Baseline metabolite profiles predict the glucose-lowering efficacy of exenatide in patients with type 2 diabetes.

AIMS: Individual heterogeneity in the glucose-lowering response to glucagon-like peptide-1 receptor agonists (GLP-1RAs), including exenatide, limits efficient treatment selection for type 2 diabetes mellitus (T2DM). This study assessed whether baseline clinical characteristics together with serum metabolomic features could predict the glucose-lowering efficacy of exenatide. METHODS: A total of 93 Chinese adults with T2DM received exenatide treatment for 16 weeks. Treatment response was defined by glycated hemoglobin (HbA1c) change value (ΔHbA1c): responders (ΔHbA1c ≤ -0.3%, n = 70) and non-responders (ΔHbA1c > -0.3%, n = 23). Baseline serum metabolites were profiled by non-targeted liquid chromatography-mass spectrometry. Predictors of exenatide-induced glucose-lowering response were screened and modeled using univariate and multivariate logistic regression analysis and evaluated with receiver-operating characteristic (ROC) analysis. RESULTS: At baseline, responders presented with a higher HbA1c level and a lower HDL-C level than non-responders. Logistic regression analysis indicated that baseline HbA1c and HDL-C levels were associated with ΔHbA1c after treatment. Metabolomic comparison analysis identified 15 discriminative serum metabolites between two groups. Among these metabolites, butenylcarnitine, LysoPC(18:2(9Z,12Z)) and PC(20:3(5Z,8Z,11Z)/20:3(5Z,8Z,11Z)) were correlated with the exenatide-induced glucose-lowering response. Baseline clinical characteristics (higher HbA1c level and lower HDL-C level) combined with the metabolomic features [lower butenylcarnitine, higher LysoPC(18:2(9Z,12Z)) and higher PC(20:3(5Z,8Z,11Z)/20:3(5Z,8Z,11Z)] predicted better glucose-lowering response to exenatide, with a sensitivity, specificity and area under the ROC curve of 78.1%, 90.0% and 0.895, respectively. CONCLUSIONS: Combination of the baseline clinical characteristics (HbA1c and HDL-C) and metabolite profiles [butenylcarnitine, LysoPC(18:2(9Z,12Z)) and PC(20:3(5Z,8Z,11Z)/20:3(5Z,8Z,11Z))] can effectively predict glucose-lowering efficacy of exenatide in patients with T2DM.