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 confirmed that tirzepatide demonstrated a significant weight loss effect compared to placebo. In summary, tirzepatide significantly decreased weight by 18.7%, BMI by 7.65 kg/m2, and WC by 14 cm compared to placebo. Moreover, it markedly increased the proportion of participants achieving weight reductions of 5%, 10%, 15%, 20%, and 25% versus placebo. Importantly, tirzepatide also significantly reduced HbA1c as well as systolic and diastolic blood pressure, highlighting its potential to decrease cardiovascular risk factors associated with excess weight. Improvements were also noted in the IWQOL-Lite and SF-36 physical functioning scores during treatment. However, the incidence of adverse events, particularly gastrointestinal effects such as nausea, vomiting, and diarrhea, was higher in the tirzepatide group compared to placebo. The risk of treatment discontinuation due to adverse effects also increased with tirzepatide. These adverse events raise concerns about the tolerability of tirzepatide, potentially limiting its acceptability among certain patients and emphasizing a need for monitoring therapy.

This review represents the first systematic review and meta-analysis of evidence from RCTs evaluating the efficacy and safety of tirzepatide in  overweight or obese patients without diabetes. Additionally, the comprehensive nature of the efficacy outcomes such as weight loss, reduction in BMI, waist circumference, A1c, blood pressure, and quality of life improvement provided a holistic view of efficacy profile of tirzepatide. The individual assessment of different adverse events, serious adverse events, and discontinuation due to adverse events allowed for a nuanced understanding of the safety profile of tirzepatide. 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. The relatively small number of included trials may limit the scope of the analysis, and publication bias was not assessed due to the limited number of studies. The dose-dependence effects of tripeptide were not analyzed due to methodological differences between trials.

Obesity is a global health concern with negative implications for overall well-being [23, 24]. The prevalence has soared internationally and nearly tripled since 1975, according to the World Health Organization (WHO) [25]. In 2016, over 650 million adults had obesity, and it is estimated that approximately 167 million additional people will become overweight or obese by 2025 [26]. Despite the existence of numerous weight management strategies, effective treatment with sustained efficacy and safety remains a challenge.

Current FDA-approved GLP-1 RAs and its analogues for obesity include liraglutide, semaglutide, and tirzepatide [15, 27]. 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 targets of more than 5%, 10%, 15%, and 20% [28, 29]. Liraglutide also can lead 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 [30].

The SURMOUNT clinical trials encompassed a sequence of studies designed to assess the efficacy and safety of tirzepatide in individuals classified as overweight or obese [17,18,19]. SURMOUNT-1 enrolled participants with obesity or overweight and examined the weight reduction effects of tirzepatide over a 72-week main phase [19]. SURMOUNT-3 introduced a 12-week intensive lifestyle intervention before administering tirzepatide. Over an extended duration of 84 weeks, participants experienced a substantial mean weight loss of 21.1% subsequent to the lifestyle intervention phase [18]. SURMOUNT-4 implemented a 36-week lead-in period with tirzepatide treatment, followed by an additional 52 weeks of ongoing tirzepatide therapy, resulting in a 25.8% weight loss [17]. Each of these studies contributes to a comprehensive understanding of the potential of tirzepatide as a transformative treatment for obesity, highlighting not only its direct effects but also the enhanced benefits when combined with lifestyle modifications.

