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Randomized Controlled Trial
. 2026 Feb 1;49(2):335-343.
doi: 10.2337/dc25-2008.

Medication Adherence in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE)

Jeffrey S Gonzalez  1   2   3   4 , Hui Wen  5 , Nicole M Butera  5 , Diane Uschner  5 , Heidi Krause-Steinrauf  5 , Michaela R Gramzinski  5 , Deborah J Wexler  6 , Helen Petrovitch  7 , Claire J Hoogendoorn  1   2 , Gladys Crespo-Ramos  2 , Caroline Presley  8 , Basma Fattaleh  9 , Violet Lagari  10 , Elizabeth A Walker  2 , Andrea L Cherrington  11 ; GRADE Research Group*
Collaborators, Affiliations
Randomized Controlled Trial

Medication Adherence in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE)

Jeffrey S Gonzalez et al. Diabetes Care. .

Abstract

Objective: To address previous inconsistencies in reports of differential adherence to diabetes medications, we examined medication adherence and evaluated treatment group differences in a substudy of participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

Research design and methods: GRADE participants (type 2 diabetes duration <10 years, HbA1c 6.8%-8.5%, on metformin alone) were randomly assigned to add insulin glargine, glimepiride, liraglutide, or sitagliptin. Adherence was measured semiannually for 3 years using a validated three-item scale (0-100, lowest to highest adherence) in a substudy (N = 1,739). Analyses included evaluation of adherence over time and testing treatment group differences in adherence and in the association between adherence and primary (HbA1c ≥7.0%) and secondary (HbA1c >7.5%) glycemic outcomes.

Results: Overall mean ± SD adherence (average of participant-level mean ± SD) was high over 3 years of follow-up at 88.7 ± 10.01, on a scale of 0-100, and decreased slightly by 3 years relative to baseline (-2.0 ± 14.7; P < 0.0001). No intergroup differences were observed until 3 years, when adherence was 5% and 3% higher for the glimepiride and sitagliptin groups, respectively, than for liraglutide (both P < 0.05). Over follow-up and across groups, a 10-point decrease in adherence was associated with 15% and 19% increased risk of reaching primary (HbA1c ≥7.0%) and secondary (HbA1c >7.5%) glycemic outcomes (both P < 0.0001). Lower adherence was somewhat more predictive of the secondary outcome for those assigned to glargine or liraglutide, compared with glimepiride or sitagliptin (each P < 0.05). No other comparisons were significant.

Conclusions: Medication adherence was consistently high in GRADE. Observed treatment group differences were small and of unclear clinical significance. Overall, lower adherence robustly predicted worsening glycemic control, highlighting the importance of ongoing assessment.

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Conflict of interest statement

Duality of Interest. J.S.G. reports participation on a data safety monitoring or advisory board for Vanderbilt University, outside of the submitted work. N.M.B. reports participation on a data safety monitoring board for Fast Antibiotic Susceptibility Testing for Gram Negative Bacteremia Trial (FAST), outside of the submitted work. D.J.W. reports participation on a data safety monitoring board for Novo Nordisk Semaglutide cardiOvascular oUtcomes trial (SOUL) and Evaluate Renal Function with Semaglutide Once Weekly (FLOW) trials, outside of the submitted work. C.J.H. reports support from grants 2PO1 AG003949 (National Institute on Aging), P30DK111022P (NIDDK), P30DK111022F (NIDDK), 4-SRA-2021-1071-M-B (JDRF), and 4-SRA-2022-1187-M-B (JDRF) outside of the submitted work. C.P. reports support from National Center for Complementary and Integrative Health and American Diabetes Association grants, outside of the submitted work. No other potential conflicts of interest relevant to this article were reported.

Figures

None
Graphical abstract
Figure 1
Figure 1
Risk of primary/secondary treatment failure by month 36 across values of medication adherence by treatment group. A: Predicted risk of treatment failure by month 36 across levels of medication adherence on the original scale. Solid lines, point estimates of the relative risk of experiencing primary or secondary treatment failure at month 36; shaded areas, 95% CIs, and dashed lines, their upper and lower bounds. B: Number of participants with adherence data at each study visit by treatment group.
See this image and copyright information in PMC

References

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