The Association of Baseline Factors with Glycemic Outcomes in the GRADE Study: A Comparative Effectiveness Randomized Clinical Trial

Objective: To describe the individual and joint associations of baseline factors with glycemia, and with differential effectiveness of medications added to metformin.

Research Design and Methods: GRADE participants (type 2 diabetes for <10 years, HbA1c 6.8%-8.5% on metformin, N=5047) were randomly assigned to a basal insulin (glargine), sulfonylurea (glimepiride), glucagon-like peptide-1 agonist (liraglutide), or dipeptidyl peptidase-4 inhibitor (sitagliptin). The glycemic outcome was HbA1c ≥7.0%, subsequently confirmed. Univariate, multivariate regression, and Classification and Regression Tree (CART) analyses described the association of baseline factors with the glycemic outcome at years 1 and 4.

Results: In univariate analyses at baseline, younger age (<58 years), Hispanic ethnicity, high fasting glucose and triglyceride levels, lower insulin secretion, and relatively greater insulin resistance were associated with the glycemic outcome at years 1 and 4. No factors were associated with differential effectiveness of the medications by year 4. In multivariate analyses, treatment group, younger age, and higher baseline HbA1c and fasting glucose were jointly associated with the glycemic outcome by year 4. The superiority of glargine and liraglutide at year 4 persisted after controlling for multiple baseline factors. CART analyses indicated that younger participants and those with baseline HbA1c ≥7.4% were more likely to fail by year 4.

Conclusions: Several baseline factors were associated with the glycemic outcome but not with differential effectiveness of the four medications. Failure to maintain HbA1c <7% was largely driven by younger age and higher HbA1c at baseline. Factors that predict earlier glycemic deterioration could help target patients for more aggressive management.