To assess whether clinical characteristics and simple biomarkers of β-cell failure are associated with individual variation in glycemic response to GLP-1 receptor agonist (GLP-1RA) therapy in patients with type 2 diabetes.

We prospectively studied 620 participants with type 2 diabetes and HbA_1c ≥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 β-cell failure and glycemic response (primary outcome HbA_1c change 0–6 months) with change in weight (0–6 months) as a secondary outcome using linear regression and ANOVA with adjustment for baseline HbA_1c and cotreatment change.

Reduced glycemic response to GLP-1RAs was associated with longer duration of 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 HbA_1c 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.

Clinical markers of low β-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.