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. 2023 May 4;18(5):e0285197. doi: 10.1371/journal.pone.0285197

Weight loss efficiency and safety of tirzepatide: A Systematic review

Fei Lin 1,2, Bin Yu 3,*, Baodong Ling 4, Guangyao Lv 5, Huijun Shang 6, Xia Zhao 1,2, Xiaoling Jie 1,2, Jing Chen 1,2, Yan Li 1,2
Editor: Inge Roggen7
PMCID: PMC10159347  PMID: 37141329

Abstract

Objective

Tirzeptide is a novel glucagon-like peptide-1 receptor (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) drug, which shows good efficiency for weight loss. Therefore, we aim to investigate the efficacy and safety of tirzepatide for weight loss in type 2 diabetes mellitus (T2DM) and obesity patients in this meta-analysis study.

Methods

Cochrane Library, PubMed, Embase, Clinical Trials, and Web of Science were searched from inception to October 5, 2022. All randomized controlled trials (RCTs) were included. The odds ratio (OR) was calculated using fixed-effects or random-effects models by Review Manager 5.3 software.

Results

In total, ten studies (12 reports) involving 9,873 patients were identified. A significant loss body weight in the tirzepatide group versus the placebo by -9.81 kg (95% CI (-12.09, -7.52), GLP-1 RAs by -1.05 kg (95% CI (-1.48, -0.63), and insulin by -1.93 kg (95% CI (-2.81, -1.05), respectively. In sub-analysis, the body weight of patients was significantly reduced in three tirzepatide doses (5 mg, 10 mg, and 15 mg) when compared with those of the placebo/GLP-1 RA/insulin. In terms of safety, the incidence of any adverse events and adverse events leading to study drug discontinuation was higher in the tirzepatide group, but the incidence of serious adverse events and hypoglycaemia was lower. Additionally, the gastrointestinal adverse events (including diarrhea, nausea, vomiting and decreased appetite) of tirzepatide were higher than those of placebo/basal insulin, but similar to GLP-1 RAs.

Conclusion

In conclusion, tirzeptide can significantly reduce the weight of T2DM and patient with obesity, and it is a potential therapeutic regimen for weight-loss, but we need to be vigilant about its gastrointestinal reaction.

Introduction

Obesity is a metabolic disease, which is related to a variety of chronic diseases in addition to affecting the quality of life [1]. Recent statistics indicate that overweight/obesity and its relentless global rise, with the number of people with excess body weight reaching > 2 billion, approximately 30% of the world population [2]. Some researchers reckon that overweight and obesity are major risk factors for cardiovascular disease [3]. Thus, weight loss can reduce the incidence of cardiovascular events and all-cause mortality in cardiovascular patients [3, 4], and lessen the incidence of diabetes [5, 6]. Currently, a growing number of drugs are used for weight loss, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs). Liraglutide was the first GLP-1RAs to be approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of obesity [7]. Additionally, more evidence supports the use of the GLP-1RAs semaglutide in people with obesity without type 2 diabetes mellitus (T2DM) [8].

As time goes on, an increasing number of drugs have been developed for the treatment of T2DM or obesity. In recent years, Glucagon-like peptide-1 receptor (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are known as incretins among the many hormones in the body that has attracted the attention of researchers, which can promote insulin release after meals, lowering blood sugar and making the body more sensitive to insulin [9, 10]. Moreover, it also contributed to weight loss by slowing gastric emptying. GLP-1RAs are now considered the choice of injectable therapy for many people with T2DM and obesity, with several members of the class having weight loss efficacy [1113]. Building on that concept, the combined GIP and GLP-1 RAs have been proposed as a novel therapeutic option for T2DM and obesity.

Tirzepatide (LY3298176, Mounjaro) is the first dual GIP and GLP-1 RAs for the treatment of T2DM, obesity, and nonalcoholic steatohepatitis [14]. It is a first-in-class GLP-1/GIP receptor agonists that FDA approved on May 13, 2022, to improve blood sugar control in adults with T2DM as an adjunct to diet and exercise [15]. Tirzepatide can lower the hemoglobin A1C level more than other medications to which it was compared [16, 17]. At the same time, there is growing evidence that tirzepatide plays a role in the weight loss of T2DM patients. Furthermore, another study showed that tirzepatide did not increase the risk of major cardiovascular events in participants with T2DM versus controls [18]. Tirzepatide also supported substantial weight loss in a recent clinical trial, potentially supporting its use as an obesity treatment [19].

In this paper, we performed a comprehensive systematic review and meta-analysis of all currently available randomized controlled trials (RCTs) of tirzepatide in individuals with T2DM and obesity to evaluate weight loss and adverse events when they were treated with tirzepatide.

Methods

Study search and selection

To conduct our study, we systematically searched PubMed, EMBASE, Cochrane library, Web of Science, and Clinical Trails databases from their inception to October 5, 2022, in the English language. "Tirzepatide" [MeSH] OR "LY3298176" OR "Mounjaro" were among the search phrases used. According to the inclusion and exclusion criteria, two researchers independently read the title and abstract of the literature for preliminary screening and also read the full text of literature that potentially met the inclusion criteria. Any disagreement was discussed and decided by the third researcher.

