or “dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist ” or “dual agonist glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor” or “dual agonist GLP-1 and GIP receptor” or “dual agonist GLP-1 and gastric inhibitory polypeptide receptor” or “glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide/gastric inhibitory peptide agonist” or “twincretin”or “a dual GIP/GLP-1 receptor co-agonist” or “mounjaro” and “Randomized Controlled Trial”.

2.2 Study selection and data extraction

The inclusion criteria were as follows: a) study design: RCTs; b) Participants diagnosed of T2DM; c) Patients in the experimental and control groups received different doses of tirzepatide with antihyperglycemic agents or placebo; d) Minimum intervention period of 4 weeks; e) with available data on body weight, glycated hemoglobin (HbA1c), FBG, fasting C-Peptide and fasting insulin.

The exclusion criteria included: a) non-human and in vitro research, non-RCTs, non-English publications, case reports, editorial materials, conference proceedings, commentaries, reviews, letters, abstract only papers, studies without raw data and repetitive publications; b) studies lacking a control group to compare with tirzepatide; c) Studies with incomplete or unclear data; d) Studies that did not provide mean change from baseline and standard deviations and for which these data could not be obtained by conversion.

Data extraction was carried out independently by two authors (ZZX and YJH) using data extraction forms. Each eligible article contained the following items: first author, year of study, type of study, duration of study, sample size, intervention and control, baseline characteristics and other outcomes of interest (mean change from baseline and corresponding standard deviation of each treatment group). We also search relevant supplementary appendixes for any missing data of specific interest. In case of disagreement, a third researcher (YL) shall be invited to solve the disagreement through consultation.

2.3 Risk of bias assessment

RCTs eligible for inclusion were assessed for bias using the Cochrane Risk of Bias Assessment Tool^[25].Two independent reviewers(JXZ and YJH), screened the titles and abstracts of the retrieved references and evaluated full text records for potentially qualified articles. Any discrepancies were discussed with the third reviewer (YL), and a consensus was reached.

2.4 Outcome measures

The primary outcomes included mean change from baseline in HbA1c, mean change from baseline in FBG, mean change from baseline in fasting insulin, mean change from baseline in fasting C-Peptide and mean change from baseline in weight.

The safety outcomes included the proportion of patients with severe AEs, AEs leading to treatment discontinuation, hypoglycemic events, treatment-emergent adverse events (TEAEs) occurring in ≥ 5% of participants and so on.

2.5 Data analysis and reporting

Based on Stata 15.1 (Stata Corporation, College Station, TX, United States), the network meta-analysis was performed. Effect estimates included standardized mean difference for continuous outcomes. For each intervention, SUCRA was used as a metric for ranking its effectiveness, as well as estimating the ranking probabilities. A higher value signifies a more effective intervention. It was determined whether there was agreement between direct and indirect comparisons using the node splitting method. When p-value > 0.05, the heterogeneity is not obvious. In order to evaluate publication bias, funnel plots were used. Publication bias can only be conducted to those outcome indicators with more than 10 articles.

3.1 Literature screening process

In accordance with a search strategy established by two independent researchers, literature was retrieved from the database. Initially, 858 articles were retrieved and 193 duplicates were removed. Firstly, they were screened by reading the titles and abstracts, and then 595 reviews, meta-analyses, case reports, editorial materials, letters, conference abstracts, animal experiments, and non-English were removed; 12 unsearched reports were excluded; finally, 18 documents were unavailable, and 23 documents without predetermined results were excluded. Finally, 17 papers^{[21, 26–41]} were included for quantitative analysis (Fig. 1).

3.2 Literature characteristics

A total of 17 literatures with 10405 patients were included. The studies in these literatures originated from multiple centers. There were 12 interventions in the test and control groups: tirzepatide 0.5 mg, tirzepatide 1 mg, tirzepatide 5 mg, tirzepatide 10 mg, tirzepatide 12 mg, tirzepatide 15 mg, dulaglutide 0.75 mg, dulaglutide 1.5 mg, semaglutide 1 mg, placebo, degludec insulin, and glargine insulin. The outcome indicators were: weight, HbA1c, FBG, fasting insulin, and fasting C-peptide. (Table 1)

