Differential Effects of Type 2 Diabetes Treatment Regimens on Diabetes Distress and Depressive Symptoms in GRADE: A Randomized Clinical Trial

Objective: We evaluated whether adding basal insulin to metformin in adults with early type 2 diabetes mellitus (T2DM) would increase emotional distress relative to other treatments. Research Design and Methods: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) study of adults with T2DM of < 10 years duration, HbA1c of 6.8-8.5%, and taking metformin monotherapy randomly assigned participants to add insulin glargine U-100, sulfonylurea glimepiride, glucagon-like peptide-1 receptor agonist liraglutide, or dipeptidyl peptidase 4 inhibitor sitagliptin. The Emotional Distress Substudy enrolled 1,739 GRADE participants (mean[SD] age, 58.0[10.2] years; 32% female; 56% non-Hispanic White, 18% non-Hispanic Black, 17% Hispanic) and assessed diabetes distress and depressive symptoms every six months. Analyses examined differences at one year and over the 3-year follow-up. Results: Across treatments, diabetes distress (-0.24, p<0.0001) and depressive symptoms (-0.67, p<0.0001) decreased over one year. Diabetes distress was lower at one year for glargine compared to the other groups combined (-0.10, p=0.002). Diabetes distress was also lower for liraglutide compared to glimepiride or sitagliptin (-0.10, p=0.008). Over the 3-year follow-up, there were no significant group differences in total diabetes distress; interpersonal diabetes distress remained lower for those assigned to liraglutide. No significant differences were observed for depressive symptoms. Conclusions: Contrary to expectations, this randomized trial found no evidence for a deleterious effect of basal insulin on emotional distress; glargine lowered diabetes distress modestly at one year rather than increasing it. Liraglutide also reduced diabetes distress at one year. Results can inform treatment decisions for adults with early T2DM.