GLP-1RA- and Incretin-Based Therapies Within Lifestyle Interventions for Adults with Overweight or Obesity: A Systematic Review and Meta-Analysis

Background/Objectives: Glucagon-like peptide-1 receptor agonist (GLP-1RA)- and incretin-based therapies are now central to obesity management. Their clinical value, however, should be interpreted beyond total weight loss, because changes in fat mass, lean mass, physical function, and cardiometabolic risk may depend on the accompanying dietary, behavioral, and exercise co-interventions. This systematic review and meta-analysis evaluated GLP-1RA- and incretin-based therapies delivered within lifestyle interventions in adults with overweight or obesity. Methods: The protocol was registered in PROSPERO (CRD420261360837). PubMed/MEDLINE, Web of Science, Scopus, CINAHL, SPORTDiscus, and CENTRAL were searched from inception to the final search dates. Records were deduplicated in Zotero. Risk of bias was assessed using the Cochrane RoB 2 tool. Random-effects meta-analyses were estimated using restricted maximum likelihood with Hartung–Knapp adjustment when pooling was appropriate. Results: Across all database sources, 1651 records were identified. After removing 113 duplicate records and 212 records with an ineligible publication type before screening, 1326 records were screened. Seventy-seven reports were sought for retrieval, five were not retrieved, 72 were assessed at full text, and 48 reports corresponding to 35 independent parent trials or trial clusters were retained for qualitative synthesis. The primary kilogram-scale meta-analysis included eight independent comparisons and showed greater body-weight reduction with GLP-1RA/incretin-based therapy delivered within a lifestyle background than with placebo/control (mean difference [MD] −10.08 kg, 95% confidence interval [CI] −12.76 to −7.39; 95% prediction interval [PI] −17.86 to −2.29; I2 = 95.6%). Percentage body-weight change was analyzed separately across 11 independent comparisons and also favored GLP-1RA/incretin-based therapy (MD −9.53 percentage points, 95% CI −11.92 to −7.14; 95% PI −17.58 to −1.48; I2 = 95.4%). Conclusions: GLP-1RA- and incretin-based therapies delivered within lifestyle interventions are associated with clinically meaningful reductions in body weight in adults with overweight or obesity. Absolute and relative body-weight change metrics should remain analytically separate. The magnitude of benefit varies across trial contexts, and certainty remains limited by risk-of-bias concerns and considerable heterogeneity. Future trials should standardize the reporting of lifestyle co-interventions, body composition, adherence, physical-function outcomes, and safety monitoring.