Table 1

**Literature characteristics** (①weight, ②HbA1c, ③FBG, ④fasting insulin, ⑤ fasting C-peptide)
	Author,year	Countries	Test groups	Control groups	Sample Size		Age(y), Mean ± SD or Median(Range)		Sexy		Courses of disease		Duration/W	Outcomes
	Author,year	Countries	Test groups	Control groups	T	C	T	C	T	C	T	C	Duration/W	Outcomes
1	Daisuke Yabe,2022	Japan	Tirzepatide 5mgQW Tirzepatide 10mgQW Tirzepatide 15mgQW	Dulaglutide 0.75mg QW	5mg:9 10mg:11 15mg:19	19	5mg:59.0 (4.2) 10mg:59.5 (9.2) 15mg:59.3 (8.6)	59.3 (8.6)	5mg:7M 10mg:10M 15mg:8M	16M	5mg:3.5 (0.9, 7.0) 10mg:8.6 (3.3,13.5) 15mg:4.0 (2.7, 9.6)	4.0 (2.7, 9.6)	32-52w	①、③、④、⑤
2	Tim Heise,2022	Germany	Tirzepatide 15mgQW	Semaglutide 1mg QW Placebo QW	45	Semaglutide:44 Placebo:28	61.1 (7.1)	Semaglutide:63.7 (5.9) Placebo:60.4 (7.6)	31M 14F	Semaglutide:34M 10F Placebo:7M 21F	10.24 (5.80)	Semaglutide:12.73 (6.10) Placebo:10.95 (6.78)	28w	①、②、③、④
3	Juan Pablo Frias,2018	Poland, Puerto Rico, Slovakia, USA	Tirzepatide 1mgQW Tirzepatide 5mgQW Tirzepatide 10mgQW Tirzepatide 15mgQW	Dulaglutide 1.5 mg QW Placebo QW	1mg:52 5mg:55 10mg:51 15mg:53	Dulaglutide:54 Placebo:51	1mg:57.4 (8.9) 5mg:57.9 (8.2) 10mg:56.5 (9.9) 15mg: 56.0 (7.6)	Dulaglutide:58.7 (7.8) Placebo:56.6 (8.9)	1mg:29M 23F 5mg:34M 21F 10mg:30M 21F 15mg:22M 31F	Dulaglutide:24M 30F Placebo:29M 22F	1mg:7.8 (5.4) 5mg: 8.9 (5.7) 10mg:7.9 (5.8) 15mg: 8.5 (6.1)	Dulaglutide:9.3 (7.1) Placebo:8.6 (7.0)	26w	①、②、③、④、⑤
4	Nobuya Inagaki,2022	Japan	Tirzepatide 5mgQW Tirzepatide 10mgQW Tirzepatide 15mgQW	Dulaglutide 0.75mg QW	5mg:159 10mg:158 15mg:160	159	5mg:56.8 (10.1) 10mg:56.2 (10.3) 15mg:56.0 (10.7)	57.5 (10.2)	5mg:113M 46F 10mg:119M 39F 15mg:132M 28F	117M 42F	5mg:4.5 (2.1–7.5) 10mg:5.1 (2.2–8.4) 15mg:5.1 (2.2–8.4)	5.0 (1.9–8.4)	52w	①、②、③、④、⑤
5	Julio Rosenstock,2021	India, Japan, Mexico, USA	Tirzepatide 5mgQW Tirzepatide 10mgQW Tirzepatide 15mgQW	Placebo QW	5mg:121 10mg:121 15mg:121	115	5mg:54.1 (11.9) 10mg:55.8 (10.4) 15mg:52.9 (12.3)	53.6 (12.8)	5mg:56M 65F 10mg:72M 49F 15mg:63M 58F	56M 59F	5mg:4.6 (5.1) 10mg:4.9 (5.6) 15mg:4.8 (5.0)	4.5 (5.9)	40w	①、②、③、④
6	W Timothy Garvey,2023	Argentina, Brazil, India, Japan, Russia, Taiwan, USA	Tirzepatide 10mgQW Tirzepatide 15mgQW	Placebo QW	10mg:312 15mg:311	315	10mg:54.3 (10.7) 15mg:53.6 (10.6)	54.7 (10.5)	10mg:154M 158F 15mg:152M 159F	156M 159F	10mg:8.8 (6.9) 15mg:8.0 (6.4)	8.8 (6.2)	72w	①、②、③、④
7	Dominik Dahl,2022	US,Japan, CzechRepublic, Germany, Poland, PuertoRico, Slovakia,Spain	Tirzepatide 5mgQW Tirzepatide 10mgQW Tirzepatide 15mgQW	Placebo QW	5mg:116 10mg:119 15mg:120	120	5mg: 62 (10) 10mg: 60 (10) 15mg:61(10)	60 (10)	5mg:61M 55F 10mg:72M 47F 15mg:65M 55F	66M 54F	5mg:14.1 (8.1) 10mg: 12.6 (6.2) 15mg: 13.7 (7.5)	12.9 (7.4)	40w	①、②、③
8	Amalia Gastaldelli,2022	Argentina, Austria, Greece, Hungary, Italy, Romania, Spain, the USA	Tirzepatide 5mgQW Tirzepatide 10mgQW Tirzepatide 15mgQW	Insulin degludec QD	5mg:71 10mg:79 15mg:72	74	5mg:56.5 (10.3) 10mg:55.6 (9.6) 15mg:56.5 (10.0)	56.5 (9.5)	5mg:44M 27F 10mg:41M 38F 15mg:47M 25F	40M 34F	5mg:7.9 (6.0) 10mg:9.4 (8.2) 15mg:8.7 (6.7)	7.0 (4.8)	52w	①、②、③
9	Leili Gao,2023	China, South Korea, Australia, India	Tirzepatide 5mgQW Tirzepatide 10mgQW Tirzepatide 15mgQW	Insulin glargine QD	5mg:230 10mg:228 15mg:229	220	5mg:53.1 (11.2) 10mg:53.5 (11.1) 15mg:54.3 (11.6)	55.6 (11.4)	5mg:124M 96F 10mg:126M 102F 15mg:129M 100F	118M 102F	5mg:7.43 (5.93) 10mg:7.90 (5.65) 15mg:7.64 (5.63)	7.65 (5.72)	40w	①、②、③
10	Bernhard Ludvik,2021	Argentina, Austria, Greece, Hungary, Italy, Poland, Puerto Rico, Romania, South Korea, Spain, Taiwan, Ukraine, the USA	Tirzepatide 5mgQW Tirzepatide 10mgQW Tirzepatide 15mgQW	Insulin degludec QD	5mg:358 10mg:360 15mg:359	360	5mg:57.2 (10.1) 10mg:57.4 (9.7) 15mg:57.5 (10.2)	57.5 (10.1)	5mg:200M 158F 10mg:195M 165F 15mg:194M 165F	213M 147F	5mg:8.5 (5.8) 10mg:8.4 (6.6) 15mg:8.5 (6.5)	8.1 (6.0)	52w	①、②
11	Takashi Kadowaki,2022	Japan	Tirzepatide 10mgQW Tirzepatide 15mgQW	Tirzepatide 5mg QW	10mg:147 15mg:148	148	10mg:56.9 (11.2) 15mg:56.5 (10.4)	57.7 (11.0)	10mg:113M 34F 15mg:104M 44F	119M 29F	10mg:9.1 (5.9–13.0) 15mg:8.5 (5.6–13.5)	8.5 (4.8–12.4)	52w	①、③、④、⑤
12	Ping Feng,2023	China	Tirzepatide 2.5–10.0mgQW Tirzepatide 2.5–15.0mgQW	Placebo QW	2.5–10.0mg:10 2.5–15.0mg:10	4	2.5–10.0mg:55.8 (5.2) 2.5–15.0mg:56.8 (5.4)	56.5 (7.5)	2.5–10.0mg:4M 6F 2.5–15.0mg:6M 4F	3M 1F	2.5–10.0mg: 6.6 (4.1) 2.5–15.0mg: 6.6 (4.0)	5.3 (2.1)	16-24w	①、②、③
13	Juan Pablo Frias,2020	the United States	Tirzepatide 12mgQW Tirzepatide 15-1mgQW Tirzepatide 15-2mgQW	Placebo QW	12mg:29 15-1mg:28 15-2mg:28	26	12mg:61.2(7.56) 15-1mg:55.5(8.54) 15-2mg:56.6(9.21)	56.0(10.13)	12mg:15M 15-1mg:16M 15-2mg:23M	12M	12mg: 10.5(7.90) 15-1mg: 8.2(4.87) 15-2mg: 8.9(6.35)	8.8(6.43)	12w	①、②、③
14	Juan P. Frías,2021	the United States, Argentina, Australia, Brazil, Canada, Israel, Mexico, the United Kingdom	Tirzepatide 5mgQW Tirzepatide 10mgQW Tirzepatide 15mgQW	Semaglutide 1mg QW	5mg:470 10mg:469 15mg:470	469	5mg:56.3(10.0) 10mg:57.2(10.5) 15mg:55.9(10.4)	56.9(10.8)	5mg:265F 10mg:231F 15mg:256F	244F	5mg:9.1(7.16) 10mg:8.4(5.90) 15mg:8.7(6.85)	8.3(5.80)	40w	①、②、③
15	Tamer Coskun,2018	USA, Singapore	LY3298176 0.5 mgQW LY3298176 5 mgQW LY3298176 5–10 mgQW LY3298176 5–15 mgQW	Placebo QW	0.5mg:9 5mg:9 5-10mg:12 5-15mg:12	Placebo:11	56.8(6.9)	56.8(6.9)	28M 25F	28M 25F			4w	①
16	Stefano Del Prato,2021	Argentina, Australia, Brazil, Canada, Greece, Israel, Mexico, Poland, Romania, Russia, Slovakia, Spain, Taiwan, the USA	Tirzepatide 5mgQW Tirzepatide 10mgQW Tirzepatide 15mgQW	Insulin glargineQD	5mg:329 10mg:328 15mg:338	1000	5mg:62.9 (8.6) 10mg:63.7 (8.7) 15mg:63.7 (8.6)	63.8 (8.5)	5mg:198F 131F 10mg:209M 119F 15mg:203M 135F	636M 364F	5mg:9.8 (6.2–15.3) 10mg:10.6 (6.5–16.2) 15mg:10.4 (5.5–15.7)	10.7 (6.3–16.5)	52w	①、②、③
17	Tadej Battelino,2022	Hungary, Poland, Romania, Spain, Ukraine, the USA	Tirzepatide 5mgQW Tirzepatide 10mgQW Tirzepatide 15mgQW	Insulin degludec QD	5mg:64 10mg:51 15mg:73	55	5mg:57.0 (10.1) 10mg:58.0 (8.5) 15mg:56.0 (10.0)	57.2 (10.1)	5mg:41M 23F 10mg:23M 28F 15mg:39M 34F	30M 25F	5mg:9.3 (7.4) 10mg:8.9 (6.8) 15mg:8.3 (5.4)	8.8 (6.6)	52w	②