Recent studies have underscored the excellent efficacy of tirzepatide in promoting significant weight loss compared to semaglutide and liraglutide. Tirzepatide consistently shows a higher likelihood of achieving substantial weight reduction targets. The odds ratio of reaching a weight loss of ≥ 5% was significantly higher with tirzepatide (OR = 21.14) compared to semaglutide (OR = 2.24) and liraglutide (OR = 2.21). Similarly, the benchmarks for 10%, 15%, and ≥ 20% weight loss further illustrate robust performance of tirzepatide (10%: OR = 20.03; 15%: OR = 23.61; ≥ 20%: OR = 26.52) against semaglutide (10%: OR = 4.17; 15%: OR = 7.05; ≥ 20%: OR = 11.85) and liraglutide (10%: OR = 3.36) based on the aggregate data from our research and key prior studies [28,29,30]. In clinical practice, weight loss exceeding 10% from baseline is considered an excellent response [31]. The weight loss caused by tirzepatide was 18.73%, which could be clinically significant. In adults with diabetes with or without obesity/overweight, tirzepatide significantly reduced body weight (MD: 11.8% to 12.4%), BMI (MD: − 3.9 kg/m2), and waist circumference (MD: − 9.2 cm) [32]. Tirzepatide was more effective than semaglutide in patients with diabetes who were obese or overweight [33]. Preliminary data from our study support the hypothesis that tirzepatide may lead to superior outcomes in weight reduction, BMI, and waist circumference compared to semaglutide and liraglutide in non-diabetic obese individuals. Alkhezi et al. also reported that tirzepatide was associated with greater efficacy while maintaining a safety profile comparable to semaglutide and liraglutide [34]. However, head-to-head randomized clinical trials are needed to confirm this hypothesis further.

Despite the potential benefits offered by tirzepatide, the significantly increased risk of adverse events was a concern for the treatment of patients with obesity. The higher risk of adverse events could be a barrier to medication adherence, and these side effects must be balanced against the benefits of treatment. In clinical trials, the most reported adverse events included nausea, vomiting, diarrhea, decreased appetite, dyspepsia, dizziness, and injection site injection [17,18,19]. Tirzepatide had a higher risk of gastrointestinal adverse events such as nausea, vomiting, diarrhea, dyspepsia, and decreased appetite than placebo based on our findings. Previous studies also reported an increased risk of gastrointestinal adverse events with tripeptide versus placebo in patients with type 2 diabetes [32, 35]. Moreover, we also observed an increased risk of injection site reaction. Injection-associated complications also can potentially reduce patient adherence [36]. Therefore, the safety profile of tirzepatide should be considered when prescribing it to patients.

Given the increased risk of gastrointestinal adverse events associated with tirzepatide, clinicians must be diligent when prescribing this medication. The frequent occurrence of adverse events like nausea and diarrhea could significantly affect the daily activities of patients and their willingness to continue with therapy. The patient selection process for tirzepatide therapy should also be strategic, with careful consideration given to the patient’s previous history of gastrointestinal sensitivity and their ability to tolerate similar therapies. This stratification could help to minimize the risk of adverse events and improve the overall tolerability profile of the medication. An important approach to minimize the possibility of adverse events could be to start treatment at the lowest tirzepatide dose and increase it gradually as needed to achieve desired efficacy at the lowest effective dose. Furthermore, the observed increase in injection site reactions raises concerns about the administration technique and formulation of tirzepatide. This highlights the need for improved injection devices and patient training in administration techniques. We also observed the increased risk of alopecia in tirzepatide group, possibly due to nutrient deficiencies and hormonal changes caused by rapid and significant weight loss [37].

As for the scheduling for administration, tirzepatide and semaglutide are administered once weekly, while liraglutide is given once daily. For injectable medications, products administered on a once-weekly basis may provide the benefit of improved adherence and greater ease of use versus once-daily treatments [38]. Therefore, once-weekly tirzepatide might offer a more convenient and patient-friendly option compared to daily liraglutide, potentially leading to greater adherence and treatment outcomes. The less frequent dosing schedule may reduce the burden on patients, making it easier to integrate the medication into their routine and maintain consistent use over time.

Future research should directly compare tirzepatide with other active treatments in this population and investigate adverse events to provide a robust understanding of its efficacy and safety. Additionally, strategies to improve the tolerability of tirzepatide may enhance its practical application. This includes patient education, dosing titration to minimize side effects, and investigating novel therapies that offer similar or greater effectiveness and safety.