Incretin Receptor Agonists and Exercise in Obesity, a Systematic Review with Exploratory Meta-analysis of Comparative and Combined Evidence

Obesity is a global health challenge that is strongly associated with type 2 diabetes and cardiovascular disease. Incretin receptor agonists produce substantial weight loss, whereas structured exercise provides distinct benefits for cardiorespiratory fitness, metabolic health, and body composition preservation. This systematic review synthesized clinical studies of GLP-1 receptor agonists, dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonists, structured exercise, and combined strategies in adults with obesity, overweight, or type 2 diabetes. Three databases were searched in accordance with PRISMA 2020, and 31 studies comprising approximately 10,044 participants were included. Pharmacotherapy trials consistently favored incretin-based treatment over placebo or usual care for the body weight and glycemic outcomes. However, direct drug-plus-exercise versus drug-alone comparisons were few, exercise prescriptions and background lifestyle programs were heterogeneous, and several studies evaluated counseling rather than supervised training. Only a subset of studies reported means and standard deviations in a form suitable for pooling, so the quantitative synthesis shown in the main figures is restricted to descriptive within-group changes from baseline to postintervention and does not estimate between-group treatment effects. Studies whose randomized contrast was dietary education or general physical activity advice were classified as background lifestyle care rather than structured exercise, and every study is classified individually so that no statement about supervised training rests on them. Direct between-group comparisons were performed on postintervention values for every outcome, and they are reported in the Supporting Information. No outcome differed significantly between groups in the studies that combined pharmacotherapy with an exercise or lifestyle cointervention, whereas body weight and body mass index favored the drug in the pharmacotherapy-only studies, as expected from established efficacy. Direct drug-plus-exercise versus drug-alone evidence was therefore summarized narratively, and heterogeneity was substantial for the glycemic outcomes. Limited evidence suggests a possible complementary benefit of combining pharmacotherapy with structured exercise, particularly for fitness, body composition, and weight maintenance, but the certainty and generalizability of this evidence remain limited. The evidence base consists of short trials conducted almost entirely in high-income settings, with limited geographic, ethnic, and socioeconomic diversity and little reporting of adherence or sex-stratified effects; therefore, it cannot establish how combined therapy would perform across diverse health systems and populations. These findings support individualized multidisciplinary obesity care while highlighting the need for adequately powered, factorial trials.