Cardioprotective Glucose-Lowering Agents and Dementia Risk: A Systematic Review and Meta-Analysis

Abstract

Importance: Although diabetes is a risk factor for dementia, the effect of glucose-lowering therapy for prevention of incident dementia is uncertain.

Objective: To determine whether cardioprotective glucose-lowering therapy (sodium-glucose cotransporter-2 inhibitors [SGLT2is], glucagon-like peptide-1 receptor agonists [GLP-1RAs], metformin, and pioglitazone), compared with controls, was associated with a reduction in risk of dementia or cognitive impairment, and among primary dementia subtypes.

Data sources: The PubMed and Embase databases were searched for studies published from inception of the database to July 11, 2024.

Study selection: Randomized clinical trials comparing cardioprotective glucose-lowering therapy with controls that reported dementia or change in cognitive scores. Cardioprotective glucose-lowering therapies were defined as drug classes recommended by guidelines for reduction of cardiovascular events, based on evidence from phase III randomized clinical trials. Inclusion criteria were assessed independently and inconsistencies were resolved by consensus.

Data extraction and synthesis: Data were screened and extracted independently by 2 authors adhering to the PRISMA guidelines in August 2024. Random-effects meta-analysis models were used to estimate a pooled treatment effect.

Main outcomes and measures: The primary outcome measure was dementia or cognitive impairment. The secondary outcomes were primary dementia subtypes, including vascular and Alzheimer dementia, and change in cognitive scores.

Results: Twenty-six randomized clinical trials were eligible for inclusion (N = 164 531 participants), of which 23 trials (n = 160 191 participants) reported the incidence of dementia or cognitive impairment, including 12 trials evaluating SGLT2is, 10 trials evaluating GLP-1RAs, and 1 trial evaluating pioglitazone (no trials of metformin were identified). The mean (SD) age of trial participants was 64.4 (3.5) years and 57 470 (34.9%) were women. Overall, cardioprotective glucose-lowering therapy was not significantly associated with a reduction in cognitive impairment or dementia (odds ratio [OR], 0.83 [95% CI, 0.60-1.14]). Among drug classes, GLP-1RAs were associated with a statistically significant reduction in dementia (OR, 0.55 [95% CI, 0.35-0.86]), but not SGLT2is (OR, 1.20 [95% CI, 0.67-2.17]; P value for heterogeneity = .04).

Conclusions and relevance: While cardioprotective glucose-lowering therapies were not associated with an overall reduction in all-cause dementia, this meta-analysis of randomized clinical trials found that glucose lowering with GLP-1RAs was associated with a statistically significant reduction in all-cause dementia.

Figure 1.. Association of Glucose-Lowering Therapy With All-Cause Dementia

Squares and bars represent the mean values and 95% CIs of the effect sizes, while the size of the squares reflects the weight of the study. Diamonds represent the combined effects and the vertical dotted lines, the lines of no effect. Arrows indicate that the values are outside the range of the x-axis. All-cause dementia events extracted from the Nørgaard et al meta-analysis (Table). ARR indicates absolute risk reduction; RE, random effects.

Figure 2.. Association of Glucose-Lowering Therapy With Vascular Dementia

Squares and bars represent the mean values and 95% CIs of the effect sizes, while the size of the squares reflects the weight of the study. Arrows indicate that the values are outside the range of the x-axis. Diamonds represent the combined effects and the vertical dotted lines, the lines of no effect. ARR indicates absolute risk reduction; RE, random effects.

Figure 3.. Association of Glucose-Lowering Therapy With Alzheimer Dementia

Squares and bars represent the mean values and 95% CIs of the effect sizes, while the size of the squares reflects the weight of the study. Arrows indicate that the values are outside the range of the x-axis. Diamonds represent the combined effects and the vertical dotted lines, the lines of no effect. ARR indicates absolute risk reduction; RE, random effects.