3.3 Risk of bias

Thirteen trials reported the correct generation method course (computer-generated randomized sequence or interaction network allocation) with low risk of bias^{[26–33, 21, 35–36, 40–41]} (Fig. 2), and four trials did not explicitly describe the random allocation method^{[34, 37–39]}. Allocation concealment was reported in 13 trials^{[26–33, 21, 35–36, 40–41]}, and 4 trials did not explicitly describe allocation concealment methods^{[34, 37–39]}. Ten studies^{[26–32, 36, 37, 39]} mentioned blinding of patients and researchers, and 7 did not use blinding^{[21, 33–35, 38, 40, 41]}. Three trials reported outcome evaluation blinding^{[27, 32, 36]}, six trials did not report outcome evaluation blinding^{[26, 28, 29, 31, 37, 39]}, and eight trials did not use outcome evaluation blinding^{[21, 30, 33–35, 38, 40, 41]}. All trials had complete outcome data and no selective reporting, which is low risk. One study^[31] illustrated the possibility of reporting bias due to gastrointestinal reactions, which is high risk, and the remaining studies had no other sources of bias, which is low risk.

3.4 Network meta-analysis

On the five indicators of weight, HbA1c, FBG, fasting insulin, and fasting C-peptide under different interventions, we conducted a network meta-analysis. To assess the consistency between the direct and indirect comparisons of the five outcome indicators, a node-split model was used. The results showed P > 0.05, which indicates direct and indirect comparisons are consistent.

Table 2. Network meta-analysis of weight, HbA1c, FBG, fasting insulin, fasting C-peptide

