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Background: Chronic brain dyscirculation is one of the frequent type 2 diabetes mellitus (DM) complications and leads to patients' disability. Sodium-glucose co-transporter type 2 inhibitors (SGLT-2i) have been proven to have advantages for cardiovascular system, but their effect on the central nervous system (CNS) has not been studied enough., Aim: To study empagliflozin effect on CNS damage functional and laboratory parameters in patients with type 2 DM and, under experimental conditions, to investigate the mechanisms of the drug neurotropic effect., Materials and Methods: The clinical part of the study included patients with type 2 DM on metformin monotherapy (n=39). Patients with a target glycated hemoglobin level formed the "MET" group (n=19), in patients with a non-target glycated hemoglobin level empagliflozin was co-administered for the following 6 months (the "MET+EMPA" group, n=20). Healthy volunteers comprised the control group (n=16). The cognitive status and neuron-specific enolase (NSE) and neurofilament light chains (NLC) concentration were studied. DM was modeled in rats, thereafter the rats were treated with empagliflozin for 8 weeks. Microglia activation was assessed using anti-Iba-1 antibodies and morphological changes in neurons when stained by the Nissl method., Results: Both in the "MET+EMPA" and the "MET" groups cognitive deficits were observed, according to the Montreal Cognitive Assessment (MOCA) (24.0 (23.0; 27.0) and 25.0 (21.0; 27.0) points) and the Mini-Mental State Examination (MMSE) (23.75 (23.0; 27.0) and 25.0 (21.0; 27.0) points). Empagliflozin therapy led to the cognitive status normalization after 6 months (26.5 (24.0; 27.0) points according to the MOCA scale and 27.5 (24.0; 28.0) points according to the MMSE). Initially, all patients had a significant increase of NSE (3.60 (2.66; 3.76) ng/ml in the "MET" group, 3.22 (2.94; 3.54) ng/ml in the "MET+EMPA» group, 2.72 (2.13; 2.72) ng/ml in the «Control» group) and NLC (4.50 (3.31; 5.56) ng/ml in the «MET» group, 5, 25 (3.75; 6.25) ng/ml in the «MET+EMPA» group comparing with 3.50 (2.25; 3.50) ng/ml in the «Control» group). Empagliflozin therapy led to a significant decrease in NLC already after 3 months (3.80 (3.25; 3.87) ng/ml), without significant influence on the NSE level. In the experiment, DM was characterized by an increased number of activated microgliocytes and destructured neurons and a decreased number of neurons with a normal structure. Empagliflozin therapy was accompanied by a decrease in the number of immunopositive microgliocytes in the CA1 zone of the hippocampus and an increase in the number of structured neurons., Conclusion: Type 2 diabetes mellitus is characterized by functional and biochemical changes in the central nervous system even under satisfactory glycemic control. Therapy with empagliflozin has a neuroprotective effect, manifested in an improvement in cognitive status and a decrease in NLC level. Empagliflozin reduces neuronal damage and abnormal microglial activation.

Aim: To evaluate the safety and efficacy of insulin Aspart-Mix biosimilar candidate GP40081 (GP-Asp30) compared with NovoMix ® 30 (NN-Asp30). Materials & methods: In a randomized open-label, active-controlled, 26-week non-inferiority clinical trial 264 patients with Type 2 diabetes mellitus were randomized 1:1 to receive once-daily GP-Asp30 or NN-Asp30. The primary safety end point was the immune response rate. Efficacy outcomes were a mean change in HbA1c (primary), frequency of achieving a glycemic g fasting plasma glucose levels, 7-point glucose profiles, and insulin doses. Results: The immune response developed in 10/126 (8%) participants in the GP-Asp30 group and in 10/125 (8%) participants in the NN-Asp30 group (p = 1.000). The mean difference in HbA1c change between groups was 0.12 (95%CI [-0.14, 0.38]). Other secondary efficacy and safety outcomes weren't statistically different between the two groups. Conclusion: GP-Asp30 demonstrated similar safety and efficacy compared with NN-Asp30 and may be considered a biosimilar insulin.

Aim: To compare safety and efficacy of GP40071 insulin aspart (GP-Asp) and NovoRapid ® (NN-Asp). Materials & methods: This randomized open-label, active-controlled, 26-week non-inferiority Phase III clinical trial enrolled 264 Type 1 diabetes mellitus patients (HbA1c: 7.1-12.0%) randomized 1:1 to once daily GP-Asp (n = 132) or NN-Asp (n = 132). The primary safety end point was immune response at week 26. Results: The groups were similar in frequency of immune response (p = 0.323) and in other safety end points. Mean HbA1c change from baseline was -0.57% for GP-Asp and -0.56% for NN-Asp and did not differ between groups (p = 0.955). Intergroup mean difference of HbA1c level change (95% CI) at week 26 from baseline was 0.00 (-0.26, 0.25) %. Insulin doses, fasting plasma glucose levels and seven-point glucose profiles were similar between groups (p > 0.05). The number of patients experiencing hypoglycemic episodes did not differ between the groups (p = 0.497). Conclusion: GP-Asp demonstrated similar safety and efficacy. Trial registration number: NCT04079413 (ClinicalTrials.gov).