The Effect of SGLT2 Inhibitors on Cognitive Functions and BDNF Levels in Patients With Type 2 Diabetes

Cognitive impairment is a common complication in diabetes for various reasons. Although glycemic control improves cognitive impairment, different antidiabetic medications' effects on cognitive functions are still being investigated. Brain-derived neurotrophic factor (BDNF) is a neuroinflammatory marker and a member of the neurotrophin family with growth factor properties. BDNF levels have been shown to decrease in mild cognitive dysfunction or in late-onset Alzheimer's disease. Our aim is to examine the effect of SGLT2 inhibitor use on cognitive functions and BDNF levels.

Type 2 diabetes is a complex metabolic disorder that can cause serious damage to various organs. Impairment in cognitive functions is one of the common complications in patients with diabetes. Impairment in cognitive functions and significant dementia were found to be approximately 1.5 times more common in individuals with diabetes than individuals without diabetes. In particular, inadequate glycemic control, the frequency of hypoglycemia, vascular diseases, insulin resistance, inflammatory cytokines and oxidative stress stand out as possible causes. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family with growth factor properties. BDNF plays a critical role in cell differentiation, migration, and survivable synaptic plasticity of neurons. BDNF also has an important role in learning and memory processes through synapses in the hippocampus. BDNF levels have been shown to decrease in mild cognitive dysfunction or in late-onset Alzheimer's disease. In animal experiments, it has been observed that BDNF values increase with the use of metformin in Parkinson's disease. Similar results were obtained with vildagliptin, alogliptin, rosiglitazone, and exendin-4 in animal experiments.

The effects of drugs used in the treatment of diabetes on protecting or improving cognitive functions have been studied for a long time. Most of these studies are at the preclinical level. In previous studies with Glucagon-Like Peptide 1 (GLP-1) agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors, there are data that both glycemia and incretins improve cognitive functions with their effects on brain structure. Similar positive results are seen for thiazolidinediones. While hyperglycemia control leads to positive results in insulin and sulfonylurea group drugs, the frequency of hypoglycemia can have a negative effect. There is not enough data on SGLT2 inhibitors.

Studies with SGLT2 inhibitors have shown a decrease in HbA1c values, weight loss, and a decrease in both systolic and diastolic blood pressure. Encouraging results have been obtained with SGLT2 inhibitors in both cardiac and renal outcomes, with heart failure in the foreground. As a result of these data, they are recommended as drugs that should be used in the foreground following metformin, especially in diabetic patients with cardiac and renal diseases. Animal studies with empagliflozin and canagliflozin show that both agents reduce cognitive impairment.

Our aim is to examine the effect of SGLT2 inhibitor use on cognitive functions and BDNF, one of the neuroinflammatory markers.

Eligibility Criteria:
Inclusion Criteria:

* giving consent
* being 60 years old or older
* HbA1c concentrations between 6.5% and 8%
* using metformin as a single agent for at least 3 months
* diabetes age \<10 years

Exclusion Criteria:

* having uncontrolled hypothyroidism, hyperthyroidism, or other diseases that may affect cognitive functions
* ketoacidosis or coma
* cerebrovascular disease or psychiatric disorder
* mental retardation, psychosis, dementia, brain trauma, epilepsy and other cerebral diseases
* alcohol or other substance abuse
* hearing loss
* Presence of diseases that will affect cognitive function such as chronic inflammatory diseases and respiratory system diseases
* chronic kidney failure (GFR \<45)
* sleep apnea syndrome
* malignancy
* using a sulfonylurea or glinide