Is Weight Loss the Main Driver for A1C Improvement by Glucagon-Like Peptide 1 (GLP-1) Receptor Agonists? A 2.5-Year Analysis in Real-World Clinical Practice.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are established treatment options for type 2 diabetes (T2D). In addition to their glycemic benefit, GLP-1 RAs also induce weight loss by suppressing appetite via hypothalamic pathways. However, it remains unclear whether weight reduction is the primary driver of glycemic improvement. METHODS: We retrospectively evaluated 256 patients with T2D who were treated with exenatide (n = 84), dulaglutide (n = 99), or semaglutide (n = 73) for 2.5 years without interruption in real-world clinical practice. Body weight and A1C were measured every 6 months. Baseline characteristics included an average age of 61.8 ± 11.9 years, 51.5% female, diabetes duration of 12.9 ± 8.3 years, weight of 103.1 ± 20.7 kg, BMI of 35.7 ± 7.5 kg/m, and A1C of 8.2% ± 1.5%. Patients were stratified into tertiles based on percentage weight change at 2.5 years within the overall cohort and for each GLP-1 RA group. RESULTS: The first tertile experienced an average weight loss of -12.2% ± 5.7% (p < 0.0001), the second tertile lost -3.5% ± 1.4% (p < 0.0001), and the third tertile gained +2.8% ± 3.4% (p < 0.0001). The average changes in A1C were - 0.98 ± 1.8% (p < 0.0001), -0.56% ± 1.4% (p < 0.001), and -0.19% ± 1.9% (p = 0.4), respectively. A1C strongly correlated with weight change (p < 0.001). The same observations were reproducible in each medication group. CONCLUSIONS: These findings suggest that the long-term improvement in glycemic control associated with GLP-1 RA therapy is primarily driven by weight loss rather than any other intrinsic effect of GLP-1 RA. This highlights the importance of weight reduction as a key therapeutic target for optimizing glycemic outcomes in patients with T2D receiving GLP-1 RAs.