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Risk of Dementia in Patients With Type 2 Diabetes Using SGLT2 Inhibitors Versus DPP-4 Inhibitors: A Systematic Review

Kiran Kumari1, Anusha Bai2, Fnu Geeta2

  • 1Ziauddin Medical University, Karachi, Pakistan.

Endocrinology, Diabetes & Metabolism
|March 4, 2026
PubMed
Abstract

Insights

Sodium-glucose cotransporter-2 (SGLT2) inhibitors significantly lower dementia risk in type 2 diabetes mellitus patients compared to dipeptidyl peptidase-4 (DPP-4) inhibitors. This finding suggests potential neuroprotective benefits of SGLT2 inhibitors.

Area of Science:

  • Endocrinology
  • Neurology
  • Pharmacology

Background:

  • Type 2 diabetes mellitus (T2DM) is a known risk factor for dementia.
  • The cognitive impact of glucose-lowering therapies is not fully understood.
  • Sodium-glucose cotransporter-2 (SGLT2) inhibitors may offer neuroprotection over dipeptidyl peptidase-4 (DPP-4) inhibitors.

Purpose of the Study:

  • To compare the risk of incident dementia in T2DM patients initiating SGLT2 inhibitors versus DPP-4 inhibitors.
  • To investigate the association between SGLT2 inhibitors and dementia risk.
  • To evaluate the impact of glucose-lowering therapies on cognitive decline.

Main Methods:

  • Systematic literature search of PubMed, Scopus, and Cochrane Central Register through June 1, 2025.
  • Primary outcome: all-cause dementia; Secondary outcomes: Alzheimer's disease, vascular dementia.
  • Random-effects models used to pool adjusted hazard ratios (HRs); subgroup analyses conducted.

Main Results:

  • Nine retrospective cohort studies included 2,433,086 individuals.
  • SGLT2 inhibitors associated with significantly lower risk of all-cause dementia (HR=0.74), Alzheimer's (HR=0.62), and vascular dementia (HR=0.54) versus DPP-4 inhibitors.
  • Dapagliflozin and empagliflozin showed benefit; canagliflozin did not. Findings consistent across age and sex subgroups.

Conclusions:

  • SGLT2 inhibitors are linked to reduced dementia risk in T2DM patients compared to DPP-4 inhibitors.
  • Potential neuroprotective effects of SGLT2 inhibitors warrant further investigation.
  • Prospective trials are needed to confirm findings and elucidate mechanisms.

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