Glucose-Lowering Medications, Glycemia, and Cognitive Outcomes: The GRADE Randomized Clinical Trial
Authors' conclusion
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.
Study context
- Population
- Metformin-treated participants with T2D of relatively short duration (<10 years) with baseline and follow-up cognitive data, 36 US clinical centers; mean (SD) T2D duration 4.3 (2.7) years, mean (SD) age 57.1 (9.8) years, 62.3% male
- Participants
- 3,721 participants
- Comparison
- Insulin glargine vs glimepiride vs liraglutide vs sitagliptin, each added to metformin
- Primary endpoint
- Digit Symbol Substitution Test score
- Follow-up
- (mean [SD] 4.1 [0.1] years)
Methodological detailsmulticentre, GRADE implemented 2013 to 2021; data analyzed February 2024 to February 2025
- Multicentre
- GRADE implemented 2013 to 2021; data analyzed February 2024 to February 2025
Primary result
As reported in the abstract
Cognitive outcomes incl. Digit Symbol Substitution Test score · follow-up
- No statistically significant differences between treatment groups in the cognitive outcomes at follow-up
Secondary outcomes
Association of 1-unit increase in time-weighted HbA1c with cognitive scores · mean (SD) 4.1 (0.1) years of follow-up
- Digit Symbol Substitution Test score
- −0.94 points; 95% CI, −1.30 to −0.57
- Spanish English Verbal Learning Test immediate recall
- −0.27 points; 95% CI, −0.49 to −0.06
- Category fluency (animal fluency)
- −0.28 points; 95% CI, −0.47 to −0.09
Safety
Severe hypoglycemia requiring assistance
- Uncommon in all 4 groups
- 34 participants [0.9%]
Parts of this Brief are withheld: the automatic checks could not confirm them against the abstract.
Original publication
Glucose-Lowering Medications, Glycemia, and Cognitive Outcomes: The GRADE Randomized Clinical Trial. JAMA Intern Med. Published 1 July 2025. doi:10.
Composed by AI from the published abstract and checked against it. How Briefs are made →