We aim to investigate the renal hemodynamic effects of empagliflozin in people with either preserved or impaired renal function with T2DM and people with impaired renal function without T2DM, all with and without adenosine blockade.
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Nephropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Investigate the effects of 7 days of therapy with the SGLT2 inhibitor
empagliflozin (10 mg QD) versus placebo on measured glomerular filtration rate
(mGFR)) in metformin and/or sulfonyl (SU) treated T2DM patients with normal
kidney function, metformin, SU and/or insulin-treated T2DM patients with
impaired kidney function and hypertensive people without T2DM with impaired
kidney function, all treated with RAS blockers.
Secondary outcome
To assess the effects of 7 days treatment with SGLT2 inhibitor empagliflozin
(10 mg QD) versus placebo in metformin and/or SU-treated T2DM patients with
normal kidney function, metformin, SU and/or insulin-treated T2DM patients with
impaired kidney function and hypertensive people without T2DM with impaired
kidney function on:
1) Renal hemodynamics including effective renal plasma flow (ERPF) and renal
vascular resistance (RVR)
2) Systemic hemodynamics (mean arterial pressure (MAP) & heart rate)
3) Caffeine-induced changes in renal hemodynamics including GFR, ERPF and RVR
4) Empagliflozin-induced proximal sodium excretion by using fractional
excretion of lithium as a surrogate of proximal sodium handling.
Background summary
Worldwide, diabetic kidney disease (DKD) is the most common cause of chronic
and end stage kidney disease. 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 type 2
Diabetes Mellitus (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 (20-40%),
indicating an unmet need for renoprotective therapies as DKD largely causes the
increased mortality risk from cardiovascular disease (CVD) in people with
diabetes.
Sodium-glucose linked transporters (SGLT-2) inhibitors are a relatively novel
glucose-lowering drug for the treatment of T2DM as they lower plasma glucose
levels by blocking renal glucose reabsorption. In addition, these agents exert
pleiotropic actions beyond glucose control. As such, SGLT-2 inhibitors decrease
proximal sodium reabsorption, reduce blood pressure, body weight and uric acid.
In large trials and likely through these pleiotropic effects, SGLT2 inhibitors
reduce cardiovascular mortality, hospitalization for heart failure and reduce
end stage kidney disease. 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 mechanisms of this observation have only been partially investigated by us
and others. From studies in peolpe with T1DM it is hypothesized that SGLT-2
inhibition increases sodium chloride delivery to the macula densa, which in
turn augments the afferent arteriolar resistances, known as tubuloglomerular
feedback (TGF), consequently reducing glomerular (hyper)filtration and
hydrostatic pressure. We recently have conducted a clinical trial in humans
with T2DM to investigate if this also holds true in these patients.
Suprisingly, this study showed that the renohemodynamic actions of SGLT-2
inhibition in T2DM are not due to afferent vasoconstriction but rather efferent
vasodilation [van Bommel/van Raalte Kidney International 2019 in press]. We
realized that the SGLT-2 associated dip in eGFR remains insufficient
understood. The increase in sodium excretion following SGLT-2 inhibition peaks
at day 2-3 after which it normalizes. It is unknown whether this drop in eGFR
is related to this peak in sodium excretion, as the drop remains after
normalization of sodium excretion. Therefore it might be possible that
glucosuria, by inducing osmotic diuresis, is the main driver of the reduction
in intraglomerular pressure more than sodium, since SGLT-2 inhibitors cause
persisting glucosuria.
Furthermore, we know that SGLT-2 induced glucosuria and possibly sodium
excretion is dependent of renal function and HbA1c and consequently is
diminished in people with CKD or without T2DM. However, the renoprotective
effects in T2DM are also observed in patients with impaired kidney function and
seem statistically independent of glucose levels. Until now it has not been
investigated whether or not the SGLT-2 induced eGFR alterations occur in people
with CKD with or without T2DM. It is clinically relevant to understand the
renal hemodynamics of SGLT-2 inhibitors in these populations since we then can
interpret the results from the ongoing trials in people with CKD without T2DM,
such as EMPA-KIDNEY and DAPA-CKD.
