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| Name | Class |
|---|---|
| University of Ljubljana, Faculty of Medicine | OTHER |
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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
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Standard Diabetes Care + SGLT2 Inhibitor | Experimental | Participants randomized to the intervention group will receive guideline-directed standard diabetes care plus treatment with an SGLT2 inhibitor (empagliflozin or dapagliflozin) according to routine clinical practice. Participants will be followed for 12 months. |
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| Standard Diabetes Care | Active Comparator | Participants randomized to the comparator group will receive guideline-directed standard diabetes care without initiation of SGLT2 inhibitor therapy during the study period. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| SGLT2 Inhibitor | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Executive Cognitive Composite Score | 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. | Baseline to 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Montreal Cognitive Assessment (MoCA) Score | 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. | Baseline to 12 months |
| Change in Glycaemic Variability Assessed by Continuous Glucose Monitoring |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Health Center | Koper | 6000 | Slovenia |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39197881 | Background | Shin A, Koo BK, Lee JY, Kang EH. Risk of dementia after initiation of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors in adults aged 40-69 years with type 2 diabetes: population based cohort study. BMJ. 2024 Aug 28;386:e079475. doi: 10.1136/bmj-2024-079475. |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D060825 | Cognitive Dysfunction |
| D009410 | Nerve Degeneration |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D000077203 | Sodium-Glucose Transporter 2 Inhibitors |
| C570240 | empagliflozin |
| C529054 | dapagliflozin |
| ID | Term |
|---|---|
| D045504 | Molecular Mechanisms of Pharmacological Action |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D007004 | Hypoglycemic Agents |
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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.
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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.
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| Standard Diabetes Care | Other | 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. |
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Percentage coefficient of variation of interstitial glucose measured by continuous glucose monitoring. Range: 0% to 100%; lower values indicate lower glycemic variability (better outcome). |
| Baseline, 6 months, and 12 months |
| Change in HbA1c | 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. | Baseline, 6 months, and 12 months |
| Change in High-Sensitivity C-Reactive Protein (hsCRP) | Serum high-sensitivity C-reactive protein (hsCRP) concentration measured in mg/L. Lower concentrations indicate lower systemic inflammation. | Baseline to 12 months |
| Change in Neurofilament Light Chain (NfL) | Serum neurofilament light chain (NfL) concentration will be measured in pg/mL. Lower concentrations indicate less neuroaxonal injury. | Baseline to 12 months |
| Change in Moderate-to-Vigorous Physical Activity | 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. | Baseline, 6 months, and 12 months |
| Incidence of Adverse Events and Serious Adverse Events | 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. | From baseline to 12 months |
| Change in Sleep Quality | 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. | Baseline, 6 months, and 12 months |
| Change in Anxiety and Depression Symptoms | 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. | Baseline, 6 months, and 12 months |
| Change in Perceived Stress | 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. | Baseline, 6 months, and 12 months |
| Change in Interleukin-6 (IL-6) | Serum interleukin-6 (IL-6) concentration measured in pg/mL. Lower concentrations indicate lower systemic inflammation. | Baseline and Month 12 |
| Change in Tumour Necrosis Factor-Alpha (TNF-α) | Serum tumour necrosis factor-alpha (TNF-α) concentration measured in pg/mL. Lower concentrations indicate lower systemic inflammation. | Baseline and Month 12 |
| Change from Baseline to Month 12 in Time in Range (3.9-10.0 mmol/L) | 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. | Baseline, 6 months, 12 months. |
| Change from Baseline to Month 12 in Time Below Range (<3.9 mmol/L) | 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. | Baseline, 6 months, 12 months |
| Change in Glial Fibrillary Acidic Protein (GFAP) | Serum glial fibrillary acidic protein (GFAP) concentration will be measured in pg/mL. Lower concentrations indicate lower astroglial activation. | Baseline to 12 month |
| Change in Phosphorylated Tau217 (p-tau217) | Serum phosphorylated tau217 (p-tau217) concentration will be measured in pg/mL. Lower concentrations indicate less Alzheimer's disease-related tau pathology. | Baseline and Month 12 |
| Change in Amyloid-beta42 (Aβ42) | 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. | Baseline and month 12 |
| D004700 | Endocrine System Diseases |
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D045505 | Physiological Effects of Drugs |