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

posted on 2024-02-28, 18:27 authored by Jeffrey S. Gonzalez, Ionut Bebu, Heidi Krause-Steinrauf, Claire J. Hoogendoorn, Gladys Crespo-Ramos, Caroline Presley, Aanand D. Naik, Shihchen Kuo, Mary L. Johnson, Deborah Wexler, Jill P. Crandall, Anne E Bantle, Valerie Arends, Andrea Cherrington

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.


The GRADE Study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health under Award Number U01DK098246. The planning of GRADE was supported by a U34 planning grant from the NIDDK (U34-DK-088043). The American Diabetes Association supported the initial planning meeting for the U34 proposal. The National Heart, Lung, and Blood Institute and the Centers for Disease Control and Prevention also provided funding support. The Department of Veterans Affairs provided resources and facilities. Additional support was provided by grant numbers P30 DK017047, P30 DK020541, P30 DK020572, P30 DK072476, P30 DK079626, P30 DK092926, U54 GM104940, UL1 TR000170, UL1 TR000439, UL1 TR000445, UL1 TR001102, UL1 TR001108, UL1 TR001409, 2UL1TR001425, UL1 TR001449, UL1 TR002243, UL1 TR002345, UL1 TR002378, UL1 TR002489, UL1 TR002529, UL1 TR002535, UL1 TR002537, UL1 TR002541 and UL1 TR002548. Educational materials were provided by the National Diabetes Education Program. Material support in the form of donated medications and supplies was provided by Becton, Dickinson and Company, Bristol-Myers Squibb, Merck & Co., Inc., Novo Nordisk, Roche Diagnostics, and Sanofi. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The GRADE Study Research Group is deeply grateful to our participants whose loyal dedication made GRADE possible. The GRADE Emotional Distress Substudy was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health under Award Number R01 DK104845. Additional support was provided by grant number P30 DK111022.


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