A total of 41 observational studies involving 3,307,483 participants indicate that certain anti-diabetic medications are linked to a reduced risk of dementia in patients with type 2 diabetes.
Sodium glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) are associated with a significantly lower risk of dementia, with odds ratios of 0.56 and 0.58, respectively.
Thiazolidinediones () and metformin also show a reduced risk of dementia, with odds ratios of 0.68 and 0.89, respectively.
SGLT-2i and GLP-1RA are associated with a decreased risk of Alzheimer's disease, while SGLT-2i and TZD are linked to a lower risk of vascular dementia.
In a network meta-analysis of randomized controlled trials, the risks of dementia among different anti-diabetic agents and placebo appear comparable.
The ranking of cognitive benefits suggests that SGLT-2i and GLP-1RA may be the most effective options for improving cognitive outcomes in patients with type 2 diabetes.
Simplified
OBJECTIVE: To evaluate the association between anti-diabetic agents and the risks of dementia in patients with type 2 diabetes (T2D).
METHODS: Literature retrieval was conducted in PubMed, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrial.gov between January 1995 and October 2024. Observational studies and randomized controlled trials (RCTs) in patients with T2D, which intercompared anti-diabetic agents or compared them with placebo, and reported the incidence of dementia were included. Conventional and network meta-analyses of these studies were implemented. Results were exhibited as the odds ratio (OR) or risk ratio (RR) with 95% confidence interval (CI).
RESULTS: A total of 41 observational studies (3,307,483 participants) and 23 RCTs (155,443 participants) were included. In the network meta-analysis of observational studies, compared with non-users, sodium glucose cotransporter-2 inhibitor (SGLT-2i) (OR = 0.56, 95%CI, 0.45 to 0.69), glucagon-like peptide-1 receptor agonist (GLP-1RA) (OR = 0.58, 95%CI, 0.46 to 0.73), thiazolidinedione () (OR = 0.68, 95%CI, 0.57 to 0.81) and metformin (OR = 0.89, 95%CI, 0.80 to 0.99) treatments were all associated with reduced risk of dementia in patients with T2D. The surface under the cumulative ranking curve (SUCRA) evaluation conferred a rank order as SGLT-2i > GLP-1RA > TZD > dipeptidyl peptidase-4 inhibitor (DPP-4i) > metformin > α-glucosidase inhibitor (AGI) > glucokinase activator (GKA) > sulfonylureas > glinides > insulin in terms of the cognitive benefits. Meanwhile, compared with non-users, SGLT-2i (OR = 0.43, 95%CI, 0.30 to 0.62), GLP-1RA (OR = 0.54, 95%CI, 0.30 to 0.96) and DPP-4i (OR = 0.73, 95%CI, 0.57 to 0.93) were associated with a reduced risk of Alzheimer's disease while a lower risk of vascular dementia was observed in patients receiving SGLT-2i (OR = 0.42, 95%CI, 0.22 to 0.80) and TZD (OR = 0.52, 95%CI, 0.36 to 0.75) treatment. In the network meta-analysis of RCTs, the risks of dementia were comparable among anti-diabetic agents and placebo.
CONCLUSION: Compared with non-users, SGLT-2i, GLP-1RA, TZD and metformin were associated with the reduced risk of dementia in patients with T2D. SGLT-2i, and GLP-1RA may serve as the optimal choice to improve the cognitive prognosis in patients with T2D.
Key numbers
0.56
Odds Ratio
Compared with of anti-diabetic agents.
0.58
Odds Ratio
Compared with of anti-diabetic agents.
0.68
Odds Ratio
Compared with of anti-diabetic agents.
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Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: For financial competing interests, LJ has received fees for lecture presentations and for consulting from AstraZeneca, Merck, Metabasis, MSD, Novartis, Eli Lilly, Roche, Sanofi-Aventis and Takeda; when LJ has no non-financial competing interests to disclose. There are no financial or non-financial conflicts of interests to reveal in any other co-authors. No other support from any organization for the submitted work other than that described above.
