Cognitive performance was not different among four classes of glucose-lowering medications for type 2 diabetes, data from the GRADE clinical trial showed.
Cognitive performance at 4.1 years of follow-up was similar in participants randomized to receive either a long-acting insulin, sulfonylurea, glucagon-like peptide (GLP)-1 receptor agonist, or dipeptidyl peptidase-4 (DPP-4) inhibitor added to metformin, reported José Luchsinger, MD, MPH, of Columbia University Irving Medical Center in New York City, and co-authors in JAMA Internal Medicine.
The primary cognitive outcome was the Digit Symbol Substitution Test (DSST) score. Secondary cognitive outcomes were immediate and delayed recall in the Spanish English Verbal Learning Test and letter and category fluency test scores. Higher scores on all tests indicate higher cognitive function.
While there were no differences between treatment groups in cognitive outcomes at 4 years, a 1-unit increase in time-weighted HbA1c levels was associated with modestly lower DSST 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).
"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 type 2 diabetes," Luchsinger and colleagues wrote. "Worse glycemic control is associated with modestly worse cognitive performance."
These findings provide important data for clinicians, especially in light of recent enthusiasm about GLP-1 receptor agonists to help prevent dementia, noted JAMA Internal Medicine editors Timothy Anderson, MD, MAS, of the University of Pittsburgh, and Deborah Grady, MD, MPH, of the University of California San Francisco.
An emulation target trial reported a decreased risk of Alzheimer's disease diagnoses for type 2 diabetes patients who used semaglutide (Ozempic), and observational data from the Veterans Affairs showed a lower dementia risk for diabetes patients using GLP-1 receptor agonists. Two newer studies also supported relationships between GLP-1 receptor agonist use and reduced dementia risk.
"However, these studies are susceptible to unmeasured confounding, a limitation shared by most pharmacoepidemiologic study designs, even when modern approaches, such as target trial emulation, are used," Anderson and Grady wrote in an editor's note.
"Claims-based data may accurately capture certain diagnoses, such as cancer and diabetes, but evidence from prospectively collected clinical data, as provided by the GRADE trial, is paramount to accurately ascertain cognitive function outcomes," they added.
GRADE randomized 5,047 people with type 2 diabetes using metformin at baseline to add either a long-acting insulin (insulin glargine U-100; Lantus, Basaglar, Toujeo), the sulfonylurea glimepiride (Amaryl), the GLP-1 receptor agonist liraglutide (Victoza), or the DPP-4 inhibitor sitagliptin (Januvia). It assessed multiple endpoints and reported that insulin glargine and liraglutide were best for glycemic control.
The mean duration of type 2 diabetes at baseline was 4.3 years and the mean age was 57.1 years. Most participants (62.3%) were male.
The GRADE cognition analysis included 3,721 participants with cognitive assessments at baseline and year 4. There were no significant baseline differences in cognitive scores, demographic characteristics, or clinical characteristics between groups.
The study had several limitations, Luchsinger and co-authors acknowledged. "The association of glycemic control with cognition demonstrated in this article was the result of an observational analysis," they pointed out. "Thus, we must be careful in making inferences about causality."
The association of time-weighted HbA1c levels became apparent only when analyses were adjusted for age -- likely because age is the strongest predictor of cognitive performance. GRADE excluded people with poor glycemic control (HbA1c level above 8.5%) and had enhanced treatment adherence due to the nature of the trial, which may limit generalizability. The researchers also could not evaluate the effects of treatments independent of metformin.
"Future and ongoing clinical trials may provide insights into whether GLP-1s may be useful in reducing the risk of dementia, whether through a unique medication class effect or their impact on blood glucose and blood pressure," Anderson and Grady noted, but for the time being, the GRADE findings "provide the best evidence available that diabetes medication class selection should not be driven by concerns about lowering dementia risk."
The ongoing phase III EVOKE and EVOKE Plus studies are investigating the disease-modifying potential of semaglutide in people with early-stage symptomatic Alzheimer's disease. The EVOKE trials, which are expected to be completed this year, also will assess the effects of semaglutide on Alzheimer's biomarkers and neuroinflammation.
Disclosures
The GRADE study was supported by a grant from the NIH/NIDDK.
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. Co-authors reported relationships with pharmaceutical companies and other entities.
Anderson and Grady are JAMA Internal Medicine editors. They reported no disclosures.
Primary Source
JAMA Internal Medicine
Source Reference: Luchsinger JA, et al "Glucose-lowering medications, glycemia, and cognitive outcomes: the GRADE randomized clinical trial" JAMA Intern Med 2025; DOI: 10.1001/jamainternmed.2025.1189.
Secondary Source
JAMA Internal Medicine
Source Reference: Anderson TS, Grady D "Optimal data sources for studies of incident dementia" JAMA Intern Med 2025; DOI:10.1001/jamainternmed.2025.1199.
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