Efficacy and safety of tirzepatide in overweight or obese adults without diabetes: systematic review and meta-analysis of randomized controlled trials

doi:10.21203/rs.3.rs-4184273/v1

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Systematic Review

Efficacy and safety of tirzepatide in overweight or obese adults without diabetes: systematic review and meta-analysis of randomized controlled trials

https://doi.org/10.21203/rs.3.rs-4184273/v1

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Background:

Tirzepatide has been studied for individuals with obesity without diabetesin randomized controlled trials (RCTs).

Objectives:

The summarize the efficacy and safety of tirzepatide to guide clinical practice.

Methods:

Databases were searched to identify RCTs that compared tirzepatide with any treatments in this population. Meta-analyses were conducted to compare tirzepatide versus placebo. Standard mean difference (SMD) or risk ratio (RR) with 95% confidence intervals (CIs) were used as appropriate.

Results:

Three RCTs with 3901 participants were included. Tirzepatide caused weight loss of 18.73% (95% CI: -21.31 to -16.15) versus placebo. The percentages of patients achieving weight loss of 5%, 10%, 15%, and 20% were 92.7%, 84.4%, 73.6%, and 56.1%, respectively. Tirzepatide had greater weight loss than placebo (SMD: -1.61, 95% CI -2.20 to -1.02). It also had a higher likelihood of achieving weight loss ≥ 5%, 10%, 15%, 20%, and 25% compared to placebo. However, tirzepatide had significantly increase in adverse events than placebo (RR: 1.53, 95% CI: 1.18 to 1.98).

Conclusions:

Tirzepatide can significantly reduce body weight in overweight or obese individuals without diabetes. This weight loss effect might be better than semaglutide and liraglutide. Nonetheless, the increased adverse events warrant careful monitoring.

Tirzepatide

meta-analysis

obesity

Our findings suggests that tirzepatide significantly reduces body weight and achieve weight loss target in adults with obesity without diabetes, presenting a potentially superior alternative to current GLP-1 receptor agonists like semaglutide and liraglutide.
However, the increased adverse events require careful patient monitoring.
Direct comparison between tirzepatide and GLP-1 receptor agonists are needed.
This evidence can guide healthcare providers in making informed treatment decisions for patients with obesity, highlighting the importance of considering tirzepatide as a viable option in weight management strategies.

Obesity remains a global concern with prevalence rate exceeding 40% worldwide [1].It is associated with type 2 diabetes, cardiovascular diseases, and sleep disorders [2]. The current guidelines advocate for the use of anti-obesity medications in conjunction with intensive lifestyle modification to manage obesity and enhance overall health outcomes [3]. However, the treatment options were limited, and the discontinuation of treatment often led to weight regain [4]. Tirzepatide, which combines the actions of glucagon-like peptide-1 (GLP-1) receptor agonists and glucose-dependent insulinotropic polypeptide (GIP), exerts significant effects on appetite, energy intake, and metabolic function [5]. Recent randomized clinical trials (RCTs) have underscored the efficacy of tirzepatide in weight reduction and cardiovascular benefits for individuals with obesity without diabetes [6-8]. However, the effect of tirzepatide on this population need to be summarized in order to make tirzepatide comparable to other pharmacological interventions that has been investigated in previous studies and provide updated evidence to support obesity management.

Aim

This systematic review and meta-analysis were aimed to consolidate current evidence on the efficacy and safety of tirzepatide in overweight and obese adults without diabetes.

Databases including PubMed, Embase, and the Cochrane Library were comprehensively searched up to January 18th, 2024, to identify relevant literature. Key search terms included tirzepatide, LY3298176, dual GIP and GLP-1RA, Zepbound, and RCTs. The detailed search strategy was included in the supplementary file. The registration number of this study was CRD42024502434.

The inclusion criteria were specified as: (1) RCTs that investigated adult participants with obesity or overweight without diabetes; (2) tirzepatide as the intervention; (3) any active treatment or placebo as the control; and (4) reporting of at least one efficacy outcome, such as the proportion of patients achieving weight loss goals of 5%, 10%, 15%, 20%, or 25%, weight change, BMI change, waist circumference (WC) change, glycated hemoglobin (HbA1c) change, 36-item short-form health survey (SF-36) physical functioning score or impact of weight on quality of life (IWQOL) score change.

