Cognitive Dysfunction, Type 2 Diabetes Mellitus (T2DM)
Conditions
Keywords
Type 2 Diabetes Mellitus, SGLT2 inhibitors, cognitive decline, mild cognitive impairment, Executive Function, Glycemic Variability, Neurodegeneration, Diabetes-Related Cognitive Dysfunction
Brief summary
This study is a prospective, randomized, open-label trial with blinded outcome assessment (PROBE design) designed to evaluate the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitor therapy on cognitive function in adults with type 2 diabetes mellitus (T2D). A total of 200 participants aged 50 years or older with T2D of at least five years' duration and HbA1c ≤8.5% will be randomized in a 1:1 ratio to receive either standard diabetes care plus an SGLT2 inhibitor or standard diabetes care without an SGLT2 inhibitor. Participants will be followed for 12 months. The primary objective is to compare changes in executive cognitive function between the two treatment groups using a composite cognitive outcome derived from standardized neuropsychological tests. Secondary objectives include assessment of global cognitive function, glycaemic variability measured by continuous glucose monitoring, metabolic control, circulating biomarkers of neurodegeneration and inflammation, functional status, and treatment safety. Baseline brain magnetic resonance imaging (MRI), APOE genotyping, frailty status, sleep quality, psychological well-being, and physical activity will be evaluated as potential modifiers of cognitive outcomes and treatment response. The study is intended to provide prospective evidence regarding the association between SGLT2 inhibitor therapy and cognitive outcomes in adults with T2D while exploring the metabolic, neurodegenerative, and behavioural factors that may contribute to cognitive changes over time.
Detailed description
Detailed Description Type 2 diabetes mellitus (T2D) is associated with an increased risk of cognitive impairment, particularly affecting executive function and processing speed. Multiple mechanisms, including chronic hyperglycaemia, glycaemic variability, vascular dysfunction, systemic inflammation, oxidative stress, and neurodegenerative processes, are thought to contribute to cognitive decline in individuals with T2D. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated cardiovascular and renal benefits and may also exert neuroprotective effects through improvements in metabolic control and modulation of inflammatory and vascular pathways. However, prospective randomized evidence regarding their effects on cognition remains limited. The SaveMinD study is a prospective, randomized, open-label trial with blinded outcome assessment (PROBE design) evaluating whether the addition of an SGLT2 inhibitor to standard diabetes care influences cognitive outcomes in adults with T2D over 12 months. The primary endpoint is change in executive cognitive function, assessed using a composite score derived from standardized neuropsychological tests. Secondary outcomes include global cognitive function, glycaemic control and variability, circulating biomarkers of neurodegeneration and inflammation, physical activity, functional status, sleep quality, psychological well-being, and safety. The study also incorporates baseline structural brain magnetic resonance imaging (MRI), APOE genotyping, frailty assessment, continuous glucose monitoring, and objective physical activity monitoring to explore biological and behavioural factors associated with cognitive change. These assessments will be used to investigate potential mechanisms underlying cognitive decline and to identify factors that may modify the response to SGLT2 inhibitor therapy. The findings are expected to improve understanding of the relationship between metabolic health and cognitive function in T2D and may contribute to the development of strategies for the prevention of diabetes-associated cognitive decline.
Interventions
DRUGSGLT2 Inhibitor
Participants randomized to the intervention group will receive empagliflozin (10 mg once daily, with optional titration to 25 mg according to clinical judgement and tolerability) or dapagliflozin (10 mg once daily) in addition to standard diabetes care. The choice of SGLT2 inhibitor will be made by the treating investigator according to routine clinical practice.
Individualized diabetes management according to current national and international clinical practice guidelines, including lifestyle counselling and glucose-lowering therapy as clinically indicated. Both study groups will receive standard diabetes care throughout the study.
