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. 2025 Jan;17(1):e70054.
doi: 10.1111/1753-0407.70054.

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

Marwa Al-Badri  1   2 , Shilton Dhaver  1   2 , Osama Hamdy  1   2
Affiliations

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

Marwa Al-Badri et al. J Diabetes. 2025 Jan.

Abstract

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/m2, 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.

Keywords: GLP‐1 receptor agonists; glycemic control; real‐world clinical practice; type 2 diabetes; weight loss.

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Conflict of interest statement

O.H. receives research support from Eli Lilly and Novo Nordisk and serves on an advisory board for Abbott Nutrition. M.A. and S.D. have no disclosures relevant to this work.

Figures

FIGURE 1
FIGURE 1
Change in A1C from baseline in each tertile of weight loss over 2.5 years among all participants. Tertile 1 (n = 83), Tertile 2 (n = 84), Tertile 3 (n = 84), Data are given as mean ± SD. *p < 0.05 compared to baseline.
FIGURE 2
FIGURE 2
Change in A1C from baseline in each tertile of weight change over 2.5 years according to the used GLP‐1 RA. Data are given as mean ± SD. *p < 0.05 compared to baseline.
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