Efficacy and Safety of Tirzepatide for Weight Management in Adults with Overweight or Obesity, with and Without Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Trials

Tirzepatide for Weight Reduction

Abstract

Background: Obesity complicated by type 2 diabetes mellitus (T2DM) represents a significant global health burden with limited pharmacological options. Tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated promising efficacy for weight management. This systematic review and meta-analysis evaluate the efficacy and safety of tirzepatide for weight loss in patients with obesity and T2DM.

Methods: We systematically searched PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from May 2022 through March 2026 for randomized controlled trials (RCTs) evaluating tirzepatide versus placebo or active comparators in adults with obesity (BMI ≥27 kg/m²) and T2DM. Primary outcomes included mean percentage change in body weight and proportion achieving ≥5%, ≥10%, ≥15%, and ≥20% weight loss. Secondary outcomes included changes in glycated hemoglobin (HbA1c), lipid profiles, and adverse events. Study quality was assessed using the Cochrane Risk of Bias 2 tool. Random-effects meta-analyses with inverse variance weighting were performed. Heterogeneity was quantified using I² statistics and meta-regression analyses were conducted to explore dose-response relationships.

Results: Five high-quality RCTs (n=5,847 participants; 3,508 tirzepatide, 2,339 comparator) met inclusion criteria. Tirzepatide induced significantly greater weight loss compared to placebo: pooled mean difference -14.30% (95% CI: -16.74% to -11.86%; p<0.0001), with substantial heterogeneity (I²=94.2%). Dose-response analysis demonstrated progressive weight loss with increasing tirzepatide doses: 5 mg (-15.0%), 10 mg (-19.5%), and 15 mg (-20.9%). Non-diabetic patients achieved greater absolute weight loss (-15.37%) compared to those with T2DM (-10.55%). Tirzepatide significantly increased the odds of achieving clinically meaningful weight loss thresholds: ≥5% (OR=11.32, 95% CI: 10.15-12.61), ≥10% (OR=14.77, 95% CI: 13.21-16.52), ≥15% (OR=18.07, 95% CI: 15.89-20.54), and ≥20% (OR=22.45, 95% CI: 19.34-26.07). In T2DM patients, tirzepatide achieved significant HbA1c reductions: 10 mg (-1.1%, 95% CI: -1.27 to -0.93) and 15 mg (-1.3%, 95% CI: -1.48 to -1.12). Gastrointestinal adverse events were more common with tirzepatide (OR=1.34, 95% CI: 1.21-1.49), primarily nausea (28.3-31.2%), diarrhea (22.1-24.5%), and vomiting (12.4-15.3%), though most were mild to moderate in severity. Serious adverse events did not differ significantly between groups (OR=1.08, 95% CI: 0.92-1.27). Treatment discontinuation due to adverse events was dose-dependent: 5 mg (4.3%), 10 mg (7.1%), 15 mg (6.2%) versus placebo (2.6%).

Conclusions: Tirzepatide demonstrates superior efficacy for weight loss in patients with obesity and T2DM compared to placebo, with a favorable risk-benefit profile. The dose-dependent weight loss, combined with improvements in glycemic control and cardiometabolic parameters, supports tirzepatide as an effective therapeutic option for this high-risk population. Future research should focus on long-term cardiovascular outcomes and strategies to mitigate gastrointestinal side effects to optimize treatment adherence.