Type 2 Diabetes Mellitus
Conditions
Interventions
Trade Name: Jardiance
Product Name: Empagliflozin
Pharmaceutical Form: Film-coated tablet
Trade Name: Trajenta
Product Name: Linagliptin
Pharmaceutical Form: Film-coated tablet
Trade Name: Gliclazid
Sponsors
VU University Medical Center
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Caucasian* • Both genders (females must be post-menopausal; no menses >1 year; in case of doubt, Follicle-Stimulating Hormone (FSH) will be determined with cut-off defined as >31 U/L) • Age: 35 - 75 years • BMI: >25 kg/m2 • HbA1c: 7.0 – 9.5% Diabetes Control and Complications Trial (DCCT) or 53 - 80 mmol/mol International Federation of Clinical Chemistry (IFCC) • Treatment with a stable dose of metformin monotherapy for at least 3 months prior to inclusion • Hypertension should be controlled, i.e. =140/90 mmHg, and treated with an ACE-I or ARB (unless prevented by side effect) for at least 3 months. • Albuminuria should be treated with a RAAS-interfering agent (ACE-I or ARB) for at least 3 months. • Written informed consent * In order to increase homogeneity Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 44 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 22
Exclusion criteria
Exclusion criteria: • Estimated GFR 3x upper limit of normal (ULN) • Recent (3 units alcohol/day) • History of diabetic ketoacidosis (DKA) requiring medical intervention (e.g., emergency room visit and/or hospitalization) within 1 month prior to the Screening visit. • Recent blood donation (< 6 months) • Allergy to any of the agents used in the study • Inability to understand the protocol and/or give informed consent • Individuals who are investigator site personnel, directly affiliated with the study, or are immediate (spouse, parent, child, or sibling, whether biological or legally adopted) family of investigator site personnel directly affiliated with the study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To determine the effects of 8-week empagliflozin (SGLT-2 inhibitor) monotherapy (10 mg QD), followed by 8-week empagliflozin and linagliptin (DPP-4 inhibitor) combination therapy (10/5 mg QD) versus 8-week linagliptin monotherapy (5 mg QD), followed by 8-week linagliptin and empagliflozin combination therapy (5/10 mg QD) versus 8-week gliclazide (Sulfonylurea) monotherapy (30 mg QD), followed by 8-week gliclazide intensification (30 mg BID) on renal hemodynamics in both the fasting and postprandial state in metformin-treated T2DM patients, measured as: • GFR (measured by the iohexol-clearance technique) • Effective renal plasma flow (ERPF; measured by the para-aminohippurate acid (PAH) clearance technique);Secondary Objective: - Renal Tubular Function -Renal damage -Blood Pressure and heart rate -Body anthropometrics and Body fat content -Glycemic variables, Lipid spectrum, Inflammation, Biochemistry and Hematology -Arterial stiffness (PWA) -Systemic hemodynamics -CANS function Exploratory objectives: -Biomarkers and gut microbiome -DNA -Insulin sensitivity -Beta-cell function -Microvascular function;Primary end point(s): Renal hemodynamics, measured as: • Glomerular filtration rate (GFR; measured by the iohexol-clearance technique) •Effective renal plasma flow (ERPF; measured by the para-aminohippurate acid (PAH) clearance technique);Timepoint(s) of evaluation of this end point: Renal hemodynamics are assessed at baseline, 8 weeks and 16 weeks of treatment. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): To investigate the effects of the above-indicated interventions on: • Renal damage markers (Week 0, 2, 8, 10, 16): o 24-hour urinary albumin excretion (glomerular) o Albumin-creatinine ratio (glomerular) • Renal tubular function (Week 0, 8, 16), measured as: o Fractional and cumulative (24-hour urine collection) sodium-, potassium-, chloride-, calcium-, magnesium-, phosphate-, uric acid, bicarbonate-, ammonium- and urea excretion o Urinary glucose excretion o Urine osmolality o Urinary pH • GFR trajectory (Week 0, 2, 8, 10, 16), measured by: o Creatinine clearance (24-hour urine collection) • Systemic hemodynamics, measured by: o Week 0, 2, 8, 10, 16: SBP, DBP, MAP and heart rate, measured by automated oscillometric blood pressure monitor (Dinamap®) o Week 0, 8, 16: SBP, DBP, MAP, heart rate (HR), stroke volume (SV), cardiac output (CO)/-index (CI), and total systemic vascular resistance (TSVR)) derived from non-invasive beat-to-beat finger blood pressure measurements (Finger photoplethysmography, Nexfin®) • Autonomic nervous system activity (Week 0, 8, 16), measured by: o Heart rate variability derived from automated, beat-to-beat blood pressure and ECG recording monitor (Finger photoplethysmography, Nexfin®) • Vascular function (Week 0, 8, 16), measured as: o Arterial stiffness (Pulse Wave Analysis), measured by radial artery applanation tonometry (SphygmoCor®) • Metabolic biomarkers o Glycated hemoglobin (HbA1c), and fasting and postprandial glucose, lipids (triglycerides (TG), total-cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and free fatty acids (FFA)), insulin, glucagon. • Body anthropometrics o Height, weight, BMI and waist/hip circumference o Body fat content, total body water (TBW) and body cell mass (BCM) measured by body impedance analysis (BIA) (Soft Tissue Analyzer®) Exploratory Objectives (The extent of these complementary measurements | — |
Countries
Netherlands
Contacts
Public ContactDaniel van Raalte
VU University Medical Center
Outcome results
None listed