Sponsors
University of Primorska
University of Ljubljana, Faculty of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
The study follows a Prospective Randomized Open-label Blinded Endpoint (PROBE) design. Owing to the nature of the intervention, participants and treating physicians will not be blinded to treatment allocation. However, investigators performing cognitive assessments, data management, and statistical analyses will remain blinded throughout the study. Laboratory personnel responsible for biomarker analyses will also be blinded to treatment allocation.
Intervention model description
Participants will be randomized in a 1:1 ratio to receive either standard diabetes care plus an SGLT2 inhibitor or standard diabetes care without initiation of an SGLT2 inhibitor. Randomization will be centrally performed using a computer-generated allocation sequence and stratified by age and educational attainment to minimize potential confounding related to cognitive performance. Participants will be followed prospectively for 12 months.
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* adults aged 50 years or older. * diagnosis of type 2 diabetes mellitus according to current American Diabetes - - association (ADA) diagnostic criteria. * duration of type 2 diabetes mellitus of at least 5 years. * glycated haemoglobin (HbA1c) ≤8.5% (≤69 mmol/mol) at screening. * estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m². * stable glucose-lowering therapy for at least 3 months before enrolment. * able to complete neuropsychological assessments and all study procedures. * willing and able to wear a continuous glucose monitoring (CGM) sensor and a physical activity monitor. * able to provide written informed consent.
Exclusion criteria
* previous or current treatment with a sodium-glucose cotransporter-2 (SGLT2) inhibitor. * Montreal Cognitive Assessment (MoCA) score \<20 at screening. * diagnosis of dementia or another major neurocognitive disorder. * history of stroke or transient ischaemic attack within the previous 6 months. * Parkinson's disease, multiple sclerosis, epilepsy, or another major neurological disorder affecting cognitive function. * severe psychiatric illness likely to interfere with study participation or cognitive assessment. * estimated glomerular filtration rate (eGFR) \<45 mL/min/1.73 m². * history of diabetic ketoacidosis. * recurrent urinary tract infections (≥3 episodes during the previous year). * contraindication to magnetic resonance imaging (MRI). * pregnancy, breastfeeding, or planned pregnancy during the study period. * active malignancy requiring systemic treatment (except adequately treated non-melanoma skin cancer). * moderate or severe hepatic impairment (Child-Pugh Class B or C). * alcohol or substance abuse likely to interfere with study participation. * presence of an established indication for mandatory SGLT2 inhibitor therapy according to current international clinical practice guidelines (e.g., symptomatic heart failure or chronic kidney disease). * participation in another interventional clinical trial within the previous 30 days. * any medical condition that, in the opinion of the investigator, could compromise participant safety, adherence to the protocol, or interpretation of study results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Executive Cognitive Composite Score | Baseline to 12 months | The primary outcome is the between-group difference in change from baseline to Month 12 in the Executive Cognitive Composite Score. The Executive Cognitive Composite Score is a standardized composite measure of executive function and processing speed calculated by averaging z-scores from the Digit Symbol Substitution Test, Trail Making Test Part A and Part B (using the Part B minus Part A completion time), the Digit Span Backward Test, and Verbal Fluency Tests (letter fluency and semantic/category fluency). The composite score is expressed as a standardized z-score and therefore has no fixed theoretical minimum or maximum value. Higher scores indicate better executive cognitive performance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Montreal Cognitive Assessment (MoCA) Score | Baseline to 12 months | Change in global cognitive function will be assessed using the Montreal Cognitive Assessment (MoCA). The MoCA total score ranges from 0 to 30, with higher scores indicating better cognitive performance. |
| Change in Glycaemic Variability Assessed by Continuous Glucose Monitoring | Baseline, 6 months, and 12 months | Percentage coefficient of variation of interstitial glucose measured by continuous glucose monitoring. Range: 0% to 100%; lower values indicate lower glycemic variability (better outcome). |
| Change in HbA1c | Baseline, 6 months, and 12 months | Glycated haemoglobin (HbA1c) will be measured in a certified clinical laboratory and reported as percentage (%) according to the National Glycohemoglobin Standardization Program (NGSP). Lower HbA1c values indicate better long-term glycaemic control. |
| Change in High-Sensitivity C-Reactive Protein (hsCRP) | Baseline to 12 months | Serum high-sensitivity C-reactive protein (hsCRP) concentration measured in mg/L. Lower concentrations indicate lower systemic inflammation. |
| Change in Neurofilament Light Chain (NfL) | Baseline to 12 months | Serum neurofilament light chain (NfL) concentration will be measured in pg/mL. Lower concentrations indicate less neuroaxonal injury. |
| Change in Moderate-to-Vigorous Physical Activity | Baseline, 6 months, and 12 months | Moderate-to-vigorous physical activity will be measured using a 14-day accelerometer and expressed as average minutes per day. Higher values indicate greater physical activity. |
| Incidence of Adverse Events and Serious Adverse Events | From baseline to 12 months | The number of participants experiencing adverse events (AEs) and serious adverse events (SAEs), including urinary tract infections, genital infections, symptoms suggestive of diabetic ketoacidosis, deterioration in renal function, treatment discontinuation due to adverse events, and other clinically relevant safety events. |
| Change in Sleep Quality | Baseline, 6 months, and 12 months | Sleep quality will be assessed using the Pittsburgh Sleep Quality Index (PSQI). Total scores range from 0 to 21, with higher scores indicating poorer sleep quality. |
| Change in Anxiety and Depression Symptoms | Baseline, 6 months, and 12 months | Symptoms of anxiety and depression will be assessed using the Hospital Anxiety and Depression Scale (HADS). Anxiety and depression subscale scores each range from 0 to 21, with higher scores indicating greater symptom severity. |
| Change in Perceived Stress | Baseline, 6 months, and 12 months | Perceived stress will be assessed using the Perceived Stress Scale-10 (PSS-10). Total scores range from 0 to 40, with higher scores indicating greater perceived stress. |
| Change in Interleukin-6 (IL-6) | Baseline and Month 12 | Serum interleukin-6 (IL-6) concentration measured in pg/mL. Lower concentrations indicate lower systemic inflammation. |
| Change in Tumour Necrosis Factor-Alpha (TNF-α) | Baseline and Month 12 | Serum tumour necrosis factor-alpha (TNF-α) concentration measured in pg/mL. Lower concentrations indicate lower systemic inflammation. |
| Change from Baseline to Month 12 in Time in Range (3.9-10.0 mmol/L) | Baseline, 6 months, 12 months. | Time in Range (TIR) measured using a 14-day continuous glucose monitoring system, defined as the percentage of time during which interstitial glucose concentrations are between 3.9 and 10.0 mmol/L. Values range from 0% to 100%, with higher percentages indicating better glycaemic control. |
| Change from Baseline to Month 12 in Time Below Range (<3.9 mmol/L) | Baseline, 6 months, 12 months | Time Below Range (TBR) measured using a 14-day continuous glucose monitoring system, defined as the percentage of time during which interstitial glucose concentrations are below 3.9 mmol/L. Values range from 0% to 100%, with lower percentages indicating fewer hypoglycaemic events. |
| Change in Glial Fibrillary Acidic Protein (GFAP) | Baseline to 12 month | Serum glial fibrillary acidic protein (GFAP) concentration will be measured in pg/mL. Lower concentrations indicate lower astroglial activation. |
| Change in Phosphorylated Tau217 (p-tau217) | Baseline and Month 12 | Serum phosphorylated tau217 (p-tau217) concentration will be measured in pg/mL. Lower concentrations indicate less Alzheimer's disease-related tau pathology. |
| Change in Amyloid-beta42 (Aβ42) | Baseline and month 12 | Serum amyloid-beta42 (Aβ42) concentration will be measured in pg/mL. Higher concentrations are generally considered indicative of less Alzheimer's disease-related amyloid pathology. |
Countries
Slovenia
Outcome results
None listed