title: Markers of β-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 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.
  
  
  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 β-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 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 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 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.
authors.affiliation: National Institute for Health Research Exeter Clinical Research Facility, University of Exeter Medical School and Royal Devon and Exeter National Health Service Foundation Trust, Exeter, U.K. angus.jones@exeter.ac.uk.
authors.forename: Angus G
authors.initials: AG
authors.lastname: Jones
authors.affiliation: National Institute for Health Research Exeter Clinical Research Facility, University of Exeter Medical School and Royal Devon and Exeter National Health Service Foundation Trust, Exeter, U.K.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: McDonald
authors.affiliation: National Institute for Health Research Exeter Clinical Research Facility, University of Exeter Medical School and Royal Devon and Exeter National Health Service Foundation Trust, Exeter, U.K.
authors.forename: Beverley M
authors.initials: BM
authors.lastname: Shields
authors.affiliation: National Institute for Health Research Exeter Clinical Research Facility, University of Exeter Medical School and Royal Devon and Exeter National Health Service Foundation Trust, Exeter, U.K.
authors.forename: Anita V
authors.initials: AV
authors.lastname: Hill
authors.affiliation: Institute of Health Research, University of Exeter Medical School, Exeter, U.K.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hyde
authors.affiliation: National Institute for Health Research Exeter Clinical Research Facility, University of Exeter Medical School and Royal Devon and Exeter National Health Service Foundation Trust, Exeter, U.K.
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Knight
authors.affiliation: National Institute for Health Research Exeter Clinical Research Facility, University of Exeter Medical School and Royal Devon and Exeter National Health Service Foundation Trust, Exeter, U.K.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight; D002096:C-Peptide / Q000187:drug effects / Q000652:urine; D003404:Creatinine / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D005215:Fasting; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D019518:Postprandial Period; D011446:Prospective Studies; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin; D003404:Creatinine; D000097789:Glucagon-Like Peptide-1 Receptor Agonists