Role of Mineralocorticoid Receptor in Diabetic Cardiovascular Disease
Aldosterone is a significant mediator of cardiovascular injury associated with heart failure and the cardiovascular benefits of mineralocorticoid receptor blockade are additive to those of angiotensin converting enzyme inhibitors or angiotensin II (ANGII) receptor blockers. This study will test the hypothesis that mineralocorticoid receptor (MR) antagonists exert beneficial cardiovascular effects, specifically by decreasing vascular injury and improving vascular function. A randomized, double-blind study will be conducted, in which participants with Type 2 Diabetes Mellitus will undergo a series of assessments to test heart, blood vessel, and kidney function at baseline, and after 2 and 6 months of treatment with one of the following drugs:
- spironolactone
- hydrochlorothiazide (HCTZ) plus potassium
- placebo
In the event of insufficient funds, randomization to the placebo arm will be stopped and primary assessment of outcomes will occur at baseline and after 6 months of treatment.
Studieoversigt
Status
Status
Betingelser
Betingelser
Intervention / Behandling
Intervention / Behandling
Undersøgelsestype
Undersøgelsestype
Tilmelding (Faktiske)
Tilmelding
Fase
Fase
- Ikke anvendelig
Kontakter og lokationer
Studiesteder
-
-
Massachusetts
-
Boston, Massachusetts, Forenede Stater, 02115
- Brigham and Women's Hospital
-
-
Deltagelseskriterier
Berettigelseskriterier
Berettigelseskriterier
Aldre berettiget til at studere
Tager imod sunde frivillige
Køn, der er berettiget til at studere
Beskrivelse
Inclusion Criteria:
- age 18-70 years
- type 2 diabetes mellitus
- with or without hypertension
Exclusion Criteria:
- ischemic changes on resting electrocardiogram,
- clinical evidence of heart disease (angina, heart failure, unstable angina),cerebrovascular or peripheral vascular disease,
- significant cardiac arrhythmias,
- aortic stenosis,
- 2nd or 3rd degree atrio-ventricular block, sinus node disease, or symptomatic bradycardia,
- bronchospastic lung disease with active wheezing,
- known hypersensitivity to adenosine,
- hemoglobin A1C (HbA1c) > 8.5%, *
- gout (If not already taking HCTZ),
- the use of Rosiglitazone,**
- estimated glomerular filtration rate (eGFR) < 60 ml/min,
- serum potassium > 5.0 mmol/L,
- use of potassium-sparing diuretics,**
- current smoker,*
- pregnancy,
- renal disease not related to diabetes mellitus,
- uncontrolled hypertension, systolic blood pressure (BP) >160 mm Hg and diastolic BP >100 mm Hg,*
- use of cyclic hormone replacement therapy
- past intolerance of angiotensin-converting enzyme (ACE) inhibitor therapy
- other major medical illnesses. Participants with evidence of a previous myocardial infarction on the first adenosine-stimulated positron emission tomography (PET) study will be withdrawn from the study.
Screening systolic blood pressure < 105 mm Hg off of anti-hypertensive medications
Participants can enroll in study and proceed with in-patient evaluations if during the run-in period adjustments of medications, diet and habits lead to improved glucose control [equivalent to HbA1c <8.5%, controlled hypertension and cessation of smoking.
- Participants who are currently taking these medications will not qualify for a screening visit. If medications were recently stopped by the participant's physician, he or she may be screened but the baseline assessment protocol must occur 3 months after stopping.
Studieplan
Hvordan er undersøgelsen tilrettelagt?
Design detaljer
- Primært formål: Behandling
- Tildeling: Randomiseret
- Interventionel model: Parallel tildeling
- Maskning: Dobbelt
Antal våben
Våben og indgreb
Deltagergruppe / ArmDeltagergruppe / Arm |
Intervention / BehandlingIntervention / Behandling |
|---|---|
|
Placebo komparator: Placebo kapsel
|
Placebo capsule daily
|
|
Eksperimentel: Spironolactone (mineralocorticoid receptor [MR] blockade)
|
25 mg capsule daily for 6 months
|
|
Aktiv komparator: Hydrochlorothiazide + potassium
|
hydrochlorothiazide (HCTZ) + potassium, 12.5 mg/10 milliequivalents (mEq) capsule daily
|
Hvad måler undersøgelsen?
