title: Should Studies of Diabetes Treatment Stratification Correct for Baseline HbA1c?
abstract: OBJECTIVE
  Baseline HbA1c is a major predictor of response to glucose lowering therapy and therefore a potential confounder in studies aiming to identify other predictors. However, baseline adjustment may introduce error if the association between baseline HbA1c and response is substantially due to measurement error and regression to the mean. We aimed to determine whether studies of predictors of response should adjust for baseline HbA1c.
  
  
  METHODS
  We assessed the relationship between baseline HbA1c and glycaemic response in 257 participants treated with GLP-1R agonists and assessed whether it reflected measurement error and regression to the mean using duplicate 'pre-baseline' HbA1c measurements not included in the response variable. In this cohort and an additional 2659 participants treated with sulfonylureas we assessed the relationship between covariates associated with baseline HbA1c and treatment response with and without baseline adjustment, and with a bias correction using pre-baseline HbA1c to adjust for the effects of error in baseline HbA1c.
  
  
  RESULTS
  Baseline HbA1c was a major predictor of response (R2 = 0.19,β = -0.44,p<0.001).The association between pre-baseline and response was similar suggesting the greater response at higher baseline HbA1cs is not mainly due to measurement error and subsequent regression to the mean. In unadjusted analysis in both cohorts, factors associated with baseline HbA1c were associated with response, however these associations were weak or absent after adjustment for baseline HbA1c. Bias correction did not substantially alter associations.
  
  
  CONCLUSIONS
  Adjustment for the baseline HbA1c measurement is a simple and effective way to reduce bias in studies of predictors of response to glucose lowering therapy.
authors.affiliation: NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom.
authors.forename: Angus G
authors.initials: AG
authors.lastname: Jones
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, United Kingdom.
authors.forename: Mike
authors.initials: M
authors.lastname: Lonergan
authors.affiliation: Institute of Health Services Research, University of Exeter Medical School, Exeter, United Kingdom.
authors.forename: William E
authors.initials: WE
authors.lastname: Henley
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, United Kingdom.
authors.forename: Ewan R
authors.initials: ER
authors.lastname: Pearson
authors.affiliation: NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.affiliation: NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom.
authors.forename: Beverley M
authors.initials: BM
authors.lastname: Shields
mesh_terms: D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy*; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; C517652:hemoglobin A1c protein, human