Studies were included for this meta-analysis if they met the following criteria: only RCT; adults of obesity patients with or without T2DM; tirzepatide is the intervention drug; comparison is placebo or antidiabetic; and outcome of efficacy and safety. Authorship; year of publication; randomization; intervention; and patient number; study design; study duration; study site; study population; therapy duration; body weight; and risk of AEs were extracted from all included studies.

Outcome indicators and the risk of bias assessment

The primary outcome indicators included body weight, glycosylated hemoglobin, type A1C (HbA1c) and the incidence of any AEs. The secondary outcome indicators included the incidence of SAEs, AE leading to study drug discontinuation, hypoglycemia, and other AEs. The Cochrane Collaboration bias assessment tool was used to evaluate the risk bias of the included studies by two researchers independently [20]. According to the tool the risk was categorized as “high risk”, “low risk”, or “unclear”. Review Manager 5.3 was used to carry out quality assessment and an investigation of publication bias.

Statistical analysis

Review Manager 5.3 was utilized to perform statistical analysis. The mean difference (MD) was used as the effect analysis statistic for continuous measurement data; Oddi ratio (OR) was used as the effect analysis statistic for dichotomous variables, and 95%CI was considered for each effect. Statistical heterogeneity between the results was analyzed by Chi-square (χ2) test, and the heterogeneity was quantitatively judged by I2. When I2 ≤ 50% and P > 0.1, the fixed effect model was applied, and when I2 > 50% and P < 0.1, the random effect model was applied. Additionally, we also investigated the source of heterogeneity with a sensitivity analysis when I2 was higher than 50%. The meta-analysis level was set as 0.05.

Results

Searching results and study characteristics

The initial 401 articles were searched, including Cochrane library (n = 38), PubMed (n = 74), Embase (n = 156), Clinical Trails (n = 25) and Web of Science (n = 108). The duplicate literature (n = 140) was first removed with EndNote X8 software, then the rest literature was further read for screening, and finally, the 10 studies that conformed to the inclusion criteria were included. A total of 9873 T2DM patients were involved. All studies were published in English. In this study, three tirzepatide doses has been giving (5 mg, 10 mg and 15 mg, subcutaneous injection, once a week), and a comparator, including placebo (two study by Frías [21, 22], SURPASS-1 [23], SURPASS-5 [24], SURMOUNT-1 [19], study by Heise [25], basal insulin [10 U/day insulin degludec (SURPASS–3) [26], and 10 U/day insulin glargine (SURPASS-4) [27]], GLP-1 RAs [1mg semaglutide (SURPASS-2) [28], and 1.5mg dulaglutide [21], 0.75 mg dulaglutide (SURPASS J–mono) [29]]. The study by Frias [21] with five groups, including tirzepatide (5 mg, 10 mg, 15 mg), placebo, and dulaglutide (1.5 mg) groups. Another one study by Frías [22] had four groups, we just including tirzepatide (15−2 mg) and placebo. The 15−2 mg tirzepatide dose-escalation regimens were 2.5 mg weeks 0–3; 7.5 mg weeks 4–7; and 15 mg weeks 8–11. Meanwhile, the duration of intervention in 4 studies was 40 weeks, 4 studies was 52 weeks, one study was 26 weeks, and another duration was 12 weeks. Ten studies were published from 2018 to 2022. The literature screening process and results are shown in Fig 1. Table 1 shows the baseline characteristics of the selected studies.

Fig 1. Flow diagram of studies searched in this meta-analysis.

Fig 1

Table 1. General baseline of included studies.

