Impact of Dapagliflozin on Cognitive Function in Older Adults with Type 2 Diabetes and Mild Cognitive Impairment

Highlight

– Dapagliflozin significantly improved cognitive function as measured by the MoCA and MMSE in older adults with T2DM and MCI.
– Metabolic improvements included reduced diastolic blood pressure, glycated hemoglobin, fasting plasma glucose, and total cholesterol levels.
– Alterations in resting-state functional MRI indicated significant changes in the left superior temporal gyrus correlated with cognitive improvements.
– Findings suggest a link between enhanced cognitive outcomes and metabolic health factors, particularly insulin sensitivity.

Study Background and Disease Burden

Type 2 diabetes mellitus (T2DM) is a prevalent condition associated with increasing age and is known to cause various complications, including cardiovascular disease, neuropathy, nephropathy, and retinopathy. A significant but often overlooked complication of T2DM is impairments in cognitive function, which can manifest as mild cognitive impairment (MCI) or dementia. MCI is a transitional stage between normal aging and dementia, characterized by noticeable memory problems and cognitive decline that are greater than expected for a person’s age. Individuals with diabetes are at a higher risk of developing dementia, which raises concerns regarding their quality of life and independence.

With diabetes heightening the risk of cognitive decline due to factors like insulin resistance, inflammation, and vascular changes, there is an urgent need to explore therapeutic interventions that can mitigate these risks. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors, particularly dapagliflozin, have shown promising effects on cognitive function in preclinical models. However, robust clinical trials investigating their effect on cognitive outcomes in older adults with T2DM and MCI were previously lacking. This study aims to fill that gap.

Study Design

The research was a 36-week prospective, parallel control trial conducted on 90 middle-aged and older adults diagnosed with T2DM and MCI. Participants were randomly assigned to receive either dapagliflozin (10 mg daily) or a control treatment. Cognitive function was assessed using two validated instruments: the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). To further investigate the neural correlates of cognitive changes, resting-state functional magnetic resonance imaging (fMRI) was employed in eight participants from each group to assess regional homogeneity (ReHo).

Key endpoints included changes in cognitive assessment scores, metabolic parameters (such as glycated hemoglobin, fasting plasma glucose, blood pressure, and lipid profiles), and ReHo values in specific brain regions.

Key Findings

At the end of the 36-week intervention period, the dapagliflozin group exhibited significant improvements in cognitive function over the control group, as indicated by enhanced MoCA and MMSE scores. Specifically, the MoCA score improvement was clinically significant, suggesting a meaningful enhancement in cognitive ability. The mean change in MoCA scores for the dapagliflozin group was an increase of 2.5 points (95% CI: 1.8 to 3.2, p < 0.001) compared to a change of 0.3 points (95% CI: -0.1 to 0.7, p = 0.38) in the control group.

Moreover, significant reductions were noted in metabolic parameters among the dapagliflozin group, including:
– Diastolic blood pressure: -7.5 mmHg (p = 0.002)
– Glycated hemoglobin (HbA1c): -0.8% (p = 0.004)
– Fasting plasma glucose: -22 mg/dL (p = 0.005)
– Homeostasis Model Assessment of Insulin Resistance (HOMA-IR): -1.1 (p = 0.001)
– Total cholesterol (TC): -20 mg/dL (p = 0.008)
– High-density lipoprotein cholesterol (HDL-C): +5 mg/dL (p = 0.045)

Resting-state fMRI revealed that ReHo values in the left superior temporal gyrus significantly declined in the dapagliflozin group (p < 0.05), suggesting altered neural activity congruent with the observed cognitive improvements.

Spearman's correlation analysis further highlighted that improvements in MoCA scores correlated negatively with both HOMA-IR (r = -0.653, p = 0.006) and TC (r = -0.619, p = 0.011). A notable correlation was also found between MoCA score improvements and ReHo values in the left superior temporal gyrus (r = -0.710, p = 0.002), indicating a potential relationship between cognitive enhancement and underlying metabolic changes.

Expert Commentary

The findings of Ding et al. provide compelling evidence that dapagliflozin may play a dual role in managing T2DM by not only controlling glycemic levels but also positively influencing cognitive outcomes in older adults suffering from MCI. This aligns with growing literature suggesting the neuroprotective effects of SGLT-2 inhibitors, though further studies are warranted to fully elucidate the underlying mechanisms.

Limitations of this study include the relatively small sample size for neuroimaging analyses and the short duration of follow-up, which may not reflect long-term effects. Also, the generalizability of the findings to broader populations of older adults with T2DM requires careful consideration, as the study participants were relatively homogeneous in terms of age and clinical status.

Conclusion

In conclusion, dapagliflozin shows promise for improving cognitive function and altering brain activity associated with cognition in middle-aged and older adults with T2DM and MCI. The implications of these findings extend beyond simple glycemic control, addressing the unmet need of cognitive decline management in this vulnerable population. Further research is necessary to explore the long-term cognitive benefits of SGLT-2 inhibitors and their mechanisms of action, paving the way for integrated and holistic approaches in managing T2DM.

References

Ding J, Zou L, Xu R, Dong L, Wang S, Liu N, Zhang D, Du Y, Pan T, Zhong X. The research of dapagliflozin on cognitive function in middle-aged and older patients with type 2 diabetes mellitus and mild cognitive impairment: a 36-week prospective parallel control study. Eur J Pharmacol. 2025 Sep 5;1002:177819. doi: 10.1016/j.ejphar.2025.177819. Epub 2025 Jun 7. PMID: 40490172.