Renohemodynamic Effects of Combined empagliflOzin and LosARtan

• Status: Completed
• Trial end date: 2021-09-27
• Target enrollment: 0
• Participant gender: All

Summary

Worldwide, diabetic kidney disease (DKD) is the most common cause of chronic and end stage kidney disease. In parallel with the ever-increasing rates of obesity and type 2 diabetes (T2D), the incidence of DKD is expected to further increase in the coming years. DKD is a multi-factorial condition, involving pathophysiological factors such as chronic hyperglycemia, obesity, systemic- and glomerular hypertension, dyslipidemia, oxidative stress and pro-inflammatory cytokines. Large-sized prospective randomized clinical trials indicate that intensified glucose and blood pressure control, the latter especially by using agents that interfere with the renin-angiotensin-aldosterone system (RAS), halts the onset and (particularly) the progression of DKD, in both type 1 diabetes mellitus (T1DM) and T2DM patients. However, despite the wide use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), a considerable amount of patients develop DKD, indicating an unmet need for renoprotective therapies. Sodium-glucose linked transporters (SGLT-2) inhibitors are a relatively novel glucose-lowering drug for the treatment of T2DM. These agents seem to exert pleiotropic actions 'beyond glucose control'. SGLT-2 inhibitors decrease proximal sodium reabsorption and decrease glomerular pressure and albuminuria in type 2 diabetes. In addition, SGLT-2 inhibitors reduce blood pressure and body weight. At this point in time, the renoprotective mechanisms involved with SGLT-2 inhibition still remain speculative, though a consistent finding is that SGLT-2 inhibitors reduce estimated eGFR after first dosing, which is reversible after treatment cessation. This "dip" indicates a renal hemodynamic phenomenon reminiscent of the RAS blockers and is thought to reflect a reduction in intraglomerular pressure. The potential renoprotective effects and mechanisms of combination therapy of SGLT-2 inhibitors and RAS inhibitors have not been sufficiently detailed in human type 2 diabetes. Therefore, the current study aims to explore the underlying mechanism of the improved renal hemodynamics and mechanistics of mono- and combination therapy with an SGLT-2 inhibitor and a RAS inhibitor on renal physiology in metformin and/or SU-treated T2DM patients.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: VU University Medical Center
• Treatments: Empagliflozin; Losartan

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 - 80 years

• BMI: >25 kg/m2

• HbA1c: 6.5 - 10.0% Diabetes Control and Complications Trial (DCCT) or 48 - 86 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 is 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 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:

• Acute coronary syndrome

• Chronic heart failure (New York Heart Association grade II-IV)

• 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