Study, year published Intervention Patient number Study duration Therapy duration Study population Study design Study site Male (%) Mean ±S.D. age
Frías JP, et al. 2018 5mg 55 Between May, 2017 and March, 2018 26–week 18–75 years with 2 type diabetes for at least 6 months, HbA1c (7.0–10.5), BMI 23–50 kg/m². phase 2b 47 sites in 4 countries 34 (62) 57.9 ± 8.2
10mg 51 30 (59) 56.5 ± 9.9
15mg 53 22 (42) 56.0 ± 7.6
1.5mg dulaglutide 54 24 (44) 58.7 ± 7.8
placebo 51 29 (57) 56.6 ± 8.9
Frías JP, et al. 2020 15mg 28 Between November, 2017 and April, 2018 12–week Type 2 diabetes for at least 6 months HbA1c 7.0–10.5, BMI 23–45 kg/m2. phase 2 13 sites in United States 23 (82.1) 56.6 ± 9.21
placebo 26 12 (46.2) 56.0 ± 10.13
Rosenstock J, et al. 2021 (SURPASS–1) 5mg 121 Between June, 2019 and Oct, 2020 40–week ≥18 years with type 2 diabetes. HbA1c 7.0–9.5, BMI≥23 kg/m², and stable weight (±5) during the previous 3 months phase 3 52 sites in 4 countries 56 (46) 54.1 ± 11.9
10mg 121 72 (60) 55.8 ± 10.4
15mg 121 63 (52) 52.9 ± 12.3
placebo 115 56 (49) 53.6 ± 12.8
Frías JP, et al. 2021 (SURPASS–2) 5mg 470 Between July, 2019 and February, 2021 40–week ≥18 years with type 2 diabetes, metformin≥ 1500 mg/d. HbA1c 7.0–10.5, BMI ≥25 kg/m², stable weight (±5) during the previous 3 months. open–label, phase 3 128 sites in 8 countries 205 (43.6) 56.3 ±10.0
10mg 469 238(50.7) 57.2 ±10.5
15mg 470 214(45.5) 55.9 ±10.4
1 mg semaglutide 469 225(48.0) 56.9 ±10.8
Ludvik B, et al. 2021 (SURPASS–3) 5mg 358 Between April, 2019 and Jan, 2021 52–week ≥18 years and type 2 diabetes, HbA1c 7.0–10.5, metformin alone or combination with an SGLT2 inhibitor for at least 3 months, BMI ≥ 25 kg/m², and stable weight (±5) during the previous3 months. open label, phase 3 122 sites in 13 countries 200 (56) 57.2 ± 10.1
10mg 360 195 (54) 57.4 ± 9.7
15mg 359 194 (54) 57.5 ± 10.2
degludec 360 213 (59) 57.5 ± 10.1
Prato SD, et al. 2021 (SURPASS–4) 5mg 329 Between Nov, 2018 and April, 2021 52–week ≥18 years with type 2 diabetes, HbA1c 7.5–10.5, three oral glucose–lowering medications either alone or in any combination, BMI ≥ 25 kg/m², and stable weight (≤5) during the previous 3 months. open–label, phase 3 187 sites in 14 countries 198 (60) 62.9 ± 8.6
10mg 328 209 (64) 63.7 ± 8.7
15mg 338 203 (60) 63.7 ± 8.6
glargine 1000 636 (64) 63.8 ± 8.5
Dahl D, et al. 2022 (SURPASS–5) 5mg 116 Between August, 2019 and January, 2021 40–week adults with type 2 diabetes, HbA1c 7.0–10.5, BMI ≥ 23 kg/m², insulin glargine (>20 IU/d or >0.25 IU/kg/d) with or without metformin (≥1500 mg/d). phase 3 45 sites in in 8 countries 60 (10) 62 ± 10
10mg 119 72 (61) 60 ± 10
15mg 120 65 (54) 61 ± 10
placebo 120 66 (55) 60 ± 10
Inagaki N, et al. 2022 (SURPASS J–mono) 5mg 159 Between May, 2019 and March, 2021 52–week ≥20 Years with type 2 diabetes, HbA1c 7.0–10.0, BMI ≥23 kg/m², stable weight (±5) during 3 months preceding phase 3 Japan 113 (71.1) 56.8 ± 10.1
10mg 158 119 (75.3) 56.2 ± 10.3
15mg 160 132 (82.5) 56.0 ± 10.7
dulaglutide 159 117 (73.6) 57.5 ± 10.2
Heise T, et al. 2022 15 mg 45 Between June 28, 2019, and April 8, 2021, 28-week 20–74 years, type 2 diabetes for at least 6 months, and were being treated with lifestyle advice and stable doses of metformin, with or without one additional stable dose of another oral anti-hyperglycaemic medicine phase 1 2 sites in Germany 31 (69.0) 61.1 ± 7.1
Semaglutide 1 mg 44 34 (77.0) 63.7 ± 5.9
Placebo 28 21 (75.0) 60.4 ± 7.6
Jastreboff, AM, et al. 2022 (SURMOUNT-1) 5mg 630 Between December 2019 and April 2022 72-week ≥18 years, BMI ≥ 30 kg/m² or BMI ≥ 27 kg/m²or more and at least one weight-related complication. phase 3 119 sites in 9 countries 204 (32.3) 45.6±12.7
10mg 636 209 (32.9) 44.7±12.4
15mg 630 205 (32.5) 44.9±12.3
placebo 643 207 (32.2) 44.4±12.5

Quality assessment

The results of the quality assessment of 10 studies are furnished in Fig 2. Five RCTs described the detailed randomization methods, allocation concealment, blinding of participants and personnel, incomplete outcome data, and other biases. Three RCTs did not have detail randomization methods and allocation concealment. Two RCTs are open-label and have a high bias risk for research. The risks of study design bias was shown in Fig 3.

Fig 2. Graphs of risk of bias for studies.

Fig 2

Fig 3. Quality assessment for risk of bias for studies.