Title and abstract screening, followed by full-text assessments to confirm trial eligibility, were conducted independently by two authors (L.L. and Y.S.). Any disagreements were resolved by involving a third researcher. Data extraction included study design, sample size, therapy duration, interventions, controls, baseline characteristics, and outcome measures. The Cochrane Risk of Bias tool for randomized controlled trials version 2 was employed to evaluate the quality of the studies. Percentage of weight loss was primary outcome. Other outcomes were secondary outcomes.

All analyses were performed using R. Generalized linear mixed models were initially performed to pool the outcomes across various trials, with mean difference (MD) between group or percentage of patients achieving weight loss goals serving as the standard for pooling the results. Then, meta-analyses were conducted to compare tirzepatide versus placebo. Standard mean difference (SMD) or risk ratio (RR) with 95% confidence intervals (CIs) were used to assess different outcomes as appropriate. Publication biases were not assessed due to limited number of studies. The I² was used to evaluate heterogeneity among trials. An I² of less than 25% indicates negligible heterogeneity and a fixed-effect model was employed. In cases when I² was above 50%, it means substantial heterogeneity, and a random-effect model was chosen. A p value of less than 0.05 was considered statistically significant.

We identified 603 potentially relevant references. After the removal of duplicates, 418 references were retrieved. Finally, three RCTs met the inclusion criteria (Figure S1), and 3901 participants were included in these trials [6–8]. The characteristics and results of the included studies were presented in Table 1. No risk of bias was observed, as summarized in Table S1.

The pooled analysis showed that the tirzepatide had 18.73% weight loss (95% CI -21.31 to -16.15) versus placebo. The percentages of patients achieving weight loss of ≥ 5%, 10%, 15%, 20%, and 25% were 92.7%, 84.4%, 73.6%, 56.1%, and 38.7%, respectively. BMI reduction favored tirzepatide over placebo (MD: -7.65 kg/m², 95% CI -10.10 to -5.20). The pooled reduction in waist circumference with tirzepatide was 14 cm (95% CI -14.94 to -13.06) compared to placebo. Additionally, tirzepatide showed a significant reduction in HbA1c (MD: -0.42%, 95% CI -0.58 to -0.26) and significantly improved IWQOL score (MD: 10.95, 95% CI 7.53 to 14.38) and SF-36 score (MD: 2.87, 95% CI 1.73 to 4.00) compared to placebo (Table 2).

Patients who took tirzepatide had greater weight loss than placebo (SMD: -1.61, 95% CI -2.20 to -1.02). The tirzepatide group also had a higher likelihood of achieving weight loss targets of 5%, 10%, 15%, 20%, and 25% compared to placebo. Similarly, the decrease in BMI from baseline also favored tirzepatide over placebo (SMD: -2.13, 95% CI -3.08 to -1.18). Furthermore, tirzepatide significantly reduced waist circumference from baseline compared to placebo (SMD: − 0.91, 95% CI - -1.14 to -0.69). SF-36 physical function score (SMD: 0.35, 95% CI: 0.13 to 0.57) and IWQOL score (SMD: 0.51, 95% CI: 0.23 to 0.79) also showed significant improvement with tirzepatide compared to placebo. However, the incidence of adverse events was significantly higher in patients who took tirzepatide than those taking placebo (RR: 1.53, 95% CI: 1.18 to 1.98), as presented in Table 2 and Figures S2, S3, S4 and S5.

Statement of key findings

In this study, we performed a meta-analysis to assess the efficacy and safety of tirzepatide in overweight or obese adults without diabetes based on data from three RCTs. The findings suggest that tirzepatide demonstrated a significant weight loss effect compared to placebo. In summary, tirzepatide significantly decreased weight by 18.73%, BMI by 7.65 kg/m², and WC by 14 cm. Moreover, it significantly increased the proportion of participants achieving weight reductions of 5%, 10%, 15%, 20%, and 25% versus placebo. It also showed positive effects on HbA1c, IWQOL and SF-36 physical functioning score. However, tirzepatide had a higher incidence of adverse events compared to placebo.