Recently, potential mediators of renal arterole tone, such as adenosine, have
been measured to gain more insight into mechanisms of SGLT-2 inhibitor-induced
changes in renal hemodynamics. Adenosine is known to augment preglomerular
arteriolar resistance. Adenosine was significantly increased after SGLT-2
inhibition, as was also observed in patients with type 1 diabetes. However, it
can also induce postglomerular vasodilation via A2aR activation in the presence
of RAS blockade. One study in T1DM rats has shown that increased adenosine
generation by the macula densa in response to SGLT-2 inhibition suppresses
hyperfiltration, as the improvements in preglomerular arteriolar resistance
were abolished after adenosine antagonist administration. To date, this has not
been investigated in T2DM humans. Therefore, this trial will assess TGF
responses with and without adenosine blockade by caffeine.
Study objective
We aim to investigate the renal hemodynamic effects of empagliflozin in people
with either preserved or impaired renal function with T2DM and people with
impaired renal function without T2DM, all with and without adenosine blockade.
Study design
A single-center, prospective, placebo-controlled, double-blind, randomized,
cross-over mechanistic intervention study to investigate the renal hemodynamic
effects of empagliflozin in type 2 diabetes mellitus patients with either
preserved or impaired renal function and normoglycemic individuals with
impaired renal function
Intervention
Empagliflozin 10 mg or placebo
Study burden and risks
Over the last 10 years, we have gained ample experience with similarly
demanding mechanistic drug intervention studies in T2DM patients on renal
hemodynamics (SAFEGUARD 2012.391, RENALIS 2013.459, ELIXIRS 2014.275, RED
2015.421, RACELINES 2017.336). Based on the positive feedback from our
participants, the low drop-out rate (max 5%) and the large proportion of
participants that returns to participate in yet another (similarly demanding)
study, we are confident that the burden on participants is perceived as not
being too high. Indeed, we have built in different ways to alleviate the burden
for participants, including clear, repeated communication, frequent contacting,
24-hour availability of research staff, study and travel reimbursement.
Finally, it should be noted that several tests are similar to currently or
previously performed in patient care for diagnostic purposes (e.g.
iohexol/PAH-clearance).
We are aware of the fact that in the current study participants will undergo
multiple tests that demand a considerable time investment from their end. The
total duration of visits is 16 hours. The renal / cardiovascular test-days may
be perceived as demanding that amongst others involves frequent blood and urine
collection, infusions, blood pressure and heart rate. As mentioned above, all
possible measures will be taken to minimize the discomfort for the participants
during the tests (e.g. comfortable beds are available which allow a
semi-recumbent position).
De Boelelaan 1117 ZH 4A65
Amsterdam 1081 HV
NL
De Boelelaan 1117 ZH 4A65
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
* 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
* For with people with diabetes - a diagnosis of T2DM with glycosylated
haemoglobin (HbA1c) *6.5% (*48 mmol/mol) and <10.5% (<91 mmol/mol); and eGFR
(CKD-EPI) between *25 and *50 mL/min/1.73m2 or >75 mL/min/1.73m2 at the
Screening Visit (Visit 1).
* In the normoglycemic, hypertensive, individuals: HbA1c <6.5% (<48 mmol/mol)
and an eGFR (CKD-EPI) between *25 and *50 mL/min/1.73m2 at the Screening Visit
(Visit 1).
* In the diabetic arm: people with an eGFR >75 ml/min/1.73m2 should be treated
with a stable dose of metformin and/or SU, people with an eGFR between *25 and
*50 mL/min/1.73m2 should be treated with a stable dose of metformin, SU and/or
insulin therapy for at least 3 months prior to inclusion
* Patient specific antihypertensive dose of an angiotensin receptor blocker
(ARB) (as per Investigator*s judgement) for at least 4 weeks prior to Visit 2
(Day 3).
* Written informed consent
Exclusion criteria
* History of unstable or rapidly progressing renal disease
* Diagnosis of polycystic kidney disease.
* Post renal transplant
* History of or current lupus nephritis.
* Abnormal vital signs, after 10 minutes supine rest, definas as any of the
following (Visit 1):
o Systolic blood pressure above 180 mmHg
o Diastolic blood pressure above 110 mmHg
* Current/chronic use of the following medication: SGLT2 inhibitors,TZD,
GLP-1RA, DPP-4 inhibitors, , antimicrobial agents or chemotherapeutics.
* 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 (<3 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
* 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-000165-16-NL |
| ClinicalTrials.gov | NCT04243850 |
| CCMO | NL72572.029.20 |