Fig 3

Efficacy analysis

In this meta-analysis, the included 10 RCT studies displayed varying degrees of weight loss efficacy. Over all, meta-analysis showed a significant reduction in body weight in the tirzepatide group versus the placebo group by -9.81 kg (95% CI (-12.09, -7.52). There were three doses investigated compared to the placebo group were affected significantly reduced the body weight of patients [5 mg: MD = -7.52 kg, 95% CI (-10.86, -4.18), P < 0.0001; I2 = 94%; 10 mg: MD = -10.48 kg, 95% CI (-15.34, -5.62), P < 0.0001; I2 = 97%; 15 mg: MD = -10.91 kg, 95% CI (-14.81, -7.01), P < 0.00001; I2 = 96%] (Fig 4). The sensitivity analysis excluding the SURMOUNT-1 [19] trial showed that statistical heterogeneity decreased from 94% to 43%, 97% to 35%, and 96% to 78%, respectively.

Fig 4. Effect of tirzepatide vs placebo on body weight.

Fig 4

The body weight of patients was significantly reduced 1.05 kg (95% CI (-1.48, -0.63) when compared with GLP-1 RAs group. There were three doses investigated [5 mg: MD = -0.53, 95% CI (-1.10, -0.05), P = 0.07; I2 = 95%; 10 mg: MD = -0.97, 95% CI (-1.80, -0.1), P = 0.02; I2 = 97%; 15 mg: MD = -1.53, 95% CI (-2.61, -0.45), P = 0.005; I2 = 98%] (Fig 5). The sensitivity analysis removing SURPASS J-mono [30] trial showed that statistical heterogeneity decreased from 95% to 0%, 97% to 90%, and 98% to 90%, respectively.

Fig 5. Effect of tirzepatide vs GLP-1 RAs (semaglutide and dulaglutide) on body weight.

Fig 5

The body weight of patients was significantly decreased 1.93 kg (95% CI (-2.81, -1.05) when compared with insulin group. Three doses were tested [5 mg: MD = -1.09, 95% CI (-1.87, -0.30), P = 0.007; I2 = 98%; 10 mg: MD = -1.50, 95% CI (-2.26, -0.73), P = 0.0001; I2 = 98%; 15 mg: MD = -3.21, 95% CI (-5.64, -0.78), P = 0.01; I2 = 100%] significantly decreased the body weight of patients when compared with insulin group (Fig 6). Initially, the heterogeneities of three tirzepatide doses were observed to be high, but when we removed any one study, the heterogeneities in both groups did not decrease remarkably. Consistently, compared with placebo, GLP-1 RAs and insulin, more participants receiving any of the three tirzepatide doses had reductions in body weight of at least 5%, 10%, or 15% (Table 2).

Fig 6. Effect of tirzepatide vs insulin (insulin degludec and insulin glargine) on body weight.

Fig 6

Table 2. Meta-analysis results for tirzepatide vs placebo, GLP-1 RAs (semaglutide and dulaglutide) and basal insulin (insulin degludec and insulin glargine) for weigh loss.

Intervention Comparator No. of participants with outcome/participants analysed OR (95% CI) I2 (%) P value
Tirzepatide arm Comparator arm
≥5% weight loss
Tirzepatide 5 mg Placebo 699/922 245/929 11.93 [9.39, 15.15] 0 < 0.00001
GLP-1 RAs 428/684 282/682 3.97 [0.97, 16.26] 95 0.06
Basal insulin 438/687 100/1360 22.66 [15.64, 32.84] 42 < 0.00001
Tirzepatide 10 mg Placebo 761/927 245/929 17.33 [13.43, 22.35] 34 < 0.00001
GLP-1 RAs 522/678 282/682 9.43 [1.58, 56.18] 97 0.01
Basal insulin 542/688 100/1360 48.54 [27.20, 86.65] 72 < 0.00001
Tirzepatide 15 mg Placebo 780/924 245/929 21.41 [16.37, 28.00] 38 < 0.00001
GLP-1 RAs 552/683 282/682 11.02 [1.66, 73.26] 97 0.01
Basal insulin 595/697 100/1360 75.38 [50.05, 113.54] 40 < 0.00001
≥10% weight loss < 0.00001
Tirzepatide 5 mg Placebo 502/922 214/929 15.82 [3.29, 76.10] 73 0.0006
GLP-1 RAs 169/525 118/523 1.64 [1.24, 2.16] 0 0.0004
Basal insulin 249/687 25/1360 27.27 [17.59, 42.25] 42 < 0.00001
Tirzepatide 10 mg Placebo 613/927 214/929 33.97 [5.62, 205.33] 79 0.0001
GLP-1 RAs 240/520 118/523 2.95 [2.25, 3.86] 52 < 0.00001
Basal insulin 365/688 25/1360 54.19 [35.06, 83.75] 34 < 0.00001
Tirzepatide 15 mg Placebo 649/924 214/929 37.79 [7.68, 186.01] 74 < 0.00001
GLP-1 RAs 288/523 118/523 4.28 [3.27, 5.61] 0 < 0.00001
Basal insulin 464/697 25/1360 96.07 [62.15, 148.50] 15 < 0.00001
≥15% weight loss
Tirzepatide 5 mg Placebo 329/922 57/929 9.95 [7.30, 13.55] 0 < 0.00001
GLP-1 RAs 73/525 38/523 2.07 [1.37, 3.14] 0 0.0006
Basal insulin 89/687 5/1360 43.49 [16.98, 111.43] 0 < 0.00001
Tirzepatide 10 mg Placebo 483/927 57/929 22.31 [16.25, 30.64] 0 < 0.00001
GLP-1 RAs 124/520 38/523 3.99 [2.71, 5.88] 38 < 0.00001
Basal insulin 176/688 5/1360 95.35 [37.61, 241.73] 32 < 0.00001
Tirzepatide 15 mg Placebo 516/924 57/929 27.14 [19.66, 37.47] 0 < 0.00001
GLP-1 RAs 182/523 38/523 6.88 [4.72, 10.04] 0 < 0.00001
Basal insulin 272/697 5/1360 174.26 [69.74, 435.43] 33 < 0.00001

