Background: To conduct a network meta-analysis comparing the safety and efficacy of five anti-obesity drugs approved by the United States Food and Drug Administration (US FDA)-Bupropion/Naltrexone combination (BUP/NLX), Liraglutide (LIRA), Orlistat (ORLI), Phentiramine/Topiramate combination (PHEN/TPM) and Simaglutide (SGT) vs placebo.

Methods: The study's eligibility criteria include randomized controlled trials (RCTs) with a focus on obese patients receiving BUP/NLX or LIRA or ORLI or PHEN/TPM or SGT versus placebo. We conducted a comprehensive search of electronic databases (PubMed, Embase, Cochrane Library, and Scopus) to identify relevant randomized controlled trials published, with no restrictions on the publication language or year. Three reviewers independently screened the studies, extracted data, and assessed the risk of bias using the Cochrane Risk of Bias tool. Bucher's and Bayesian Meta-regression Simulation Method were used for indirect head-to-head comparison between various active drugs. RevMan Version 5.4^® along with A Network Meta- Analysis Toolkit by Cochrane Methods were used. p-value less than 0.05 was considered significant.

Results: Total 28 studies were included in this meta-analysis. PHEN/TPM combination exhibited (odds ratio :0.568, p value <0.001, cl 95%) ORLI (odds ratio: 0.889, p value <0.001, cl 95%), SGT (odds ratio: 0.922, p value <0.001, cl 95%). BUP/NLX combination exhibited a high (odds ratio: 4.61, p value <0.001, cl 95%) LIRA displayed the lowest (odds ratio: 1.109, p value <0.001, cl 95%). Network meta-analysis revealed. BUP/NLX combination exhibited highest Efficacy. ORLI found as safest among the evaluated drugs. SGT had significant likelihood of adverse events (odds ratio = 1.328, p-value<0.0001, Cl 95%) compared to ORLI (odds ratio = 0.138, p-value<0.0001, Cl 95%), BUP/NLX (odds ratio = 0.197, p-value<0.0001, cl 95%), and LIRA (odds ratio = 0.456, p-value < 0.001, Cl 95%), PHEN/TPM (odds ratio = 0.456, p-value<0.0001, Cl 95%).

Discussion: These findings have important clinical implications for the management of obesity. The BUP/NLX , LIRA , and SGT can be considered as effective treatment options for weight reduction. However, healthcare providers need to carefully consider the safety profiles and potential side-effects of these medications when making treatment decisions. The study relied on aggregated data, which might introduce bias. High attrition rates and heterogeneity among studies limit the findings. It only compared common gastrointestinal side effects and didn't use the GRADE approach for evidence quality.

Conclusion: Study provides evidence supporting the efficacy of anti-obesity medications compared to placebo. BUP/NLX combination, LIRA, and SGT emerged as the most effective agents, considering safety profile. Findings can guide clinicians about options for obesity management.

Study Registration: The study is registered with PROSPERO (CRD42023465989).