A phase 4, monocenter, randomized, double-blind, placebo-controlled, 4-armed cross-over mechanistic intervention study to assess the renal hemodynamic effect of mono- and combination therapy with empagliflozin (SGLT-2 inhibitor) and losartan (RAS inhibitor) in metformin and/or SU-treated patients with type 2 diabetes mellitus

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 24

Inclusion Criteria

* Caucasian, Asian or Middle Eastern (sub-Saharan patients are not eligible);
* 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: 45 - 80 years
* BMI: >25 kg/m2
* HbA1c: 6.5 * 10.5% Diabetes Control and Complications Trial (DCCT) or 48 - 91
mmol/mol International Federation of Clinical Chemistry (IFCC)
* Treatment with a stable dose of metformin and/or SU therapy for at least 3
months prior to inclusion
* Written informed consent

Exclusion Criteria

* History of unstable or rapidly progressing renal disease
* Macroalbuminuria; defined as ACR of 300mg/g.
* Estimated GFR <60 mL/min/1.73m2 (determined by the Modification of Diet in
Renal Disease (CKD-EPI) study equation)
* Only use of alpha blockers and/or beta blockers are allowed as
antihypertensive background therapy. Patients using an antihypertensive agent
will be considered if this agent can be stopped (i.e. blood pressure adequate
to stop at screening) or replaced by an alpha or beta blocker. In these
patients, a 4 week wash-out/run-in period will be observed prior to visit 2.
* Current/chronic use of the following medication: SGLT2 inhibitors, RAS
inhibitors, TZD, GLP-1RA, DPP-4 inhibitors, glucocorticoids, immune
suppressants, antimicrobial agents, chemotherapeutics, antipsychotics,
tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs).
Subjects on diuretics will only be excluded when these drugs cannot be stopped
for the duration of the study.
* Volume depleted patients. Patients at risk for volume depletion due to
co-existing conditions or concomitant medications, such as loop diuretics
should have careful monitoring of their volume status.
* 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 drug
can be taken within a time-frame of 2 weeks prior to renal-testing
* History of diabetic ketoacidosis (DKA) requiring medical intervention (e.g.
emergency room visit and/or hospitalization) within 1 month prior to the
Screening visit.
* Current urinary tract infection and active nephritis
* Recent (<6 months) history of cardiovascular disease, including:
o Acute coronary syndrome
o Chronic heart failure (New York Heart Association grade II-IV)
o Stroke or transient ischemic neurologic disorder
* Complaints compatible with neurogenic bladder and/or incomplete bladder
emptying (as determined by ultrasonic bladder scan)
* Severe hepatic insufficiency and/or significant abnormal liver function
defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN)
and/or alanine aminotransferase (ALT) >3x ULN
* (Unstable) thyroid disease; defined as fT4 outside of laboratory reference
values or change in treatment within 3 months prior to screening visit
* History of or actual malignancy (except basal cell carcinoma)
* History of or actual severe mental disease
* Substance abuse (alcohol: defined as >4 units/day)
* Allergy to any of the agents used in the study
* 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
* Inability to understand the study protocol or give informed consent

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Renal hemodynamics (defined as GFR and effective renal plasma flow; ERPF),<br /><br>measured by combined iohexol/para-aminohippurate acid; PAH) clearance<br /><br>techniques, based on timed urine sampling (Day 7+-1) </p><br>

Secondary Outcome Measures