Interventions for Cognitive Impairment in Type 2 Diabetes Mellitus: An Umbrella Review of Pharmacological and Lifestyle Strategies, Mechanisms, and Clinical Implications
- 1Kabale University School of Medicine
Abstract
O_ST_ABSBackgroundC_ST_ABSType 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.
AimTo 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.
MethodsWe 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 I{superscript 2} 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.
ResultSodium 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 (Cohens 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).
ConclusionsSGLT2 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 RegistrationThe trial was registered in PROSPERO under number CRD420261453178
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BibTeX
@misc{ninsiima2026interventions,
title = {{Interventions for Cognitive Impairment in Type 2 Diabetes Mellitus: An Umbrella Review of Pharmacological and Lifestyle Strategies, Mechanisms, and Clinical Implications}},
author = {H. I. Ninsiima and E. E. Daniel and N. I. Kisakye and I. Mandera and H. E. Ainamani and M. Akambasisa and G. Ayebazibwe and D. Matovu},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.23.26366288},
url = {https://www.medrxiv.org/content/10.64898/2026.10.23.26366288v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Interventions for Cognitive Impairment in Type 2 Diabetes Mellitus: An Umbrella Review of Pharmacological and Lifestyle Strategies, Mechanisms, and Clinical Implications
AU - H. I. Ninsiima
AU - E. E. Daniel
AU - N. I. Kisakye
AU - I. Mandera
AU - H. E. Ainamani
AU - M. Akambasisa
AU - G. Ayebazibwe
AU - D. Matovu
PY - 2026
DA - 2026/10/23
PB - medRxiv
DO - 10.64898/2026.10.23.26366288
UR - https://www.medrxiv.org/content/10.64898/2026.10.23.26366288v1
AB - O_ST_ABSBackgroundC_ST_ABSType 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. AimTo 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. MethodsWe 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 I{superscript 2} 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. ResultSodium 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 (Cohens 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). ConclusionsSGLT2 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 RegistrationThe trial was registered in PROSPERO under number CRD420261453178
ER -