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Review
. 2025 Jun 7;17(6):e85531.
doi: 10.7759/cureus.85531. eCollection 2025 Jun.

Dose-Dependent Efficacy and Safety of Tirzepatide for Weight Loss in Non-diabetic Adults With Obesity: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Alousious Kasagga  1 , Amanuel Kefyalew Assefa  2 , Maysaa N Amin  3 , Rahma Hashish  4 , Khaled Agha Tabari  5 , Shivling S Swami  6 , Kevin Nakasagga  7
Affiliations
Review

Dose-Dependent Efficacy and Safety of Tirzepatide for Weight Loss in Non-diabetic Adults With Obesity: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Alousious Kasagga et al. Cureus. .

Abstract

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist, has shown promising weight-loss effects in previous trials. However, its dose-dependent efficacy and safety in obese adults without diabetes have not been fully defined. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating tirzepatide in obese adults without diabetes. PubMed, Cochrane CENTRAL, and ClinicalTrials.gov were searched from January 2020 to April 2025. Eligible studies compared tirzepatide (5-15 mg or maximum tolerated dose (MTD)) to a placebo over a minimum duration of 52 weeks. The primary outcome was the percent change in body weight. Secondary outcomes included changes in body mass index (BMI), waist circumference, hemoglobin A1c (HbA1c), systolic blood pressure (SBP), quality-of-life scores (Short-Form Health Survey Version 2 (SF-36v2) and the Impact of Weight on Quality of Life-Lite Clinical Trials version (IWQOL-Lite-CT)), and achievement of categorical weight-loss thresholds. Safety outcomes included the incidence of adverse events. Data were pooled using fixed- or random-effects models, and dose-response meta-regression was performed. Four RCTs (n = 3,553 participants) met the inclusion criteria. Tirzepatide significantly reduced the percentage body weight compared to placebo (mean difference -16.54%; 95% CI -17.48 to -15.59; p < 0.00001), with a clear dose-response relationship (meta-regression β = -0.72% per 1 mg increase; p = 0.0014). Participants receiving tirzepatide were markedly more likely to achieve clinically meaningful weight-loss thresholds, such as ≥15% (OR 23.25; 95% CI 18.06-29.94). Tirzepatide also improved BMI (-7.09 kg/m²), waist circumference (-12.77 cm), HbA1c (-0.42%), and quality-of-life scores. Gastrointestinal adverse events, including nausea (OR 4.20), vomiting (OR 6.93), and diarrhea (OR 3.80) were more frequent with tirzepatide; however, the rate of serious adverse events was comparable to placebo (OR 0.97). Sensitivity analyses confirmed the reliability of the findings. In conclusion, tirzepatide produces substantial, dose-dependent weight loss and improves metabolic and quality-of-life outcomes in obese adults without diabetes. Despite a higher incidence of gastrointestinal side effects, the lack of increased serious adverse events supports its favorable risk-benefit profile for long-term obesity treatment.

Keywords: dose response; dual incretin therapy; gip/glp-1 agonist; meta-analysis; meta-regression; non-diabetic adults; obesity treatment; systematic review; tirzepatide; weight loss therapy.

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Conflict of interest statement

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Figures

Figure 1
Figure 1. PRISMA flowchart of the study selection process
PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Figure 2
Figure 2. (A) Risk of bias assessment across studies. (B) Summary of risk of bias proportions across domains
SURMOUNT, SURMOUNT-CN, and SURMOUNT-J refer to individual phase 3 randomized controlled trials evaluating tirzepatide for chronic weight management in global, Chinese, and Japanese adult populations, respectively. Note: This figure was generated using robvis, a visualization tool based on the Cochrane Risk of Bias 2.0 tool, both available under the Creative Commons Attribution 4.0 License (CC BY 4.0).
Figure 3
Figure 3. Forest plot for percent weight change
Figure 4
Figure 4. Meta-regression plot for percent weight change
Figure 5
Figure 5. Forest plot for BMI change
Figure 6
Figure 6. Meta-regression plot for BMI change
Figure 7
Figure 7. Forest plot for waist circumference change
Figure 8
Figure 8. Meta-regression plot for waist circumference change
Figure 9
Figure 9. Forest plot for HbA1c change
Figure 10
Figure 10. Meta-regression plot for HbA1c change
Figure 11
Figure 11. Forest plot for systolic blood pressure change
Figure 12
Figure 12. Meta-regression plot for systolic blood pressure change
Figure 13
Figure 13. Forest plot for SF-36v2 score change
SF-36v2: Short-Form Health Survey version 2.
Figure 14
Figure 14. Forest plot for IWQOL-Lite-CT score change
IWQOL-Lite-CT: Impact of Weight on Quality of Life-Lite Clinical Trials version.
Figure 15
Figure 15. Forest plot for achievement of ≥5%, ≥10%, ≥15%, ≥20%, and ≥25% weight loss
Figure 16
Figure 16. Forest plots for (A) any adverse events, (B) serious adverse events, and (C) discontinuations due to adverse events
Figure 17
Figure 17. Forest plot for nausea events
Figure 18
Figure 18. Forest plot for vomiting events
Figure 19
Figure 19. Forest plot for diarrhea events
See this image and copyright information in PMC

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