In people with mild to moderate obesity (BMI 30‑39.9), the drug tirzepatide works about as well as the most common weight‑loss surgeries and better than other medicines. For very severe obesity (BMI > 40), surgery still beats the drug. This means tirzepatide can be a practical, non‑surgical first‑line option for many who want big weight loss without the risks of an operation.

We aimed at comparing different approved strategies (obesity management medications-OMM, endoscopic bariatric procedures-EBP, and metabolic bariatric surgery-MBS) with lifestyle intervention/placebo/no therapy (LSI/Pbo/NT) for the treatment of different BMI-based classes of obesity (i.e., overweight-BMI: 25-29.9 kg/m²; class I-BMI: 30-34.9 kg/m²; class II-BMI: 35-39.9 kg/m²; class III-BMI >39.9 kg/m²). This systematic review (SR) and network meta-analysis (NMA) included randomised clinical trials (RCTs) comparing OMM, EBP, and MBS versus either LSI/Pbo/NT or active comparators in individuals with overweight or obesity. A Medline and Embase search was performed up to 31st January 2025 for RCTs on EMA (European Medicines Agency)-approved weight-loss interventions in adults with overweight/obesity. The primary endpoint was total body weight loss (TBWL%), analysed at different time points: 26-52, 53-104, 105-156, and ≥156 weeks. Secondary endpoints included all-cause mortality, quality of life, and serious adverse events (SAE). Weighted mean difference and 95% confidence intervals (WMD, 95% CI) for continuous variables and Mantel-Haenszel odds ratio (MH-OR, 95% CI) for categorical variables were calculated using random effect models. The study was registered on the PROSPERO website (CRD42024625338). In trials enroling subjects in class I of obesity, tirzepatide resulted in equal effectiveness to both OAGB and RYGB, and it was significantly superior to all the other comparisons. In trials on class II of obesity, tirzepatide was significantly superior to all the other comparisons and inferior to both OAGB and RYGB. Semaglutide was associated with a higher TBWL% than the other OMMs (with the notable exception of tirzepatide), and it was equally effective to EBP, GCP, and LAGB. In trials enroling patients with a mean BMI >40 kg/m², the procedure with the highest estimated weight loss was BPD. Semaglutide was statistically less effective than SG and gastric bypass, but not inferior to GCP and LAGB. Both RYGB and OAGB were superior to SG. In patients affected by mild to moderate obesity, newer OMMs (i.e., tirzepatide and semaglutide) appear to be valid alternatives to EBP and MBS. They could be preliminarily chosen as a first-line option based on similar efficacy and greater safety and tolerability. Higher degrees of obesity could be more effectively treated with MBS, the efficacy of which, with the notable exception of LAGB and GCP, appears superior to other treatments, especially in the long term.