Interventions for Cognitive Impairment in Type 2 Diabetes Mellitus: An Umbrella Review of Pharmacological and Lifestyle Strategies, Mechanisms, and Clinical Implications
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Background
Type 2 diabetes mellitus (T2DM) is one of the fastest-growing epidemics associated with cognitive impairment and dementia. This reduces quality of life among patients with diabetes. Several trials on the management of cognitive impairment have been done although their effectiveness and mechanisms are still unclear.
Aim
To synthesize evidence from systematic reviews and meta-analyses of RCTs examining interventions for cognitive impairment in T2DM, stratified by intervention category, comparator, patient characteristics, mechanisms and clinical outcomes.
Methods
We identified eleven systematic reviews (n = 213,604 participants) reporting effects of cognitive impairment interventions through comprehensive literature search. Using random effect models, a meta-meta-analysis was conducted and heterogeneity assessed using I² statistics. AMSTAR and GRADE were used to assess for quality of reviews. Subgroup analyses were conducted for intervention category, cognitive severity, age, diabetes duration, sex, and follow-up duration.
Result
Sodium glucose co-transporter inhibitors showed the strongest cognitive improvement effect (pooled OR = 0.44, 95% CI: 0.35–0.55; SUCRA = 94.5%), followed by GLP-1 receptor agonists (RR/OR = 0.60, 95% CI: 0.50–0.72; SUCRA = 92.1%). Among lifestyle interventions, multi-component exercise was the most effective (SMD = 0.69–1.04). The lower baseline cognition (MMSE < 23) benefited more from GLP-1 receptor agonists (Cohen’s d = -3.00, p < 0.001). Advanced age (≥60 years) and prolonged intervention time (≥24 weeks for medications; ≥6 months for exercise) were associated with greater effects. Female gender showed greater benefit from GLP-1 receptor agonists (HR = 0.63 vs 0.81 for male gender).
Conclusions
SGLT2 inhibitors and GLP-1 receptor agonists have the greatest effect on cognition in T2DM, and the multi-component exercise as the most effective lifestyle component. The review therefore recommends individualized intervention selection based on patient characteristics and baseline cognitive status. This calls for high quality trials with prolonged follow-up to strengthen the evidence base.
PROSPERO Registration
The trial was registered in PROSPERO under number CRD420261453178
