Differential impact of glucagon-like peptide-1 (GLP-1) receptor agonists for weight loss in the type 2 diabetic and non-diabetic populations.

“Differential impact of glucagon-like peptide-1 (GLP-1) receptor agonists for weight loss in the type 2 diabetic and non-diabetic populations. Jia IT(1), Bloomfield GC(1), Chen MY(1), Cunningham MH(1), Wang A(2), Daly SC(2), Hinojosa MW(2), Smith BR(2), Nguyen NT(2), Azagury DE(3), Prindeze NJ(4). Author information: (1)School of Medicine, Georgetown University, Washington, DC, USA. (2)Division of Gastrointestinal Surgery, Department of Surgery, Irvine Medical Center, University of California, Irvine, 101 The City Drive South, Orange, CA, 92868, USA. (3)Department of Surgery, Stanford University School of Medicine, Palo Alto, CA, USA. (4)Division of Gastrointestinal Surgery, Department of Surgery, Irvine Medical Center, University of California, Irvine, 101 The City Drive South, Orange, CA, 92868, USA. nprindez@hs.uci.edu. BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as a cornerstone therapy for obesity management, yet long-term comparative effectiveness across diabetes status, adherence, and specific agents remains unclear. This study evaluates multi-year weight-loss outcomes associated with GLP-1 therapy and characterizes medication- and phenotype-specific differences. METHODS: This study represents a subgroup analysis of a large-scale meta-analysis including clinical trials, observational and case-control studies published from 2010 to 2025 reporting long-term weight outcomes for GLP-1 agents. Outcomes were evaluated across mixed, intention-to-treat (ITT), and treatment-adherent populations and stratified by diabetes status. Mixed-effects meta-regression was performed to evaluate independent predictors of weight loss. RESULTS: A total of 56,580 patients from 45 studies were included. GLP-1 therapy consistently produced greater weight loss than placebo across all populations. Non-diabetic participants achieved the greatest reductions, losing 15.7% of baseline weight at 12 months versus 5.1% in diabetic users in the mixed cohort. ITT results were similar but modestly attenuated, whereas adherent patients demonstrated the largest reductions. Diabetes status was a strong effect modifier: non-diabetic individuals achieved 2.5-4 × greater reductions than diabetics receiving the same agents. Meta-regression confirmed diabetes status as an independent negative predictor of weight loss (β =  - 1.77, p < 0.001). Semaglutide produced significantly greater reductions than liraglutide after adjustment (β =  + 1.67, p < 0.001), while baseline BMI was inversely associated with percent weight change (β =  + 0.46, p < 0.001). CONCLUSION: GLP-1 therapies produce durable weight loss with outcomes strongly influenced by diabetes status, adherence, and agent selection. These findings support a personalized, phenotype-based approach to GLP-1 prescribing. © 2026. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. Conflict of interest statement: Declarations. Disclosures: All authors including Ms. Iwanger-T-Ter Jia, Ms. Grace Bloomfield, Mr. Mike Chen, Mr. Marcus Cunningham, Dr. Annie Wang, Dr. Shaun Daly, Dr. Marcelo Hinojosa, Dr. Brian Smith, Dr. Ninh Nguyen, Dr. Dan Azagury, and Dr. Nicholas Prindeze have no conflict of interest or financial ties to disclose.”