Circulating GDF15 and HbA1c Response to Add-On Exenatide Therapy in Type 2 Diabetes: A Post Hoc Analysis from a Multicenter Trial

<b>Objectives</b>: To assess the influences of growth differentiation factor 15 (GDF15) on the reduction in glycated hemoglobin (ΔHbA1c) induced by exenatide in type 2 diabetes mellitus (T2DM). <b>Methods</b>: This analysis included 166 participants with T2DM who received exenatide as add-on therapy for 16 weeks. The effect of baseline GDF15 on ΔHbA1c was evaluated using univariate, multivariate, and bidirectional stepwise linear regression models. Baseline GDF15 was categorized into tertiles with the lowest tertile (tertile 1) serving as reference. A subgroup analysis was performed in the participants aged >35 years to investigate whether age influenced the effect of GDF15 on ΔHbA1c. <b>Results</b>: GDF15 levels were significantly increased from baseline following 16 weeks of exenatide treatment [721.9 (513.6, 997.8) pg/mL vs. 741.4 (510.0, 1203.4) pg/mL, <i>p</i> = 0.031]. Univariate linear regression analysis revealed a positive association between baseline GDF15 (tertile 3: <i>β</i> = 0.553, 95% CI 0.115 to 0.991, <i>p</i> = 0.014) and ΔHbA1c. However, no significant relationship was found between GDF15 (tertile 2: <i>p</i> = 0.403; tertile 3: <i>p</i> = 0.217) and ΔHbA1c after adjusting for age and diabetes duration. Further stepwise regression analysis indicated a non-robust association for GDF15 in the absence of age as GDF15 was excluded from the model. Among the participants >35 years old, GDF15 (tertile 3: <i>β</i> = 0.383, 95% CI 0.002 to 0.764, <i>p</i> = 0.049) remained positively associated with ΔHbA1c, even after adjusting for age. <b>Conclusions</b>: Elevated GDF15 might potentially diminish the reduction in HbA1c following 16-week exenatide treatment, with this effect moderated by age.