Diabetes Mellitus, Diabetic Kidney Disease, Hypertension
Conditions
Brief summary
SGLT2 inhibitors such as ertugliflozin improve blood pressure and kidney outcomes in people living with diabetes through incompletely understood mechanisms, however, not all patients treated with SGLT2 inhibition have improved outcomes. Changes in kidney sodium handling is among the mechanisms by which SGLT2 inhibition may reduce blood pressure and drive beneficial kidney outcomes. This process is heavily dependent on daily sodium intake by patients receiving SGLT2 inhibitor treatment. In this study, the effect of daily sodium intake on SGLT2-inhibitor induced physiological effect is studied, including blood pressure regulation and kidney physiology.
Interventions
OTHERSalt-Diet and/or Ertugliflozin
The interventions consist of an determined amount of dietary sodium intake in combination with either Ertugliflozin 15mg once daily or placebo
SGLT2i
Sponsors
Amsterdam UMC, location VUmc
Merck Sharp & Dohme LLC
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
While the treatment by ertugliflozin or placebo will be blinded, the sodium interventions are open-label.
Eligibility
Sex/Gender
ALL
Age
35 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Adults with previously diagnosed T2DM according to American Diabetes Association (ADA) criteria * HbA1c 6.5-10% * Age 35-80 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, insulin * All participants need to be on a stable dose of RAS inhibition
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, 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: * Acute coronary syndrome * Chronic heart failure (New York Heart Association grade II-IV) * 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 * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Investigate the Modifying Effect of Sodium Intake on Ertugliflozin on Blood Pressure | 24 weeks | 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 |
Countries
Netherlands
Participant flow
Pre-assignment details
Of 61 individuals screened, 41 were enrolled. The required sample size was 34 participants; additional participants were enrolled to account for anticipated dropouts.
Baseline characteristics
| Characteristic | — |
|---|---|
| 24 hour urinary sodium excretion | 132.5 mmol |
| Age, Continuous | 69.9 years STANDARD_DEVIATION 8.7 |
| BMI | 28.4 kg/m² |
| diastolic blood pressure | 80 mmHg STANDARD_DEVIATION 7 |
| eGFR | 80.9 mL/min/1.73 m² STANDARD_DEVIATION 11.7 |
| Hba1c | 7.7 % glycated hemoglobin |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 30 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 29 Participants |
| systolic blood pressure | 131 mmHg STANDARD_DEVIATION 10 |
| Urinary volume | 1900 mL |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 34 | 0 / 34 | 0 / 34 |
| other Total, other adverse events | 0 / 34 | 2 / 34 | 0 / 34 | 0 / 34 |
| serious Total, serious adverse events | 0 / 34 | 0 / 34 | 0 / 34 | 0 / 34 |
Outcome results
None listed