Markers of beta-Cell Failure Predict Poor Glycemic Response to GLP-1 Receptor Agonist Therapy in Type 2 Diabetes

Abstract

OBJECTIVE: To assess whether clinical characteristics and simple biomarkers of beta-cell failure are associated with individual variation in glycemic response to GLP-1 receptor agonist (GLP-1RA) therapy in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We prospectively studied 620 participants with type 2 diabetes and HbA1c >/=58 mmol/mol (7.5%) commencing GLP-1RA therapy as part of their usual diabetes care and assessed response to therapy over 6 months. We assessed the association between baseline clinical measurements associated with beta-cell failure and glycemic response (primary outcome HbA1c change 0-6 months) with change in weight (0-6 months) as a secondary outcome using linear regression and ANOVA with adjustment for baseline HbA1c and cotreatment change. RESULTS: Reduced glycemic response to GLP-1RAs was associated with longer duration diabetes, insulin cotreatment, lower fasting C-peptide, lower postmeal urine C-peptide-to-creatinine ratio, and positive GAD or IA2 islet autoantibodies (P </= 0.01 for all). Participants with positive autoantibodies or severe insulin deficiency (fasting C-peptide </=0.25 nmol/L) had markedly reduced glycemic response to GLP-1RA therapy (autoantibodies, mean HbA1c change -5.2 vs. -15.2 mmol/mol (-0.5 vs. -1.4%), P = 0.005; C-peptide <0.25 nmol/L, mean change -2.1 vs. -15.3 mmol/mol (-0.2 vs. -1.4%), P = 0.002). These markers were predominantly present in insulin-treated participants and were not associated with weight change. CONCLUSIONS: Clinical markers of low beta-cell function are associated with reduced glycemic response to GLP-1RA therapy. C-peptide and islet autoantibodies represent potential biomarkers for the stratification of GLP-1RA therapy in insulin-treated diabetes.