The changes of HbA1c of patients was also collected. When compared with placebo, tirzepatide can significantly reduce the HbA1c of patients [5 mg: MD = -1.55%, 95% CI (-1.72, -1.39), P < 0.00001; I2 = 85%; 10 mg: MD = -1.75%, 95% CI (-1.92, -1.58), P < 0.00001; I2 = 71%; 15 mg: MD = -1.87%, 95% CI (-2.03, -1.70), P < 0.00001; I2 = 86%]. The same results were found in comparing tirzepatide with GLP-1 RAs group and insulin group, the level of HbA1c of all patients was significantly reduced [GLP-1 RAs: 5 mg: MD = -0.51%, 95% CI (-0.62–0.39), P < 0.00001; I2 = 96%; 10 mg: MD = -0.73%, 95% CI (-0.85, -0.62), P < 0.00001; I2 = 96%; 15 mg: MD = -0.89%, 95% CI (-1.00, -0.77), P < 0.00001; I2 = 97%; Insulin: 5 mg: MD = -0.71%, 95% CI (-0.80, -0.63), P < 0.00001; I2 = 81%; 10 mg: MD = -0.94%, 95% CI (-1.03, -0.85), P < 0.00001; I2 = 50%; 15 mg: MD = -1.10%, 95% CI (-1.18, -1.01), P < 0.00001; I2 = 30%].

Safety analysis

For the safety, meta-analysis showed a significant difference the incidence of any adverse events between tirzepatide group and placebo group [OR = 1.59, 95% CI (1.29, 1.95), P < 0.00001, I² = 53%], GLP-1 RAs group [OR = 1.15, 95% CI (1.00, 1.32), P = 0.05, I² = 0%], and basal insulin [OR = 1.55, 95% CI (1.25, 1.91), P < 0.0001, I² = 69%], respectively. In the sub-analysis, the incidence of any adverse events was lower in the tirzepatide group than in the placebo group and basal insulin. But when compared to GLP-1 RAs, there was no significant difference in the tirzepatide 5 mg [OR = 1.01, 95% CI (0.80, 1.28), P = 0.92] and 10mg [OR = 1.17, 95% CI (0.92, 1.48), P = 0.2] groups (Table 3). Additionally, there was a statistically significant difference in the incidence of adverse events leading to study drug discontinuation between tirzepatide and placebo, between tirzepatide (15mg) and GLP-1 RAs, and between tirzepatide (5mg) and basal insulin. However, no significant statistics were found between tirzepatide and GLP-1 RAs (5mg and 10 mg) or between tirzepatide (10mg and 15 mg) and basal insulin.

Table 3. The results of safety in meta-analysis.

