Pharmacological management of obesity in adults: a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy and safety of obesity management medications

Background : There are different types of obesity management medications (OMMs) are available but their effectiveness in reducing body weight and preventing or reversing obesity-related complications (ORC) can vary significantly. We therefore evaluated the efficacy and safety of OMMs in the treatment of obesity and related complications. Methods : This systematic review and network meta-analysis included randomized clinical trials (RCTs) with at least a 48-week treatment period, comparing OMM versus placebo or active comparators in patients with obesity (body mass index; BMI ≥30 kg/m ² ) or overweight (BMI ≥25 kg/m ² ). A Medline and Embase search was performed up to January 31, 2025 for RCTs on OMMs adopted by at least one EASO member country in adults. The primary endpoint was the percentage of total body weight loss (TBWL%) at the end of the study. Secondary endpoints included TBWL% at 1, 2, and ≥3 years, lipid profile, blood pressure, HbA1c, fasting plasma glucose, mental health, serious adverse events (SAE), quality of life, cardiovascular morbidity and mortality, obesity-associated comorbid condition remission, and all-cause mortality. Weighted mean difference and 95% confidence intervals (CI) were estimated for continuous variables. Mantel-Haenzel odds ratios and 95% CIs were estimated for categorical variables, using random effect models. The study was registered with PROSPERO (registration number CRD42024625338). Findings There were 55 clinical trials identified, they included orlistat (n=21), semaglutide (n=12), liraglutide (n=9), tirzepatide (n=6), naltrexone/bupropion (n=5), and phentermine/topiramate (n=2), enrolling 62,861 patients (33,986 and 28,804 with active compound and placebo, respectively). At the primary endpoint (mean follow-up duration 68 weeks), all OMMs showed a significantly greater TBWL% versus placebo (all p<0.0001). The estimated endpoint TBWL% was greater than 10% for semaglutide and tirzepatide. The type of OMM impacted the magnitude of changes in the secondary outcomes examined. Serious adverse effects (SAE) were reported in most studies, and OMMs were not associated with an increased risk of SAE compared to placebo, except for naltrexone/bupropion. Semaglutide was associated with a lower risk of mortality. Interpretation : The present findings support the need to tailor OMMs to the presence and severity of ORC, as different OMMs produce varying degrees of weight loss and have differing impacts on specific ORCs.