Interpretation

Current FDA-approved GLP-1s and its analogues for obesity include liraglutide, semaglutide, and tirzepatide [9, 10]. Previous meta-analyses have demonstrated that semaglutide can significantly reduce weight (MD: -10.1 to -11.8%), BMI (MD: -3.7 to -4.5 kg/m²), and WC (MD: -8.28 to -9.4 cm), with a higher proportion of participants achieving weight loss thresholds of more than 5%, 10%, 15%, and 20% [11, 12]. Liraglutide also led to a significant reduction in body weight (MD: -5.04 kg), BMI (MD: -1.95 kg/m²), and waist circumference (MD: -3.64 cm), with a higher percentage of participants achieving 5% and 10% weight loss [13].

Based on results of tirzepatide from our study and previous studies on semaglutide and liraglutide [11–13], tirzepatide might have a higher likelihood of achieving ≥ 5% weight loss (RR = 2.21 for liraglutide; RR = 2.24 for semaglutide; RR = 21.14 for tirzepatide), 10% weight loss (RR = 3.36 for liraglutide; RR = 4.17 for semaglutide; RR = 20.03 for tirzepatide), ≥ 15% weight loss (RR = 7.05 for semaglutide; OR = 23.61 for tirzepatide), and weight loss ≥ 20% (RR = 11.85 for semaglutide; OR = 26.52 for tirzepatide) than semaglutide and/or liraglutide.

In clinical practice, weight loss exceeding 10 percent from baseline is considered an excellent response [14]. The weight loss caused by tirzepatide was 18.73%, which is clinically significant. In adults with obesity or diabetes, tirzepatide significantly reduced body weight (MD: 11.8 to 12.4%), BMI (MD: -3.9 kg/m²), and waist circumference (MD: -9.2 cm) [15]. Tirzepatide might be superior to semaglutide in patients with diabetes who were obese or overweight [16]. Similarly, based on the preliminary data from our study, tirzepatide might lead to greater weight loss, BMI reduction, WC reduction than semaglutide and liraglutide in patients with obesity without diabetes.

Despite the potential benefits that tirzepatide offered, the significantly increased risk of adverse events was a concern for the treatment of patients with obesity. The most common adverse events included nausea, vomiting, diarrhea, and constipation [6–8]. Tirzepatide might have higher risk of gastrointestinal adverse events such as nausea, vomiting, diarrhea, and constipation than placebo based on the results of these trials [6–8]. Previous study also reported increased risk of gastrointestinal adverse events with tirzepatide versus placebo [17].

Strength, limitations and further research

This study represents the first systematic review and meta-analysis of evidence from RCTs evaluating the efficacy and safety of tirzepatide in patients with obesity or overweight without diabetes. A comprehensive analysis of various outcomes was conducted to thoroughly assess the impact of tirzepatide on patients with obesity. However, it is important to acknowledge some limitations of this study. To date, only three RCTs have been conducted in this population, all comparing tirzepatide to placebo. Moreover, we only reported the total adverse events, and the incidence of specific adverse events were not investigated individually. Future research should directly compare tirzepatide with other active treatments in this population and investigate more on adverse events to provide a more robust understanding of its efficacy and safety.

In conclusion, this meta-analysis confirms the potential of tirzepatide to reduce body weight, improve HbA1c and quality of life in overweight or obese individuals without diabetes. Nonetheless, the increased incidence of adverse events warrants careful monitoring and close follow-up. This study underscores the need for continued research to fully elucidate the therapeutic role of tirzepatide in obesity management.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Funding:

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author Contributions

Ligang Liu and Milap Nahata contributed to the study conception and design. Data collection and analysis were performed by Ligang Liu, Hekai, Shi, Yuxiao Sun, and Merilyn Xie. The first draft of the manuscript was written by Ligang Liu, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data Availability

The data are available on request from the authors.

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Tables 1 to 2 are available in the Supplementary Files section

The authors declare no competing interests.

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Efficacy and safety of tirzepatide in overweight or obese adults without diabetes: systematic review and meta-analysis of randomized controlled trials

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Introduction

Method

Results

Discussion

Statement of key findings

Interpretation

Strength, limitations and further research

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References

Tables

Additional Declarations

Supplementary Files

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