Intervention Comparator Studies (n) Tirzepatide arm (n) Comparator arm (n) I2 (%) Effect Estimate P value
Any Adverse events
Tirzepatide 5 mg Placebo 4 718/922 647/929 0 1.55 [1.25, 1.91] < 0.0001
GLP-1 RAs 3 478/684 475/682 0 1.01 [0.80, 1.28] 0.92
Basal insulin 2 451/687 872/1360 0 1.23 [1.01, 1.50] 0.04
Tirzepatide 10 mg Placebo 4 722/927 647/929 62 1.48 [0.98, 2.23] 0.06
GLP-1 RAs 3 493/678 475/682 0 1.17 [0.92, 1.48] 0.2
Basal insulin 2 489/688 872/1360 69 1.58 [1.09, 2.29] 0.02
Tirzepatide 15 mg Placebo 6 780/997 682/983 71 2.06 [1.24, 3.43] 0.005
GLP-1 RAs 4 553/728 518/726 0 1.28 [1.01, 1.63] 0.04
Basal insulin 2 522/697 872/1360 74 1.91 [1.26, 2.89] 0.002
Serious adverse events
Tirzepatide 5 mg Placebo 4 55/922 59/929 0 0.94 [0.64, 1.38] 0.76
GLP-1 RAs 3 59/684 30/682 37 2.08 [1.32, 3.28] 0.002
Basal insulin 2 77/687 215/1360 71 0.94 [0.51, 1.75] 0.85
Tirzepatide 10 mg Placebo 4 62/927 59/929 0 1.06 [0.73, 1.54] 0.74
GLP-1 RAs 3 53/678 30/682 0 1.87 [1.17, 2.98] 0.008
Basal insulin 2 74/688 215/1360 0 0.84 [0.63, 1.13] 0.24
Tirzepatide 15 mg Placebo 5 45/969 61/957 0 0.72 [0.49, 1.07] 0.11
GLP-1 RAs 4 55/728 30/726 0 1.91 [1.20, 3.01] 0.006
Basal insulin 2 67/697 215/1360 77 0.80 [0.39, 1.64] 0.54
Adverse event leading to study drug discontinuation
Tirzepatide 5 mg Placebo 4 43/922 25/929 0 1.77 [1.07, 2.92] 0.03
GLP-1 RAs 2 33/525 25/523 0 1.34 [0.78, 2.29] 0.29
Basal insulin 2 62/687 59/1360 63 3.09 [1.33, 7.18] 0.009
Tirzepatide 10 mg Placebo 4 64/927 25/929 0 2.68 [1.68, 4.30] < 0.0001
GLP-1 RAs 2 43/520 25/523 72 1.23 [0.30, 5.09] 0.78
Basal insulin 2 65/688 59/1360 89 3.46 [0.69, 17.43] 0.13
Tirzepatide 15 mg Placebo 6 74/997 29/983 48 2.57 [1.67, 3.96] < 0.0001
GLP-1 RAs 3 54/568 24/567 0 2.40 [1.46, 3.95] 0.0005
Basal insulin 2 75/697 59/1360 87 4.00 [0.96, 16.79] 0.06
Hypoglycemia (blood glucose <70 mg/dL)
Tirzepatide 5 mg Placebo 3 81/292 76/286 44 1.22 [0.76, 1.96] 0.4
GLP-1 RAs 2 7/525 4/523 0 1.76 [0.51, 6.13] 0.37
Basal insulin 2 142/687 811/1360 94 0.17 [0.06, 0.48] 0.0008
Tirzepatide 10 mg Placebo 3 88/291 76/286 51 1.42 [0.89, 2.27] 0.14
GLP-1 RAs 2 6/520 4/523 25 1.59 [0.44, 5.73] 0.48
Basal insulin 2 156/688 811/1360 72 0.22 [0.15, 0.34] < 0.00001
Tirzepatide 15 mg Placebo 5 92/367 81/340 24 1.25 [0.81, 1.93] 0.3
GLP-1 RAs 4 17/728 5/726 0 3.29 [1.25, 8.69] 0.02
Basal insulin 2 178/697 811/1360 86 0.25 [0.14, 0.46] < 0.00001
Nausea
Tirzepatide 5 mg Placebo 4 195/922 74/929 0 3.15 [2.34, 4.17] < 0.00001
GLP-1 RAs 3 112/684 112/682 35 1.00 [0.65, 1.56] 0.99
Basal insulin 2 80/687 29/1360 0 6.38 [4.02, 10.11] < 0.00001
Tirzepatide 10 mg Placebo 4 260/927 74/929 0 4.59 [3.46, 6.07] < 0.00001
GLP-1 RAs 3 132/678 112/682 77 1.31 [0.62, 2.75] 0.48
Basal insulin 2 134/688 29/1360 58 11.02 [5.21, 23.31] < 0.00001
Tirzepatide 15 mg Placebo 6 281/997 83/983 53 4.19 [2.37, 7.39] < 0.00001
GLP-1 RAs 4 168/728 125/726 54 1.51 [0.94, 2.44] 0.09
Basal insulin 2 161/697 29/1360 0 14.34 [9.30, 22.10] < 0.00001
Diarrhea
Tirzepatide 5 mg Placebo 4 153/922 70/929 39 2.13 [1.30, 3.48] 0.003
GLP-1 RAs 3 96/684 74/682 63 1.34 [0.97, 1.85] 0.08
Basal insulin 2 96/687 58/1360 0 3.63 [2.53, 5.19] < 0.00001
Tirzepatide 10 mg Placebo 4 180/927 70/929 59 2.59 [1.41, 4.76] 0.002
GLP-1 RAs 3 104/678 74/682 0 1.50 [1.09, 2.06] 0.01
Basal insulin 2 125/688 58/1360 0 5.20 [3.69, 7.32] < 0.00001
Tirzepatide 15 mg Placebo 6 214/997 78/983 50 2.65 [1.58, 4.44] 0.0002
GLP-1 RAs 4 104/728 87/726 0 1.23 [0.90, 1.67] 0.19
Basal insulin 2 130/697 58/1360 0 5.47 [3.90, 7.68] < 0.00001
Vomiting
Tirzepatide 5 mg Placebo 4 59/922 17/929 50 3.67 [2.13, 6.33] < 0.00001
GLP-1 RAs 3 42/684 46/682 79 1.16 [0.25, 5.34] 0.85
Basal insulin 2 37/687 20/1360 0 3.94 [2.19, 7.09] < 0.00001
Tirzepatide 10 mg Placebo 4 77/927 17/929 60 4.86 [2.86, 8.27] < 0.00001
GLP-1 RAs 3 52/678 46/682 35 1.25 [0.60, 2.59] 0.55
Basal insulin 2 61/688 20/1360 0 6.77 [3.91, 11.71] < 0.00001
Tirzepatide 15 mg Placebo 6 102/997 19/983 37 5.76 [3.51, 9.45] < 0.00001
GLP-1 RAs 4 76/728 51/726 69 1.75 [0.66, 4.61] 0.26
Basal insulin 2 65/697 20/1360 0 7.13 [4.15, 12.26] < 0.00001
Decreased appetite
Tirzepatide 5 mg Placebo 4 83/922 25/929 0 3.60 [2.28, 5.68] < 0.00001
GLP-1 RAs 3 68/684 35/682 54 2.39 [1.15, 4.96] 0.02
Basal insulin 2 51/687 7/1360 0 15.83 [6.93, 36.18] < 0.00001
Tirzepatide 10 mg Placebo 4 109/927 25/929 1 4.85 [3.11, 7.56] < 0.00001
GLP-1 RAs 3 68/678 35/682 64 2.58 [1.11, 5.99] 0.03
Basal insulin 2 73/688 7/1360 0 22.72 [9.99, 51.68] < 0.00001
Tirzepatide 15 mg Placebo 6 126/997 32/983 25 4.27 [2.84, 6.43] < 0.00001
GLP-1 RAs 4 114/728 66/726 79 2.18 [0.86, 5.50] 0.1
Basal insulin 2 78/697 7/1360 0 23.59 [10.38, 53.61] < 0.00001
Injection site reactions
Tirzepatide 5 mg Placebo 4 29/922 5/929 0 4.78 [1.83, 12.49] 0.001
GLP-1 RAs 3 14/684 19/682 80 0.78 [0.09, 6.65] 0.82
Basal insulin 2 2/687 10/1360 0 0.31 [0.07, 1.40] 0.13
Tirzepatide 10 mg Placebo 4 47/927 5/929 36 6.18 [1.80, 21.17] 0.004
GLP-1 RAs 3 22/678 19/682 80 1.29 [0.20, 8.15] 0.79
Basal insulin 2 8/688 10/1360 0 1.13 [0.44, 2.94] 0.8
Tirzepatide 15 mg Placebo 5 53/969 17/957 81 2.78 [0.45, 17.40] 0.27
GLP-1 RAs 4 34/728 31/726 83 0.68 [0.07, 6.36] 0.74
Basal insulin 2 9/697 10/1360 0 1.19 [0.46, 3.06] 0.72
Nasopharyngitis
Tirzepatide 5 mg Placebo 3 28/292 39/289 0 0.69 [0.41, 1.16] 0.16
GLP-1 RAs 2 32/214 32/213 23 1.00 [0.58, 1.70] 0.99
Basal insulin 2 21/687 87/1360 0 0.47 [0.28, 0.77] 0.003
Tirzepatide 10 mg Placebo 3 18/291 39/289 0 0.42 [0.24, 0.76] 0.004
GLP-1 RAs 2 27/209 32/213 31 0.83 [0.48, 1.45] 0.52
Basal insulin 2 30/688 87/1360 0 0.69 [0.45, 1.07] 0.1
Tirzepatide 15 mg Placebo 4 33/339 42/317 0 0.70 [0.43, 1.14] 0.15
GLP-1 RAs 3 32/258 40/257 0 0.76 [0.46, 1.26] 0.29
Basal insulin 2 31/697 87/1360 0 0.70 [0.45, 1.07] 0.1