Table 2a. Network meta-analysis of weight (A-L:tirzepatide 0.5mg, tirzepatide 1mg, tirzepatide 5mg, tirzepatide 10mg, tirzepatide 12mg, tirzepatide 15mg, dulaglutide 0.75mg, dulaglutide 1.5mg, semaglutide 1mg, placebo, degludec insulin, and glargine insulin)
F	0.23 (-0.28,0.74)				0.28 (0.18,0.37)		0.68 (0.58,0.78)				0.81 (0.60,1.01)			1.22 (0.86,1.59)			1.39 (0.63,2.15)			1.53 (1.38,1.68)			1.52 (1.15,1.89)			1.78 (1.52,2.05)			1.97 (1.77,2.18)				2.14 (1.96,2.32)
-0.23 (-0.74,0.28)	E				0.05 (-0.46,0.56)		0.45 (-0.06,0.97)				0.58 (0.03,1.12)			0.99 (0.37,1.61)			1.16 (0.25,2.07)			1.30 (0.79,1.81)			1.29 (0.67,1.92)			1.55 (0.98,2.12)			1.74 (1.20,2.29)				1.91 (1.38,2.45)
-0.28 (-0.37,-0.18)	-0.05 (-0.56,0.46)				D		0.41 (0.31,0.50)				0.53 (0.32,0.74)			0.94 (0.58,1.31)			1.11 (0.35,1.87)			1.25 (1.10,1.40)			1.24 (0.87,1.62)			1.51 (1.24,1.77)			1.70 (1.49,1.90)				1.86 (1.68,2.04)
-0.68 (-0.78,-0.58)	-0.45 (-0.97,0.06)				-0.41 (-0.50,-0.31)		C				0.12 (-0.09,0.33)			0.54 (0.17,0.90)			0.71 (-0.05,1.47)			0.85 (0.69,1.00)			0.84 (0.47,1.21)			1.10 (0.84,1.37)			1.29 (1.08,1.50)				1.46 (1.28,1.64)
-0.81 (-1.01,-0.60)	-0.58 (-1.12,-0.03)				-0.53 (-0.74,-0.32)		-0.12 (-0.33,0.09)				I			0.42 (0.00,0.83)			0.58 (-0.20,1.37)			0.72 (0.48,0.96)			0.72 (0.30,1.13)			0.98 (0.65,1.30)			1.17 (0.89,1.45)				1.33 (1.07,1.60)
-1.22 (-1.59,-0.86)	-0.99 (-1.61,-0.37)				-0.94 (-1.31,-0.58)		-0.54 (-0.90,-0.17)				-0.42 (-0.83,-0.00)			H			0.17 (-0.67,1.00)			0.31 (-0.06,0.68)			0.30 (-0.15,0.75)			0.56 (0.12,1.01)			0.75 (0.34,1.16)				0.92 (0.52,1.32)
-1.39 (-2.15,-0.63)	-1.16 (-2.07,-0.25)				-1.11 (-1.87,-0.35)		-0.71 (-1.47,0.05)				-0.58 (-1.37,0.20)			-0.17 (-1.00,0.67)			A			0.14 (-0.62,0.90)			0.13 (-0.71,0.97)			0.40 (-0.41,1.20)			0.58 (-0.20,1.37)				0.75 (-0.03,1.53)
-1.53 (-1.68,-1.38)	-1.30 (-1.81,-0.79)				-1.25 (-1.40,-1.10)		-0.85 (-1.00,-0.69)				-0.72 (-0.96,-0.48)			-0.31 (-0.68,0.06)			-0.14 (-0.90,0.62)			J			-0.01 (-0.38,0.37)			0.26 (-0.04,0.55)			0.44 (0.20,0.69)				0.61 (0.39,0.83)
-1.52 (-1.89,-1.15)	-1.29 (-1.92,-0.67)				-1.24 (-1.62,-0.87)		-0.84 (-1.21,-0.47)				-0.72 (-1.13,-0.30)			-0.30 (-0.75,0.15)			-0.13 (-0.97,0.71)			0.01 (-0.37,0.38)			B			0.26 (-0.19,0.71)			0.45 (0.03,0.87)				0.62 (0.21,1.02)
-1.78 (-2.05,-1.52)	-1.55 (-2.12,-0.98)				-1.51 (-1.77,-1.24)		-1.10 (-1.37,-0.84)				-0.98 (-1.30,-0.65)			-0.56 (-1.01,-0.12)			-0.40 (-1.20,0.41)			-0.26 (-0.55,0.04)			-0.26 (-0.71,0.19)			G			0.19 (-0.14,0.51)				0.36 (0.05,0.66)
-1.97 (-2.18,-1.77)	-1.74 (-2.29,-1.20)				-1.70 (-1.90,-1.49)		-1.29 (-1.50,-1.08)				-1.17 (-1.45,-0.89)			-0.75 (-1.16,-0.34)			-0.58 (-1.37,0.20)			-0.44 (-0.69,-0.20)			-0.45 (-0.87,-0.03)			-0.19 (-0.51,0.14)			K				0.17 (-0.09,0.43)
-2.14 (-2.32,-1.96)	-1.91 (-2.45,-1.38)				-1.86 (-2.04,-1.68)		-1.46 (-1.64,-1.28)				-1.33 (-1.60,-1.07)			-0.92 (-1.32,-0.52)			-0.75 (-1.53,0.03)			-0.61 (-0.83,-0.39)			-0.62 (-1.02,-0.21)			-0.36 (-0.66,-0.05)			-0.17 (-0.43,0.09)				L
Table 2b. Network meta-analysis of HbA1c (A-K:tirzepatide 1mg, tirzepatide 5mg, tirzepatide 10mg, tirzepatide 12mg, tirzepatide 15mg, dulaglutide 0.75mg, dulaglutide 1.5mg, semaglutide 1mg, placebo, degludec insulin, and glargine insulin)
E		0.03 (-0.55,0.61)				0.31 (-0.92,1.55)			0.43 (-1.39,2.26)			0.75 (-0.45,1.96)				0.76 (0.15,1.37)			1.12 (-0.53,2.76)			1.29 (-0.38,2.96)			1.20 (0.19,2.21)			1.46 (-0.18,3.11)				2.37 (1.63,3.11)
-0.03 (-0.61,0.55)		C				0.28 (-0.99,1.56)			0.40 (-1.48,2.28)			0.72 (-0.48,1.93)				0.73 (0.11,1.35)			1.09 (-0.56,2.73)			1.26 (-0.41,2.94)			1.17 (0.16,2.18)			1.43 (-0.22,3.08)				2.34 (1.55,3.13)
-0.31 (-1.55,0.92)		-0.28 (-1.56,0.99)				H			0.12 (-2.05,2.28)			0.44 (-1.23,2.11)				0.44 (-0.84,1.73)			0.80 (-1.20,2.81)			0.98 (-1.06,3.02)			0.89 (-0.66,2.43)			1.15 (-0.86,3.15)				2.06 (0.73,3.38)
-0.43 (-2.26,1.39)		-0.40 (-2.28,1.48)				-0.12 (-2.28,2.05)			D			0.32 (-1.84,2.49)				0.33 (-1.57,2.22)			0.68 (-1.73,3.10)			0.86 (-1.60,3.32)			0.77 (-1.30,2.83)			1.03 (-1.38,3.45)				1.94 (0.11,3.76)
-0.75 (-1.96,0.45)		-0.72 (-1.93,0.48)				-0.44 (-2.11,1.23)			-0.32 (-2.49,1.84)			K				0.00 (-1.21,1.21)			0.36 (-1.62,2.34)			0.54 (-1.46,2.54)			0.45 (-1.05,1.94)			0.71 (-1.28,2.69)				1.62 (0.26,2.97)
-0.76 (-1.37,-0.15)		-0.73 (-1.35,-0.11)				-0.44 (-1.73,0.84)			-0.33 (-2.22,1.57)			-0.00 (-1.21,1.21)				B			0.36 (-1.30,2.01)			0.53 (-1.14,2.21)			0.44 (-0.58,1.46)			0.71 (-0.95,2.36)				1.61 (0.78,2.44)
-1.12 (-2.76,0.53)		-1.09 (-2.73,0.56)				-0.80 (-2.81,1.20)			-0.68 (-3.10,1.73)			-0.36 (-2.34,1.62)				-0.36 (-2.01,1.30)			G			0.18 (-2.12,2.48)			0.08 (-1.79,1.96)			0.35 (-1.68,2.38)				1.25 (-0.43,2.94)
-1.29 (-2.96,0.38)		-1.26 (-2.94,0.41)				-0.98 (-3.02,1.06)			-0.86 (-3.32,1.60)			-0.54 (-2.54,1.46)				-0.53 (-2.21,1.14)			-0.18 (-2.48,2.12)			F			-0.09 (-1.99,1.80)			0.17 (-2.13,2.47)				1.08 (-0.71,2.86)
-1.20 (-2.21,-0.19)		-1.17 (-2.18,-0.16)				-0.89 (-2.43,0.66)			-0.77 (-2.83,1.30)			-0.45 (-1.94,1.05)				-0.44 (-1.46,0.58)			-0.08 (-1.96,1.79)			0.09 (-1.80,1.99)			J			0.26 (-1.61,2.14)				1.17 (-0.02,2.35)
-1.46 (-3.11,0.18)		-1.43 (-3.08,0.22)				-1.15 (-3.15,0.86)			-1.03 (-3.45,1.38)			-0.71 (-2.69,1.28)				-0.71 (-2.36,0.95)			-0.35 (-2.38,1.68)			-0.17 (-2.47,2.13)			-0.26 (-2.14,1.61)			A				0.91 (-0.78,2.60)
