Al-Badri Marwa, Dhaver Shilton, Hamdy Osama
Joslin Diabetes Center, Affiliated With Harvard Medical School, Boston, Massachusetts, USA.
Harvard Medical School, Boston, Massachusetts, USA.
J Diabetes. 2025 Jan;17(1):e70054. doi: 10.1111/1753-0407.70054.
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.
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.
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.
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.
胰高血糖素样肽-1受体激动剂（GLP-1 RAs）是2型糖尿病（T2D）的既定治疗选择。除了对血糖有益外，GLP-1 RAs还通过下丘脑途径抑制食欲来促进体重减轻。然而，体重减轻是否是血糖改善的主要驱动因素仍不清楚。
我们回顾性评估了256例T2D患者，这些患者在现实世界的临床实践中接受了艾塞那肽（n = 84）、度拉鲁肽（n = 99）或司美格鲁肽（n = 73）治疗2.5年且未中断。每6个月测量一次体重和糖化血红蛋白（A1C）。基线特征包括平均年龄61.8±11.9岁，女性占51.5%，糖尿病病程12.9±8.3年，体重103.1±20.7 kg，体重指数（BMI）35.7±7.5 kg/m²，A1C为8.2%±1.5%。根据整个队列以及每个GLP-1 RA组在2.5年时的体重变化百分比，将患者分为三分位数。
第一三分位数的患者平均体重减轻了-12.2%±5.7%（p < 0.0001），第二三分位数减轻了-3.5%±1.4%（p < 0.0001），第三三分位数体重增加了+2.8%±3.4%（p < 0.0001）。A1C的平均变化分别为-0.98±1.8%（p < 0.0001）、-0.56%±1.4%（p < 0.001）和-0.19%±1.9%（p = 0.4）。A1C与体重变化密切相关（p < 0.001）。在每个药物组中都可重复观察到相同的结果。
这些发现表明，与GLP-1 RA治疗相关的血糖控制长期改善主要是由体重减轻驱动的，而非GLP-1 RA的任何其他内在作用。这突出了体重减轻作为接受GLP-1 RAs治疗的T2D患者优化血糖结局的关键治疗靶点的重要性。
