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Randomized Controlled Trial
. 2025 Jul 1;185(7):778-787.
doi: 10.1001/jamainternmed.2025.1189.

Glucose-Lowering Medications, Glycemia, and Cognitive Outcomes: The GRADE Randomized Clinical Trial

José A Luchsinger  1   2 , Samuel P Rosin  3 , Erin J Kazemi  3 , Naji Younes  3 , Colleen E Suratt  3 , Basma N Fattaleh  4 , Hermes J Florez  5   6   7 , Jeffrey S Gonzalez  8   9   10 , Priscilla Hollander  11 , Sophia H Hox  12 , Shihchen Kuo  13 , Melissa S Lee  14 , Thomas Martens  15 , Rodica Pop-Busui  13 , Elizabeth R Seaquist  16 , Andrea H Waltje  13 , Joshua I Barzilay  17   18 ; GRADE Research Group
Collaborators, Affiliations
Randomized Controlled Trial

Glucose-Lowering Medications, Glycemia, and Cognitive Outcomes: The GRADE Randomized Clinical Trial

José A Luchsinger et al. JAMA Intern Med. .

Abstract

Importance: Type 2 diabetes (T2D) is a risk factor for cognitive impairment. Whether the choice of the second-line glucose-lowering treatment added to metformin or glycemic control affects cognitive performance in T2D of relatively short duration (<10 years) is not known.

Objective: To compare the relative effect of 4 classes of glucose-lowering medications that were randomly added to metformin on cognitive performance and to examine the association of longitudinal glycemic levels with cognitive performance.

Design, setting, and participants: This randomized clinical trial (the GRADE study) was conducted at 36 clinical centers in the US and included 3721 participants with T2D with baseline and follow-up cognitive performance data. GRADE was implemented 2013 to 2021, and data for this study were analyzed from February 2024 to February 2025.

Interventions: For the primary objective, the exposure was randomization of metformin-treated participants to receive long-acting insulin (insulin glargine U-100), sulfonylurea (glimepiride), glucagon-like peptide-1 receptor agonist (liraglutide), or dipeptidyl peptidase-4 inhibitor (sitagliptin). The secondary objective assessed time-weighted hemoglobin A1c levels over the follow-up period.

Main outcomes and measures: The primary cognitive outcome was the Digit Symbol Substitution Test score; the secondary cognitive outcomes were the immediate and delayed recall in the Spanish English Verbal Learning Test and letter and category fluency test scores.

Results: At baseline, the mean (SD) duration of T2D was 4.3 (2.7) years, and the mean (SD) age was 57.1 (9.8) years. Most participants were male (2320 [62.3%]; 1401 female individuals [37.7%]) and non-Hispanic (3015 [81.6%]; 681 Hispanic individuals [18.4%]); 712 (19.1%) were Black and 2452 (65.9%) were White; 777 (20.9%) were recruited from Veterans Affairs medical centers. There were no statistically significant differences between treatment groups in the cognitive outcomes at follow-up. However, a 1-unit increase in time-weighted hemoglobin A1c levels was associated with modestly lower Digit Symbol Substitution Test scores (-0.94 points; 95% CI, -1.30 to -0.57), Spanish English Verbal Learning Test scores (immediate recall, -0.27 points; 95% CI, -0.49 to -0.06), and category fluency test scores (animal fluency, -0.28 points; 95% CI, -0.47 to -0.09) over the mean (SD) of 4.1 (0.1) years of follow-up. Severe hypoglycemia requiring assistance was uncommon in all 4 groups (34 participants [0.9%]).

Conclusions and relevance: The results of this randomized clinical trial suggest that choice of second-line glucose-lowering medication class added to metformin is not associated with change in cognitive performance in persons with early T2D. Worse glycemic control is associated with modestly worse cognitive performance.

Trial registration: ClinicalTrials.gov Identifier: NCT01794143.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Luchsinger reported consulting fees from Merck and Novo Nordisk during the conduct of the study as well as a stipend from Wolters Kluwer and royalties from Springer outside the submitted work. Dr Younes reported grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) during the conduct of the study. Dr Florez reported grants from the Medical University of South Carolina during the conduct of the study. Dr Martens reported grants from Abbott, Dexcom, Insulet, Lilly, Medtronic, Novo Nordisk, Sanofi, and Tandem during the conduct of the study as well as grants from Medscape, a patent for an ambulatory glucose profile CGM visualization format pending, and a salary from the HealthPartners Institute outside the submitted work. Dr Pop-Busui reported grants and personal fees from Novo Nordisk and Lexicon Pharma, grants from Bayer, and personal fees from Roche, Nevro, and Averitas outside the submitted work. Dr Seaquist reported personal fees from Lilly and nonfinancial support from Zucara outside the submitted work. Dr Barzilay reported grants from the National Institutes of Health (NIH)/NIDDK outside the submitted work. No other disclosures were reported.

Comment on

References

    1. Biessels GJ, Whitmer RA. Cognitive dysfunction in diabetes: how to implement emerging guidelines. Diabetologia. 2020;63(1):3-9. doi: 10.1007/s00125-019-04977-9 - DOI - PMC - PubMed
    1. Lawrence JM, Divers J, Isom S, et al. ; SEARCH for Diabetes in Youth Study Group . Trends in prevalence of type 1 and type 2 diabetes in children and adolescents in the US, 2001-2017. JAMA. 2021;326(8):717-727. doi: 10.1001/jama.2021.11165 - DOI - PMC - PubMed
    1. Tahmi M, Luchsinger JA. Metformin in the prevention of Alzheimer’s disease and Alzheimer’s disease related dementias. J Prev Alzheimers Dis. 2023;10(4):706-717. doi: 10.14283/jpad.2023.113 - DOI - PubMed
    1. Nathan DM, Lachin JM, Balasubramanyam A, et al. ; GRADE Study Research Group . Glycemia reduction in type 2 diabetes—glycemic outcomes. N Engl J Med. 2022;387(12):1063-1074. doi: 10.1056/NEJMoa2200433 - DOI - PMC - PubMed
    1. Nathan DM, Buse JB, Kahn SE, et al. ; GRADE Study Research Group . Rationale and design of the glycemia reduction approaches in diabetes: a comparative effectiveness study (GRADE). Diabetes Care. 2013;36(8):2254-2261. doi: 10.2337/dc13-0356 - DOI - PMC - PubMed

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