Design of the Magnetic Resonance Imaging Evaluation of Mineralocorticoid Receptor Antagonism in Diabetic Atherosclerosis (MAGMA) Trial
Mineralocorticoid receptor (MR) activation plays an essential role in promoting inflammation, fibrosis, and target organ damage. Currently, no studies are investigating MR antagonism in patients with type 2 diabetes mellitus (T2DM) with chronic kidney disease, at high risk for cardiovascular complic...
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| Published in | Clinical cardiology (Mahwah, N.J.) Vol. 40; no. 9; pp. 633 - 640 |
|---|---|
| Main Authors | , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York
Wiley Periodicals, Inc
01.09.2017
John Wiley & Sons, Inc |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0160-9289 1932-8737 1932-8737 |
| DOI | 10.1002/clc.22718 |
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| Abstract | Mineralocorticoid receptor (MR) activation plays an essential role in promoting inflammation, fibrosis, and target organ damage. Currently, no studies are investigating MR antagonism in patients with type 2 diabetes mellitus (T2DM) with chronic kidney disease, at high risk for cardiovascular complications, who are otherwise not candidates for MR antagonism by virtue of heart failure. Further, there is limited information on candidate therapies that may demonstrate differential benefit from this therapy. We hypothesized that MR antagonism may provide additional protection from atherosclerosis progression in higher‐risk patients who otherwise may not be candidates for such a therapeutic approach. In this double‐blind, randomized, placebo‐controlled trial, subjects with T2DM with chronic kidney disease (≥ stage 3) will be randomized in a 1:1 manner to placebo or spironolactone (12.5 mg with eventual escalation to 25 mg daily over a 4‐week period). The co‐primary efficacy endpoint will be percentage change in total atheroma volume in thoracic aorta and left ventricular mass at 52 weeks in patients treated with spironolactone vs placebo. Secondary outcomes include 24‐hour mean systolic blood pressure, central aortic blood pressure, and insulin resistance (HOMA‐IR) at 6 weeks. A novel measure in the study will be changes in candidate miRNAs that regulate expression of NR3C2 (MR gene) as well as measuring monocyte/macrophage polarization in response to therapy with spironolactone. We envision that our strategy of simultaneously probing the effects of a drug combined with analysis of mechanisms of action and predictive response will likely provide key information with which to design event‐based trials. |
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| AbstractList | Mineralocorticoid receptor (
MR
) activation plays an essential role in promoting inflammation, fibrosis, and target organ damage. Currently, no studies are investigating
MR
antagonism in patients with type 2 diabetes mellitus (
T2DM
) with chronic kidney disease, at high risk for cardiovascular complications, who are otherwise not candidates for
MR
antagonism by virtue of heart failure. Further, there is limited information on candidate therapies that may demonstrate differential benefit from this therapy. We hypothesized that
MR
antagonism may provide additional protection from atherosclerosis progression in higher‐risk patients who otherwise may not be candidates for such a therapeutic approach. In this double‐blind, randomized, placebo‐controlled trial, subjects with
T2DM
with chronic kidney disease (≥ stage 3) will be randomized in a 1:1 manner to placebo or spironolactone (12.5 mg with eventual escalation to 25 mg daily over a 4‐week period). The co‐primary efficacy endpoint will be percentage change in total atheroma volume in thoracic aorta and left ventricular mass at 52 weeks in patients treated with spironolactone vs placebo. Secondary outcomes include 24‐hour mean systolic blood pressure, central aortic blood pressure, and insulin resistance (
HOMA‐IR
) at 6 weeks. A novel measure in the study will be changes in candidate
miRNAs
that regulate expression of
NR3C2
(
MR
gene) as well as measuring monocyte/macrophage polarization in response to therapy with spironolactone. We envision that our strategy of simultaneously probing the effects of a drug combined with analysis of mechanisms of action and predictive response will likely provide key information with which to design event‐based trials. Mineralocorticoid receptor (MR) activation plays an essential role in promoting inflammation, fibrosis, and target organ damage. Currently, no studies are investigating MR antagonism in patients with type 2 diabetes mellitus (T2DM) with chronic kidney disease, at high risk for cardiovascular complications, who are otherwise not candidates for MR antagonism by virtue of heart failure. Further, there is limited information on candidate therapies that may demonstrate differential benefit from this therapy. We hypothesized that MR antagonism may provide additional protection from atherosclerosis progression in higher-risk patients who otherwise may not be candidates for such a therapeutic approach. In this double-blind, randomized, placebo-controlled trial, subjects with T2DM with chronic kidney disease (≥ stage 3) will be randomized in a 1:1 manner to placebo or spironolactone (12.5 mg with eventual escalation to 25 mg daily over a 4-week period). The co-primary efficacy endpoint will be percentage change in total atheroma volume in thoracic aorta and left ventricular mass at 52 weeks in patients treated with spironolactone vs placebo. Secondary outcomes include 24-hour mean systolic blood pressure, central aortic blood pressure, and insulin resistance (HOMA-IR) at 6 weeks. A novel measure in the study will be changes in candidate miRNAs that regulate expression of NR3C2 (MR gene) as well as measuring monocyte/macrophage polarization in response to therapy with spironolactone. We envision that our strategy of simultaneously probing the effects of a drug combined with analysis of mechanisms of action and predictive response will likely provide key information with which to design event-based trials. Mineralocorticoid receptor (MR) activation plays an essential role in promoting inflammation, fibrosis, and target organ damage. Currently, no studies are investigating MR antagonism in patients with type 2 diabetes mellitus (T2DM) with chronic kidney disease, at high risk for cardiovascular complications, who are otherwise not candidates for MR antagonism by virtue of heart failure. Further, there is limited information on candidate therapies that may demonstrate differential benefit from this therapy. We hypothesized that MR antagonism may provide additional protection from atherosclerosis progression in higher-risk patients who otherwise may not be candidates for such a therapeutic approach. In this double-blind, randomized, placebo-controlled trial, subjects with T2DM with chronic kidney disease (≥ stage 3) will be randomized in a 1:1 manner to placebo or spironolactone (12.5 mg with eventual escalation to 25 mg daily over a 4-week period). The co-primary efficacy endpoint will be percentage change in total atheroma volume in thoracic aorta and left ventricular mass at 52 weeks in patients treated with spironolactone vs placebo. Secondary outcomes include 24-hour mean systolic blood pressure, central aortic blood pressure, and insulin resistance (HOMA-IR) at 6 weeks. A novel measure in the study will be changes in candidate miRNAs that regulate expression of NR3C2 (MR gene) as well as measuring monocyte/macrophage polarization in response to therapy with spironolactone. We envision that our strategy of simultaneously probing the effects of a drug combined with analysis of mechanisms of action and predictive response will likely provide key information with which to design event-based trials.Mineralocorticoid receptor (MR) activation plays an essential role in promoting inflammation, fibrosis, and target organ damage. Currently, no studies are investigating MR antagonism in patients with type 2 diabetes mellitus (T2DM) with chronic kidney disease, at high risk for cardiovascular complications, who are otherwise not candidates for MR antagonism by virtue of heart failure. Further, there is limited information on candidate therapies that may demonstrate differential benefit from this therapy. We hypothesized that MR antagonism may provide additional protection from atherosclerosis progression in higher-risk patients who otherwise may not be candidates for such a therapeutic approach. In this double-blind, randomized, placebo-controlled trial, subjects with T2DM with chronic kidney disease (≥ stage 3) will be randomized in a 1:1 manner to placebo or spironolactone (12.5 mg with eventual escalation to 25 mg daily over a 4-week period). The co-primary efficacy endpoint will be percentage change in total atheroma volume in thoracic aorta and left ventricular mass at 52 weeks in patients treated with spironolactone vs placebo. Secondary outcomes include 24-hour mean systolic blood pressure, central aortic blood pressure, and insulin resistance (HOMA-IR) at 6 weeks. A novel measure in the study will be changes in candidate miRNAs that regulate expression of NR3C2 (MR gene) as well as measuring monocyte/macrophage polarization in response to therapy with spironolactone. We envision that our strategy of simultaneously probing the effects of a drug combined with analysis of mechanisms of action and predictive response will likely provide key information with which to design event-based trials. |
| Author | Connelly, Kim Broadwater, Kylene Fares, Anas Farkouh, Michael Alaiti, M. Amer Gaztanaga, Juan Dobre, Mirela Weir, Matthew R. Goud, Aditya Rajagopalan, Sanjay Kreatsoulas, Catherine Fink, Jeffrey C. Shirazian, Shayan |
| AuthorAffiliation | 8 Division of Nephrology University Hospitals, Cleveland Medical Center Ohio 4 Keenan Research Centre for Biomedical Science St. Michael's Hospital Toronto Ontario Canada 7 Department of Cardiology, Peter Munk Cardiac Centre University Health Network Toronto Ontario Canada 3 Division of Internal Medicine, Department of Cardiology NYU Winthrop Hospital Mineola New York 6 Harvard School of Public Health Harvard University Cambridge Massachusetts 1 Division of Cardiovascular Medicine, Harrington Heart and Vascular Institute University Hospitals, Cleveland Medical Center Ohio 2 University of Maryland School of Medicine Baltimore 5 Division of Nephrology and Hypertension, Diabetes and Obesity Research Center NYU Winthrop Hospital Mineola New York |