-2.37 (-3.11,-1.63)		-2.34 (-3.13,-1.55)				-2.06 (-3.38,-0.73)			-1.94 (-3.76,-0.11)			-1.62 (-2.97,-0.26)				-1.61 (-2.44,-0.78)			-1.25 (-2.94,0.43)			-1.08 (-2.86,0.71)			-1.17 (-2.35,0.02)			-0.91 (-2.60,0.78)				I
Table 2c. Network meta-analysis of FBG (A-K:tirzepatide 1mg, tirzepatide 5mg, tirzepatide 10mg, tirzepatide 12mg, tirzepatide 15mg, dulaglutide 0.75mg, dulaglutide 1.5mg, semaglutide 1mg, placebo, degludec insulin, and glargine insulin)
E		0.03 (-0.31,0.37)				0.27 (-0.72,1.25)			0.31 (-0.05,0.67)			0.42 (-0.27,1.11)				0.46 (-0.64,1.57)			0.81 (-0.16,1.77)			1.11 (0.14,2.08)			1.59 (0.86,2.31)			1.66 (0.89,2.42)				1.67 (1.23,2.11)
-0.03 (-0.37,0.31)		C				0.24 (-0.74,1.22)			0.28 (-0.08,0.65)			0.39 (-0.30,1.08)				0.43 (-0.70,1.57)			0.78 (-0.19,1.75)			1.08 (0.11,2.05)			1.56 (0.81,2.30)			1.63 (0.86,2.39)				1.64 (1.18,2.11)
-0.27 (-1.25,0.72)		-0.24 (-1.22,0.74)				J			0.05 (-0.94,1.03)			0.16 (-1.01,1.32)				0.20 (-1.27,1.66)			0.54 (-0.81,1.89)			0.84 (-0.51,2.20)			1.32 (0.12,2.52)			1.39 (0.18,2.60)				1.41 (0.36,2.46)
-0.31 (-0.67,0.05)		-0.28 (-0.65,0.08)				-0.05 (-1.03,0.94)			B			0.11 (-0.58,0.80)				0.15 (-0.99,1.29)			0.49 (-0.48,1.47)			0.80 (-0.18,1.78)			1.27 (0.52,2.03)			1.34 (0.58,2.11)				1.36 (0.87,1.85)
-0.42 (-1.11,0.27)		-0.39 (-1.08,0.30)				-0.16 (-1.32,1.01)			-0.11 (-0.80,0.58)			K				0.04 (-1.25,1.33)			0.38 (-0.77,1.54)			0.69 (-0.47,1.85)			1.16 (0.19,2.13)			1.23 (0.25,2.22)				1.25 (0.47,2.03)
-0.46 (-1.57,0.64)		-0.43 (-1.57,0.70)				-0.20 (-1.66,1.27)			-0.15 (-1.29,0.99)			-0.04 (-1.33,1.25)				D			0.34 (-1.10,1.79)			0.65 (-0.80,2.09)			1.12 (-0.18,2.42)			1.19 (-0.14,2.52)				1.21 (0.10,2.31)
-0.81 (-1.77,0.16)		-0.78 (-1.75,0.19)				-0.54 (-1.89,0.81)			-0.49 (-1.47,0.48)			-0.38 (-1.54,0.77)				-0.34 (-1.79,1.10)			G			0.30 (-0.89,1.50)			0.78 (-0.40,1.96)			0.85 (-0.35,2.05)				0.87 (-0.13,1.86)
-1.11 (-2.08,-0.14)		-1.08 (-2.05,-0.11)				-0.84 (-2.20,0.51)			-0.80 (-1.78,0.18)			-0.69 (-1.85,0.47)				-0.65 (-2.09,0.80)			-0.30 (-1.50,0.89)			A			0.48 (-0.70,1.66)			0.55 (-0.66,1.75)				0.56 (-0.43,1.56)
-1.59 (-2.31,-0.86)		-1.56 (-2.30,-0.81)				-1.32 (-2.52,-0.12)			-1.27 (-2.03,-0.52)			-1.16 (-2.13,-0.19)				-1.12 (-2.42,0.18)			-0.78 (-1.96,0.40)			-0.48 (-1.66,0.70)			H			0.07 (-0.95,1.09)				0.09 (-0.70,0.87)
-1.66 (-2.42,-0.89)		-1.63 (-2.39,-0.86)				-1.39 (-2.60,-0.18)			-1.34 (-2.11,-0.58)			-1.23 (-2.22,-0.25)				-1.19 (-2.52,0.14)			-0.85 (-2.05,0.35)			-0.55 (-1.75,0.66)			-0.07 (-1.09,0.95)			F				0.02 (-0.83,0.86)
-1.67 (-2.11,-1.23)		-1.64 (-2.11,-1.18)				-1.41 (-2.46,-0.36)			-1.36 (-1.85,-0.87)			-1.25 (-2.03,-0.47)				-1.21 (-2.31,-0.10)			-0.87 (-1.86,0.13)			-0.56 (-1.56,0.43)			-0.09 (-0.87,0.70)			-0.02 (-0.86,0.83)				I
Table 2d. Network meta-analysis of fasting insulin (A-H: tirzepatide 1mg, tirzepatide 5mg, tirzepatide 10mg, tirzepatide 15mg, dulaglutide 0.75mg, dulaglutide 1.5mg, semaglutide 1mg, placebo)
D			0.12 (0.00,0.24)					0.11 (-0.29,0.50)					0.28 (0.15,0.42)					0.44 (0.12,0.77)			0.46 (0.32,0.60)						0.50 (0.17,0.83)				0.72 (0.50,0.94)
-0.12 (-0.24,-0.00)			C					-0.01 (-0.42,0.39)					0.16 (0.03,0.30)					0.32 (-0.00,0.65)			0.34 (0.19,0.49)						0.38 (0.05,0.71)				0.60 (0.38,0.81)
-0.11 (-0.50,0.29)			0.01 (-0.39,0.42)					G					0.18 (-0.23,0.59)					0.34 (-0.17,0.84)			0.35 (-0.05,0.75)						0.39 (-0.12,0.90)				0.61 (0.16,1.06)
-0.28 (-0.42,-0.15)			-0.16 (-0.30,-0.03)					-0.18 (-0.59,0.23)					B					0.16 (-0.17,0.49)			0.18 (0.01,0.35)						0.22 (-0.12,0.55)				0.44 (0.22,0.66)
-0.44 (-0.77,-0.12)			-0.32 (-0.65,0.00)					-0.34 (-0.84,0.17)					-0.16 (-0.49,0.17)					F			0.02 (-0.31,0.35)						0.06 (-0.34,0.46)				0.28 (-0.10,0.66)
-0.46 (-0.60,-0.32)			-0.34 (-0.49,-0.19)					-0.35 (-0.75,0.05)					-0.18 (-0.35,-0.01)					-0.02 (-0.35,0.31)			H						0.04 (-0.30,0.38)				0.26 (0.01,0.51)
-0.50 (-0.83,-0.17)			-0.38 (-0.71,-0.05)					-0.39 (-0.90,0.12)					-0.22 (-0.55,0.12)					-0.06 (-0.46,0.34)			-0.04 (-0.38,0.30)						A				0.22 (-0.16,0.60)
-0.72 (-0.94,-0.50)			-0.60 (-0.81,-0.38)					-0.61 (-1.06,-0.16)					-0.44 (-0.66,-0.22)					-0.28 (-0.66,0.10)			-0.26 (-0.51,-0.01)						-0.22 (-0.60,0.16)				E
Table 2e. Network meta-analysis of fasting C-peptide (A-G: tirzepatide 1mg, tirzepatide 5mg, tirzepatide 10mg, tirzepatide 15mg, dulaglutide 0.75mg, dulaglutide 1.5mg, and placebo)
C				0.08 (-0.22,0.38)						0.34 (-0.18,0.85)					0.38 (0.09,0.68)					0.42 (-0.10,0.93)				0.53 (0.01,1.04)						0.86 (0.46,1.26)
-0.08 (-0.38,0.22)				D						0.26 (-0.26,0.77)					0.30 (0.01,0.60)					0.34 (-0.18,0.85)				0.45 (-0.07,0.96)						0.78 (0.38,1.18)
-0.34 (-0.85,0.18)				-0.26 (-0.77,0.26)						G					0.05 (-0.47,0.56)					0.08 (-0.52,0.67)				0.19 (-0.40,0.78)						0.52 (-0.08,1.13)
-0.38 (-0.68,-0.09)				-0.30 (-0.60,-0.01)						-0.05 (-0.56,0.47)					B					0.03 (-0.48,0.54)				0.14 (-0.37,0.65)						0.47 (0.07,0.88)
-0.42 (-0.93,0.10)				-0.34 (-0.85,0.18)						-0.08 (-0.67,0.52)					-0.03 (-0.54,0.48)					A				0.11 (-0.48,0.70)						0.44 (-0.16,1.05)
-0.53 (-1.04,-0.01)				-0.45 (-0.96,0.07)						-0.19 (-0.78,0.40)					-0.14 (-0.65,0.37)					-0.11 (-0.70,0.48)				F						0.33 (-0.27,0.94)
-0.86 (-1.26,-0.46)				-0.78 (-1.18,-0.38)						-0.52 (-1.13,0.08)					-0.47 (-0.88,-0.07)					-0.44 (-1.05,0.16)				-0.33 (-0.94,0.27)						E

