Throughout the past few decades, the prevalence of obesity has been gradually increasing worldwide, and the trend is expected to further increase in the upcoming years.1 Obesity significantly increases the risk of certain comorbidities, all of which contribute to a decline in both quality of life and life expectancy.2 Obesity has been reported to cause a chronic inflammatory state that, in turn, increases the risk of oxidation of low-density lipoprotein (LDL) cholesterol and, hence, atherogenesis.2 Additionally, obesity could lead to an altered lipid profile, type 2 diabetes mellitus (T2DM), and hypertension, all of which contribute to atherogenesis and, thus, increase the risk of developing cardiovascular disease. On the other hand, weight loss and chronic weight control are related to reductions in the overall risk of morbidity and mortality.3 Although the core of most weight loss strategies is lifestyle adjustment, including dietary changes and exercise,4 due to physiologic factors that limit weight loss and encourage weight return,5 lifestyle adjustment alone is frequently insufficient to produce clinically meaningful weight loss. Given the risk that obesity poses to public health and the difficulties of adopting consistent lifestyle modifications, pharmaceutical treatments for weight loss in some individuals are required.6

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as liraglutide and semaglutide, produce several times the amount of GLP-1 receptor agonism as natural GLP-1.7 These drugs, although initially introduced to treat T2DM, were found to be successful in lowering not only the blood glucose levels but also body weight.8 As a result, a once-daily subcutaneous dosage of 3.0-mg liraglutide and 2.4-mg semaglutide for the treatment of obesity was established.9 These medications function by stimulating the pancreatic GLP-1 receptors, which results in increased insulin release and decreased glucagon release, both of which are glucose-dependent responses.10 GLP-1 RAs have also shown an effect in delaying gastric emptying, reducing hunger, and prospective food consumption. This leads to reduced appetite and increased energy expenditure, which helps control weight in individuals with obesity.11, 12, 13

Alongside their impact on weight loss, GLP-1 RAs have demonstrated significant therapeutic effects on cardiometabolic parameters.14 Cardiometabolic health encompasses a range of factors, including those related to the cardiovascular system, such as blood pressure (BP), and metabolic regulatory mechanisms, such as effects on body weight, body mass index (BMI), and lipid profile.15 Notably, GLP-1 RAs have shown efficacy in lowering the BP levels and have also demonstrated efficacy in alleviating symptoms of heart failure in patients with preserved ejection.16 The results of the LEADER and SUSTAIN-6 trials also confirm the noninferiority of liraglutide and semaglutide on their impact on cardiovascular outcomes in a population with diabetes.17,18

Previous studies on GLP-1 RAs analyzed their efficacy in improving glycemic index and weight loss in individuals with diabetes.19,20 However, there are a limited number of studies collectively analyzing all available GLP-1 RAs regarding their efficacy in obese individuals but without diabetes. Therefore, we aimed to conduct this meta-analysis to consolidate data from various trials involving Food and Drug Administration–approved GLP-1 RAs, such as semaglutide, liraglutide, and exenatide, as well as forthcoming potential medications, such as tirzepatide, as a dual incretin, and orforglipron to determine whether different GLP-1 RAs result in improvement in obesity and cardiometabolic parameters and assess their safety in individuals with obesity without diabetes. In addition, we intended to analyze any differences in efficacy between various subtypes of GLP-1 RAs.