Primære resultatmål
Primære resultatmål
Resultatmål |
Foranstaltningsbeskrivelse |
Tidsramme |
|---|---|---|
|
Change in Coronary Flow Reserve From Baseline to 6 Months
Tidsramme: Baseline and six months
|
Coronary flow reserve (CFR), or myocardial perfusion reserve, was assessed via cardiac positron emission tomography (PET).
CFR is the ratio of adenosine-stimulated blood flow through myocardium to resting blood flow through myocardium.
An improvement in coronary flow reserve is beneficial.
|
Baseline and six months
|
Sekundære resultatmål
Sekundære resultatmål
Resultatmål |
Foranstaltningsbeskrivelse |
Tidsramme |
|---|---|---|
|
Change in Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function
Tidsramme: Baseline and six months
|
Diastolic function was assessed via tissue doppler imaging (TDI) by echocardiography to determine left ventricular diastolic function before and after 6 months of treatment.
|
Baseline and six months
|
|
Mitral Annulus Velocities on Tissue Doppler (Delta E/e' Ratio), a Measure of Diastolic Function (With Angiotensin II)
Tidsramme: Baseline and six months
|
Diastolic function was assessed via tissue doppler imaging (TDI) by echocardiography to determine left ventricular diastolic function before and after 6 months of treatment; and in response to acute administration (3 nanograms/kg/min for 60 min) of the vasoactive agent, Angiotensin II.
|
Baseline and six months
|
|
Change in Renal Plasma Flow
Tidsramme: Baseline and six months
|
Renal vasculature was assessed by examining renal plasma flow, or para-aminohippurate (PAH) clearance, basally and in response to acute administration (3 nanograms/kg/min for 60 min) of the vasoactive agent, Angiotensin II.
|
Baseline and six months
|
Samarbejdspartnere og efterforskere
Sponsor
Sponsor
Samarbejdspartnere
Samarbejdspartnere
Efterforskere
Efterforskere
- Ledende efterforsker: Gail K Adler, MD, PhD, Brigham and Women's Hospital
Publikationer og nyttige links
Generelle publikationer
- Haas AV, Rosner BA, Kwong RY, Rao AD, Garg R, Di Carli MF, Adler GK. Sex Differences in Coronary Microvascular Function in Individuals With Type 2 Diabetes. Diabetes. 2019 Mar;68(3):631-636. doi: 10.2337/db18-0650. Epub 2018 Nov 8.
- Garg R, Rao AD, Baimas-George M, Hurwitz S, Foster C, Shah RV, Jerosch-Herold M, Kwong RY, Di Carli MF, Adler GK. Mineralocorticoid receptor blockade improves coronary microvascular function in individuals with type 2 diabetes. Diabetes. 2015 Jan;64(1):236-42. doi: 10.2337/db14-0670. Epub 2014 Aug 14.
Datoer for undersøgelser
Studer store datoer
Studiestart
Studiestart
Primær færdiggørelse (Faktiske)
Primær færdiggørelse
Studieafslutning (Faktiske)
Studieafslutning
Datoer for studieregistrering
Først indsendt
Først indsendt
Først indsendt, der opfyldte QC-kriterier
Først indsendt, der opfyldte QC-kriterier
Først opslået (Skøn)
Først opslået
Opdateringer af undersøgelsesjournaler
Sidste opdatering sendt (Faktiske)
Sidste opdatering sendt
Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier
Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier
Sidst verificeret
Sidst verificeret
Mere information
Begreber relateret til denne undersøgelse
Yderligere relevante MeSH-vilkår
- Glukosemetabolismeforstyrrelser
- Metaboliske sygdomme
- Sygdomme i det endokrine system
- Diabetes mellitus
- Hjerte-kar-sygdomme
- Diabetes mellitus, type 2
- Karsygdomme
- Lægemidlers fysiologiske virkninger
- Molekylære mekanismer for farmakologisk virkning
- Antihypertensive midler
- Hormoner, hormonsubstitutter og hormonantagonister
- Natriuretiske midler
- Membrantransportmodulatorer
- Diuretika
- Hormonantagonister
- Mineralokortikoid-receptorantagonister
- Diuretika, Kaliumbesparende
- Natriumchlorid Symporter-hæmmere
- Spironolacton
- Hydrochlorthiazid
Andre undersøgelses-id-numre
Andre undersøgelses-id-numre
- 2007-P-000564
- 1R01HL087060-01A2 (U.S. NIH-bevilling/kontrakt)
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