3.4.1 Weight

A total of 16 publications with 9121 patients addressed body weight with 12 interventions: A-L:tirzepatide 0.5mg, tirzepatide 1mg, tirzepatide 5mg, tirzepatide 10mg, tirzepatide 12mg, tirzepatide 15mg, dulaglutide 0.75mg, dulaglutide 1.5mg, semaglutide 1mg, placebo, degludec insulin, and glargine insulin.

The results of network meta-analysis indicated that F was statistically significant (P < 0.05) compared to A B C G H I J K L, manifesting that F was superior to A B C G H I J K L; E was statistically significant (P < 0.05) compared to A B G H I J K L, indicating that E was superior to A B G H I J K L; D was statistically significant (P < 0.05) compared to A B C G H I J K L, indicating that D was superior to A B G H I J K L; C I was statistically significant (p < 0.05) compared to H J B G K L, indicating that C I was superior to H J B G K L; and there was no statistical significance between C I (p > 0.05). Compared with G K L, H was statistically significant (P < 0.05), indicating that H was superior to G K L; compared with K L, J B was statistically significant (P < 0.05),indicating that J B was superior to K L; compared with L, G was statistically significant (P < 0.05),indicating that G was superior to L; and there was no statistical significance in the remaining comparisons between measures (P > 0.05).(Fig. 3a, Table 2a)

The result of SUCRA was: F (98.3%) > E (88.0%) > D (85.7%) > C (71.7%) > I (64.1%) > H (50.3%) > A (40.4%) > J (35.0%) > B (34.8%) > G (20.2%) > K (10.1%) > L (1.3%). (Fig. 4a)

3.4.2 HbA1c

There were 14 publications with 8813 patients involving HbA1c and 11 interventions: A-K:tirzepatide 1mg, tirzepatide 5mg, tirzepatide 10mg, tirzepatide 12mg, tirzepatide 15mg, dulaglutide 0.75mg, dulaglutide 1.5mg, semaglutide 1mg, placebo, degludec insulin, and glargine insulin.

The results of the network meta-analysis concluded that E C has statistical significance (P < 0.05) compared with B J I, indicating that E and C were superior to B J I; H D K B was statistically significant (P < 0.05) compared with I, indicating that H D K B was superior to I; and comparisons between the remaining measures were not statistically significant (P > 0.05). (Fig. 3b, Table 2b)

The result of SUCRA was: E (85.7%) > C (84.1%) > H (70.3%) > D (63.8%) > K (52.3%) > B (51.2%) > G (40.3%) > F (35.1%) > J (34.5%) > A (28.9%) > I (3.8%). (Fig. 4b)

3.4.3 FBG

There were 14 publications with 7686 patients involving FBG and 11 interventions: A-K:tirzepatide 1mg, tirzepatide 5mg, tirzepatide 10mg, tirzepatide 12mg, tirzepatide 15mg, dulaglutide 0.75mg, dulaglutide 1.5mg, semaglutide 1mg, placebo, degludec insulin, and glargine insulin.

Network meta-analysis showed that E C was statistically significant (P < 0.05) compared with A H F I, indicating that E and C were superior to A H F; J B K was statistically significant (P < 0.05) compared with A H I, indicating that J B K was superior to A H I; D was statistically significant (P < 0.05) compared with I, indicating that D was superior to I; and comparisons among the remaining measures were not statistically significant ( P > 0.05). (Fig. 3c, Table 2c)

The result of SUCRA was: E (88.2%) > C (86.2%) > J (69.7%) > B (65.8%) > K (61.6%) > D (60.8%) > G (45.4%) > A (33.2%) > H (15.3%) > F (12.9%) > I (10.9%). (Fig. 4c)

3.4.4 Fasting insulin

There were 7 papers with 2941 patients involving Fasting insulin and a total of 8 interventions: A-H: tirzepatide 1mg, tirzepatide 5mg, tirzepatide 10mg, tirzepatide 15mg, dulaglutide 0.75mg, dulaglutide 1.5mg, semaglutide 1mg, placebo.

Network meta-analysis showed that compared with A B C E F H, D was statistically significant (P < 0.05), indicating that D was superior to A B C E F H; compared with B H A E, C was statistically significant (P < 0.05), indicating that C was superior to B H A; compared with E, G H was statistically significant (P < 0.05), indicating that G H was superior to E; compared with H E, B was statistically significant (P < 0.05), indicating that G H was superior to E; and compared with H E, B was statistically significant (P < 0.05), indicating that B was statistically significant (P < 0.05). 0.05),indicating that B was superior to H E; the remaining comparisons between measures were not statistically significant (P > 0.05). (Fig. 3d, Table 2d)

The result of SUCRA was: D (95.4%) > C (77.9%) > G (77.6%) > B (55.7%) > F (34.0%) > H (29.6%) > A (26.3%) > E (3.4%). (Fig. 4d)

3.4.5 Fasting C-peptide

There were four papers with 1441 patients involving Fasting C-peptide and a total of 7 interventions: A-G: tirzepatide 1mg, tirzepatide 5mg, tirzepatide 10mg, tirzepatide 15mg, dulaglutide 0.75mg, dulaglutide 1.5mg, and placebo.