GLP-1 Ras: semaglutide and dulaglutide; Basal insulin: insulin degludec and insulin glargine.

In this study, there was no significant difference in the incidence of serious adverse events between tirzepatide and placebo, and basal insulin, but significant difference to GLP-1 RAs. Hypoglycemia is the major SAEs, hypoglycemia definition as blood glucose < 70 mg/dL. Across all trials, the hypoglycemia risk of tirzepatide did not differ compared with placebo and GLP-1 RAs, and was lower with tirzepatide compared with basal insulin.

After consuming tirzepatide, most of the patients experienced diarrhea, nausea, vomiting, decreased appetite, constipation, injection site reactions, and nasopharyngitis. Compared with basal insulin and placebo, more frequent gastrointestinal adverse events occurred, including diarrhea, nausea, vomiting, decreased appetite, and constipation in all tirzepatide groups. When compared with the GLP-1 RAs, the tirzepatide group showed a similar risk of nausea, diarrhea, vomiting, and constipation. While tirzepatide 5 mg and 10 mg were also associated with a higher incidence of decreased appetite. Meanwhile, there were no statistically significant differences in the incidence of injection site reactions between tirzepatide and GLP-1 RAs, and basal insulin. When compared with placebo, the incidence of injection site reactions was lower in tirzepatide (5 mg and 10 mg), but no significant difference in tirzepatide (15 mg). Besides, there was no significant difference in the incidence of nasopharyngitis was noticed between tirzepatide and placebo, GLP-1 RAs, and basal insulin.

