Clinical trial NCT03804411: Prognostic Predictors of Response to Hypoglycemic Therapy
Official title: Search for Highly Specific Predictors of Response to Different Hypoglycemic Therapy for Cardiovascular Prognosis
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Lead sponsor: Federal State Budgetary Institution, V. A. Almazov Federal North-West Medical Research Centre, of the Ministry of Health
Sponsor class: OTHER
First posted: 2019-01-15
Enrollment: 800
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: This is a randomized controlled trial aimed to determine highly specific personified predictors of response to the therapy by different groups of hypoglycemic drugs (SGLT-2 inhibitors, DPP-4 inhibitors, GLP-1 receptor agonists, sulfonylureas) in patients with type 2 diabetes mellitus, develop an algorithm of personalized therapy based on them, design an organizational and methodological model for prevention of the cardiovascular complications, and create an automated decision-making system for therapy selection to reduce the incidence of cardiovascular events and related adverse outcomes compared to the traditional approach. This is an interventional, randomized controlled trial, open-label study.

Detailed description: The study aims to determine highly specific personified predictors of response to the therapy by different groups of hypoglycemic drugs in patients with type 2 diabetes mellitus, to develop on their basis a mathematical model that allows to objectify the choice of therapy for each patient, and validate it in clinical practice with assessment of dynamic of cardiovascular risk markers (vascular wall condition, markers of fibrosis and inflammation, molecular-genetic markers of vascular damage, dynamic of intestinal microbiota, clinical outcomes, psychological parameters of quality of life, eating, treatment satisfaction) and pharmaco-economic component. Patients with type 2 diabetes mellitus and non-target HbA1c will be randomized to receive antidiabetic drugs (SGLT-2 inhibitors, DPP-4 inhibitors, GLP-1 receptor agonists, sulfonylureas) in open prospective study according to: 1) standard recommendations; 2) predictors chosen with automated decision-making system developed on the literature analysis. At baseline and 3, 6, 12, and 24 months into the study patients will be asked to complete the questionnaires on eating behavior, appetite, propensity to alcohol consumption, smoking, level of physical activity, general health condition, level of anxiety and depression, cognitive functions, adherence to treatment and treatment satisfaction. At baseline and 3, 6, 12, and 24 months into the study there will be physical examination and laboratory tests, including: fasting and 1.5 hours post meal glucose, glycated hemoglobin, insulin with calculation of HOMA-IR index, indicators of lipid metabolism (total cholesterol, TG, LDL, calculation of HDL and VLDL), markers of kidney function (serum creatinine with GFR calculation, urine albumin-to-creatinine ratio), biochemical parameters of therapy safety (ALT, AST, bilirubin, uric acid, fibrinogen, alkaline phosphatase, amylase 5), levels of orexigenic / anorexigenic hormones (GLP1, GIP, ghrelin, leptin, glucagon, adiponectin, C-peptide). The study will also include the evaluation of endothelial dysfunction (using EndoPAT 2000), state of the vascular wall (using the SphygmoCor), thickness of intima-media complex of carotid arteries, echocardiographic study, estimation of the global longitudinal strain (2-D Speckle-tracking echocardiographic analysis), MRI of the heart, biomarkers of inflammation (CRP level by the ultrasensitive method, adhesion molecules E-selectin and sICAM-1), markers of oxidative stress (myeloperoxidase, paraoxanase-1), markers of fibrosis (PICP, PIIINP, CITP, MMP / TIMP, TGF-β, galectin-3), markers of heart failure (NT-proBNP, sST2). The investigators will conduct immunophenotyping of circulating progenitor cells (CD45 + / CD34 + / collagen-I +) by flow cytometry, and assess molecular-genetic markers of endothelial damage (microRNA-126, microRNA-21, microRNA-27, miRNA-125 and miRoRNA-155).

Eligibility criteria: Inclusion Criteria:

1. Male and female aged 17-70 years
2. Type 2 diabetes mellitus with non-target HbA1c exciding less than 1% (\<1%)
3. Initiation of the treatment by SGLT- 2 inhibitors, dipeptidyl peptidase-4 inhibitors, GLP-1 analogues
4. Stable hypoglycemic therapy for 12 weeks before enrollment
5. Signed informed consent

Exclusion Criteria:

1. Type 1 diabetes mellitus
2. Recent acute coronary syndrome or acute disturbance of cerebral blood circulation (less than 2 months ago)
3. Decompensation of chronic heart failure, chronic heart failure class IV (NYHA), acute heart failure
4. Confirmed non-diabetic kidney disease (glomerulonephritis, pyelonephritis, amyloidosis)
5. Chronic kidney disease requiring hemodialysis and/or urinary albumin concentration (morning spot) \>1000 mg/L
6. Regular nephrotoxic drugs intake (long-term intake of NSAIDs, aminoglycosides, sulfonamides, cyclosporine, lithium preparations)
7. Anamnesis of malignancy.
8. Diabetic foot ulcer and neuropathic osteoarthropathy
9. Anamnesis of bariatric surgery or surgical interventions on the gastrointestinal tract leading to malabsorption.
10. Treatment with drugs reducing body weight less than 3 months ago or any other drugs use that can lead to a change in body weight.
11. Liver disorders with elevation of ALT/AST exceeding three-fold the upper limit of normal
12. Immunosuppressive therapy or regular nonsteroidal anti-inflammatory drugs intake
13. Change in the dosage of thyroid hormones less than 6 weeks ago.

Primary outcomes:
measure: HbA1c
timeFrame: baseline and 3, 12, and 24 months after intervention
measure: Body mass index
timeFrame: baseline and 3, 12, and 24 months after intervention
Secondary outcomes:
measure: Estimated glomerular filtration rate
timeFrame: baseline, 12 and 24 months after intervention
measure: HOMA-IR index
timeFrame: baseline, 6 and 12 months after intervention
measure: Urinary creatinine-adjusted excretion of albumin
timeFrame: baseline, 12 and 24 months after intervention
measure: Cardiovascular parameters of PAT and IMT
timeFrame: baseline, 6 and 12 months after intervention
measure: LDL cholesterol
timeFrame: baseline, 6 and 12 months after intervention
measure: Triglycerides
timeFrame: baseline, 6 and 12 months after intervention
measure: NT-proBNP
timeFrame: baseline, 6 and 12 months after intervention
measure: hsCRP
timeFrame: baseline, 6 and 12 months after intervention
measure: PAT
timeFrame: baseline, 6 and 12 months after intervention
measure: IMT
timeFrame: baseline, 6 and 12 months after intervention
measure: LV ejection fraction
timeFrame: baseline, 6 and 12 months after intervention
measure: LV mass index
timeFrame: baseline, 6 and 12 months after intervention
measure: GLS by 2D-STE
timeFrame: baseline, 6 and 12 months after intervention
measure: Molecular-genetic markers of endothelial damage
timeFrame: baseline, 6 and 12 months after intervention
Other outcomes:
Locations:
city: Saint-Petersburg
country: Russian Federation
facility: Alina Babenko
Study officials:
References: