A phase 4, monocenter, randomized, double-blind, comparator-controlled, 3-armed parallel mechanistic intervention trial to assess the effect of 8-week empagliflozin (SGLT-2 inhibitor) monotherapy, followed by 8-week empagliflozin and linagliptin (DPP-4 inhibitor) combination therapy versus 8-week linagliptin monotherapy, followed by 8-week linagliptin and empagliflozin combination therapy versus 8-week gliclazide (Sulfonylurea derivate), followed by 8-week gliclazide intensification therapy on r

Phase 4

Completed

Conditions: 10018424
10029149
10003216
Adult-onset diabetes
Type 2 Diabetes Mellitus

Registration Number: NL-OMON48622

Lead Sponsor: Vrije Universiteit Medisch Centrum

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 66

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

Main study:
* Estimated GFR <45 mL/min/1.73m2 (determined by the Modification of Diet in
Renal Disease (MDRD) study equation)
* Hemoglobin level < 7.0 mmol/L
* Current urinary tract infection and/or active nephritis
* History of unstable or rapidly progressing renal disease
* Macroalbuminuria; defined as ACR of >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 (<6 months) history of cardiovascular disease, including
o Acute coronary syndrome
o Stroke or transient ischemic neurologic disorder or chronic heart failure
(NYHA grade II-IV)
* Complaints compatible with or established neurogenic bladder and/or
incomplete bladder emptying (as determined by ultrasonic bladder scan)
* Substance abuse (alcohol: defined as >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

Sub study:
Exclusion criteria
* History of gout
* Current/chronic use of the following medication: diuretics, SGLT-2 inhibitor,
uric acid lowering medication, pyranizamide, vitamin K antagonists,
salicylates, thiazide diuretics.
* Estimated GFR <60 mL/min/1.73m2 (determined by the Modification of Diet in
Renal Disease (MDRD) study equation)
* Current urinary tract infection and active nephritis
* Recent (<6 months) kidney stones
* History of unstable or rapidly progressing renal disease
* Macroalbuminuria; defined as ACR of >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

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>To determine the effects of 8-week empagliflozin (SGLT-2 inhibitor) monotherapy<br /><br>(10 mg QD), followed by 8-week empagliflozin and linagliptin (DPP-4 inhibitor)<br /><br>combination therapy (10/5 mg QD) versus 8-week linagliptin monotherapy (5 mg<br /><br>QD), followed by 8-week linagliptin and empagliflozin combination therapy (5/10<br /><br>mg QD) versus 8-week gliclazide (Sulfonylurea) monotherapy (30 mg QD), followed<br /><br>by 8-week gliclazide intensification (30 mg BID) on renal hemodynamics in both<br /><br>the fasting and postprandial state in metformin-treated T2DM patients, measured<br /><br>as:<br /><br><br /><br>* GFR (measured by the iohexol-clearance technique)<br /><br>* Effective renal plasma flow (ERPF; measured by the para-aminohippurate acid<br /><br>(PAH) clearance technique)</p><br>

Secondary Outcome Measures