The results of the network Meta-analysis showed that C was statistically significant (P < 0.05) compared to B F E, indicating that C was superior to B F E; D was statistically significant (P < 0.05) compared to B E, indicating that D was superior to B E; B was statistically significant (P < 0.05) compared to E, indicating that B was superior to E; and the comparisons between the remaining measures were not statistically significant (P > 0.05). (Fig. 3e, Table 2e)

The result of SUCRA was: C (91.8%) > D (91.8%) > G (52.3%) > B (45.0%) > A (43.1%) > F (30.5%) > E (4.4%). (Fig. 4e)

3.5 Adverse events

A total of 7407 (72%) ^{[21, 27–41]} had ≥ 1 treatment-emergent adverse events. As shown in Table 3, the 15mg dose of tirzepatide has the higher incidence of TEAEs. And tirzepatide 15mg has the highest incidence of gastrointestinal adverse events comprising decreased appetite, nausea, vomiting, diarrhea, dyspepsia and constipation. There were 83 deaths in this study, mainly in tirzepatide-5mg and Insulin groups, all considered unrelated to study medication by the corresponding RCTs investigators. Severe AEs were reported in 19% in the tirzepatide 5mg, 21% in the tirzepatide 10mg, 18% in the tirzepatide 15mg, 29% in the insulin groups, 7% in the selective GLP-1RA groups. AEs leading to treatment discontinuation were reported in tirzepatide 5, 10, 15 mg, selective GLP-1RA groups and insulin groups, 20%, 29%, 34%, 4%, 9% and 3% respectively. The incidence of hypoglycemic events ( plasma glucose ≤ 70 mg/dL) was similar across the tirzepatide group (18–24%), and it was lower than that for insulin groups (28%) .

Table 3

Adverse events
Events	Total	Tirzepatide 5mg	Tirzepatide 10mg	Tirzepatide 15mg	Selective GLP-RAs	Insulin	Placebo
≥ 1 TEAEs	7407	1487(20%)	1819(25%)	1967(27%)	507(7%)	1108(15%)	465(6%)
Severe AEs	842	160(19%)	180(21%)	155(18%)	57(7%)	246(29%)	41(5%)
Deaths	83	20(24%)	8 (10%)	14 (17%)	1(1%)	38(46%)	2(2%)
Adverse events leading to discontinuation of treatment	698	139(20%)	199(29%)	238(34%)	30(4%)	66(9%)	24(3%)
Decreased appetite	1095	233(21%)	346(32%)	416(38%)	66(6%)	7(1%)	19(2%)
Nausea	1629	299(18%)	499(31%)	618(38%)	125(8%)	36(2%)	42(3%)
Vomiting	743	127(17%)	224(30%)	290(39%)	51(7%)	25(3%)	18(2%)
Diarrhea	1564	335(21%)	480(31%)	519(33%)	87(6%)	66(4%)	60(4%)
Dyspepsia	552	115(21%)	184(33%)	165(30%)	49(9%)	16(3%)	18(3%)
Constipation	516	115(22%)	148(29%)	171(33%)	55(11%)	9(2%)	16(3%)
Hypoglycaemia(plasma glucose ≤ 70 mg/dL)	1089	196(18%)	244(22%)	262(24%)	7(1%)	300(28%)	77(7%)

3.6 Publication bias

Comparison-correction funnel plots were constructed using the effect size of each indicator as the horizontal coordinate and the standard error as the vertical coordinate and are shown in Supplementary Figs. 1–3. There are different colors of points in the inverted funnel plots for direct comparisons of different interventions, while number of same-colored points represents the number of two-by-two comparisons. From the results, it can be seen that each scatter involving body weight, FBG, and HbA1c is basically within the scope of the inverted funnel plot and the graphs are roughly symmetric around the zero line, indicating low probability of publication bias or small-sample effect.

Our network meta-analysis identified 14 RCTs out of seventeen studies. And included patients with T2DM have been assigned to 12 interventions, including different doses of tirzepatide (0.5mg, 1mg, 5mg, 10mg, 12mg, 15mg), selective GLP-1RAs(semaglutide 1mg, dulaglutide 0.75mg, dulaglutide 1.5mg), basal insulin (degludec and glargine) and placebo. The study findings suggested that tirzepatide 15mg, followed by the tirzepatide 10mg showed a significant reduction in HbA1c, body weight, FBG, fasting insulin and fasting C-Peptide, compared with Insulin, GLP-RAs and placebo.

Regarding bodyweight reduction, tirzepatide(15mg, 12mg, 10mg) decreased body weight more than semaglutide 1mg and dulaglutide 1.5mg. Juan P. Frías et al. showed that bodyweight reduction with tirzepatide was superior to semaglutide in a dose-dependent manner. Tirzepatide achieved a mean body weight reduction of 7.6 kg, 9.3 kg, and 11.2 kg at doses of 5 mg, 10 mg, and 15 mg, respectively, whereas semaglutide reduced body weight by 5.7 kg^[38]. Also, Tim Heise et al. reported both tirzepatide and semaglutide reduced body weight compared with placebo, with tirzepatide resulting in significantly greater weight loss than semaglutide^[27]. Nobuya Inagaki et al. reported that tirzepatide at all doses reduces bodyweight more than dulaglutide0.75mg, reducing bodyweight level from 7.8–13.9% with tirzepatide (dose-dependent range) and 0.7% reduction with dulaglutide0.75mg after 52 weeks followup^[29].

A meta analysis by Yasmin Luz Lima de Mesquita et al. statemented more notable bodyweight reduction with tirzepatide 5 mg, 10mg and 15 mg than placebo^[42]. As reported by previous network meta analysis, tirzepatide administered at all doses demonstrated higher weight loss effectiveness in comparison with with glargine, degludec. When compared with GLP-1RA, a statistically significant reduction in body weight was observed with 10mg and 15 mg of tirzepatide, among that, 15 mg of tirzepatide has the best effection reducing body weight (SUCRA probability: 99.7%)^[43]. This is similar to our findings, suggesting that tirzepatide has a clear advantage in weight loss with T2DM, especially 15mg of tirzepatide.