Discussions

Tirzepatide as the first dual GIP and GLP-1 RA drug, which shown effects on hypoglycemia, body weight and cardiovascular indicators in previous studies [3133]. Its effect on body weight could make it useful as a weight loss drug. Thus, in this meta-analysis, a systematic review to assess the weight loss efficacy and safety of tirzepatide is conducted. Based on our findings, both doses of tirzepatide (5 mg, 10 mg and 15 mg) were more effective than other drugs in reducing body weight.

With the increase of obese people, the drugs for obesity treatment has been on the rise, and most of the drugs currently used to treat obesity started out as treatments for diabetes [34]. Based on our findings, both doses of tirzepatide were more effective in reducing bodyweight compared with other drugs. In this study, we included 10 RCT (12 reports) and compared the weight loss effects of tirzepatide with placebo, insulin, and GLP-1 RAs. The results showed that tirzepatide could reduce the weight of T2DM and obese patients. This is the same as the previous study showed [32, 35]. At the same time, the network meta-analysis results of Alkhezi et al. also showed that compared with liragrutide and semaglutide, tirzepatide had better weight reduction in non-diabetes patients, and the safety results were similar without difference [36]. Furthermore, some studies found that meaningful weight loss is achieve 5 ~ 10% [37]. In our study, tirzepatide were more effective than other drugs in reducing bodyweight of 5%, 10%, or 15%. More importantly, compared with placebo, GLP-1 RAs and insulin, tirzepatide can significantly reduce their HbA1c level of patients, and the results were same with other studies [32, 38].

For the safety, a significant difference the incidence of any adverse events between tirzepatide group and placebo/GLP-1 RAs/basal insulin. This is contrary to the results of a study by Bhagavathula et al. the results shown that no significant difference the incidence of any adverse events [32]. In addition, no significant difference in the incidence of SAEs between tirzepatide and placebo, and basal insulin, but significant difference to GLP-1 RAs. Across all trials, the risk of hypoglycemia with tirzepatide did not differ compared to placebo and GLP-1 RAs, but was lower with tirzepatide than with basal insulin. In the same results has been found in the study by Karagiannis et al. that incidence of serious adverse events did not differ between any of the tirzepatide doses and any comparator [35].

Gastrointestinal adverse events were the most common adverse events in all groups. In this study, the incidence of gastrointestinal adverse events, including diarrhea, nausea, vomiting, and decreased appetite, and the incidence of diarrhea, nausea, vomiting, and constipation were similar when comparing tirzepatide with GLP-1 RAs. However, in comparison with placebo or basal insulin, tirzepatide increased the odds of diarrhea, nausea, vomiting, decreased appetite, and constipation. The results were the same as this study [35]. The clinical trials of SURPASS reported on the gastrointestinal system, and nausea, diarrhea and vomiting were the most common AEs [17]. The results from other studies found that GLP-1 receptor agonists are often accompanied by nausea, emesis, and undesired anorexia. Importantly, the hypophagic and emetic effects of GLP-1 receptor agonists are caused by activation of central GLP-1 receptors [39]. Gastrointestinal side effects of high-dose GLP-1 RAs and co-agonists occurred in 30% ~ 70% of patients, mostly arising within the first 2 weeks of the first dose, being mild or moderate in severity, and transient [40]. A study found the incidence of gastrointestinal bleeding occurred most frequently 0 ~ 4 weeks after the first dose and was higher for the 15 mg tirzepatide group [41].

In addition, all the included studies were RCT, and some studies have a high bias risk for research because they did not have detailed randomization methods and allocation concealment or open-label. Of these, this may affect the positive outcomes. Moreover, this study could have a higher effect on weight loss due to participants of the SURMOUNT-1 study not having T2DM and the SURPASS J-Combo study with only Japanese populations. Sensitive analysis results showed that statistical heterogeneity was decreased after removing the SURMOUNT-1 study and the SURPASS J-Combo study, but the statistical effect did not change.

There are limitations in the current study. First, as all the RCTs involved the pharmaceutical industry, the positive outcomes should be interpreted cautiously [42, 43]. Second, only one study focused on the obesity patients in all 10 RCTs (12 reports), and RCTs have generally carried out in selected populations of T2DM or obesity patients. More research is suggested in the available guidance. Fortunately, 20 additional trials [17, 44, 45] aiming to investigate the efficacy of tirzepatide in the clinical setting of T2DM or obesity are ongoing. We can obtain more data to analyze after these trials are completed in the near future.

Conclusion

To sum up, this meta-analysis indicated that tirzepatide could significantly decrease body weight in T2DM and obesity patients, and it is a potential therapeutic regimen for weight-loss, but we need to be vigilant about its gastrointestinal reaction.

Supporting information

S1 Table. The data of meta-analysis.

(XLSX)

S1 Checklist. PRISMA 2020 checklist.

(DOCX)

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. The data of meta-analysis.

(XLSX)

S1 Checklist. PRISMA 2020 checklist.

(DOCX)

Data Availability Statement

All relevant data are within the paper and its Supporting Information files.


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