| AuthorAffiliation_xml | – name: 2 University of Maryland School of Medicine Baltimore – name: 7 Department of Cardiology, Peter Munk Cardiac Centre University Health Network Toronto Ontario Canada – name: 6 Harvard School of Public Health Harvard University Cambridge Massachusetts – name: 4 Keenan Research Centre for Biomedical Science St. Michael's Hospital Toronto Ontario Canada – name: 8 Division of Nephrology University Hospitals, Cleveland Medical Center Ohio – name: 1 Division of Cardiovascular Medicine, Harrington Heart and Vascular Institute University Hospitals, Cleveland Medical Center Ohio – name: 5 Division of Nephrology and Hypertension, Diabetes and Obesity Research Center NYU Winthrop Hospital Mineola New York – name: 3 Division of Internal Medicine, Department of Cardiology NYU Winthrop Hospital Mineola New York |
| Author_xml | – sequence: 1 givenname: Sanjay surname: Rajagopalan fullname: Rajagopalan, Sanjay email: sanjay.rajagopalan@uhhospitals.org organization: University of Maryland School of Medicine – sequence: 2 givenname: M. Amer orcidid: 0000-0002-3625-717X surname: Alaiti fullname: Alaiti, M. Amer organization: University Hospitals, Cleveland Medical Center – sequence: 3 givenname: Kylene surname: Broadwater fullname: Broadwater, Kylene organization: University of Maryland School of Medicine – sequence: 4 givenname: Aditya surname: Goud fullname: Goud, Aditya organization: University Hospitals, Cleveland Medical Center – sequence: 5 givenname: Juan surname: Gaztanaga fullname: Gaztanaga, Juan organization: NYU Winthrop Hospital – sequence: 6 givenname: Kim surname: Connelly fullname: Connelly, Kim organization: St. Michael's Hospital – sequence: 7 givenname: Anas surname: Fares fullname: Fares, Anas organization: University Hospitals, Cleveland Medical Center – sequence: 8 givenname: Shayan surname: Shirazian fullname: Shirazian, Shayan organization: NYU Winthrop Hospital – sequence: 9 givenname: Catherine surname: Kreatsoulas fullname: Kreatsoulas, Catherine organization: Harvard University – sequence: 10 givenname: Michael surname: Farkouh fullname: Farkouh, Michael organization: University Health Network – sequence: 11 givenname: Mirela surname: Dobre fullname: Dobre, Mirela organization: University Hospitals, Cleveland Medical Center – sequence: 12 givenname: Jeffrey C. surname: Fink fullname: Fink, Jeffrey C. organization: University of Maryland School of Medicine – sequence: 13 givenname: Matthew R. surname: Weir fullname: Weir, Matthew R. organization: University of Maryland School of Medicine |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28555959$$D View this record in MEDLINE/PubMed |
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| CitedBy_id | crossref_primary_10_1161_ATVBAHA_119_312954 crossref_primary_10_1161_CIRCULATIONAHA_123_067620 crossref_primary_10_1080_00207454_2020_1802265 crossref_primary_10_1152_ajpcell_00372_2022 crossref_primary_10_1159_000480652 crossref_primary_10_34067_KID_0000922020 crossref_primary_10_1097_FJC_0000000000001364 crossref_primary_10_1016_j_molimm_2018_02_006 |
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| Keywords | Magnetic Resonance Imaging Monocyte Atherosclerosis miRNA Inflammation Mineralocorticoid Receptor Macrophage |
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| SubjectTerms | Aorta, Thoracic - diagnostic imaging Aorta, Thoracic - drug effects Aorta, Thoracic - pathology Aortic Diseases - diagnostic imaging Aortic Diseases - etiology Aortic Diseases - pathology Aortic Diseases - prevention & control Atherosclerosis Atherosclerosis - diagnostic imaging Atherosclerosis - etiology Atherosclerosis - pathology Atherosclerosis - prevention & control Blood pressure Clinical Protocols Diabetes Diabetes Mellitus, Type 2 - complications Diabetes Mellitus, Type 2 - diagnosis Diabetes Mellitus, Type 2 - drug therapy Diabetic Angiopathies - diagnostic imaging Diabetic Angiopathies - etiology Diabetic Angiopathies - pathology Diabetic Angiopathies - prevention & control Double-Blind Method Female Humans Inflammation Kidney diseases Macrophage Magnetic Resonance Imaging Male Middle Aged Mineralocorticoid Receptor Mineralocorticoid Receptor Antagonists - adverse effects Mineralocorticoid Receptor Antagonists - therapeutic use miRNA Monocyte Plaque, Atherosclerotic Predictive Value of Tests Proof of Concept Study Prospective Studies Research Design Signal Transduction - drug effects Spironolactone - adverse effects Spironolactone - therapeutic use Treatment Outcome Trial Designs United States Ventricular Function, Left - drug effects Ventricular Remodeling - drug effects |
| Title | Design of the Magnetic Resonance Imaging Evaluation of Mineralocorticoid Receptor Antagonism in Diabetic Atherosclerosis (MAGMA) Trial |
| URI | https://onlinelibrary.wiley.com/doi/abs/10.1002%2Fclc.22718 https://www.ncbi.nlm.nih.gov/pubmed/28555959 https://www.proquest.com/docview/1942640902 https://www.proquest.com/docview/1903941108 https://pubmed.ncbi.nlm.nih.gov/PMC6490527 |
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