Regarding the HbA1c level, tirzepatide (15mg, 10mg, 5mg), semaglutide significantly decreased HbA1c level. And the HbA1c level reduction with tirzepatide at 15mg, 10mg was greater than semaglutide and glargine. These results were consistent with the previous study^{[34, 38]}. Tim Heise et al. stated that tirzepatide15mg and semaglutide 1 mg reduced HbA1c more than placebo, and tirzepatide significantly reduced HbA1c levels more than semaglutide^[27]. As revealed by a bayesian network meta-analysis, tirazepatide at all doses generally reduced HbA1c more effectively than both glargine and degludec, while 10 mg and 15 mg of tirzepatide were significantly more effective than dulaglutide and semaglutide^[43]. According to these findings, tirzepatide provides better control of blood sugar levels

Regarding the FBG level, tirzepatide 15mg, tirzepatide 10mg, degludec, tirzepatide 5mg and glargine significantly lowered FBG level. The reduction with tirzepatide 15mg, 10mg was significantly better than semaglutide, dulaglutide and placebo. Tim Heise et al. concluded that both tirzepatide15mg and semaglutide 1 mg reduced FBG more than placebo^[27], and the reduction in FBG level with tirzepatide was significantly greater than with semaglutide^{[27, 38]}. Another network meta-analysis confirmed our findings about FBG reduction. It suggested that higher reduction in fasting plasma glucose with tirzepatide, compared with GLP-1RA (dulaglutide 1.5mg, semaglutide 1mg)^[44]. Another Cochrane meta-analysis stated that the lowering of FBG with tirzepatide was significantly greater than that of dulaglutide, semaglutide, degludec, glargine or placebo^[45]. Overall, a significant FBG reduction was observed with tirzepatide compared with other comparators.

Regarding fasting insulin, tirzepatide15mg, tirzepatide10mg, semaglutide, tirzepatide5mg significantly lowered fasting insulin level in our study. As for fasting C-Peptide, tirzepatide at 15mg, 10mg, 5mg significantly decreased more than dulaglutide 0.75mg, 1.5mg. Tim Heise et al. stated that both tirzepatide15mg and semaglutide 1mg significantly reduced fasting insulin when compared with placebo^[27]. Juan Pablo Frias et al. Also found better reduction of fasting insulin at tirzepatide10 mg and tirzepatide15mg compared to dulullutide1.5mg^[28]. Furthermore, Nobuya Inagaki et al. demonstrated significantly reduction in fasting insulin and fasting C-Peptide with tirzepatide at all doses compared to dulaglutide. At the same time, all doses of tirzepatide significantly increased insulin sensitivity and beta cell function^[29]. A study conducted by Takashi Kadowaki et al. showed all doses of tirzepatide reduced fasting C-Peptide, in particular 15mg^[35]The reduction of fasting insulin and fasting C-Peptide with all doses of tirzepatide were also obvious in Clare J. Lee et al, which reflected the improvement of islet function and insulin resistance^[46]. These results showed that tirzepatide could be a potential antihyperglycemic agents for improvement in islet function and insulin resistance in patients with T2DM.

As for the safety, it can be seen from the Table 3 that the incidence of TEAEs with tirzepatide seems to be higher than that of insulin and selective GLP-1 RAs groups. For the reason that may be due to the smaller sample size of the insulin and selective GLP-1 RAs groups. TEAEs tend to be mild to moderate in severity. And the higher the dose of tirzepatide, the higher the incidence of gastrointestinal adverse events. Zhuqing Meng et al. and Rahul Mishra et al. demonstrated that the incidence rate of gastrointestinal adverse events of tirzepatide was similar to that of GLP-1 RAs^[47–48]. Researchers found that tirzepatide was more likely to cause gastrointestinal adverse reactions than insulin or placebo. This is consistent with previous studies^[43]. In addition, it is important to mention that tirzepatide has a lower occurrence of hypoglycemia compared to insulin, indicating that the hypoglycemic impact of tirzepatide is unrelated to the heightened risk of hypoglycemia.

To date, most of the meta-analyses of tirzepatide were conducted to investigate the efficacy of glycemic control and weight loss including HbA1c, FBG and body weight. For example, an earlier meta-analysis conducted by Thomas Karagiannis et al^[49]. To our knowledge, there was a published bayesian network meta analysis to compare the efficacy and safety of different doses of tirzepatide with placebo or other glucose-lowering drugs among patients with T2DM only included eight RCTs ^[43]. Nevertheless, our article included 14 RCTs, 3 randomized control trails in 2023 were also contained in this network meta-analysis. In addition, a comparison of the efficacy betweent different doses of tirzepatide and other glucose-lowering drugs on fasting insulin and fasting C-Peptide was conducted, which goes hand in hand with beta cell function and insulin resistance.

Lastly, We are limited by the fact that we only included English studies in our study and some trails had a short duration. Secondly, some trails had a small sample size of the semaglutide, dulaglutide and comparison of selective GLP-1RAs at higher doses was lacking. Thirdly, there were few RCTs specifically designed to the evaluation of effect of tirzepatide on beta-cell function and insulin sensitivity in the included studies. Finally, this network meta analysis was absence of the assessment on HOMA-IR and HOMA-B, resulted from the less RCTs raw data (some data could not be obtained, some are incomplete). Consequently, Our results need to be confirmed and strengthened through further head-to-head trials between tirzepatide and higher doses of selective GLP-1RA.

In summary, all doses of tirzepatide have a favourable efficacy in treating T2DM. Tirzepatide at 15mg, 10mg had a greater reduction on HbA1c, body weight, FBG, fasting insulin and fasting C-Peptide compared with basal insulin (glargine or degludec) and selective GLP-1RA (dulaglutide or semaglutide) with an acceptable safety profile.Tirzepatide has shown great promise for managing T2DM, islet function, insulin resistance, and weight loss.

Data availability statement

Article/Supplementary Material contains the original contributions. The raw data can be obtained from the authors.

Acknowledgements

None.

Author contributions

JXZ and YJH conceptualized this study. The manuscript was drafted by JXZ, YJH, YL and YW. JXZ, YJH, YL, YW, HYL and WL designed the analysis scheme for data synthesis. The manuscript was overseen, critically evaluated, and verified by ZZZ. All authors contributed to the article and approved the submitted version.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No: 8217150016).

Conflict of Interest

The authors declare no conflict of interest.

Competing Interest Statement

The authors declare no conflict of competing interest.

Approved the study

Not applicable. This study is network meta-analysis, this type of article does not require approval.

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No competing interests reported.

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Efficacy and safety of different doses of tirzepatide in patients with type 2 diabetes mellitus: a systematic review and network meta-analysis

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Abstract

Figures

1 Introduction

2 Methods

2.1 Search strategy

2.2 Study selection and data extraction

2.3 Risk of bias assessment

2.4 Outcome measures

2.5 Data analysis and reporting

3 Results

3.1 Literature screening process

3.2 Literature characteristics

3.3 Risk of bias

3.4 Network meta-analysis

3.4.1 Weight

3.4.2 HbA1c

3.4.3 FBG

3.4.4 Fasting insulin

3.4.5 Fasting C-peptide

3.5 Adverse events

3.6 Publication bias

4 Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

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