Renohemodynamic Effects of Combined empagliflOzin and LosARtan

NCT04238702 | Completed Phase 4

• 1 other identifier: DC2019RECOLAR01
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Diabetes Mellitus, Type 2; Diabetic Kidney Disease

Keywords

RAS inhibition; Sodium Glucose Cotransport 2 inhibitors

Outcome Measures

Primary Outcomes (2)

• Glomerular Filtration Rate (GFR)

  change in mGFR after 7 days of treatment using iohexol

  7 days

• Effective Renal Plasma Flow (ERPF)

  change in ERPF after 7 days of treatment using iohexol

  7 days

Secondary Outcomes (7)

• Glomerular Hydrostatic Pressure

  7 days

• Arteriolar resistance

  7 days

• Renal tubular function

  7 days

• GFR trajectory

  7 days

• Systemic hemodynamics

  7 days

Study Arms (4)

Empagliflozin + Losartan

EXPERIMENTAL

Empagliflozin + Losartan

Drug: Empagliflozin 10 MG; Drug: Losartan 50Mg Tab

Losartan + Placebo

EXPERIMENTAL

Losartan + Placebo

Drug: Losartan 50Mg Tab; Other: Placebo

Empagliflozin + Placebo

EXPERIMENTAL

Losartan + Placebo

Drug: Empagliflozin 10 MG; Other: Placebo

Placebo + Placebo

PLACEBO COMPARATOR

Placebo + Placebo

Other: Placebo

Interventions

Empagliflozin 10 MG DRUG

Empagliflozin 10 MG 7 days intervention period

Also known as: Jardiance

Empagliflozin + Losartan; Empagliflozin + Placebo

Losartan 50Mg Tab DRUG

Losartan 50 MG 7 days intervention period

Also known as: Cozaar

Empagliflozin + Losartan; Losartan + Placebo

Placebo OTHER

Placebo 7 days intervention period

Empagliflozin + Placebo; Losartan + Placebo; Placebo + Placebo

Eligibility Criteria

• Age: 35 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• Written informed consent

You may not qualify if:

• 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

Sponsors & Collaborators

• Amsterdam UMC, location VUmc: lead

Study Sites (1)

VU University Medical Center

Amsterdam, North Holland, 1081HV, Netherlands

Location

Related Publications (2)

• Natale P, Tunnicliffe DJ, Toyama T, Palmer SC, Saglimbene VM, Ruospo M, Gargano L, Stallone G, Gesualdo L, Strippoli GF. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors for people with chronic kidney disease and diabetes. Cochrane Database Syst Rev. 2024 May 21;5(5):CD015588. doi: 10.1002/14651858.CD015588.pub2.

  PMID: 38770818 DERIVED

• Natale P, Palmer SC, Navaneethan SD, Craig JC, Strippoli GF. Angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease. Cochrane Database Syst Rev. 2024 Apr 29;4(4):CD006257. doi: 10.1002/14651858.CD006257.pub2.

  PMID: 38682786 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Diabetic Nephropathies

Interventions

empagliflozin; Losartan

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Complications

Intervention Hierarchy (Ancestors)

Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tetrazoles

Study Officials

• Daniel van Raalte, MD PhD

  Amsterdam UMC, location VU Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principle Investigator

Model Details: A phase 4, monocenter, randomized, double-blind, placebo-controlled, 4-armed cross-over mechanistic intervention study

Study Record Dates

• First Submitted: September 11, 2019
• First Posted: January 23, 2020
• Study Start: November 4, 2020
• Primary Completion: September 27, 2021
• Study Completion: September 27, 2021
• Last Updated: October 8, 2021

Record last verified: 2021-10

Locations

NL (1)