Adult-onset diabetes Type 2 Diabetes Mellitus
Conditions
Interventions
Sponsors
Vrije Universiteit Medisch Centrum
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: Main study * 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 Sub study * Treatment with a stable dose of oral antihyperglycemic agents for at least 3 months prior to inclusion * Metformin monotherapy * Combination of metformin and low-dose SU derivative
Exclusion criteria
Exclusion criteria: Main study: * Estimated GFR 300 mg/g. * Current/chronic use of the following medication: thiazolidinediones, sulfonylurea derivatives, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitor, oral glucocorticoids, immune suppressants, antimicrobial agents, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MOAIs). * Patients on diuretics will only be excluded when these drugs cannot be stopped 3 months prior randomization and for the duration of the study. * Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) will not be allowed, unless used as incidental medication (1-2 tablets) for non-chronic indications (i.e. sports injury, head-ache or back ache). However, no such drugs can be taken within a time-frame of 2 weeks prior to renal-testing * Pregnancy * History of or actual severe mental disease * History of or actual severe somatic disease (e.g. systemic disease) * History of or actual malignancy (except basal cell carcinoma) * History of or actual pancreatic disease * (Unstable) thyroid disease * Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) >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 (300 mg/g. * Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) will not be allowed, unless used as incidental medication (1-2 tablets) for non-chronic indications (i.e. sports injury, head-ache or back ache). However, no such drugs can be taken within a time-f
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 is conditional to | — |
Countries
The Netherlands
Outcome results
None listed