This study has been transitioned to CTIS with ID 2023-510257-42-01 check the CTIS register for the current data. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lead to a lowering of blood pressure and confer cardiovascular and renal protection in…
ID
Source
Brief title
Condition
- Diabetic complications
- Nephropathies
- Vascular hypertensive disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To investigate the modifying effects of WHO-recommended sodium intake (90 mmol
per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of
ertugliflozin 15 mg daily, versus placebo, on 24-hour blood pressure in
overweight/obese adults with type 2 diabetes.
Secondary outcome
To investigate the efficacy of ertugliflozin 15 mg daily, versus placebo, in
overweight/obese adults with type 2 diabetes to reduce the hypertensive effects
of a high-sodium diet (250 mmol per day) versus 24-hour blood pressure
measurement during participant*s normal diet (170 mmol/per day) obtained at
screening visit.
Background summary
Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease
(CKD) and dialysis in the developed world, and a major cause of premature
mortality. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lead to a lowering
of blood pressure and confer cardiovascular and renal protection in many, but
not all people with type 2 diabetes (T2D). The mechanisms of these salutary
cardiorenal benefits remain unclear, and are incompletely explained by the
modest improvements in glycemic control, body weight, and serum uric acid (2).
An important hypothesis by which SGLT2 inhibitors could improve cardiorenal
outcomes is renal sodium handling. Therefore, the efficacy of the drug may be
mediated by sodium intake of the patient/participant. A better understanding of
the mechanism of cardio-renal protection in response to SGLT2 inhibition is
therefore needed to determine which patients would see the greatest benefit
from this drug class and also how to augment the beneficial effects with
complimentary drugs and/or lifestyle changes such as changes in dietary sodium
intake.
Study objective
This study has been transitioned to CTIS with ID 2023-510257-42-01 check the CTIS register for the current data.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors lead to a lowering of blood
pressure and confer cardiovascular and renal protection in many, but not all
people with type 2 diabetes (T2D), possibly due to a difference in sodium
intake. with this mechanistic study we will have the ability to increase our
understanding of the interaction between SGLT2-inhibitors and sodium intake and
maximize the treatment response. In addition, we will be able to investigate if
differences in dietary habits might contribute to the differences in the
cardiovascular en renal protective function of SGLT2 inhibitors observed among
different ethnicities.
Study design
The study is a bi-center randomized, placebo-controlled, crossover intervention
study. Total number of included participants is 34, which undergo 4 conditions
in randomized order. Rrandomization list generated by computer and supervised
by pharmacy; blinded to investigator. While the treatment will be blinded for
all participants, the sodium interventions are open-label.
The 4 conditions are:
1) low-sodium diet; placebo
2) low-sodium diet; ertugliflozin 15 once daily
3) high-sodium diet; placebo
4) high-sodium diet; ertugliflozin 15 mg once daily
A 24-hr blood pressure measurement as well 24-hr sodium excretion is measured
prior to the dietary blocks. Than, for each condition there is a 10-day diet
run in period, followed by a 10-day intervention period, followed by the test
visit. Between conditions there is a 4-week wash out.
Intervention
The interventions of the study consist of a low-sodium diet versus a high
sodium diet and a placebo versus ertugliflozin 15 once daily
Study burden and risks
Risks
All participants within the study group will receive ertugliflozin, an SGLT-2
inhibitor which is approved for the for blood-glucose lowering treatment in
T2DM patients and based on currently available data is considered to be safe.
The most common adverse effects for ertugliflozin are genital mycotic- and
urinary tract infections, pruritus, polyuria, frequent voiding and nycturia. As
in all drug intervention trials, in this study, we will closely monitor
patients for adverse drug and study events.. Participants can contact the
research staff 24 hours a day. As for the testing agents, at our research
centre at Amsterdam UMC we have done > 500 iohexol and PAH clearances in the
last 5 years and not encountered a single problem.
Benefits
Moreover, SGLT-2 inhibitors may have beneficial effects in general and are
associated with a decrease in blood pressure and body weight, as well as a
reduction in kidney function decline and hospitalisation forhesrt failure.
De Boelelaan 1117
Amsterdam 1081HV
NL
De Boelelaan 1117
Amsterdam 1081HV
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all
of the following criteria:
• Adults with previously diagnosed T2DM according to American Diabetes
Association (ADA) criteria
• HbA1c 6.5-10%
• Age 18 - 85 years of age
• Overweight or obese with BMI: >25 kg/m2
• We will make every effort to enrol participants of all races/ethnicities.*
• Both sexes (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)
• Ability to provide signed and dated, written informed consent prior to any
study procedures
• Estimated GFR 60-90 ml/min/1.73m2 by CKD-EPI matching the eGFR range of most
participants in VERTIS-CV
• Sodium intake at baseline < 200 mmol/day
• UACR < 30 mg/mmol
• All participants need to be on a stable dose of diabetes medication,
including Metformin, SU, DPP4-inhibitors, or insulin.
• Participants suffering from hypertension need to be on a stable dose of RAS
inhibitors. In case RAS inhibition is not tolerated, the participant should to
be on a stable dose of other antihypertensive treatment.
Exclusion criteria
• History of unstable or rapidly progressing renal disease
• Estimated GFR <60 mL/min/1.73m2 or eGFR > 90 mL/min/1.73m2 determined by
CKD-EPI
• UACR > 30 mg/mmol
• Current/chronic use of the following medication: SGLT2 inhibitors, TZD,
GLP-1RA, glucocorticoids, immune suppressants, antimicrobial agents,
chemotherapeutics Participants should be on a stable dose of 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.
• 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, headache or back ache). However, no such drug
can be taken within a timeframe 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
• 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
• Active malignancy. History of malignancy is allowed unless the participant
still has active treatment other than hormonal therapy.
• 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
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 |
|---|---|
| EU-CTR | CTIS2023-510257-42-01 |
| EudraCT | EUCTR2021-005474-25-NL |
| CCMO | NL80772.029.22 |